Considerations for U-series dating of sediments: insights from the Flinders Ranges, South Australia

Uranium isotope ratios have been determined for the fine-grained detrital fraction of Pleistocene Wilkawillina valley-fill sediments, four local Proterozoic bedrock samples and fine-grained aeolian material from a sand dune deposit of the Flinders Ranges, South Australia. The aim was to quantify the comminution age, i.e. the time elapsed since physical weathering of the bedrock, and residence time of the valley-fill sediments and to place tighter constraints on input parameters for the comminution age calculation. Despite using two independent approaches for determination of the recoil lost fraction of 234U from the sediment (weighted geometric and surface area estimates), samples fail to produce realistic comminution ages and hence, residence times. The issues involved in the ability to determine sediment comminution ages are discussed. The (234U/238U) activity ratio of the local bedrock is not in secular equilibrium, despite the bedrock being much older than 1Ma, i.e. the timeframe for 234U and 238U to reach secular equilibrium in a closed system. Using the average Flinders Ranges bedrock (234U/238U) ratio instead of an assumed (234U/238U) activity ratio of unity for the source would significantly reduce calculated residence times. This result warrants concern for future studies using the comminution approach for which a secular equilibrium source (234U/238U) activity ratio is assumed. Significant input of aeolian material may modify the measured (234U/238U) activity ratios. Such input may be more tightly constrained in future studies using rare earth element and radiogenic isotopic data. Future comminution studies would benefit from further consideration of the importance of 1) leaching lost 234U from source rock and bulk sediment samples, 2) wind deposition of fine-grained material and 3) the appropriateness and robustness of sample pre-treatment procedures

PerR controls oxidative stress defence and aerotolerance but not motility-associated phenotypes of Campylobacter jejuni

The foodborne bacterial pathogen Campylobacter jejuni is an obligate microaerophile, which is exposed to atmospheric oxygen during transmission through the food chain. Survival under aerobic conditions requires the concerted control of oxidative stress systems, which in C. jejuni are intimately connected with iron metabolism via the PerR and Fur regulatory proteins. Here we have characterised the roles of C. jejuni PerR in oxidative stress- and motility phenotypes, and its regulon at the level of transcription, protein expression and promoter interactions. Insertional inactivation of perR in the C. jejuni reference strains NCTC 11168, 81-176 and 81116 did not result in any growth deficiencies, but strongly increased survival in atmospheric oxygen conditions, and allowed growth around filter discs infused with up to 30% H2O2 (8.8 M). Expression of catalase, alkyl hydroperoxide reductase, thioredoxin reductase and the Rrc desulforubrerythrin were increased in the perR mutant, and this was mediated at the transcriptional level as shown by electrophoretic mobility shift assays of the katA, ahpC and trxB promoters using purified PerR. Differential RNA-seq analysis of a fur perR mutant allowed the identification of eight previously unknown transcription start sites of genes controlled by either Fur and/or PerR. Finally, inactivation of perR in C. jejuni did not result in reduced motility, and did not reduce killing of Galleria melonella wax moth larvae. In conclusion, PerR plays an important role in controlling oxidative stress resistance and aerobic survival of C. jejuni, but this role does not extend into control of motility and associated phenotypes

Effective health care for older people living and dying in care homes: A realist review

Background: Care home residents in England have variable access to health care services. There is currently no coherent policy or consensus about the best arrangements to meet these needs. The purpose of this review was to explore the evidence for how different service delivery models for care home residents support and/or improve wellbeing and health-related outcomes in older people living and dying in care homes. Methods: We conceptualised models of health care provision to care homes as complex interventions. We used a realist review approach to develop a preliminary understanding of what supported good health care provision to care homes. We completed a scoping of the literature and interviewed National Health Service and Local Authority commissioners, providers of services to care homes, representatives from the Regulator, care home managers, residents and their families. We used these data to develop theoretical propositions to be tested in the literature to explain why an intervention may be effective in some situations and not others. We searched electronic databases and related grey literature. Finally the findings were reviewed with an external advisory group. Results: Strategies that support and sustain relational working between care home staff and visiting health care professionals explained the observed differences in how health care interventions were accepted and embedded into care home practice. Actions that encouraged visiting health care professionals and care home staff jointly to identify, plan and implement care home appropriate protocols for care, when supported by ongoing facilitation from visiting clinicians, were important. Contextual factors such as financial incentives or sanctions, agreed protocols, clinical expertise and structured approaches to assessment and care planning could support relational working to occur, but of themselves appeared insufficient to achieve change. Conclusion: How relational working is structured between health and care home staff is key to whether health service interventions achieve health related outcomes for residents and their respective organisations. The belief that either paying clinicians to do more in care homes and/or investing in training of care home staff is sufficient for better outcomes was not supported.This research was funded by National Institute of Health Research Health Service Delivery and Research programme (HSDR 11/021/02)

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Very long hillslope transport timescales determined from uranium-series isotopes in river sediments from a large, tectonically stable catchment

The uranium-series isotopic compositions of soils and sediments evolve in response to time and weathering conditions. Therefore, these isotopes can be used to constrain the timescales of river sediment transport. Catchment evolution depends on the sediment dynamic timescales, on which erosion imparts a major control. Erosion rates in tectonically stable catchments are expected to be lower than those in tectonically active catchments, implying longer sediment residence times in tectonically stable catchments. Mineralogical, elemental and isotopic data are presented for modern channel sediments, alluvial and colluvial deposits from the Murrumbidgee River, a large catchment in the passive margin highlands of south-eastern Australia and three of its tributaries from the headwaters to the alluvial plain. Low variability in Si-based Weathering Index indicates that there is little chemical weathering occurring in the Murrumbidgee River during sediment transport. However, quartz content increases and plagioclase content decreases downstream, indicating progressive mineralogical sorting and/or physical comminution with increasing transport distance. U-series isotopic ratios in the Murrumbidgee River trunk stream sediments show no systematic downstream variation. The weathering ages of sediments within the catchment were determined using a loss-gain model of U-series isotopes. Modern sediments from a headwater tributary, the Bredbo River at Frogs Hollow, have a weathering age of 76 ± 30 kyr but all other modern channel sediments from the length of the Murrumbidgee River and its main tributaries have weathering ages ∼400 ± 180 kyr. The two headwater colluvial deposits have weathering ages of 57 ± 13 and 47 ± 11 kyr, respectively. All the alluvial deposits have weathering ages similar to those of modern sediments. No downstream trend in weathering age is observed. Together with the soil residence time of up to 30 kyr for ridge-top soils at Frogs Hollow in the upper catchment area of the Murrumbidgee River (Suresh et al., 2013), the current results indicate, for the first time, that sediments in the Murrumbidgee catchment are stored in hill slope for long time (∼200 kyr) before carried by the river. The long residence times of sediments indicate a low erosion rate from the catchment. The sediment transport timescales estimated are up to two orders of magnitude higher than those reported for tectonically active catchments in Iceland (Vigier et al., 2006) and in the Himalayas (Granet et al., 2007), indicating the influence of tectonism on catchment erosion

Sediment residence times constrained by uranium-series isotopes: a critical appraisal of the comminution approach

Quantifying the rates of landscape evolution in response to climate change is inhibited by the difficulty of dating the formation of continental detrital sediments. We present uranium isotope data for Cooper Creek palaeochannel sediments from the Lake Eyre Basin in semi-arid South Australia in order to attempt to determine the formation ages and hence residence times of the sediments. To calculate the amount of recoil loss of 234U, a key input parameter used in the comminution approach, we use two suggested methods (weighted geometric and surface area measurement with an incorporated fractal correction) and typical assumed input parameter values found in the literature. The calculated recoil loss factors and comminution ages are highly dependent on the method of recoil loss factor determination used and the chosen assumptions. To appraise the ramifications of the assumptions inherent in the comminution age approach and determine individual and combined comminution age uncertainties associated to each variable, Monte Carlo simulations were conducted for a synthetic sediment sample. Using a reasonable associated uncertainty for each input factor and including variations in the source rock and measured (234U/238U) ratios, the total combined uncertainty on comminution age in our simulation (for both methods of recoil loss factor estimation) can amount to ±220–280 ka. The modelling shows that small changes in assumed input values translate into large effects on absolute comminution age. To improve the accuracy of the technique and provide meaningful absolute comminution ages, much tighter constraints are required on the assumptions for input factors such as the fraction of α-recoil lost 234Th and the initial (234U/238U) ratio of the source material. In order to be able to directly compare calculated comminution ages produced by different research groups, the standardisation of pre-treatment procedures, recoil loss factor estimation and assumed input parameter values is required. We suggest a set of input parameter values for such a purpose. Additional considerations for calculating comminution ages of sediments deposited within large, semi-arid drainage basins are discussed