Genetics of rheumatoid arthritis contributes to biology and drug discovery

A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological data sets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here we performed a genome-wide association study meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single-nucleotide polymorphisms. We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 101 (refs 2, 3, 4). We devised an in silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci6 and pathway analyses7, 8, 9—as well as novel methods based on genetic overlap with human primary immunodeficiency, haematological cancer somatic mutations and knockout mouse phenotypes—to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery.

Factors associated with depression among male casual laborers in urban Vietnam

This study examined the level, the prevalence of and the factors associated with depression among male casual laborers in Hanoi. Social mapping was done to recruit and interview 450 men aged over 18 years, mostly unskilled and unregistered laborers from 135 street venues across 13 districts of the city using a structured questionnaire. Most were from rural and mountainous provinces and did manual works such as motorbike taxi drivers, porters, construction workers, small traders and others in the current city. The prevalence of self-reported depressive symptoms (25 %) was high. Structural equation modeling showed that marriage, family separation and living with peers or partners were three significant distal risk factors, while illicit drug use and low social connectedness were proximal predictors of depression. Of all factors, social connectedness appeared to be the most important because it plays a mediating role. Drug use was an independent risk factor. This study provides a model to understand the mental health of male casual laborers and to develop culturally appropriate intervention programs for these men

Sleepy driving and drink driving: attitudes, behaviours, and perceived legitimacy of enforcement of younger and older drivers

Sleepy driving and drink driving are two risky driving behaviours that substantially contribute to road crashes. Several studies demonstrate equivalent levels of impairment from both sleepy and drink driving. Yet, drivers perceive sleepy and drink driving distinctly different, with younger and older drivers engaging in these two risky driving behaviours at different rates. The current study sought to examine the sleepy and drink driving behaviours and perceptions in a sample of 114 younger (17-29 years) and 177 older (30+ years) drivers. Compared to older drivers, younger drivers reported more positive attitudes toward sleepy and drink driving behaviours, as well as more negative views regarding perceived legitimacy of sleepy driving enforcement. Younger drivers were also more likely to report performing sleepy driving behaviours than older drivers. Younger drivers reported greater likelihood to drive while sleepy, lower perceptions of legitimacy for sleepy driving, and more positive attitudes towards sleepy driving when compared to drink driving and the same pattern was found for older drivers as well. Subsequently, the self-reported likelihood of driving while sleepy was greater than drink driving in both age groups. Overall, the results suggest that sleepy driving is not viewed as equally dangerous as drink driving with younger drivers��� perceptions being more lenient than older drivers��� perceptions. It is likely that change is needed regarding the perceptions of dangerousness of sleepy driving with a particular focus on younger drivers seemingly needed.

Social influences on risky driving behaviours among young drivers in Oman

Young drivers represent approximately 20% of the Omani population, yet account for over one third of crash injuries and fatalities on Oman's roads. Internationally, research has demonstrated that social influences play an important role within young driver safety, however, there is little research examining this within Arab gulf countries. This study sought to explore young driver behaviour using Akers' social learning theory. A self-report survey was conducted by 1319 (72.9% male and 27.1% female) young drivers aged 17-25 years. A hierarchical regression model was used to investigate the contribution of social learning variables (norms and behaviour of significant others, personal attitudes towards risky behaviour, imitation of significant others, beliefs about the rewards and punishments offered by risky behaviour), socio-demographic characteristics (age and gender), driving experience (initial training, time driving and previous driving without supervision) and sensitivity to rewards and punishments upon the self-reported risky driving behaviours of young drivers. It was found that 39.6% of the young drivers reported that they have been involved in at least one crash since the issuance of their driving licence and they were considered ‘at fault’ in 60.7% of these crashes. The hierarchical multiple regression models revealed that socio-demographic characteristics and driving experience alone explained 14.2% of the variance in risky driving behaviour. By introducing social learning factors into the model a further 37.0% of variance was explained. Finally, 7.9% of the variance in risky behaviour could be explained by including individual sensitivity to rewards and punishments. These findings and the implications are discussed.

Crystal structures of the endoplasmic reticulum aminopeptidase-1 (ERAP1) reveal the molecular basis for N-terminal peptide trimming

Endoplasmatic reticulum aminopeptidase 1 (ERAP1) is a multifunctional enzyme involved in trimming of peptides to an optimal length for presentation by major histocompatibility complex (MHC) class I molecules. Polymorphisms in ERAP1 have been associated with chronic inflammatory diseases, including ankylosing spondylitis (AS) and psoriasis, and subsequent in vitro enzyme studies suggest distinct catalytic properties of ERAP1 variants. To understand structure-activity relationships of this enzyme we determined crystal structures in open and closed states of human ERAP1, which provide the first snapshots along a catalytic path. ERAP1 is a zinc-metallopeptidase with typical H-E-X-X-H-(X)18-E zinc binding and G-A-M-E-N motifs characteristic for members of the gluzincin protease family. The structures reveal extensive domain movements, including an active site closure as well as three different open conformations, thus providing insights into the catalytic cycle. A K 528R mutant strongly associated with AS in GWAS studies shows significantly altered peptide processing characteristics, which are possibly related to impaired interdomain interactions.

The emerging role of extracellular vesicle-mediated drug resistance in cancers: Implications in advanced prostate cancer

Emerging evidence has shown that the extracellular vesicles (EVs) regulate various biological processes and can control cell proliferation and survival, as well as being involved in normal cell development and diseases such as cancers. In cancer treatment, development of acquired drug resistance phenotype is a serious issue. Recently it has been shown that the presence of multidrug resistance proteins such as Pgp-1 and enrichment of the lipid ceramide in EVs could have a role in mediating drug resistance. EVs could also mediate multidrug resistance through uptake of drugs in vesicles and thus limit the bioavailability of drugs to treat cancer cells. In this review, we discussed the emerging evidence of the role EVs play in mediating drug resistance in cancers and in particular the role of EVs mediating drug resistance in advanced prostate cancer. The role of EV-associated multidrug resistance proteins, miRNA, mRNA, and lipid as well as the potential interaction(s) among these factors was probed. Lastly, we provide an overview of the current available treatments for advanced prostate cancer, considering where EVs may mediate the development of resistance against these drugs.

Label-free isolation of a prostate cancer cell among blood cells and the single-cell measurement of drug accumulation using an integrated microfluidic chip

Circulating tumor cells (CTCs) are found in the blood of patients with cancer. Although these cells are rare, they can provide useful information for chemotherapy. However, isolation of these rare cells from blood is technically challenging because they are small in numbers. An integrated microfluidic chip, dubbed as CTC chip, was designed and fabricated for conducting tumor cell isolation. As CTCs usually show multidrug resistance (MDR), the effect of MDR inhibitors on chemotherapeutic drug accumulation in the isolated single tumor cell is measured. As a model of CTC isolation, human prostate tumor cells were mixed with mouse blood cells and the labelfree isolation of the tumor cells was conducted based on cell size difference. The major advantages of the CTC chip are the ability for fast cell isolation, followed by multiple rounds of single-cell measurements, suggesting a potential assay for detecting the drug responses based on the liquid biopsy of cancer patients.

Prevalence and characteristics of road traffic injuries among young drivers in Oman, 2009-2011

Objectives Studies from different parts of the world have indicated that the impact of road traffic incidents disproportionally affects young adults. Few known studies have been forthcoming from Arabian Gulf countries. Within Oman, a high proportion of the population is under the age of 20. Coupled with the drastic increase of motorization in recent years there is a need to understand the state of road safety among young people in Oman. The current research aimed to explore the prevalence and characteristics of road traffic injuries among young drivers aged 17-25 years. Methods Crash data from 2009-2011 was extracted from the Directorate General of Traffic, Royal Oman Police (ROP) database in Oman. The data was analyzed to explore the impact of road crashes on young people (17-25 years), the characteristics of young driver crashes and how these differ from older drivers and to identify key predictors of fatalities in young driver crashes. Results Overall, young people were over-represented in injuries and fatalities within the sample time period. While it is true that many young people in crashes were driving at the time, it was also evident that young people were often a victim in a crash caused by someone else. Thus, to reduce the impact of road crashes on young people, there is a need to generally address road safety within Oman. When young drivers were involved in crashes they were predominantly male. The types of crashes these drivers have can be broadly attributed to risk taking and inexperience. Speeding and night time driving were the key risk factors for fatalities. Conclusion The results highlight the need to address young driver safety in Oman. From these findings, the introduction of a graduated driver licensing system with night time driving restrictions could significantly improve young driver safety.

A road safety strategy for Norfolk Island, an Australian external territory

Norfolk Island is an Australian external territory in Oceania. The significant road safety reforms in Australia from the 1970s onward bypassed the island, and most road safety ‘silver bullets’ adopted in other Australian jurisdictions were not introduced. While legislative amendments in 2010 introduced mandatory seat belt wearing for vehicle occupants on Norfolk Island, other critical issues face the community including drink driving by residents and visitors, occupant protection for vehicle passengers, and the provision of a more protective road environment. The release of the first Norfolk Island road safety strategy 2014-2016 proposed, inter alia: • a lower BAC of 0.05 and the introduction of compulsory driver alcohol and drug testing by police; • targeted enforcement of occupant protection for vehicle passengers, particularly for passengers riding on vehicle tray backs; • education interventions to challenge values held by some members of the community that support unsafe road use; • ensuring that driver information, training and testing is adequate for all drivers; • identification and rectification of hazardous roadside infrastructure, particularly barrier protection at “high drop locations” within the road network; and • developing a specification for vehicle standards for vehicles imported into Norfolk Island. Norfolk Island is engaging in a process of integration with the Australian community, and wider issues relating to funding and resources have impacted on the implementation of the road safety strategy. The response to the strategy will be discussed, particularly in terms of current attempts to address drink driving and the provision of a safer road environment.

Drink driving among Indigenous people in Far North Queensland and northern New South Wales: A summary of the qualitative findings

Purpose In response to the threat that drink drivers pose to themselves and others, drink driving programs form an important part of a suite of countermeasures used in Australia and internationally. Unlike New Zealand/Aotearoa, United States and Canada that have programs catering for their First Peoples, all Australian programs are designed for the general driver population. The aim of this study was to identify the factors that contribute to Indigenous drink driving in order to inform appropriate recommendations related to developing a community-based program for Indigenous communities. Broader drivers licensing policy recommendations are also discussed. Methods A sample of 73 Indigenous people from Queensland and in New South Wales with one or more drink driving convictions completed a semi-structured interview in respect of the to their drink driving behaviour. Participants were asked to disclose information regarding their drink driving history, and alcohol and drug use. If participants self-reported no longer drink driving, they were probed about what factors had assisted them to avoid further offending. Results Key themes which emerged to maintain drink driving include motivations to drink and drive, and belief in the ability to manage the associated risks. Factors that appeared to support others from avoiding further offending include re-connecting with culture and family support. Conclusions and Implications A range of recommendations regarding delivery and content of a program for regional and remote communities as well as other policy implications are discussed.

Examining novice education: What can we learn from a compulsory program delivered to both mature-age and young pre-learner licence drivers?

This paper reports results from a qualitative evaluation of a compulsory pre-Learner driver education program within the Australian Capital Territory(ACT), Australia. Two methods were used to obtain feedback from those involved in the delivery of the program as well as those who participated in programs. The first, semi-structured interviews, was undertaken with class room teachers who run the program in their schools, group facilitators running the program with more mature-age students at private facilities (n = 15 in total), and former participants in both school-based and private-based versions of the program (n = 19). The second method used an on-line survey for students (n = 79). Results from both methods were consistent with each other, indicating that strengths of the program were perceived as being its interactive components and the high level of engagement of the target audience. There was strong support from young and mature-age students for the program to remain compulsory. However, consistent with other findings on novice driver education, mature-age participants identified that the program was less relevant to them. It may be that to have greater relevance to mature-age learners, content could address and challenge perceptions about behaviours other than intentional high-risk behaviours (e.g. low level speeding, fatigue) as well as encourage planning/strategies to avoid them. While a longer term, outcome focussed, evaluation of the pre-learner education program is needed, this study suggests that the program is well received by pre-licence drivers and that teachers and facilitators perceive it as both effective and beneficial.

Observations of road safety behaviours and practices of motorcycle rickshaw drivers in Lahore, Pakistan

Motorcycle Rickshaws (MRs) are an informal paratransit mode in Pakistan. They are locally manufactured and very popular but there are concerns about their crash involvement and overall safety. The first study of the current PhD program revealed that rickshaws (both MRs and auto-rickshaws) were involved in 51,992 road crashes attended by emergency ambulances in Punjab province, Pakistan between 2011-2013. This study aims to examine the road safety behaviours and practices of Motorcycle Rickshaw Drivers (MRDs) that may be contributing to these crashes. MRDs were observed at 12 major signalised intersections in Lahore. Vehicle characteristics and driver behaviours were recorded using a paper-based survey between 9am-7pm for a full week in May 2015. Of the 500 MRDs observed, about 23.4% appeared to be younger than the minimum driver licensing age of 18 years. More than half (52.6%) of the MRDs entered on the red light and 17.4% crossed when the signal was turning from yellow to green or red. MR traffic conflicts were observed in 62.8% of cases and one crash and 15 near-miss crashes were witnessed. Additionally, about half of MRs were overloaded, no MRD wore a helmet, and 3.8% were using a mobile phone while driving. This study provides the first scientific evidence to substantiate public concerns regarding the safety of MRs. It demonstrates that about a quarter of MRDs are underage,almost half of MRs are overloaded and more than half disobey traffic signals. This research could inform authorities to manage MR related transport and road safety issues.

Influence of road traffic environment and mobile phone distraction on the speed selection behaviour of young drivers

Travel speed is one of the most critical parameters for road safety; the evidence suggests that increased vehicle speed is associated with higher crash risk and injury severity. Both naturalistic and simulator studies have reported that drivers distracted by a mobile phone select a lower driving speed. Speed decrements have been argued to be a risk compensatory behaviour of distracted drivers. Nonetheless, the extent and circumstances of the speed change among distracted drivers are still not known very well. As such, the primary objective of this study was to investigate patterns of speed variation in relation to contextual factors and distraction. Using the CARRS-Q high-fidelity Advanced Driving Simulator, the speed selection behaviour of 32 drivers aged 18-26 years was examined in two phone conditions: baseline (no phone conversation) and handheld phone operation. The simulator driving route contained five different types of road traffic complexities, including one road section with a horizontal S curve, one horizontal S curve with adjacent traffic, one straight segment of suburban road without traffic, one straight segment of suburban road with traffic interactions, and one road segment in a city environment. Speed deviations from the posted speed limit were analysed using Ward’s Hierarchical Clustering method to identify the effects of road traffic environment and cognitive distraction. The speed deviations along curved road sections formed two different clusters for the two phone conditions, implying that distracted drivers adopt a different strategy for selecting driving speed in a complex driving situation. In particular, distracted drivers selected a lower speed while driving along a horizontal curve. The speed deviation along the city road segment and other straight road segments grouped into a different cluster, and the deviations were not significantly different across phone conditions, suggesting a negligible effect of distraction on speed selection along these road sections. Future research should focus on developing a risk compensation model to explain the relationship between road traffic complexity and distraction.

Is there such a thing as a love drug?

This paper considers recent discussion of the possible use of ‘love drugs’ and ‘anti-love drugs’ as a way of enhancing or diminishing romantic relationships. The primary focus is on the question of whether the idea of using such products commits its proponents to an excessively reductionist conception of love, and on whether the resulting ‘love’ in the use of ‘love drugs’ would be authentic, to the extent that it would be brought about artificially.

Analysis of human immunodeficiency virus type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377)

In Pediatric AIDS Clinical Trials Group 377, antiretroviral therapy-experienced children were randomized to 4 treatment arms that included different combinations of stavudine, lamivudine (3TC), nevirapine (Nvp), nelfinavir (Nfv), and ritonavir (Rtv). Previous treatment with zidovudine (Zdv), didanosine (ddI), or zalcitabine (ddC) was acceptable. Drug resistance ((R)) mutations were assessed before study treatment (baseline) and at virologic failure. Zdv(R), ddI(R), and ddC(R) mutations were detected frequently at baseline but were not associated with virologic failure. Children with drug resistance mutations at baseline had greater reductions in virus load over time than did children who did not. Nvp(R) and 3TC(R) mutations were detected frequently at virologic failure, and Nvp(R) mutations were more common among children receiving 3-drug versus 4-drug Nvp-containing regimens. Children who were maintained on their study regimen after virologic failure accumulated additional Nvp(R) and 3TC(R) mutations plus Rtv(R) and Nfv(R) mutations. However, Rtv(R) and Nfv(R) mutations were detected at unexpectedly low rates.