Anatomy of Heinrich Layer 1 and its role in the last deglaciation

X-ray fluorescence (XRF) core scanning and X-ray computed tomography data were measured every 1 mm to study the structure of Heinrich Event 1 during the last deglaciation at International Ocean Discovery Program Site U1308. Heinrich Layer 1 comprises two distinct layers of ice-rafted detritus (IRD), which are rich in detrital carbonate (DC) and poor in foraminifera. Each DC layer consists of poorly sorted, coarse-grained clasts of IRD embedded in a dense, fine-grained matrix of glacial rock flour that is partially cemented. The radiocarbon ages of foraminifera at the base of the two layers indicate a difference of 1400 $^{14}$C years, suggesting that they are two distinct events, but the calendar ages depend upon assumptions made for surface reservoir ages. The double peak indicates at least two distinct stages of discharge of the ice streams that drained the Laurentide Ice Sheet through Hudson Strait during HE1 or, alternatively, the discharge of two independent ice streams containing detrital carbonate. Heinrich Event 1.1 was the larger of the two events and began at ~16.2 ka (15.5–17.1 ka) when the polar North Atlantic was already cold and Atlantic Meridional Overturning Circulation (AMOC) weakened. The younger peak (H1.2) at ~15.1 ka (14.3 to 15.9 ka) was a weaker event than H1.1 that was accompanied by minor cooling. Our results support a complex history for Heinrich Stadial 1 (HS1) with reduction in AMOC during the early part (~20–16.2 ka) possibly driven by melting of European ice sheets, whereas the Laurentide Ice Sheet assumed a greater role during the latter half (~16.2–14.7 ka).This research used data acquired at the XRF Core Scanner Lab at the MARUM–Center for Marine Environmental Sciences, University of Bremen, Germany. This research used samples provided by the International Ocean Discovery Program (IODP). Funding for this research was provided by the UK Natural Environmental Research Council (NERC) to Hodell. The NERC Radiocarbon Facility supported two radiocarbon dates, and Wally Broecker generously supported the remainder with funding from the Comer Family Foundation. Research by Rodríguez-Tovar and Dorador was financed by Project CGL2015-66835-P. B.M. acknowledges support from the CSIC-Ramón y Cajal postdoctoral programme RYC-2013-14073. J.F.E. would like to acknowledge funding under ERC Advanced grant 320750- Nanopaleomagnetism

A randomised controlled trial and cost-effectiveness evaluation of "booster" interventions to sustain increases in physical activity in middle-aged adults in deprived urban neighbourhoods

Background: Systematic reviews have identified a range of brief interventions which increase physical activity in previously sedentary people. There is an absence of evidence about whether follow up beyond three months can maintain long term physical activity. This study assesses whether it is worth providing motivational interviews, three months after giving initial advice, to those who have become more active. Methods/Design: Study candidates (n = 1500) will initially be given an interactive DVD and receive two telephone follow ups at monthly intervals checking on receipt and use of the DVD. Only those that have increased their physical activity after three months (n = 600) will be randomised into the study. These participants will receive either a "mini booster" (n = 200), "full booster" (n = 200) or no booster (n = 200). The "mini booster" consists of two telephone calls one month apart to discuss physical activity and maintenance strategies. The "full booster" consists of a face-to-face meeting with the facilitator at the same intervals. The purpose of these booster sessions is to help the individual maintain their increase in physical activity. Differences in physical activity, quality of life and costs associated with the booster interventions, will be measured three and nine months from randomisation. The research will be conducted in 20 of the most deprived neighbourhoods in Sheffield, which have large, ethnically diverse populations, high levels of economic deprivation, low levels of physical activity, poorer health and shorter life expectancy. Participants will be recruited through general practices and community groups, as well as by postal invitation, to ensure the participation of minority ethnic groups and those with lower levels of literacy. Sheffield City Council and Primary Care Trust fund a range of facilities and activities to promote physical activity and variations in access to these between neighbourhoods will make it possible to examine whether the effectiveness of the intervention is modified by access to community facilities. A one-year integrated feasibility study will confirm that recruitment targets are achievable based on a 10% sample.Discussion: The choice of study population, study interventions, brief intervention preceding the study, and outcome measure are discussed

N-acetyltransferase 2 (NAT2) gene polymorphisms in Parkinson's disease

BACKGROUND: Parkinson's disease (PD) is a movement disorder caused by the degeneration of dopaminergic neurons in the substantia nigra of the midbrain. The molecular basis of this neural death is unknown, but genetic predisposition and environmental factors may cause the disease. Sequence variations in N-acetyltransferase 2 (NAT2) gene leading to slow acetylation process have been associated with PD, but results are contradictory. METHODS: We analyzed three NAT2 genetic variations, c.481C>T, c.590G>A (p.R197Q) and c.857G>A (p.G286E), which are known to result in a slow acetylator phenotype. Using validated PCR-RFLP assays, we genotyped 243 healthy unrelated Caucasian control subjects and 124 PD patients for these genetic variations. Further, we have undertaken a systematic review of NAT2 studies on PD and we incorporated our results in a meta-analysis consisting of 10 studies, 1,206 PD patients and 1,619 control subjects. RESULTS: Overall, we did not find significant differences in polymorphic acetylation genotypes in PD and control subjects. In the meta-analysis of slow acetylators from 10 studies and representing 604/1206 PD vs. 732/1619 control subjects, a marginally significant odds ratio (OR) of 1.32 (95% CI 1.12–1.54, p < 0.05) was obtained. Re-analysis of the data to exclude the only two studies showing positive association of slow acetylators to PD, resulted in a non-significant OR (1.07, 95% CI 0.9–1.28). Furthermore, meta-analysis of studies for c.590G>A, where both allele and genotype frequencies in PD vs. control subjects were analyzed, did not give significant summary odds ratios as well. CONCLUSION: We found little evidence for differences in polymorphic acetylation genotypes in PD and control subjects. Results of the meta-analyses did not also provide conclusive evidence for an overall association of NAT2 slow acetylator genotypes to PD

Prevalence of soil transmitted nematodes on Nukufetau, a remote Pacific island in Tuvalu

BACKGROUND: The population of Nukufetau, a remote coral atoll island in Tuvalu in the Western Pacific, received annual mass drug administration (MDA) of diethylcarbamazine and albendazole under the Pacific Elimination of Lymphatic Filariasis program in 2001, 2002 and 2003, with the last MDA occurring six months before a cross-sectional survey of the whole population for soil transmitted helminths (STH). METHODS: A cross-sectional survey in May 2004 recruited 206 residents (35.2% of the population) who provided a single faecal sample that was preserved, concentrated and examined microscopically. RESULTS: Overall prevalence of STH was 69.9%; only hookworm and Trichuris trichiura were diagnosed. Trichuris was present in 68.4% with intensity of infection being light in 56.3%, medium in 11.7% and heavy in 0.5%. Hookworm occurred in 11.7% with intensity of infection 11.2% being light and medium in 0.5%. Twenty individuals (9.7%) had dual infections. The prevalence of Trichuris was constant across all ages while the prevalence of hookworm was significantly lower in residents below 30 years of age. In the age group 5–12 years comparison of results with a 2001 survey [1] suggested that the prevalence of STH has declined minimally, due to sustained high prevalence of Trichuris, while hookworm has declined dramatically from 34.4% to 1.6%. CONCLUSION: The results of this survey suggest that although the MDA appears to have reduced hookworm prevalence in residents below 30 years of age, there has been minimal effect on Trichuris prevalence. An integrated program to control STH is required

Regionalisation of trauma care in England

Aims We aimed to determine whether there is evidence of improved patient outcomes in Major Trauma Centres following the regionalisation of trauma care in England. Patients and Methods An observational study was undertaken using the Trauma Audit and Research Network (TARN), Hospital Episode Statistics (HES) and national death registrations. The outcome measures were indicators of the quality of trauma care, such as treatment by a senior doctor and clinical outcomes, such as mortality in hospital. Results and Conclusion A total of 20 181 major trauma cases were reported to TARN during the study period, which was 270 days before and after each hospital became a Major Trauma Centre. Following regionalisation of trauma services, all indicators of the quality of care improved, fewer patients required secondary transfer between hospitals and a greater proportion were discharged with a Glasgow Outcome Score of “good recovery”. In this early post-implementation analysis, there were a number of apparent process improvements (e.g. time to CT) but no differences in either crude or adjusted mortality. The overall number of deaths following trauma in England did not change following the national reconfiguration of trauma services. Evidence from other countries that have regionalised trauma services suggests that further benefits may become apparent after a period of maturing of the trauma system

Missing steps in a staircase: a qualitative study of the perspectives of key stakeholders on the use of adaptive designs in confirmatory trials

Background Despite the promising benefits of adaptive designs (ADs), their routine use, especially in confirmatory trials, is lagging behind the prominence given to them in the statistical literature. Much of the previous research to understand barriers and potential facilitators to the use of ADs has been driven from a pharmaceutical drug development perspective, with little focus on trials in the public sector. In this paper, we explore key stakeholders’ experiences, perceptions and views on barriers and facilitators to the use of ADs in publicly funded confirmatory trials. Methods Semi-structured, in-depth interviews of key stakeholders in clinical trials research (CTU directors, funding board and panel members, statisticians, regulators, chief investigators, data monitoring committee members and health economists) were conducted through telephone or face-to-face sessions, predominantly in the UK. We purposively selected participants sequentially to optimise maximum variation in views and experiences. We employed the framework approach to analyse the qualitative data. Results We interviewed 27 participants. We found some of the perceived barriers to be: lack of knowledge and experience coupled with paucity of case studies, lack of applied training, degree of reluctance to use ADs, lack of bridge funding and time to support design work, lack of statistical expertise, some anxiety about the impact of early trial stopping on researchers’ employment contracts, lack of understanding of acceptable scope of ADs and when ADs are appropriate, and statistical and practical complexities. Reluctance to use ADs seemed to be influenced by: therapeutic area, unfamiliarity, concerns about their robustness in decision-making and acceptability of findings to change practice, perceived complexities and proposed type of AD, among others. Conclusions There are still considerable multifaceted, individual and organisational obstacles to be addressed to improve uptake, and successful implementation of ADs when appropriate. Nevertheless, inferred positive change in attitudes and receptiveness towards the appropriate use of ADs by public funders are supportive and are a stepping stone for the future utilisation of ADs by researchers

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna

Application of ecological momentary assessment in stress-related diseases

Many physical diseases have been reported to be associated with psychosocial factors. In these diseases, assessment relies mainly on subjective symptoms in natural settings. Therefore, it is important to assess symptoms and/or relationships between psychosocial factors and symptoms in natural settings. Symptoms are usually assessed by self-report when patients visit their doctors. However, self-report by recall has an intrinsic problem; "recall bias". Recently, ecological momentary assessment (EMA) has been proposed as a reliable method to assess and record events and subjective symptoms as well as physiological and behavioral variables in natural settings. Although EMA is a useful method to assess stress-related diseases, it has not been fully acknowledged, especially by clinicians. Therefore, the present brief review introduces the application and future direction of EMA for the assessment and intervention for stress-related diseases

Cataract-Causing Defect of a Mutant γ-Crystallin Proceeds through an Aggregation Pathway Which Bypasses Recognition by the α-Crystallin Chaperone

Background: The transparency of the eye lens depends upon maintenance of the native state of the γ- and β-crystallins, which is aided by the abundant chaperones αA- and αB-crystallin. Mature onset cataract, the leading cause of blindness worldwide, involves the polymerization of covalently damaged or partially unfolded crystallins into light-scattering aggregates. A number of single amino acid substitutions and truncations of γ-crystallins result in congenital cataract in both humans and mice, though in many cases the coupling between the protein alterations and the accumulation of aggregates is poorly defined. Methodology/Principal Findings: We have studied the aggregation properties and chaperone interactions of human γD-crystallin carrying substitutions of two buried core mutants, I90F and V75D, which cause congenital cataract in mice. The in vitro aggregation pathway competing with productive refolding was not altered by either substitution. Furthermore, this aggregation pathway for both mutant proteins–originating from a partially folded intermediate–was efficiently suppressed by αB-crystallin. Thus the cataract pathology was unlikely to be associated with a direct folding defect. The native state of wild-type human γD-crystallin exhibited no tendency to aggregate under physiological conditions. However both I90F and V75D native-like proteins exhibited slow (days) aggregation to high molecular weight aggregates under physiological conditions. The perturbed conformation of I90F was recognized and bound by both αA and αB chaperones. In contrast, the aggregation derived from the perturbed state of V75D was not suppressed by either chaperone, and the aggregating species were not bound by the chaperone. Conclusions/Significance: The cataract phenotype of I90F in mice may be due to premature saturation of the finite α- crystallin pool. The V75D aggregation pathway and its escape from chaperone surveillance and aggregation suppression can account for the congenital cataract pathology of this mutant. Failure of chaperone recognition may be an important source of pathology for many other protein folding defects.National Eye Institute (Grant no. EY015834 )National Institutes of Health (U.S.) (Grant no. GM17980