International meta-analysis of PTSD genome-wide association studies identifies sex- and ancestry-specific genetic risk loci.

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations

Financial considerations in the conduct of multi-centre randomised controlled trials: evidence from a qualitative study.

National Coordinating Centre for Research Methodology; Medical Research Council, UK Department of Health; Chief Scientist OfficeNot peer reviewedPublisher PD

Improving breast cancer services for African-American women living in St. Louis

A mixed methods, community-based research study was conducted to understand how provider-level factors contribute to the African-American and white disparity in breast cancer mortality in a lower socioeconomic status area of North St. Louis. This study used mixed methods including: (1) secondary analysis of Missouri Cancer Registry data on all 885 African-American women diagnosed with breast cancer from 2000 to 2008 while living in the geographic area of focus; (2) qualitative interviews with a subset of these women; (3) analysis of data from electronic medical records of the women interviewed; and (4) focus group interviews with community residents, patient navigators, and other health care professionals. 565 women diagnosed with breast cancer from 2000 to 2008 in the geographic area were alive at the time of secondary data analysis; we interviewed (n = 96; 17 %) of these women. Provider-level obstacles to completion of prescribed treatment included fragmented navigation (separate navigators at Federally Qualified Health Centers, surgical oncology, and medical oncology, and no navigation services in surgical oncology). Perhaps related to the latter, women described radiation as optional, often in the same words as they described breast reconstruction. Discontinuous and fragmented patient navigation leads to failure to associate radiation therapy with vital treatment recommendations. Better integrated navigation that continues throughout treatment will increase treatment completion with the potential to improve outcomes in African Americans and decrease the disparity in mortality

Novel essential amino acid supplements enriched with L-leucine facilitate increased protein and energy intakes in older women: a randomised controlled trial

Background: Inadequate protein intake (PI), containing a sub-optimal source of essential amino acids (EAAs), and reduced appetite are contributing factors to age-related sarcopenia. The satiating effects of dietary protein per se may negatively affect energy intake (EI), thus there is a need to explore alternative strategies to facilitate PI without compromising appetite and subsequent EI. Methods: Older women completed two experiments (EXP1 and EXP2) where they consumed either a Bar (565 kJ), a Gel (477 kJ), both rich in EAAs (7.5 g, 40% L-leucine), or nothing (Control). In EXP1, participants (n=10, 68±5 years, mean±SD) consumed Bar, Gel or Control with appetite sensations and appetite-related hormonal responses monitored for one hour, followed by consumption of an ad libitum breakfast (ALB). In EXP2, participants (n=11, 69±5 years) ingested Bar, Gel or Control alongside an ALB. Results: In EXP1, EI at ALB was not different (P=0.674) between conditions (1179±566, 1254±511, 1206±550 kJ for the Control, Bar, and Gel respectively). However, total EI was significantly higher in the Bar and Gel compared to the Control after accounting for the energy content of the supplements (P<0.0005). Analysis revealed significantly higher appetite Area under the Curve (AUC) (P<0.007), a tendency for higher acylated ghrelin AUC (P=0.087), and significantly lower pancreatic polypeptide AUC (P=0.02) in the Control compared with the Bar and Gel. In EXP2, EI at ALB was significantly higher (P=0.028) in the Control (1282±513 kJ) compared to the Bar (1026±565 kJ) and Gel (1064±495 kJ). However, total EI was significantly higher in the Bar and Gel after accounting for the energy content of the supplements (P<0.007). Conclusions: Supplementation with either the Bar or Gel increased total energy intake whether consumed one hour before or during breakfast. This may represent an effective nutritional means for addressing protein and total energy deficiencies in older women

Angiogenin protects motoneurons against hypoxic injury.

Cells can adapt to hypoxia through the activation of hypoxia-inducible factor-1 (HIF-1), which in turn regulates the expression of hypoxia-responsive genes. Defects in hypoxic signaling have been suggested to underlie the degeneration of motoneurons in amyotrophic lateral sclerosis (ALS). We have recently identified mutations in the hypoxia-responsive gene, angiogenin (ANG), in ALS patients, and have shown that ANG is constitutively expressed in motoneurons. Here, we show that HIF-1alpha is sufficient and required to activate ANG in cultured motoneurons exposed to hypoxia, although ANG expression does not change in a transgenic ALS mouse model or in sporadic ALS patients. Administration of recombinant ANG or expression of wild-type ANG protected motoneurons against hypoxic injury, whereas gene silencing of ang1 significantly increased hypoxia-induced cell death. The previously reported ALS-associated ANG mutations (Q12L, K17I, R31K, C39W, K40I, I46V) all showed a reduced neuroprotective activity against hypoxic injury. Our data show that ANG plays an important role in endogenous protective pathways of motoneurons exposed to hypoxia, and suggest that loss of function rather than loss of expression of ANG is associated with ALS

Who Benefits Most from a University Degree?: A Cross-National Comparison of Selection and Wage Returns in the US, UK, and Germany

Recent research on economic returns to higher education in the United States suggests that those with the highest wage returns to a college degree are least likely to obtain one. We extend the study of heterogeneous returns to tertiary education across multiple institutional contexts, investigating how the relationship between wage returns and the propensity to complete a degree varies by the level of expansion, differentiation, and cost of higher education. Drawing on panel data and matching techniques, we compare findings from the US with selection into degree completion in Germany and the UK. Contrary to previous studies, we find little evidence for population level heterogeneity in economic returns to higher education

The emergence of inequality in social groups: network structure and institutions affect the distribution of earnings in cooperation games

From small communities to entire nations and society at large, inequality in wealth, social status, and power is one of the most pervasive and tenacious features of the social world. What causes inequality to emerge and persist? In this study, we investigate how the structure and rules of our interactions can increase inequality in social groups. Specifically, we look into the effects of four structural conditions—network structure, network fluidity, reputation tracking, and punishment institutions—on the distribution of earnings in network cooperation games. We analyze 33 experiments comprising 96 experimental conditions altogether. We find that there is more inequality in clustered networks compared to random networks, in fixed networks compared to randomly rewired and strategically updated networks, and in groups with punishment institutions compared to groups without. Secondary analyses suggest that the reasons inequality emerges under these conditions may have to do with the fact that fixed networks allow exploitation of the poor by the wealthy and clustered networks foster segregation between the poor and the wealthy, while the burden of costly punishment falls onto the poor, leaving them poorer. Surprisingly, we do not find evidence that inequality is affected by reputation in a systematic way but this could be because reputation needs to play out in a particular network environment in order to have an effect. Overall, our findings suggest possible strategies and interventions to decrease inequality and mitigate its negative impact, particularly in the context of mid- and large-sized organizations and online communities

Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder

Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N = 4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P = 6.9 X 10(-4)). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD

The Safe Development Paradox in Flood Risk Management: A Critical Review

Climate change and continued urban development in flood-prone areas exacerbate flood risks. Flood Risk Management authorities often turn to structural protection measures to minimise losses. However, these measures often lead to infrastructural lock-ins with potential unintended consequences as increased safety can induce increased development, ultimately leading to higher losses in the event of failures of the structural safe-guards in place. This process has been referred to as the Safe Development Paradox: a cross-cutting science-policy-practice challenge that requires a systematic understanding in the context of climate change and the United Nations Sustainable Development Goals. Yet, there are no comprehensive review studies, to date, that summarize the state of knowledge of the Safe Development Paradox. This paper provides the first evidence base through a critical review of the state-of-the-art and quantitative analysis of the peer-reviewed English-language literature since 2000, highlighting key knowledge gaps and issues hindering progress in addressing the Safe Development Paradox. It was identified that current research is compounded by a lack of consistent terminology, limited geographic distribution of case studies, and skewed emphasis on fluvial flooding. The review ends with potential directions across the science, policy, and practice domains for increasing knowledge and tackling the Safe Development Paradox.EPSRC grant number EP/T518116/

Agent-Based Socio-Spatial Modelling of Coupled Human-Flood Interactions along the UK Coast

This study uses agent-based modelling (ABM) to assess the socio-hydrological impacts of structural coastal flood protections (SCFPs) under different climate change scenarios considering three contrasting UK case studies: Southport, Weston-super-Mare, and Portsmouth. By integrating extreme coastal water level (ECWL) projections and population dynamics, the ABM simulations reveal five distinct phases: Design, Implementation, Latency, Flood, and Post-Flood. The results highlight that the Latency phase, whereby SCFP initially stabilises affected population (AfP), inadvertently encourages population growth in residual risk areas. This process exacerbates long-term flood exposure, leading to significant increases in AfP when ECWL exceeds the SCFP crest height, negating gains in flood protection from the initial construction/upgrade. As such, Southport and Weston-super-Mare saw a significant increase in coastal population within protected floodplains, with these populations potentially having limited experience with flooding, preparedness, and consequently heightened vulnerability. Conversely, Portsmouth, with limited residential development near SCFPs, demonstrated how existing land-use and high population density can reduce the unintended socio-hydrological consequences of SCFPs in densely-populated coastal settings. These findings reveal two key pathways that influence coastal population in response to SCFPs: Land-use Driven, where non-residential land-use limits population increase, and Population Driven, where high-density areas limit further growth. This study advances our understanding of the coupled human-flood dynamics by evaluating how SCFPs can increase flood impacts in the long-term by influencing socio-spatial distribution over the short- to medium-term. Moreover, it demonstrates how ABMs can provide valuable insights by simulating complex coupled human-flood dynamics; critical for supporting adaptive, resilient coastal management strategies in a changing climate.This research was funded by the EPSRC grant number EP/T518116/1