Workers in Australian prebake aluminium smelters: update on risk of mortality and cancer incidence in the Healthwise cohort.

OBJECTIVES: To investigate mortality and the rates of incident cancer among a cohort of aluminium industry workers. METHODS: Among 4507 male employees who worked in either of two Australian prebake smelters for at least 3 months, data linkage was undertaken with the Australian National Death Index and Australian Cancer Database. Standardised Mortality Ratios (SMRs) and Standardised Incidence Rates (SIRs) were estimated for the whole cohort and for: production; maintenance and office workers. SMRs and SIRs were calculated by time since first employment. RESULTS: Among production workers, there was an excess risk of mortality from mesothelioma (SMR 2.8, 95% CI 1.3 to 5.2), lung (SMR 1.4, 95% CI 1.0 to 1.8), prostate (SMR 1.9, 95% CI 1.3 to 2.7) and liver cancer (SMR 2.0, 95% CI 1.1 to 3.4) and the SIR was also increased for overall respiratory cancers, specifically lung cancers. An excess risk of death from stomach cancer (SMR 2.9, 95% CI 1.2 to 6.1) and Alzheimer's disease (SMR 3.4, 95% CI 1.1 to 7.9) was seen among maintenance workers. The overall risk of death was similar to that of the Australian general population, as was mortality from cancers overall and non-malignant respiratory disease. CONCLUSIONS: No excess risk of death from bladder cancer or non-malignant respiratory disease was found. Excess lung cancer mortality and incidence may be explained by smoking and excess mortality from mesothelioma may be explained by asbestos exposure. An excess risk of mortality from liver and prostate cancer has been shown in production workers and requires further investigation.

Discovery of 42 genome-wide significant loci associated with dyslexia.

Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

Rapid auditory processing and medial geniculate nucleus anomalies in Kiaa0319 knockout mice.

Developmental dyslexia is a common neurodevelopmental disorder characterized by difficulties in reading and writing. Although underlying biological and genetic mechanisms remain unclear, anomalies in phonological processing and auditory processing have been associated with dyslexia. Several candidate risk genes have also been identified, with KIAA0319 as a main candidate. Animal models targeting the rodent homolog (Kiaa0319) have been used to explore putative behavioral and anatomic anomalies, with mixed results. For example after downregulation of Kiaa0319 expression in rats via shRNA, significant adult rapid auditory processing impairments were reported, along with cortical anomalies reflecting atypical neuronal migration. Conversely, Kiaa0319 knockout (KO) mice were reported to have typical adult auditory processing, and no visible cortical anomalies. To address these inconsistencies, we tested Kiaa0319 KO mice on auditory processing tasks similar to those used previously in rat shRNA knockdown studies. Subsequent neuroanatomic analyses on these same mice targeted medial geniculate nucleus (MGN), a receptive communication-related brain structure. Results confirm that Kiaa0319 KO mice exhibit significant auditory processing impairments specific to rapid/brief stimuli, and also show significant volumetric reductions and a shift toward fewer large and smaller neurons in the MGN. The latter finding is consistent with post mortem MGN data from human dyslexic brains. Combined evidence supports a role for KIAA0319 in the development of auditory CNS pathways subserving rapid auditory processing functions critical to the development of speech processing, language, and ultimately reading. Results affirm KIAA0319 variation as a possible risk factor for dyslexia specifically via anomalies in central acoustic processing pathways.

The selfish environment meets the selfish gene: Coevolution and inheritance of RNA and DNA pools: A model for organismal life incorporating coevolution, horizontal transfer, and inheritance of internal and external RNA and DNA pools.: A model for organismal life incorporating coevolution, horizontal transfer, and inheritance of internal and external RNA and DNA pools.

Throughout evolution, there has been interaction and exchange between RNA pools in the environment, and DNA and RNA pools of eukaryotic organisms. Metagenomic and metatranscriptomic sequencing of invertebrate hosts and their microbiota has revealed a rich evolutionary history of RNA virus shuttling between species. Horizontal transfer adapted the RNA pool for successful future interactions which lead to zoonotic transmission and detrimental RNA viral pandemics like SARS-CoV2. In eukaryotes, noncoding RNA (ncRNA) is an established mechanism derived from prokaryotes to defend against viral attack through innate immunity and regulation of host-derived mRNA. Transgenerational inheritance of ncRNA is evidence for feedforward adaptive immunity and epigenetically encoded environmental change across generations, which may explain the ''missing heritability'' of common disease. Causal graph theory and the Price Equation can model epigenetic inheritance involving dynamic internal and external RNA pools. Experimental designs should include metatranscriptomic analyses to understand how ncRNA responds to rapidly changing environmental conditions, within and between organisms, and across generations.

Long-term impact of exposure to coalmine fire emitted PM2.5 on emergency ambulance attendances.

BACKGROUND: Little is known about the long-term health effects of coalmine fire smoke exposure. The 2014 Hazelwood coalmine fire event in southeast Australia released smoke into surrounding areas for 6 weeks. OBJECTIVES: We aimed to investigate whether individual-level exposure to coalmine fire-related PM2.5 was associated with a long-term increase in ambulance attendances following a coalmine fire event. METHODS: A total of 2223 residents from the most exposed town of Morwell were assessed for ambulance attendances after the Hazelwood event from April 1, 2014 to December 31, 2017. PM2.5 exposure was estimated for each individual using participant self-reported location diary data during the event and modelled PM2.5 concentrations. Recurrent event survival analysis was used to evaluate the relationship between PM2.5 exposure and ambulance attendances. RESULTS: For each 10 µg/m3 increase in mean coalmine fire-related PM2.5 exposure, there was a 10% (adjusted hazard ratio [HR]:1.10, 95%CI:1.03-1.17) increase in the overall risk of ambulance attendances within 3.5 years after the coalmine fire. Exposure to PM2.5 was also associated with increased risk of respiratory (HR: 1.21, 95%CI: 1.02-1.44) and cardiovascular (HR: 1.13, 95%CI: 1.01-1.28) related ambulance attendances. CONCLUSION: These results demonstrate that exposure to coalmine fire smoke during the Hazelwood event was associated with a long-term health risk post the fire event, specifically for respiratory and cardiovascular conditions. These findings are important for effective implementation of health care services following future extended coalmine fire PM2.5 events.

Associations between self-reported respiratory symptoms and non-specific psychological distress following exposure to a prolonged landscape fire.

We investigated the association between respiratory symptoms and psychological distress in the context of a prolonged smoke event, and evaluated whether smoke exposure, or pre-existing respiratory and mental health conditions, influenced the association. Three thousand ninety-six residents of a rural town heavily exposed to smoke from the 6-week Hazelwood coal mine fire, and 960 residents of a nearby unexposed town, completed Kessler's psychological distress questionnaire (K10) and a modified European Community Respiratory Health Survey. Logistic regression models evaluated associations between distress and respiratory symptoms, with interactions fitted to evaluate effect modification. Smoke exposed participants reported higher levels of distress than those unexposed, and participants reporting respiratory symptoms recorded higher levels of distress than participants without respiratory symptoms, irrespective of exposure. 5-unit increments in K10 scores were associated with 21%-48% increases in the odds of reporting respiratory symptoms. There were significant interactions with pre-existing asthma, chronic obstructive pulmonary disease and mental health conditions, but not with smoke exposure. Although participants with pre-existing conditions were more likely to report respiratory symptoms, increasing distress was most strongly associated with respiratory symptoms among those without pre-existing conditions. Communities exposed to landscape fire smoke could benefit from interventions to reduce both psychological and respiratory distress.

Impacts of High Concentration, Medium Duration Coal Mine Fire Related PM2.5 on Cancer Incidence: 5-Year Follow-Up of the Hazelwood Health Study.

No studies have investigated the cancer outcomes from high level medium duration coal mine fire fine particulate matter ⩽2.5 µm in diameter (PM2.5) exposure. We included 2208 Morwell residents (exposed) and 646 Sale residents (unexposed) who participated in the Hazelwood Health Study Adult Survey. Competing risk regression models were used to evaluate relationships between coal mine fire exposure and cancer incidence, adjusting for known confounders. There were 137 cancers in the exposed and 27 in the unexposed over 14 849 person-years of follow-up. A higher risk of cancer incidence was observed for Morwell participants (HR = 1.67 [95% CI 1.05-2.67]), but no evidence to suggest associations between PM2.5 exposure and incidence of all cancers (HR = 1.02 [95% CI 0.91-1.13]), or site-specific cancers. There is no strong evidence that exposure to high concentrations of mine fire-related PM2.5 over a prolonged period could explain the higher risk in exposed population in this study.

Caustic Mist Exposure and Respiratory Outcomes in a Cohort Study of Alumina Refinery Workers.

A common chemical exposure in alumina refining is caustic mist. Although recognized as a strong airways irritant, little is known of the chronic respiratory effects of caustic mist in alumina refining. A suitable metric for caustic mist exposure assessment in alumina refining for epidemiological purposes has not been identified. Peak exposure is likely to be important, but is difficult to assess in epidemiological studies. In this study, we investigate the respiratory effects of caustic mist in an inception cohort (n = 416) of alumina refinery workers and describe the development and use of a peak exposure metric for caustic mist. We then compare the results with a metric based on duration of exposure. Participants were interviewed annually about respiratory symptoms and had a lung function test. Job history data were collected from each interview and levels of caustic mist were measured periodically by air monitoring. We found a weak association between the caustic mist peak exposure metric and reported cough (P for linear trend = 0.079) with the highest peak exposure group odds ratio = 2.32 (95% confidence interval: 1.27, 4.22). For lung function, we found declines in the forced expiratory volume in 1 second and forced vital capacity for changes in annual and absolute lung function for both metrics of exposure, but only the ratio of absolute lung function was statistically associated with an increasing duration of caustic exposure (P for linear trend = 0.011). In this cohort, we did not observe an association with respiratory symptoms or consistent decrements in lung function. There was little difference between the exposure metrics used for investigation of the chronic effects from caustic mist.

An epigenetic, transgenerational model of increased mental health disorders in children, adolescents and young adults.

Prevalence rates of mental health disorders in children and adolescents have increased two to threefold from the 1990s to 2016. Some increase in prevalence may stem from changing environmental conditions in the current generation which interact with genes and inherited genetic variants. Current measured genetic variant effects do not explain fully the familial clustering and high heritability estimates in the population. Another model considers environmental conditions shifting in the previous generation, which altered brain circuits epigenetically and were transmitted to offspring via non-DNA-based mechanisms (intergenerational and transgenerational effects). Parental substance use, poor diet and obesity are environmental factors with known epigenetic intergenerational and transgenerational effects, that regulate set points in brain pathways integrating sensory-motor, reward and feeding behaviors. Using summary statistics for eleven neuropsychiatric and three metabolic disorders from 128,989 families, an epigenetic effect explains more of the estimated heritability when a portion of parental environmental effects are transmitted to offspring alongside additive genetic variance.

Pooling for SARS-CoV2 Surveillance: Validation and Strategy for Implementation in K-12 Schools.

Repeated testing of a population is critical for limiting the spread of the SARS-CoV-2 virus and for the safe reopening of educational institutions such as kindergarten-grade 12 (K-12) schools and colleges. Many screening efforts utilize the CDC RT-PCR based assay which targets two regions of the novel Coronavirus nucleocapsid gene. The standard approach of testing each person individually, however, poses a financial burden to these institutions and is therefore a barrier to using testing for re-opening. Pooling samples from multiple individuals into a single test is an attractive alternate approach that promises significant cost savings-however the specificity and sensitivity of such approaches needs to be assessed prior to deployment. To this end, we conducted a pilot study to evaluate the feasibility of analyzing samples in pools of eight by the established RT-PCR assay. Participants (1,576) were recruited from amongst the Tufts University community undergoing regular screening. Each volunteer provided two swabs, one analyzed separately and the other in a pool of eight. Because the positivity rate was very low, we spiked approximately half of the pools with laboratory-generated swabs produced from known positive cases outside the Tufts testing program. The results of pooled tests had 100% correspondence with those of their respective individual tests. We conclude that pooling eight samples does not negatively impact the specificity or sensitivity of the RT-PCR assay and suggest that this approach can be utilized by institutions seeking to reduce surveillance costs.

Genome-wide association study reveals new insights into the heritability and genetic correlates of developmental dyslexia.

Developmental dyslexia (DD) is a learning disorder affecting the ability to read, with a heritability of 40-60%. A notable part of this heritability remains unexplained, and large genetic studies are warranted to identify new susceptibility genes and clarify the genetic bases of dyslexia. We carried out a genome-wide association study (GWAS) on 2274 dyslexia cases and 6272 controls, testing associations at the single variant, gene, and pathway level, and estimating heritability using single-nucleotide polymorphism (SNP) data. We also calculated polygenic scores (PGSs) based on large-scale GWAS data for different neuropsychiatric disorders and cortical brain measures, educational attainment, and fluid intelligence, testing them for association with dyslexia status in our sample. We observed statistically significant (p < 2.8 × 10-6) enrichment of associations at the gene level, for LOC388780 (20p13; uncharacterized gene), and for VEPH1 (3q25), a gene implicated in brain development. We estimated an SNP-based heritability of 20-25% for DD, and observed significant associations of dyslexia risk with PGSs for attention deficit hyperactivity disorder (at pT = 0.05 in the training GWAS: OR = 1.23[1.16; 1.30] per standard deviation increase; p = 8 × 10-13), bipolar disorder (1.53[1.44; 1.63]; p = 1 × 10-43), schizophrenia (1.36[1.28; 1.45]; p = 4 × 10-22), psychiatric cross-disorder susceptibility (1.23[1.16; 1.30]; p = 3 × 10-12), cortical thickness of the transverse temporal gyrus (0.90[0.86; 0.96]; p = 5 × 10-4), educational attainment (0.86[0.82; 0.91]; p = 2 × 10-7), and intelligence (0.72[0.68; 0.76]; p = 9 × 10-29). This study suggests an important contribution of common genetic variants to dyslexia risk, and novel genomic overlaps with psychiatric conditions like bipolar disorder, schizophrenia, and cross-disorder susceptibility. Moreover, it revealed the presence of shared genetic foundations with a neural correlate previously implicated in dyslexia by neuroimaging evidence.

Respiratory outcomes among refinery workers exposed to inspirable alumina dust: A longitudinal study in Western Australia.

BACKGROUND: Information is scarce about the occupational health effects of exposure to alumina dust. This study examines the respiratory effects of inspirable alumina dust exposure in alumina refineries. METHODS: An inception cohort study at three alumina refineries in Western Australia recruited 416 participants (351 males, 65 females) between 1995 and 2000 who were followed up annually until 2008 or until exit from study. At each health interview a respiratory questionnaire and lung function test was undertaken, measuring forced expiratory volume in one second (FEV1 ) and forced vital capacity (FVC). Participants provided job histories which were combined with air monitoring data to calculate cumulative exposure to inspirable alumina dust (mg/m3 -years). Generalized estimating equations with Poisson distribution and mixed effects models were used to examine the effects of alumina exposure. RESULTS: The number of exposed participants was relatively small (n = 82, 19.7%). There was no association between alumina dust exposure and prevalence of cough, wheeze or rhinitis. No associations were found between measures of lung function and tertiles of alumina exposure in the first two follow-ups, or the whole follow-up period, though there was a suggestive dose-response trend across exposed groups for decline in absolute FEV1 (p for trend = .06). For mean annual change in FEV1 and FVC based on the first three follow-ups it was not possible to rule out an effect above a threshold level of exposure. CONCLUSION: There is no evidence of an association between exposure to alumina and the reporting of respiratory symptoms but some evidence for an effect on lung function.

Predictive value of non-specific bronchial challenge testing for respiratory symptoms and lung function in aluminium smelter workers.

OBJECTIVE: To assess the predictive value of bronchial hyper-responsiveness (BHR) for the subsequent development of respiratory symptoms, airflow limitation and decline in lung function among aluminium smelter workers. METHODS: An inception cohort study of new employees at two Australian aluminium smelters was conducted. Participants completed a modified British Medical Research Council respiratory questionnaire, spirometry and a methacholine bronchial challenge test at baseline and at annual follow-up reviews. BHR was defined as PD20 ≤4000 µg. Poisson and mixed effects models were fitted to respiratory symptoms and lung function (forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC)). RESULTS: Baseline interview and lung function testing were completed by 278 workers, who were followed for a median of 4 years. BHR at baseline, present in 82 workers, was not associated with incident wheeze risk ratio (RR)=1.07 (95% CI 0.74 to 1.55) and cough RR=0.78 (95% CI 0.45, 1.35), but there was some increased risk of chest tightness RR=1.40 (95% CI 0.99, 1.98) after adjustment for age, sex, smoking and atopy. BHR at baseline was associated with lower FEV1 and FVC, although the rate of annual decline in FEV1 or FVC was similar between those with or without BHR. The specificity of BHR was 77% for wheeze, 70% for cough and 77% for chest tightness, but the sensitivity was poor, at 33%, 24% and 39%, respectively. CONCLUSION: Methacholine challenge testing at entry to employment was not sufficiently predictive of later adverse respiratory outcomes, and notwithstanding the study limitations is unlikely to be a useful pre-employment or preplacement screening test in the aluminium smelting industry.

Associations between Respiratory Health Outcomes and Coal Mine Fire PM2.5 Smoke Exposure: A Cross-Sectional Study.

In 2014, wildfires ignited a fire in the Morwell open cut coal mine, Australia, which burned for six weeks. This study examined associations between self-reported respiratory outcomes in adults and mine fire-related PM2.5 smoke exposure. Self-reported data were collected as part of the Hazelwood Health Study Adult Survey. Eligible participants were adult residents of Morwell. Mine fire-related PM2.5 concentrations were provided by the Commonwealth Scientific and Industrial Research Organisation Oceans & Atmosphere Flagship. Personalised mean 24-h and peak 12-h mine fire-related PM2.5 exposures were estimated for each participant. Data were analysed by multivariate logistic regression. There was some evidence of an association between respiratory outcomes and mine fire PM2.5 exposure. Chronic cough was associated with an odds ratio (OR) of 1.13 (95% confidence interval 1.03 to 1.23) per 10 µg/m3 increment in mean PM2.5 and 1.07 (1.02 to 1.12) per 100 µg/m3 increment in peak PM2.5. Current wheeze was associated with peak PM2.5, OR = 1.06 (1.02 to 1.11) and chronic phlegm with mean PM2.5 OR = 1.10 (1.00 to 1.20). Coal mine PM2.5 smoke exposure was associated with increased odds of experiencing cough, phlegm and wheeze. Males, participants 18-64 years, and those residing in homes constructed from non-brick/concrete materials or homes with tin/metal roofs had higher estimated ORs. These findings contribute to the formation of public health policy responses.

Human VPS13A is associated with multiple organelles and influences mitochondrial morphology and lipid droplet motility.

The VPS13A gene is associated with the neurodegenerative disorder Chorea Acanthocytosis. It is unknown what the consequences are of impaired function of VPS13A at the subcellular level. We demonstrate that VPS13A is a peripheral membrane protein, associated with mitochondria, the endoplasmic reticulum and lipid droplets. VPS13A is localized at sites where the endoplasmic reticulum and mitochondria are in close contact. VPS13A interacts with the ER residing protein VAP-A via its FFAT domain. Interaction with mitochondria is mediated via its C-terminal domain. In VPS13A-depleted cells, ER-mitochondria contact sites are decreased, mitochondria are fragmented and mitophagy is decreased. VPS13A also localizes to lipid droplets and affects lipid droplet motility. In VPS13A-depleted mammalian cells lipid droplet numbers are increased. Our data, together with recently published data from others, indicate that VPS13A is required for establishing membrane contact sites between various organelles to enable lipid transfer required for mitochondria and lipid droplet related processes.

Genome-wide association scan identifies new variants associated with a cognitive predictor of dyslexia.

Developmental dyslexia (DD) is one of the most prevalent learning disorders, with high impact on school and psychosocial development and high comorbidity with conditions like attention-deficit hyperactivity disorder (ADHD), depression, and anxiety. DD is characterized by deficits in different cognitive skills, including word reading, spelling, rapid naming, and phonology. To investigate the genetic basis of DD, we conducted a genome-wide association study (GWAS) of these skills within one of the largest studies available, including nine cohorts of reading-impaired and typically developing children of European ancestry (N = 2562-3468). We observed a genome-wide significant effect (p < 1 × 10-8) on rapid automatized naming of letters (RANlet) for variants on 18q12.2, within MIR924HG (micro-RNA 924 host gene; rs17663182 p = 4.73 × 10-9), and a suggestive association on 8q12.3 within NKAIN3 (encoding a cation transporter; rs16928927, p = 2.25 × 10-8). rs17663182 (18q12.2) also showed genome-wide significant multivariate associations with RAN measures (p = 1.15 × 10-8) and with all the cognitive traits tested (p = 3.07 × 10-8), suggesting (relational) pleiotropic effects of this variant. A polygenic risk score (PRS) analysis revealed significant genetic overlaps of some of the DD-related traits with educational attainment (EDUyears) and ADHD. Reading and spelling abilities were positively associated with EDUyears (p ~ [10-5-10-7]) and negatively associated with ADHD PRS (p ~ [10-8-10-17]). This corroborates a long-standing hypothesis on the partly shared genetic etiology of DD and ADHD, at the genome-wide level. Our findings suggest new candidate DD susceptibility genes and provide new insights into the genetics of dyslexia and its comorbities.