Association Study of 167 Candidate Genes for Schizophrenia Selected by a Multi-Domain Evidence-Based Prioritization Algorithm and Neurodevelopmental Hypothesis

Integrating evidence from multiple domains is useful in prioritizing disease candidate genes for subsequent testing. We ranked all known human genes (n = 3819) under linkage peaks in the Irish Study of High-Density Schizophrenia Families using three different evidence domains: 1) a meta-analysis of microarray gene expression results using the Stanley Brain collection, 2) a schizophrenia protein-protein interaction network, and 3) a systematic literature search. Each gene was assigned a domain-specific p-value and ranked after evaluating the evidence within each domain. For comparison to this
ranking process, a large-scale candidate gene hypothesis was also tested by including genes with Gene Ontology terms related to neurodevelopment. Subsequently, genotypes of 3725 SNPs in 167 genes from a custom Illumina iSelect array were used to evaluate the top ranked vs. hypothesis selected genes. Seventy-three genes were both highly ranked and involved in neurodevelopment (category 1) while 42 and 52 genes were exclusive to neurodevelopment (category 2) or highly ranked (category 3), respectively. The most significant associations were observed in genes PRKG1, PRKCE, and CNTN4 but no individual SNPs were significant after correction for multiple testing. Comparison of the approaches showed an excess of significant tests using the hypothesis-driven neurodevelopment category. Random selection of similar sized genes from two independent genome-wide association studies (GWAS) of schizophrenia showed the excess was unlikely by chance. In a further meta-analysis of three GWAS datasets, four candidate SNPs reached nominal significance. Although gene ranking using integrated sources of prior information did not enrich for significant results in the current experiment, gene selection using an a priori hypothesis (neurodevelopment) was superior to random selection. As such, further development of gene ranking strategies using more carefully selected sources of information is warranted.

Sediment changes upstream and downstream of the Altnahinch Dam in the River Bush in Northern Ireland: A preliminary study

The River Bush must reach a standard of good ecological potential (GEP) by 2015 due to the requirements of the water framework directive. The role of sediments within a water body is extremely important to all aspects of a river's regime. The aim of this research is to investigate the effects of Altnahinch Dam on sediment distribution in the River Bush (a heavily modified water body) with comparison made against the Glendun River (an unmodified water body). Samples collected from the rivers were analysed by physical (pebble count, sieve analysis) and statistical methods (ANOVA, GRADISTAT). An increase in fine sediments upstream of the dam provides evidence that the dam is impacting sediment distribution. Downstream effects are not shown to be significant. The output of this study also implies similar impacts at other drinking water storage impoundments. This research recommends that a sediment management plan be put in place for Altnahinch Dam and that further studies be carried-out concentrating on fine sediment distribution upstream of the dam. 

SORBS1 gene, a new candidate for diabetic nephropathy: results from a multi-stage genome-wide association study in patients with type 1 diabetes

Aims/hypothesis

National trends in main causes of hospitalization: a multi-cohort register study of the Finnish working-age population, 1976-2010

Principal Findings: Over the period of 35 years, the risk of hospitalization for cardiovascular diseases and respiratory diseases decreased. Hospitalization for musculoskeletal diseases increased whereas mental and behavioral hospitalizations slightly decreased. The risk of cancer hospitalization decreased marginally in men, whereas in women an upward trend was observed.

Conclusions/Significance: A considerable health transition related to hospitalizations and a shift in the utilization of health care services of working-age men and women took place in Finland between 1976 and 2010.

Background: The health transition theory argues that societal changes produce proportional changes in causes of disability and death. The aim of this study was to identify long-term changes in main causes of hospitalization in working-age population within a nation that has experienced considerable societal change.

Methodology: National trends in all-cause hospitalization and hospitalizations for the five main diagnostic categories were investigated in the data obtained from the Finnish Hospital Discharge Register. The seven-cohort sample covered the period from 1976 to 2010 and consisted of 3,769,356 randomly selected Finnish residents, each cohort representing 25% sample of population aged 18 to 64 years.

Sediment accumulation rates in subarctic lakes: insights into age-depth modeling from 22 dated lake records from the Northwest Territories, Canada

Age-depth modeling using Bayesian statistics requires well-informed prior information about the behavior of sediment accumulation. Here we present average sediment accumulation rates (represented as deposition times, DT, in yr/cm) for lakes in an Arctic setting, and we examine the variability across space (intra- and inter-lake) and time (late Holocene). The dataset includes over 100 radiocarbon dates, primarily on bulk sediment, from 22 sediment cores obtained from 18 lakes spanning the boreal to tundra ecotone gradients in subarctic Canada. There are four to twenty-five radiocarbon dates per core, depending on the length and character of the sediment records. Deposition times were calculated at 100-year intervals from age-depth models constructed using the ‘classical’ age-depth modeling software Clam. Lakes in boreal settings have the most rapid accumulation (mean DT 20 ± 10 years), whereas lakes in tundra settings accumulate at moderate (mean DT 70 ± 10 years) to very slow rates, (>100 yr/cm). Many of the age-depth models demonstrate fluctuations in accumulation that coincide with lake evolution and post-glacial climate change. Ten of our sediment cores yielded sediments as old as c. 9,000 cal BP (BP = years before AD 1950). From between c. 9,000 cal BP and c. 6,000 cal BP, sediment accumulation was relatively rapid (DT of 20 to 60 yr/cm). Accumulation slowed between c. 5,500 and c. 4,000 cal BP as vegetation expanded northward in response to warming. A short period of rapid accumulation occurred near 1,200 cal BP at three lakes. Our research will help inform priors in Bayesian age modeling.

In situ, high-resolution imaging of labile phosphorus in sediments of a large eutrophic lake

Understanding the labile status of phosphorus (P) in sediments is crucial for managing a eutrophic lake, but it is hindered by lacking in situ data particularly on a catchment scale. In this study, we for the first time characterized in situ labile P in sediments with the Zr-oxide diffusive gradients in thin films (Zr-oxide DGT) technique at a two-dimensional (2D), submillimeter resolution in a large eutrophic lake (Lake Taihu, China, with an area of 2338km²). The concentration of DGT-labile P in the sediment profiles showed strong variation mostly ranging from 0.01 to 0.35mgL^-1 with a considerable number of hotspots. The horizontal heterogeneity index of labile P varied from 0.04 to 4.5. High values appeared at the depths of 0-30mm, likely reflecting an active layer of labile P under the sediment-water interface (SWI). Concentration gradients of labile P were observed from the high-resolution 1D DGT profiles in both the sediment and overlying water layers close to the SWI. The apparent diffusion flux of P across the SWI was calculated between -21 and 65ngcm^-2d^-1, which showed that the sediments tended to be a source and sink of overlying water P in the algal- and macrophyte-dominated regions, respectively. The DGT-labile P in the 0-30mm active layer showed a better correlation with overlying water P than the labile P measured by ex situ chemical extraction methods. It implies that in situ, high-resolution profiling of labile P with DGT is a more reliable approach and will significantly extend our ability in in situ monitoring of the labile status of P in sediments in the field.

Is China's fifth-largest inland lake to dry-up? Incorporated hydrological and satellite-based methods for forecasting Hulun Lake water levels

Hulun Lake, China's fifth-largest inland lake, experienced severe declines in water level in the period of 2000-2010. This has prompted concerns whether the lake is drying up gradually. A multi-million US dollar engineering project to construct a water channel to transfer part of the river flow from a nearby river to maintain the water level was completed in August 2010. This study aimed to advance the understanding of the key processes controlling the lake water level variation over the last five decades, as well as investigate the impact of the river transfer engineering project on the water level. A water balance model was developed to investigate the lake water level variations over the last five decades, using hydrological and climatic data as well as satellite-based measurements and results from land surface modelling. The investigation reveals that the severe reduction of river discharge (-364±64 mm/yr, ∼70% of the five-decade average) into the lake was the key factor behind the decline of the lake water level between 2000 and 2010. The decline of river discharge was due to the reduction of total runoff from the lake watershed. This was a result of the reduction of soil moisture due to the decrease of precipitation (-49±45 mm/yr) over this period. The water budget calculation suggests that the groundwater component from the surrounding lake area as well as surface run off from the un-gauged area surrounding the lake contributed ∼ net 210 Mm3/yr (equivalent to ∼ 100 mm/yr) water inflows into the lake. The results also show that the water diversion project did prevent a further water level decline of over 0.5 m by the end of 2012. Overall, the monthly water balance model gave an excellent prediction of the lake water level fluctuation over the last five decades and can be a useful tool to manage lake water resources in the future.

Young, Old, and Weathered Carbon—Part 1: Using Radiocarbon and Stable Isotopes to Identify Carbon Sources in an Alkaline, Humic Lake

This article presents a case study of Lower Lough Erne, a humic, alkaline lake in northwest Ireland, and uses the radiocarbon method to determine the source and age of carbon to establish whether terrestrial carbon is utilized by heterotrophic organisms or buried in sediment. Stepped combustion was used to estimate the degree of the burial of terrestrial carbon in surface sediment. ∆14C, δ13C, and δ15N values were measured for phytoplankton, dissolved inorganic carbon (DIC), dissolved organic carbon (DOC), and particulate organic carbon (POC). ∆14C values were used to indicate the presence of different sources of carbon, including bedrock-derived inorganic carbon, “modern,” “recent,” “subsurface,” and “subfossil” terrestrial carbon in the lake. The use of 14C in conjunction with novel methods (e.g. stepped combustion) allows the determination of the pathway of terrestrial carbon in the system, which has implications for regional and global carbon cycling.

Adherence to treatment in children and adolescents with cystic fibrosis: a cross-sectional, multi-method study investigating the influence of beliefs about treatment and parental depressive symptoms

BACKGROUND: Adherence to treatment is often reported to be low in children with cystic fibrosis. Adherence in cystic fibrosis is an important research area and more research is needed to better understand family barriers to adherence in order for clinicians to provide appropriate intervention. The aim of this study was to evaluate adherence to enzyme supplements, vitamins and chest physiotherapy in children with cystic fibrosis and to determine if any modifiable risk factors are associated with adherence.

METHODS: A sample of 100 children (≤18 years) with cystic fibrosis (44 male; median [range] 10.1 [0.2-18.6] years) and their parents were recruited to the study from the Northern Ireland Paediatric Cystic Fibrosis Centre. Adherence to enzyme supplements, vitamins and chest physiotherapy was assessed using a multi-method approach including; Medication Adherence Report Scale, pharmacy prescription refill data and general practitioner prescription issue data. Beliefs about treatments were assessed using refined versions of the Beliefs about Medicines Questionnaire-specific. Parental depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale.

RESULTS: Using the multi-method approach 72% of children were classified as low-adherers to enzyme supplements, 59% low-adherers to vitamins and 49% low-adherers to chest physiotherapy. Variations in adherence were observed between measurement methods, treatments and respondents. Parental necessity beliefs and child age were significant independent predictors of child adherence to enzyme supplements and chest physiotherapy, but parental depressive symptoms were not found to be predictive of adherence.

CONCLUSIONS: Child age and parental beliefs about treatments should be taken into account by clinicians when addressing adherence at routine clinic appointments. Low adherence is more likely to occur in older children, whereas, better adherence to cystic fibrosis therapies is more likely in children whose parents strongly believe the treatments are necessary. The necessity of treatments should be reinforced regularly to both parents and children.

UK medical graduates’ preparedness for practice (P4P): A multi-site qualitative study

Introduction Previous research has demonstrated mixed findings in terms of graduates’ P4P in terms of their knowledge and skills, and interpersonal, systemic and technological aspects (Monrouxe et al. 2014). Few studies have included diverse stakeholders from multiple sites and employing longitudinal methods. We therefore aimed to understand the extent to which UK medical graduates are prepared for practice as Foundation doctors. Methods Cross-sectional qualitative narrative interview and longitudinal audio-diary (LAD) studies with participants from England, Scotland, Wales and Northern Ireland. Study 1 comprised 27 group and 84 individual interviews (n=185) with participants representing different stakeholders (F1s, fully registered trainees, clinical educators, undergraduate/postgraduate deans/foundation programme directors, other healthcare professionals, employers, policy makers, government representatives, and patient/public representatives). Study 2 comprised LADs with 26 F1s over 4-months. Results Participants found it hard initially to conceptualise the term ‘preparedness for practice’. We identified 2187 personal incident narratives (i.e. stories of P4P experiences) across our data: 506 (23%) were classed as ‘prepared’, 730 (33%) as ‘unprepared’ and 951 (44%) as ‘unspecified’. We identified factors that facilitated (e.g. supportive supervisors/colleagues, opportunities for shadowing) and hindered (e.g. unsupportive or disrespectful colleagues, poor organization, understaffing) transitions into and through the Foundation programme. The LADs suggested that trainees felt more confident and competent over time, but that such development was not always linear as challenging circumstances (e.g. new rotations) sometimes made trainees feel unprepared for situations where they had previously indicated preparedness. Conclusion Our findings add to the existing evidence on medical graduates’ P4P in the UK (e.g. Goldacre et al. 2008; Illing et al. 2013). Our findings support the role of assistantships and supportive supervisors for smoothing transitions from student to F1. Further longitudinal and action research studies are now needed to follow students through their final-year assistantships and into their F2 year.

Late-Pleistocene palaeoclimate and glacial activity recorded from lake sediments in the Eastern Alps

Greenland ice core data show that the last glaciation in the Northern Hemisphere was characterized by relatively short and rapid warming-cooling cycles. While the Last Glacial Maximum (LGM) and the following Late Glacial are well documented in the Eastern Alps, continuous and well dated records of the time period preceding the LGM are only known from stalagmites. Although most of the sediment that filled the Alpine valleys prior to the LGM was eroded, thick successions have been locally preserved as terraces along the flanks of large longitudinal valleys. The Inn valley in Tyrol (Austria) offers the most striking examples of Pleistocene terraces in the Eastern Alps. A large number of drill cores provides the opportunity to study these sediments for the first time in great detail. Our study focuses on the river terrace of Unterangerberg near Wörgl, where LGM gravel and till were deposited on top of (glacio)lacustrine sediments. The cores comprise mostly silty material, ranging from organic-rich to organic-poor and dropstone-rich beds. A diamictic layer classified as basal till is present at the bottom of the lake sediments. Radiocarbon ages of plant macro remains from the lake sequences indicate deposition between ~40 and >50 cal. ka BP. Luminescence ages obtained from fine-grain polymineral (4-11 μm) samples suggest an age of the lake deposits between ~40 to 60 ka and are consistent with the radiocarbon dates. Sedimentological analyses indicate that sedimentation in these palaeolakes was driven by local processes, but also by climatically induced changes in nearby glacier activity. These observations strongly hint towards a significant ice advance in the Eastern Alps during the early last glacial and subsequent mild interstadial conditions, supporting a local coniferous forest vegetation.