Whanau Maori and Pacific peoples' knowledge, perceptions, expectations and solutions regarding antibiotic treatment of upper respiratory tract infections: a qualitative study.

INTRODUCTION: The rate of community antibiotic use is high in Aotearoa New Zealand (NZ) when compared to other nations, and in NZ, as in most other nations, antibiotics are very commonly prescribed for self-limiting upper respiratory tract infections (URTIs). Resources that build knowledge, perceptions and understanding can potentially reduce unnecessary antibiotic consumption. METHODS: To inform the content of educational resources, we conducted an in-depth qualitative study with 47 participants via 6 focus groups of the knowledge, attitudes, and expectations of whanau Maori and Pacific peoples about antibiotics and URTIs. RESULTS: Focus groups with 47 participants identified four themes: Knowledge that might influence expectations to receive antibiotics for URTIs; Perceptions - the factors that influence when and why to seek medical care for URTI; Expectations - the features of successful medical care for URTI; Solutions - how to build community knowledge about URTI and their treatment and prevention. Knowledge that might reduce expectations to receive antibiotics for URTI included confidence in the use of alternative remedies, knowledge that URTI are usually caused by viruses, and concerns about antibiotic adverse effects. Participants commonly reported that they would confidently accept their doctor's recommendation that an antibiotic was not necessary for an URTI, provided that a thorough assessment had been performed and that treatment decisions were clearly communicated. CONCLUSION: These findings suggest that building patients' knowledge and skills about when antibiotics are necessary, and increasing doctors' confidence and willingness not to prescribe an antibiotic for patients with an URTI, could significantly reduce inappropriate antibiotic prescribing in NZ.

Three major dimensions of human brain cortical ageing in relation to cognitive decline across the eighth decade of life.

Different brain regions can be grouped together, based on cross-sectional correlations among their cortical characteristics; this patterning has been used to make inferences about ageing processes. However, cross-sectional brain data conflate information on ageing with patterns that are present throughout life. We characterised brain cortical ageing across the eighth decade of life in a longitudinal ageing cohort, at ages ~73, ~76, and ~79 years, with a total of 1376 MRI scans. Volumetric changes among cortical regions of interest (ROIs) were more strongly correlated (average r = 0.805, SD = 0.252) than were cross-sectional volumes of the same ROIs (average r = 0.350, SD = 0.178). We identified a broad, cortex-wide, dimension of atrophy that explained 66% of the variance in longitudinal changes across the cortex. Our modelling also discovered more specific fronto-temporal and occipito-parietal dimensions that were orthogonal to the general factor and together explained an additional 20% of the variance. The general factor was associated with declines in general cognitive ability (r = 0.431, p < 0.001) and in the domains of visuospatial ability (r = 0.415, p = 0.002), processing speed (r = 0.383, p < 0.001) and memory (r = 0.372, p < 0.001). Individual differences in brain cortical atrophy with ageing are manifest across three broad dimensions of the cerebral cortex, the most general of which is linked with cognitive declines across domains. Longitudinal approaches are invaluable for distinguishing lifelong patterns of brain-behaviour associations from patterns that are specific to aging.

Assessment of the effect of the COVID-19 lockdown on glycaemic control in people with type 1 diabetes using flash glucose monitoring.

AIM: To describe the effect of the stringent lockdown measures, introduced in the UK on 23 March 2020 to curtail the transmission of COVID-19, on glycaemic control in people with type 1 diabetes using flash glucose monitoring. METHODS: We undertook an observational study of 572 individuals with type 1 diabetes for whom paired flash glucose monitoring data were available between early March and May 2020. The primary outcome was change in flash glucose monitoring variables. We also assessed clinical variables associated with change in glycaemic control. RESULTS: Percentage of time in range increased between March and May 2020 [median (interquartile range) 53 (41-64)% vs 56 (45-68)%; P < 0.001], with associated improvements in standard deviation of glucose (P <0.001) and estimated HbA1c (P <0.001). There was a small reduction in the number of individuals meeting the hypoglycaemia target of <5% per day (64% vs 58%; P = 0.004). Comparing changes in flash glucose monitoring data from March to May in 2019 with the same period in 2020 confirmed that these differences were confined to 2020. Socio-economic deprivation was an independent predictor of a ≥5% reduction in time in range during lockdown (odds ratio 0.45 for people in the two most affluent Scottish Index of Multiple Deprivation quintiles; P <0.001). CONCLUSIONS: Lockdown was not associated with a significant deterioration in glycaemic control in people with type 1 diabetes using flash glucose monitoring. However, socio-economic deprivation appeared to increase the risk of decline in glycaemic control, which has implications for how support is focused in challenging times.

Modelling the Wolbachia incompatible insect technique: strategies for effective mosquito population elimination.

BACKGROUND: The Wolbachia incompatible insect technique (IIT) shows promise as a method for eliminating populations of invasive mosquitoes such as Aedes aegypti (Linnaeus) (Diptera: Culicidae) and reducing the incidence of vector-borne diseases such as dengue, chikungunya and Zika. Successful implementation of this biological control strategy relies on high-fidelity separation of male from female insects in mass production systems for inundative release into landscapes. Processes for sex-separating mosquitoes are typically error-prone and laborious, and IIT programmes run the risk of releasing Wolbachia-infected females and replacing wild mosquito populations. RESULTS: We introduce a simple Markov population process model for studying mosquito populations subjected to a Wolbachia-IIT programme which exhibit an unstable equilibrium threshold. The model is used to study, in silico, scenarios that are likely to yield a successful elimination result. Our results suggest that elimination is best achieved by releasing males at rates that adapt to the ever-decreasing wild population, thus reducing the risk of releasing Wolbachia-infected females while reducing costs. CONCLUSIONS: While very high-fidelity sex separation is required to avoid establishment, release programmes tend to be robust to the release of a small number of Wolbachia-infected females. These findings will inform and enhance the next generation of Wolbachia-IIT population control strategies that are already showing great promise in field trials.

Novel chyme reinfusion device for gastrointestinal fistulas and stomas: feasibility study.

BACKGROUND: High-output enterostomies and enteroatmospheric fistulas are common causes of intestinal failure, and may necessitate parenteral nutrition and prolonged hospital stay. Reinfusing lost chyme into the distal gut is known to be beneficial, but implementation has been limited because manual reinfusion is unpleasant and labour-intensive, and no devices are available. A new device is presented for reinfusing chyme easily and efficiently, with first-in-human data. METHODS: The device comprises a compact centrifugal pump that fits inside a standard stoma appliance. The pump is connected to an intestinal feeding tube inserted into the distal intestinal limb. The pump is activated across the appliance by magnetic coupling to a hand-held driver unit, effecting intermittent bolus reinfusion while avoiding effluent contact. Safety, technical and clinical factors were evaluated. RESULTS: Following microbiological safety testing, the device was evaluated in ten patients (median duration of installation 39·5 days; total 740 days). Indications included remediation of high-output losses (8 patients), dependency on parenteral nutrition (5), and gut rehabilitation before surgery (10). Reinfusion was well tolerated with use of regular boluses of approximately 200 ml, and no device-related serious adverse events occurred. Clinical benefits included resumption of oral diet, cessation of parenteral nutrition (4 of 5 patients), correction of electrolytes and liver enzymes, and hospital discharge (6 of 10). Of seven patients with intestinal continuity restored, one experienced postoperative ileus. CONCLUSION: A novel chyme reinfusion device was developed and found to be safe, demonstrating potential benefits in remediating high-output losses, improving fluid and electrolyte balance, weaning off parenteral nutrition and improving surgical recovery. Pivotal trials and regulatory approvals are now in process.

ANTECEDENTES: Las ostomías y las fístulas entero-atmosféricas de alto débito son causas frecuentes de insuficiencia intestinal y pueden precisar nutrición parenteral (NP) y una hospitalización prolongada. Se sabe que la reinfusión del quimo perdido en el intestino distal es beneficiosa, pero su práctica se ha visto limitada porque la reinfusión manual es desagradable, laboriosa y no hay dispositivos disponibles. Se presenta un nuevo dispositivo para reinfundir el quimo de forma fácil y eficiente, junto con los primeros datos en humanos. MÉTODOS: El dispositivo constaba de una bomba centrífuga compacta que cabe dentro de una bolsa de ostomía estándar. Esta bomba iba conectada a una sonda intestinal colocada en el intestino distal. La bomba se activa manualmente mediante el acoplamiento magnético de una manivela, que evita el contacto con el efluente y permite efectuar la reinfusión de bolos discontinuos. Se evaluaron factores de seguridad, técnicos y clínicos. RESULTADOS: Después de las pruebas de seguridad microbiológica, se evaluó el dispositivo en 10 pacientes (mediana de tiempo de funcionamiento 39,5 días; total 740 días). Las indicaciones abarcaron la paliación de pérdidas cuantiosas (n = 8), la dependencia de NP (n = 5) y la rehabilitación intestinal antes de la cirugía (n = 10). La reinfusión se toleró bien utilizando bolos repetidos de ~200 ml, y no hubo efectos adversos graves relacionados con el dispositivo. Los beneficios clínicos incluyeron la reanudación de la dieta oral, el cese de la NP (4/5 pacientes), la corrección de trastornos electrolitos y de las enzimas hepáticas y el alta hospitalaria (6/10). De los 7 pacientes en los que se reconstruyó el tránsito digestivo, uno experimentó un íleo postoperatorio. CONCLUSIÓN: Se ha desarrollado un nuevo dispositivo de reinfusión de quimo que ha demostrado su seguridad y beneficios potenciales para paliar pérdidas cuantiosas, restaurar el equilibrio hidroelectrolítico, retirar la NP y mejorar la recuperación quirúrgica. Están en marcha los ensayos clínicos pivotales y el proceso para obtener los permisos reglamentarios.

The effect of DAFNE education, continuous subcutaneous insulin infusion, or both in a population with type 1 diabetes in Scotland.

AIM: To investigate the effect of DAFNE and continuous subcutaneous insulin infusion in clinical practice. METHODS: Within NHS Lothian, continuous subcutaneous insulin infusion started in 2004 and DAFNE education began in 2006. We extracted anonymized data from the national database for all those aged > 18 years with type 1 diabetes having a Dose Adjustment For Normal Eating course or continuous subcutaneous insulin infusion start date (n = 4617). RESULTS: In total, 956 persons received DAFNE education, and 505 had received an insulin pump, 208 of whom had DAFNE education followed by insulin pump. Mean (SD) HbA1c before DAFNE education was 68 (15) mmol/mol (8.4% [1.4%]) and 66 (13) mmol/mol (8.2% [1.2%]) before continuous subcutaneous insulin infusion. In the year following DAFNE education, the mean fall in within-person HbA1c was 3.8 mmol/mol (95% CI 4.0 to 3.4; 0.3% [0.4% to 0.3%]). Those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]) experienced the largest decline (15.7 mmol/mol [1.4%]). Those in the lowest HbA1c band at initiation (< 53 mmol/mmol [7.0%]) experienced a rise. In the year following continuous subcutaneous insulin infusion initiation there was a mean fall in within-person HbA1c of 6.6 mmol/mol (6.8 to 6.4; 0.6% [0.6% to 0.6%]). In those with the poorest control (HbA1c ≥ 85 mmol/mol [9.9%]), the mean fall in HbA1c was 22.2 mmol/mol (23 to 21; 2.0% [2.1% to 1.9%]). Continuous subcutaneous insulin infusion effectiveness was not different with or without DAFNE education. The effects of both interventions were sustained over 5 years. CONCLUSIONS: Both DAFNE education and insulin pump therapy had the greatest effect on HbA1c in those with higher baseline values. There was little difference to attained HbA1c when Dose Adjustment For Normal Eating education was introduced before insulin pump therapy.

A combined analysis of genetically correlated traits identifies 187 loci and a role for neurogenesis and myelination in intelligence.

Intelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including a wide range of physical, and mental health variables. Education is strongly genetically correlated with intelligence (rg = 0.70). We used these findings as foundations for our use of a novel approach-multi-trait analysis of genome-wide association studies (MTAG; Turley et al. 2017)-to combine two large genome-wide association studies (GWASs) of education and intelligence, increasing statistical power and resulting in the largest GWAS of intelligence yet reported. Our study had four goals: first, to facilitate the discovery of new genetic loci associated with intelligence; second, to add to our understanding of the biology of intelligence differences; third, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predicts phenotypic intelligence in an independent sample. By combining datasets using MTAG, our functional sample size increased from 199,242 participants to 248,482. We found 187 independent loci associated with intelligence, implicating 538 genes, using both SNP-based and gene-based GWAS. We found evidence that neurogenesis and myelination-as well as genes expressed in the synapse, and those involved in the regulation of the nervous system-may explain some of the biological differences in intelligence. The results of our combined analysis demonstrated the same pattern of genetic correlations as those from previous GWASs of intelligence, providing support for the meta-analysis of these genetically-related phenotypes.

Brain age predicts mortality.

Age-associated disease and disability are placing a growing burden on society. However, ageing does not affect people uniformly. Hence, markers of the underlying biological ageing process are needed to help identify people at increased risk of age-associated physical and cognitive impairments and ultimately, death. Here, we present such a biomarker, 'brain-predicted age', derived using structural neuroimaging. Brain-predicted age was calculated using machine-learning analysis, trained on neuroimaging data from a large healthy reference sample (N=2001), then tested in the Lothian Birth Cohort 1936 (N=669), to determine relationships with age-associated functional measures and mortality. Having a brain-predicted age indicative of an older-appearing brain was associated with: weaker grip strength, poorer lung function, slower walking speed, lower fluid intelligence, higher allostatic load and increased mortality risk. Furthermore, while combining brain-predicted age with grey matter and cerebrospinal fluid volumes (themselves strong predictors) not did improve mortality risk prediction, the combination of brain-predicted age and DNA-methylation-predicted age did. This indicates that neuroimaging and epigenetics measures of ageing can provide complementary data regarding health outcomes. Our study introduces a clinically-relevant neuroimaging ageing biomarker and demonstrates that combining distinct measurements of biological ageing further helps to determine risk of age-related deterioration and death.

Structural brain imaging correlates of general intelligence in UK Biobank.

The associations between indices of brain structure and measured intelligence are unclear. This is partly because the evidence to-date comes from mostly small and heterogeneous studies. Here, we report brain structure-intelligence associations on a large sample from the UK Biobank study. The overall N = 29,004, with N = 18,426 participants providing both brain MRI and at least one cognitive test, and a complete four-test battery with MRI data available in a minimum N = 7201, depending upon the MRI measure. Participants' age range was 44-81 years (M = 63.13, SD = 7.48). A general factor of intelligence (g) was derived from four varied cognitive tests, accounting for one third of the variance in the cognitive test scores. The association between (age- and sex- corrected) total brain volume and a latent factor of general intelligence is r = 0.276, 95% C.I. = [0.252, 0.300]. A model that incorporated multiple global measures of grey and white matter macro- and microstructure accounted for more than double the g variance in older participants compared to those in middle-age (13.6% and 5. 4%, respectively). There were no sex differences in the magnitude of associations between g and total brain volume or other global aspects of brain structure. The largest brain regional correlates of g were volumes of the insula, frontal, anterior/superior and medial temporal, posterior and paracingulate, lateral occipital cortices, thalamic volume, and the white matter microstructure of thalamic and association fibres, and of the forceps minor. Many of these regions exhibited unique contributions to intelligence, and showed highly stable out of sample prediction.

Polygenic risk score for schizophrenia and structural brain connectivity in older age: A longitudinal connectome and tractography study.

Higher polygenic risk score for schizophrenia (szPGRS) has been associated with lower cognitive function and might be a predictor of decline in brain structure in apparently healthy populations. Age-related declines in structural brain connectivity-measured using white matter diffusion MRI -are evident from cross-sectional data. Yet, it remains unclear how graph theoretical metrics of the structural connectome change over time, and whether szPGRS is associated with differences in ageing-related changes in human brain connectivity. Here, we studied a large, relatively healthy, same-year-of-birth, older age cohort over a period of 3 years (age ∼ 73 years, N = 731; age ∼76 years, N = 488). From their brain scans we derived tract-averaged fractional anisotropy (FA) and mean diffusivity (MD), and network topology properties. We investigated the cross-sectional and longitudinal associations between these structural brain variables and szPGRS. Higher szPGRS showed significant associations with longitudinal increases in MD in the splenium (ß = 0.132, pFDR = 0.040), arcuate (ß = 0.291, pFDR = 0.040), anterior thalamic radiations (ß = 0.215, pFDR = 0.040) and cingulum (ß = 0.165, pFDR = 0.040). Significant declines over time were observed in graph theory metrics for FA-weighted networks, such as mean edge weight (ß = -0.039, pFDR = 0.048) and strength (ß = -0.027, pFDR = 0.048). No significant associations were found between szPGRS and graph theory metrics. These results are consistent with the hypothesis that szPGRS confers risk for ageing-related degradation of some aspects of structural connectivity.

Genetic risk of major depressive disorder: the moderating and mediating effects of neuroticism and psychological resilience on clinical and self-reported depression.

BACKGROUND: Polygenic risk scores (PRS) for depression correlate with depression status and chronicity, and provide causal anchors to identify depressive mechanisms. Neuroticism is phenotypically and genetically positively associated with depression, whereas psychological resilience demonstrates negative phenotypic associations. Whether increased neuroticism and reduced resilience are downstream mediators of genetic risk for depression, and whether they contribute independently to risk remains unknown. METHODS: Moderating and mediating relationships between depression PRS, neuroticism, resilience and both clinical and self-reported depression were examined in a large, population-based cohort, Generation Scotland: Scottish Family Health Study (N = 4166), using linear regression and structural equation modelling. Neuroticism and resilience were measured by the Eysenck Personality Scale Short Form Revised and the Brief Resilience Scale, respectively. RESULTS: PRS for depression was associated with increased likelihood of self-reported and clinical depression. No interaction was found between PRS and neuroticism, or between PRS and resilience. Neuroticism was associated with increased likelihood of self-reported and clinical depression, whereas resilience was associated with reduced risk. Structural equation modelling suggested the association between PRS and self-reported and clinical depression was mediated by neuroticism (43-57%), while resilience mediated the association in the opposite direction (37-40%). For both self-reported and clinical diagnoses, the genetic risk for depression was independently mediated by neuroticism and resilience. CONCLUSIONS: Findings suggest polygenic risk for depression increases vulnerability for self-reported and clinical depression through independent effects on increased neuroticism and reduced psychological resilience. In addition, two partially independent mechanisms - neuroticism and resilience - may form part of the pathway of vulnerability to depression.

Antibacterials dispensed in the community comprise 85%-95% of total human antibacterial consumption.

WHAT IS KNOWN AND OBJECTIVE: Interventions intended to slow the emergence and spread of antibacterial resistance through enhanced antimicrobial stewardship will be more effective if informed by an accurate knowledge of current patterns of antibacterial consumption. For example, knowledge of the relative magnitude of community antibacterial consumption in relation to hospital antibacterial consumption within each nation or region should help guide decisions about the relative importance of community and hospital antimicrobial stewardship programmes. It is commonly stated that community antibacterial consumption comprises approximately 80% of total national antibacterial consumption. We aimed to determine this proportion across a large range of nations. METHODS: We measured community and hospital antibacterial consumption in New Zealand during 2015, from both reimbursement and purchase data, and compared the New Zealand data with those reported from a large range of other nations during similar time periods. RESULTS AND DISCUSSION: Community antibacterial consumption comprised approximately 85%-95% of total antibacterial consumption in all nations for which data were available, and in New Zealand comprised a higher proportion than in any other nation. The proportion of total antibacterial consumption comprised by community consumption was significantly higher in countries with relatively high levels of total antibacterial consumption than in countries with relatively low levels of total antibacterial consumption. WHAT IS NEW AND CONCLUSION: The high proportion of total antibacterial consumption comprised by community antibacterial consumption suggests devoting particular attention to improved community antimicrobial stewardship. These results suggest that improving antimicrobial stewardship in the community may provide greater overall benefits in combating antibacterial resistance than improving antimicrobial stewardship in hospitals.

Genome-wide association study of cognitive functions and educational attainment in UK Biobank (N=112 151).

People's differences in cognitive functions are partly heritable and are associated with important life outcomes. Previous genome-wide association (GWA) studies of cognitive functions have found evidence for polygenic effects yet, to date, there are few replicated genetic associations. Here we use data from the UK Biobank sample to investigate the genetic contributions to variation in tests of three cognitive functions and in educational attainment. GWA analyses were performed for verbal-numerical reasoning (N=36 035), memory (N=112 067), reaction time (N=111 483) and for the attainment of a college or a university degree (N=111 114). We report genome-wide significant single-nucleotide polymorphism (SNP)-based associations in 20 genomic regions, and significant gene-based findings in 46 regions. These include findings in the ATXN2, CYP2DG, APBA1 and CADM2 genes. We report replication of these hits in published GWA studies of cognitive function, educational attainment and childhood intelligence. There is also replication, in UK Biobank, of SNP hits reported previously in GWA studies of educational attainment and cognitive function. GCTA-GREML analyses, using common SNPs (minor allele frequency>0.01), indicated significant SNP-based heritabilities of 31% (s.e.m.=1.8%) for verbal-numerical reasoning, 5% (s.e.m.=0.6%) for memory, 11% (s.e.m.=0.6%) for reaction time and 21% (s.e.m.=0.6%) for educational attainment. Polygenic score analyses indicate that up to 5% of the variance in cognitive test scores can be predicted in an independent cohort. The genomic regions identified include several novel loci, some of which have been associated with intracranial volume, neurodegeneration, Alzheimer's disease and schizophrenia.

Shared genetic aetiology between cognitive functions and physical and mental health in UK Biobank (N=112 151) and 24 GWAS consortia.

Causes of the well-documented association between low levels of cognitive functioning and many adverse neuropsychiatric outcomes, poorer physical health and earlier death remain unknown. We used linkage disequilibrium regression and polygenic profile scoring to test for shared genetic aetiology between cognitive functions and neuropsychiatric disorders and physical health. Using information provided by many published genome-wide association study consortia, we created polygenic profile scores for 24 vascular-metabolic, neuropsychiatric, physiological-anthropometric and cognitive traits in the participants of UK Biobank, a very large population-based sample (N=112 151). Pleiotropy between cognitive and health traits was quantified by deriving genetic correlations using summary genome-wide association study statistics and to the method of linkage disequilibrium score regression. Substantial and significant genetic correlations were observed between cognitive test scores in the UK Biobank sample and many of the mental and physical health-related traits and disorders assessed here. In addition, highly significant associations were observed between the cognitive test scores in the UK Biobank sample and many polygenic profile scores, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, autism, major depressive disorder, body mass index, intracranial volume, infant head circumference and childhood cognitive ability. Where disease diagnosis was available for UK Biobank participants, we were able to show that these results were not confounded by those who had the relevant disease. These findings indicate that a substantial level of pleiotropy exists between cognitive abilities and many human mental and physical health disorders and traits and that it can be used to predict phenotypic variance across samples.

Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci.

Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.

Fatigue and cognitive function in systemic lupus erythematosus: associations with white matter microstructural damage. A diffusion tensor MRI study and meta-analysis.

Objective The objective of this study was to investigate fatigue and cognitive impairments in systemic lupus erythematous (SLE) in relation to diffuse white matter microstructural brain damage. Methods Diffusion tensor MRI, used to generate biomarkers of brain white matter microstructural integrity, was obtained in patients with SLE and age-matched controls. Fatigue and cognitive function were assessed and related to SLE activity, clinical data and plasma biomarkers of inflammation and endothelial dysfunction. Results Fifty-one patients with SLE (mean age 48.8 ± 14.3 years) were included. Mean diffusivity (MD) was significantly higher in all white matter fibre tracts in SLE patients versus age-matched healthy controls ( p < 0.0001). Fatigue in SLE was higher than a normal reference range ( p < 0.0001) and associated with lower MD ( ß = -0.61, p = 0.02), depression ( ß = 0.17, p = 0.001), anxiety ( ß = 0.13, p = 0.006) and higher body mass index ( ß = 0.10, p = 0.004) in adjusted analyses. Poorer cognitive function was associated with longer SLE disease duration ( p = 0.003) and higher MD ( p = 0.03) and, in adjusted analysis, higher levels of IL-6 ( ß = -0.15, p = 0.02) but not with MD. Meta-analysis (10 studies, n = 261, including the present study) confirmed that patients with SLE have higher MD than controls. Conclusion Patients with SLE have more microstructural brain white matter damage for age than the general population, but this does not explain increased fatigue or lower cognition in SLE. The association between raised IL-6 and worse current cognitive function in SLE should be explored in larger datasets.

The wMel Wolbachia strain blocks dengue and invades caged Aedes aegypti populations.

Dengue fever is the most important mosquito-borne viral disease of humans with more than 50 million cases estimated annually in more than 100 countries. Disturbingly, the geographic range of dengue is currently expanding and the severity of outbreaks is increasing. Control options for dengue are very limited and currently focus on reducing population abundance of the major mosquito vector, Aedes aegypti. These strategies are failing to reduce dengue incidence in tropical communities and there is an urgent need for effective alternatives. It has been proposed that endosymbiotic bacterial Wolbachia infections of insects might be used in novel strategies for dengue control. For example, the wMelPop-CLA Wolbachia strain reduces the lifespan of adult A. aegypti mosquitoes in stably transinfected lines. This life-shortening phenotype was predicted to reduce the potential for dengue transmission. The recent discovery that several Wolbachia infections, including wMelPop-CLA, can also directly influence the susceptibility of insects to infection with a range of insect and human pathogens has markedly changed the potential for Wolbachia infections to control human diseases. Here we describe the successful transinfection of A. aegypti with the avirulent wMel strain of Wolbachia, which induces the reproductive phenotype cytoplasmic incompatibility with minimal apparent fitness costs and high maternal transmission, providing optimal phenotypic effects for invasion. Under semi-field conditions, the wMel strain increased from an initial starting frequency of 0.65 to near fixation within a few generations, invading A. aegypti populations at an accelerated rate relative to trials with the wMelPop-CLA strain. We also show that wMel and wMelPop-CLA strains block transmission of dengue serotype 2 (DENV-2) in A. aegypti, forming the basis of a practical approach to dengue suppression.

Successful establishment of Wolbachia in Aedes populations to suppress dengue transmission.

Genetic manipulations of insect populations for pest control have been advocated for some time, but there are few cases where manipulated individuals have been released in the field and no cases where they have successfully invaded target populations. Population transformation using the intracellular bacterium Wolbachia is particularly attractive because this maternally-inherited agent provides a powerful mechanism to invade natural populations through cytoplasmic incompatibility. When Wolbachia are introduced into mosquitoes, they interfere with pathogen transmission and influence key life history traits such as lifespan. Here we describe how the wMel Wolbachia infection, introduced into the dengue vector Aedes aegypti from Drosophila melanogaster, successfully invaded two natural A. aegypti populations in Australia, reaching near-fixation in a few months following releases of wMel-infected A. aegypti adults. Models with plausible parameter values indicate that Wolbachia-infected mosquitoes suffered relatively small fitness costs, leading to an unstable equilibrium frequency <30% that must be exceeded for invasion. These findings demonstrate that Wolbachia-based strategies can be deployed as a practical approach to dengue suppression with potential for area-wide implementation.

Projections of increased and decreased dengue incidence under climate change.

Dengue is the world's most prevalent mosquito-borne disease, with more than 200 million people each year becoming infected. We used a mechanistic virus transmission model to determine whether climate warming would change dengue transmission in Australia. Using two climate models each with two carbon emission scenarios, we calculated future dengue epidemic potential for the period 2046-2064. Using the ECHAM5 model, decreased dengue transmission was predicted under the A2 carbon emission scenario, whereas some increases are likely under the B1 scenario. Dengue epidemic potential may decrease under climate warming due to mosquito breeding sites becoming drier and mosquito survivorship declining. These results contradict most previous studies that use correlative models to show increased dengue transmission under climate warming. Dengue epidemiology is determined by a complex interplay between climatic, human host, and pathogen factors. It is therefore naive to assume a simple relationship between climate and incidence, and incorrect to state that climate warming will uniformly increase dengue transmission, although in general the health impacts of climate change will be negative.

The impact of insecticide-treated cloth targets on the survival of Stegomyia polynesiensis (= Aedes polynesiensis) under laboratory and semi-field conditions in French Polynesia.

The impact of deltamethrin-impregnated cloth targets on Stegomyia polynesiensis (= Aedes polynesiensis) (Marks) (Diptera: Culicidae) was assessed under laboratory and semi-field settings in French Polynesia. Stegomyia polynesiensis females were released into small laboratory cages and large field cages containing either a deltamethrin-treated or an untreated navy blue cloth, and mosquito knock-down and mortality were assessed. The 24-h mortality rate in mosquitoes exposed to the insecticide-treated target in small cages was 98.0%. These mosquitoes also demonstrated significantly higher levels of knock-down than those exposed to the untreated target. Mortality in field cages was assessed at 24 and 48 h. The 24-h mortality rate in mosquitoes exposed to the control target was 31.2%, whereas that in those exposed to the deltamethrin-treated target was 54.3%. The 48-h mortality rate was also elevated in mosquitoes exposed to the deltamethrin-treated target, but this result did not differ significantly from that observed in mosquitoes exposed to the control target. The significant suppression of female S. polynesiensis by deltamethrin-treated resting targets in this study indicates that these targets could play a role in the control of an important disease vector in the South Pacific region.