Challenge of Pigs with Classical Swine Fever Viruses after C-Strain Vaccination Reveals Remarkably Rapid Protection and Insights into Early Immunity

Pre-emptive culling is becoming increasingly questioned as a means of controlling animal diseases, including classical swine fever (CSF). This has prompted discussions on the use of emergency vaccination to control future CSF outbreaks in domestic pigs. Despite a long history of safe use in endemic areas, there is a paucity of data on aspects important to emergency strategies, such as how rapidly CSFV vaccines would protect against transmission, and if this protection is equivalent for all viral genotypes, including highly divergent genotype 3 strains. To evaluate these questions, pigs were vaccinated with the Riemser® C-strain vaccine at 1, 3 and 5 days prior to challenge with genotype 2.1 and 3.3 challenge strains. The vaccine provided equivalent protection against clinical disease caused by for the two challenge strains and, as expected, protection was complete at 5 days post-vaccination. Substantial protection was achieved after 3 days, which was sufficient to prevent transmission of the 3.3 strain to animals in direct contact. Even by one day post-vaccination approximately half the animals were partially protected, and were able to control the infection, indicating that a reduction of the infectious potential is achieved very rapidly after vaccination. There was a close temporal correlation between T cell IFN-γ responses and protection. Interestingly, compared to responses of animals challenged 5 days after vaccination, challenge of animals 3 or 1 days post-vaccination resulted in impaired vaccine-induced T cell responses. This, together with the failure to detect a T cell IFN-γ response in unprotected and unvaccinated animals, indicates that virulent CSFV can inhibit the potent antiviral host defences primed by C-strain in the early period post vaccination

Do schools differ in suicide risk? the influence of school and neighbourhood on attempted suicide, suicidal ideation and self-harm among secondary school pupils

<br>Background: Rates of suicide and poor mental health are high in environments (neighbourhoods and institutions) where individuals have only weak social ties, feel socially disconnected and experience anomie - a mismatch between individual and community norms and values. Young people spend much of their time within the school environment, but the influence of school context (school connectedness, ethos and contextual factors such as school size or denomination) on suicide-risk is understudied. Our aim is to explore if school context is associated with rates of attempted suicide and suicide-risk at age 15 and self-harm at age 19, adjusting for confounders.</br> <br>Methods: A longitudinal school-based survey of 1698 young people surveyed when aged 11, (primary school), 15 (secondary school) and in early adulthood (age 19). Participants provided data about attempted suicide and suicide-risk at age 15 and deliberate self-harm at 19. In addition, data were collected about mental health at age 11, social background (gender, religion, etc.), and at age 15, perception of local area (e.g. neighbourhood cohesion, safety/civility and facilities), school connectedness (school engagement, involvement, etc.) and school context (size, denomination, etc.). A dummy variable was created indicating a religious 'mismatch', where pupils held a different faith from their school denomination. Data were analysed using multilevel logistic regression.</br> <br>Results: After adjustment for confounders, pupils attempted suicide, suicide-risk and self-harm were all more likely among pupils with low school engagement (15-18% increase in odds for each SD change in engagement). While holding Catholic religious beliefs was protective, attending a Catholic school was a risk factor for suicidal behaviours. This pattern was explained by religious 'mismatch': pupils of a different religion from their school were approximately 2-4 times more likely to attempt suicide, be a suicide-risk or self-harm.</br> <br>Conclusions: With several caveats, we found support for the importance of school context for suicidality and self-harm. School policies promoting school connectedness are uncontroversial. Devising a policy to reduce risks to pupils holding a different faith from that of their school may be more problematic.</br&gt

A systematic review of task- shifting for HIV treatment and care in Africa

BACKGROUND: Shortages of human resources for health (HRH) have severely hampered the rollout of antiretroviral therapy (ART) in sub-Saharan Africa. Current rollout models are hospital- and physician-intensive. Task shifting, or delegating tasks performed by physicians to staff with lower-level qualifications, is considered a means of expanding rollout in resource-poor or HRH-limited settings. METHODS: We conducted a systematic literature review. Medline, the Cochrane library, the Social Science Citation Index, and the South African National Health Research Database were searched with the following terms: task shift*, balance of care, non-physician clinicians, substitute health care worker, community care givers, primary healthcare teams, cadres, and nurs* HIV. We mined bibliographies and corresponded with authors for further results. Grey literature was searched online, and conference proceedings searched for abstracts. RESULTS: We found 2960 articles, of which 84 were included in the core review. 51 reported outcomes, including research from 10 countries in sub-Saharan Africa. The most common intervention studied was the delegation of tasks (especially initiating and monitoring HAART) from doctors to nurses and other non-physician clinicians. Five studies showed increased access to HAART through expanded clinical capacity; two concluded task shifting is cost effective; 9 showed staff equal or better quality of care; studies on non-physician clinician agreement with physician decisions was mixed, with the majority showing good agreement. CONCLUSIONS: Task shifting is an effective strategy for addressing shortages of HRH in HIV treatment and care. Task shifting offers high-quality, cost-effective care to more patients than a physician-centered model. The main challenges to implementation include adequate and sustainable training, support and pay for staff in new roles, the integration of new members into healthcare teams, and the compliance of regulatory bodies. Task shifting should be considered for careful implementation where HRH shortages threaten rollout programmes

Psychological characteristics of religious delusions

Purpose Religious delusions are common and are considered to be particularly difficult to treat. In this study we investigated what psychological processes may underlie the reported treatment resistance. In particular, we focused on the perceptual, cognitive, affective and behavioural mechanisms held to maintain delusions in cognitive models of psychosis, as these form the key treatment targets in cognitive behavioural therapy. We compared religious delusions to delusions with other content. Methods Comprehensive measures of symptoms and psychological processes were completed by 383 adult participants with delusions and a schizophrenia spectrum diagnosis, drawn from two large studies of cognitive behavioural therapy for psychosis. Results Binary logistic regression showed that religious delusions were associated with higher levels of grandiosity (OR 7.5; 95 % CI 3.9–14.1), passivity experiences, having internal evidence for their delusion (anomalous experiences or mood states), and being willing to consider alternatives to their delusion (95 % CI for ORs 1.1–8.6). Levels of negative symptoms were lower. No differences were found in delusional conviction, insight or attitudes towards treatment. Conclusions Levels of positive symptoms, particularly anomalous experiences and grandiosity, were high, and may contribute to symptom persistence. However, contrary to previous reports, we found no evidence that people with religious delusions would be less likely to engage in any form of help. Higher levels of flexibility may make them particularly amenable to cognitive behavioural approaches, but particular care should be taken to preserve self-esteem and valued aspects of beliefs and experiences

Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials

Background: Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages. Methods: In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups. Findings: 14 483 (8%) of 186 854 participants in the 28 trials were older than 75 years at randomisation, and the median follow-up duration was 4·9 years. Overall, statin therapy or a more intensive statin regimen produced a 21% (RR 0·79, 95% CI 0·77–0·81) proportional reduction in major vascular events per 1·0 mmol/L reduction in LDL cholesterol. We observed a significant reduction in major vascular events in all age groups. Although proportional reductions in major vascular events diminished slightly with age, this trend was not statistically significant (ptrend=0·06). Overall, statin or more intensive therapy yielded a 24% (RR 0·76, 95% CI 0·73–0·79) proportional reduction in major coronary events per 1·0 mmol/L reduction in LDL cholesterol, and with increasing age, we observed a trend towards smaller proportional risk reductions in major coronary events (ptrend=0·009). We observed a 25% (RR 0·75, 95% CI 0·73–0·78) proportional reduction in the risk of coronary revascularisation procedures with statin therapy or a more intensive statin regimen per 1·0 mmol/L lower LDL cholesterol, which did not differ significantly across age groups (ptrend=0·6). Similarly, the proportional reductions in stroke of any type (RR 0·84, 95% CI 0·80–0·89) did not differ significantly across age groups (ptrend=0·7). After exclusion of four trials which enrolled only patients with heart failure or undergoing renal dialysis (among whom statin therapy has not been shown to be effective), the trend to smaller proportional risk reductions with increasing age persisted for major coronary events (ptrend=0·01), and remained non-significant for major vascular events (ptrend=0·3). The proportional reduction in major vascular events was similar, irrespective of age, among patients with pre-existing vascular disease (ptrend=0·2), but appeared smaller among older than among younger individuals not known to have vascular disease (ptrend=0·05). We found a 12% (RR 0·88, 95% CI 0·85–0·91) proportional reduction in vascular mortality per 1·0 mmol/L reduction in LDL cholesterol, with a trend towards smaller proportional reductions with older age (ptrend=0·004), but this trend did not persist after exclusion of the heart failure or dialysis trials (ptrend=0·2). Statin therapy had no effect at any age on non-vascular mortality, cancer death, or cancer incidence. Interpretation: Statin therapy produces significant reductions in major vascular events irrespective of age, but there is less direct evidence of benefit among patients older than 75 years who do not already have evidence of occlusive vascular disease. This limitation is now being addressed by further trials. Funding: Australian National Health and Medical Research Council, National Institute for Health Research Oxford Biomedical Research Centre, UK Medical Research Council, and British Heart Foundation

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4-2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in genera

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio