The Cell and Molecular Biology of Neurodegenerative Diseases: An Overview

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The aggradation of alluvial fans in response to monsoon variability over the last 400 ka in the Hajar Mountains, south-east Arabia

The preservation and interpretation of past external forcings within sedimentary archives can be complicated. Marine proxy records show that, throughout the Mid-Late Quaternary, monsoon rainfall in south-east Arabia has varied at precessional timescales (∼ 23 ka). By contrast, terrestrial environmental records from the region, such as speleothems and palaeolake sequences, generally only capture rainfall variability at eccentricity (∼ 100 ka) timescales and geomorphological archives rarely record events over multiple glacial cycles. Previous work has suggested that the alluvial fan systems of the Hajar Mountains record aggradation coincident with precessional peaks because of more northerly Indian Ocean Summer Monsoon (IOSM) rainfall, relative to present. However, the alluvial record is complex: there is a growing body of ‘anomalous’ aggradation age data from periods of precessional minima and it is spatially uneven, mainly being derived from fans at either the northern- or southern-most extents of the western side of the mountains. We present optically stimulated luminescence (OSL) ages of alluvial aggradation from new sites in the central portion of the western and eastern sides of the Hajar mountains. Sedimentary units that show evidence of more sustained flow conditions, such as coarse conglomerate deposition and the development of thick floodplain deposits, typically date to periods of higher IOSM rainfall at precessional timescales. Sites where there is evidence of deposition under more ephemeral flow conditions, like today, yield ages corresponding to precessional minima. We synthesise these data with similarly interpreted alluvial and lacustrine deposits from across the region, employing a hierarchical clustering approach to generate clusters of ages representing periods of increased hydrological activity. This objective approach to regional chronological data suggests that ten periods of more sustained hydrological activity are evidenced across the Hajar region, broadly aligning to precessional and eccentricity peaks over the last 400 ka. These clusters show that Hajar fans predominately aggrade because of increasing rainfall over their catchments, with the central ages of clusters often aligning with the onset of precessional forcing. Hajar alluvial systems preserve important records of Quaternary climate variability over long timescales in an arid region where terrestrial records are scarce due to preservation issues

Re‐analysis of late Quaternary dust mass accumulation rates in Serbia using new luminescence chronology for loess–palaeosol sequence at Surduk

Despite numerous palaeoenvironmental investigations of loess–palaeosol sequences across the Carpathian Basin, well‐dated high‐resolution records are scarce. This paper presents a new high‐resolution chronology for the loess‐palaeosol sequence at Surduk (Serbia), based on optically stimulated luminescence (quartz) and post‐infrared infrared stimulated luminescence (polymineral) dating. The presented record spans 53–19 ka, with primary loess deposition occurring after 52±2 ka, and differs from previously published chronologies that relied on less precise and now superseded dating protocols. Based on the new chronology, mass accumulation rates (MAR s) for Surduk were constructed and compared with sites in the Carpathian Basin. The results demonstrate that accumulation periods across this area are not consistent in timing or rates. The high‐resolution dating strategy identifies a disturbance in sediment deposition that occurred after 45±2 ka and implies that site contains a hiatus. Finally, we show samples that failed routine dose recovery and preheat plateau tests, and had low fast ratios. Supported by bulk sample geochemical analysis it is proposed that a potential abrupt source shift, during the Last Glacial Maximum, may be the cause of the anomalous luminescence behaviour

Comparing the Importance of Iodine and Isoprene on Tropospheric Photochemistry

Isoprene, arguably the most studied biogenically emitted gas, is thought to have a large impact on tropospheric composition. Other naturally emitted species have been considered to play a less important role. Here the GEOS-Chem model is used to compare the impacts of isoprene and iodine emissions on present-day tropospheric composition. Removing isoprene emissions leads to a 3.4 burden, a smaller absolute change than the 5.9+0.60.05 whereas isoprene has a substantial impact on both (−4.34.2. Isoprene emissions and chemistry are seen as essential for tropospheric chemistry models, but iodine is often not. We suggest that iodine should receive greater attention in model development and experimental research to allow improved predictions of past, present, and future tropospheric O3

Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients agedPeer reviewe

Idiopathic intracranial hypertension: the association between weight loss and the requirement for systemic treatment

<p>Abstract</p> <p>Background</p> <p>To determine whether weight loss is significantly associated with a discontinuation of treatment for idiopathic intracranial hypertension</p> <p>Methods</p> <p>The notes of 36 patients with idiopathic intracranial hypertension under regular review for at least 12 months by a single neuro-ophthalmologist were retrospectively reviewed. Weight was recorded at each assessment and weight loss recommended. Treatment was adjusted according to symptoms, visual function including visual fields and optic disc appearance only. Patients were divided according to duration of continuous follow-up, and then sub-divided as to whether they were on or not on treatment at most recent review and whether weight loss had been achieved compared to presentation. Survival analysis was performed to assess the probability of remaining on treatment having lost weight.</p> <p>Results</p> <p>Considering the patients as 3 groups, those with at least 12 months follow-up (n = 36), those with at least 18 months follow-up (n = 24) and those with 24 months or more follow-up (n = 19), only the group with 24 months or more follow-up demonstrated a significant association between weight loss and stopping systemic treatment (Fisher's exact test, p = 0.04). Survival analysis demonstrated that the probability of being on treatment at 5 years having gained weight was 0.63 and having lost weight was 0.38 (log rank test, p = 0.04). The results suggest that final absolute body mass index is more important than the change in body mass index for patients who stop treatment (Mann Whitney U, p = 0.05).</p> <p>Conclusion</p> <p>This is the first study to demonstrate that weight loss is associated with discontinuation of treatment. Unlike previous studies, our results suggest that final absolute body mass index is more important for stopping treatment than a proportional reduction in weight.</p

Evaluation of a complex intervention (Engager) for prisoners with common mental health problems, near to and after release: study protocol for a randomised controlled trial.

INTRODUCTION: The 'Engager' programme is a 'through-the-gate' intervention designed to support prisoners with common mental health problems as they transition from prison back into the community. The trial will evaluate the clinical and cost-effectiveness of the Engager intervention. METHODS AND ANALYSIS: The study is a parallel two-group randomised controlled trial with 1:1 individual allocation to either: (a) the Engager intervention plus standard care (intervention group) or (b) standard care alone (control group) across two investigation centres (South West and North West of England). Two hundred and eighty prisoners meeting eligibility criteria will take part. Engager is a person-centred complex intervention delivered by practitioners and aimed at addressing offenders' mental health and social care needs. It comprises one-to-one support for participants prior to release from prison and for up to 20 weeks postrelease. The primary outcome is change in psychological distress measured by the Clinical Outcomes in Routine Evaluation-Outcome Measure at 6 months postrelease. Secondary outcomes include: assessment of subjective met/unmet need, drug and alcohol use, health-related quality of life and well-being-related quality of life measured at 3, 6 and 12 months postrelease; change in objective social domains, drug and alcohol dependence, service utilisation and perceived helpfulness of services and change in psychological constructs related to desistence at 6 and 12 months postrelease; and recidivism at 12 months postrelease. A process evaluation will assess fidelity of intervention delivery, test hypothesised mechanisms of action and look for unintended consequences. An economic evaluation will estimate the cost-effectiveness. ETHICS AND DISSEMINATION: This study has been approved by the Wales Research Ethics Committee 3 (ref: 15/WA/0314) and the National Offender Management Service (ref: 2015-283). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations. TRIAL REGISTRATION NUMBER: ISRCTN11707331; Pre-results

Interrogating intervention delivery and participants' emotional states to improve engagement and implementation: A realist informed multiple case study evaluation of Engager.

BACKGROUND: 'Engager' is an innovative 'through-the-gate' complex care intervention for male prison-leavers with common mental health problems. In parallel to the randomised-controlled trial of Engager (Trial registration number: ISRCTN11707331), a set of process evaluation analyses were undertaken. This paper reports on the depth multiple case study analysis part of the process evaluation, exploring how a sub-sample of prison-leavers engaged and responded to the intervention offer of one-to-one support during their re-integration into the community. METHODS: To understand intervention delivery and what response it elicited in individuals, we used a realist-informed qualitative multiple 'case' studies approach. We scrutinised how intervention component delivery lead to outcomes by examining underlying causal pathways or 'mechanisms' that promoted or hindered progress towards personal outcomes. 'Cases' (n = 24) were prison-leavers from the intervention arm of the trial. We collected practitioner activity logs and conducted semi-structured interviews with prison-leavers and Engager/other service practitioners. We mapped data for each case against the intervention logic model and then used Bhaskar's (2016) 'DREIC' analytic process to categorise cases according to extent of intervention delivery, outcomes evidenced, and contributing factors behind engagement or disengagement and progress achieved. RESULTS: There were variations in the dose and session focus of the intervention delivery, and how different participants responded. Participants sustaining long-term engagement and sustained change reached a state of 'crises but coping'. We found evidence that several components of the intervention were key to achieving this: trusting relationships, therapeutic work delivered well and over time; and an in-depth shared understanding of needs, concerns, and goals between the practitioner and participants. Those who disengaged were in one of the following states: 'Crises and chaos', 'Resigned acceptance', 'Honeymoon' or 'Wilful withdrawal'. CONCLUSIONS: We demonstrate that the 'implementability' of an intervention can be explained by examining the delivery of core intervention components in relation to the responses elicited in the participants. Core delivery mechanisms often had to be 'triggered' numerous times to produce sustained change. The improvements achieved, sustained, and valued by participants were not always reflected in the quantitative measures recorded in the RCT. The compatibility between the practitioner, participant and setting were continually at risk of being undermined by implementation failure as well as changing external circumstances and participants' own weaknesses. TRIAL REGISTRATION NUMBER: ISRCTN11707331, Wales Research Ethics Committee, Registered 02-04-2016-Retrospectively registered https://doi.org/10.1186/ISRCTN11707331

Identifying parkinsonism in mild cognitive impairment.

Introduction Clinical parkinsonism is a core diagnostic feature for mild cognitive impairment with Lewy bodies (MCI-LB) but can be challenging to identify. A five-item scale derived from the Unified Parkinson’s Disease Rating Scale (UPDRS) has been recommended for the assessment of parkinsonism in dementia. This study aimed to determine whether the five-item scale is effective to identify parkinsonism in MCI. Methods Participants with MCI from two cohorts (n=146) had a physical examination including the UPDRS and [123I]-FP-CIT SPECT striatal dopaminergic imaging. Participants were classified as having clinical parkinsonism (P+) or no parkinsonism (P-), and with abnormal striatal dopaminergic imaging (D+) or normal imaging (D-). The five-item scale was the sum of UPDRS tremor at rest, bradykinesia, action tremor, facial expression, and rigidity scores. The ability of the scale to differentiate P+D+ and P-D- participants was examined. Results The five-item scale had an AUROC of 0.92 in Cohort 1, but the 7/8 cut-off defined for dementia had low sensitivity to identify P+D+ participants (sensitivity 25%, specificity 100%). Optimal sensitivity and specificity was obtained at a 3/4 cut-off (sensitivity 83%, specificity 88%). In Cohort 2, the five-item scale had an AUROC of 0.97, and the 3/4 cut-off derived from Cohort 1 showed sensitivity of 100% and a specificity of 82% to differentiate P+D+ from P-D- participants. The five-item scale was not effective in differentiating D+ from D- participants. Conclusions The five-item scale is effective to identify parkinsonism in MCI, but a lower threshold must be used in MCI compared with dementia