The future burden of lung cancer attributable to current modifiable behaviours: a pooled study of seven Australian cohorts

BACKGROUND: Knowledge of preventable disease and differences in disease burden can inform public health action to improve health and health equity. We quantified the future lung cancer burden preventable by behavioural modifications across Australia. METHODS: We pooled seven Australian cohort studies (n = 367 058) and linked them to national registries to identify lung cancers and deaths. We estimated population attributable fractions and their 95% confidence intervals (CIs) for modifiable risk factors, using risk estimates from the cohort data and risk factor exposure distribution from contemporary national health surveys. RESULTS: During the first 10-year follow-up, there were 2025 incident lung cancers and 20 349 deaths. Stopping current smoking could prevent 53.7% (95% CI, 50.0-57.2%) of lung cancers over 40 years and 18.3% (11.0-25.1%) in 10 years. The smoking-attributable burden is highest in males, those who smoke <20 cigarettes per day, are <75 years of age, unmarried, of lower educational attainment, live in remote areas or are healthy weight. Increasing physical activity and fruit consumption, if causal, could prevent 15.6% (6.9-23.4%) and 7.5% (1.3-13.3%) of the lung cancer burden, respectively. Jointly, the three behaviour modifications could prevent up to 63.0% (58.0-67.5%) of lung cancers in 40 years, and 31.2% (20.9-40.1%) or 43 300 cancers in 10 years. The preventable burden is highest among those with multiple risk factors. CONCLUSIONS: Smoking remains responsible for the highest burden of lung cancer in Australia. The uneven burden distribution distinguishes subgroups that could benefit the most from activities to control the world's deadliest cancer

Late Silurian zircon U–Pb ages from the Ludlow and Downton bone beds, Welsh Basin, UK

The Ludlow Bone Bed (Welsh Basin) is a critical stratigraphic horizon and contains a rich assemblage of fish scales. Units above provide insights into the early evolution of animal and plant life. The bed has not yet been radioisotopically dated. Here, we report 207 secondary ion mass spectrometry (SIMS) ages from 102 zircon (ZrSiO4) grains from the Ludlow (n = 2) and stratigraphically higher Downton (n = 1) bone beds. SIMS ages are middle Ordovician (471.6 ± 20.7 Ma) to late Devonian (375.7 ± 14.6 Ma, 238U–206Pb, ±1σ analytical uncertainty). Cathodoluminescence images show that the youngest ages appear affected by alteration. Chemical abrasion isotope dilution thermal ionization mass spectrometry (CA-ID-TIMS) U–Pb geochronology was utilized to improve precision. Detrital zircon grains from Downton yield 424.91 ± 0.34/0.42/0.63 Ma and from Ludlow 424.85 ± 0.32/0.41/0.62 Ma (n = 5 each, 238U–206Pb, ±2σ analytical, tracer or systematic uncertainty). These ages provide a maximum deposition age. Results overlap the basal Přídolí age (423.0 ± 2.3 Ma) in its stratotype (Požáry Section, Reporyje, Prague, Czech Republic). The Ludlow Bone Bed marks the base of the local Downton Group, which has previously been correlated with the base of the Přídolí Series. The CA-ID-TIMS ages are older than those for other land arthropod-bearing sediments, such as the Cowie Harbour Fish Bed and Rhynie Chert.© 2020 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/ licenses/by/4.0/). Published by The Geological Society of London. Publishing disclaimer: www.geolsoc.org.uk/pub_ethic

Adipocyte mitochondrial genes and the forkhead factor FOXC2 are decreased in type 2 diabetes patients and normalized in response to rosiglitazone

<p>Abstract</p> <p>Background</p> <p>FOXC2 has lately been implicated in diabetes and obesity as well as mitochondrial function and biogenesis and also as a regulator of mtTFA/Tfam. In this study, the expression of FOXC2 and selected genes involved in mitochondrial function and biogenesis in healthy subjects and in a matched cohort with type 2 diabetes patients before and after treatment with rosiglitazone was determined. Quantitative real time PCR was used to analyze both RNA and DNA from biopsies from subcutaneous adipose tissue.</p> <p>Methods</p> <p>Blood samples and subcutaneous abdominal fat biopsies were collected from 12 T2D patients, of which 11 concluded the study, pre-treatment and 90 days after initiation of rosiglitazone treatment, and from 19 healthy control subjects on the first and only visit from healthy subjects. Clinical parameters were measured on the blood samples. RNA and DNA were prepared from the fat biopsies and gene expression was measured with real time PCR.</p> <p>Results</p> <p>The expression level of genes in the mitochondrial respiratory complexes I - IV were significantly downregulated in the diabetic patients and restored in response to rosiglitazone treatment. Rosiglitazone treatment also increased the relative number of mitochondria in diabetic patients compared with controls. Furthermore, the transcription factors FOXC2 and mtTFA/Tfam displayed a response pattern identical to the mitochondrial genes.</p> <p>Conclusions</p> <p>FOXC2, mtTFA/Tfam and subunits of the respiratory complexes I - IV show equivalent regulation in gene expression levels in response to TZD treatment. This, together with the knowledge that FOXC2 has a regulatory function of mtTFA/Tfam and mitochondrial biogenesis, suggests that FOXC2 has a possible functional role in the TZD activated mitochondrial response.</p

Compliance with continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea among privately paying patients- a cross sectional study

Background: To evaluate the compliance, benefits and side effects associated with continuous positive airway pressure (CPAP) therapy among Pakistani patients treated for obstructive sleep apnea (OSA) in private sector.Methods: Patients diagnosed to have OSA based on overnight study who were recommended for CPAP therapy, between 1998 and 2003, were evaluated by telephonic survey and review of hospital notes. Compliance, benefits and side effects associated with CPAP therapy were assessed.Results: Out of 135 patients who were prescribed CPAP therapy, 75 could be contacted. Sixty (80%) started using CPAP within one month of diagnosis and 46 (61%) continued to use it long-term (beyond one year). Compliance with CPAP therapy was associated with higher body mass index, higher Epworth sleepiness scale score, history of witnessed apnea, and reduction in daytime sleepiness with CPAP therapy. OSA severity as assessed by apnea-hypopnea index did not affect compliance with CPAP therapy. Use of anti-depressants and CPAP induced sleep disturbances were associated with poor compliance with CPAP therapy.CONCLUSIONS: Obesity, excessive daytime sleepiness, witnessed apnea and improvement of daytime symptoms following use of CPAP were predictors of improved compliance. Use of antidepressants and CPAP induced sleep disturbances were predictors of poor compliance

Lower age at menarche affects survival in older Australian women: results from the Australian Longitudinal Study of Ageing

Extent: 10p.Background: While menarche indicates the beginning of a woman's reproductive life, relatively little is known about the association between age at menarche and subsequent morbidity and mortality. We aimed to examine the effect of lower age at menarche on all-cause mortality in older Australian women over 15 years of follow-up. Methods: Data were drawn from the Australian Longitudinal Study of Ageing (n = 1,031 women aged 65-103 years). We estimated the hazard ratio (HR) associated with lower age at menarche using Cox proportional hazards models, and adjusted for a broad range of reproductive, demographic, health and lifestyle covariates. Results: During the follow-up period, 673 women (65%) died (average 7.3 years (SD 4.1) of follow-up for decedents). Women with menses onset < 12 years of age (10.7%; n = 106) had an increased hazard of death over the follow-up period (adjusted HR 1.28; 95%CI 0.99-1.65) compared with women who began menstruating aged ≥ 12 years (89.3%; n = 883). However, when age at menarche was considered as a continuous variable, the adjusted HRs associated with the linear and quadratic terms for age at menarche were not statistically significant at a 5% level of significance (linear HR 0.76; 95%CI 0.56 - 1.04; quadratic HR 1.01; 95%CI 1.00-1.02). Conclusion: Women with lower age at menarche may have reduced survival into old age. These results lend support to the known associations between earlier menarche and risk of metabolic disease in early adulthood. Strategies to minimise earlier menarche, such as promoting healthy weights and minimising family dysfunction during childhood, may also have positive longer-term effects on survival in later life.Lynne C Giles, Gary FV Glonek, Vivienne M Moore, Michael J Davies and Mary A Luszc

Measuring walking within and outside the neighborhood in Chinese elders: reliability and validity

Background : Walking is a preferred, prevalent and recommended activity for aging populations and is influenced by the neighborhood built environment. To study this influence it is necessary to differentiate whether walking occurs within or outside of the neighborhood. The Neighborhood Physical Activity Questionnaire (NPAQ) collects information on setting-specific physical activity, including walking, inside and outside one\u27s neighborhood. While the NPAQ has shown to be a reliable measure in adults, its reliability in older adults is unknown. Additionally its validity and the influence of type of neighborhood on reliability and validity have yet to be explored. Methods : The NPAQ walking component was adapted for Chinese speaking elders (NWQ-CS). Ninety-six Chinese elders, stratified by social economic status and neighborhood walkability, wore an accelerometer and completed a log of walks for 7 days. Following the collection of valid data the NWQ-CS was interviewer-administered. Fourteen to 20 days (average of 17 days) later the NWQ-CS was re-administered. Test-retest reliability and validity of the NWQ-CS were assessed. Results : Reliability and validity estimates did not differ with type of neighborhood. NWQ-CS measures of walking showed moderate to excellent reliability. Reliability was generally higher for estimates of weekly frequency than minutes of walking. Total weekly minutes of walking were moderately related to all accelerometry measures. Moderate-to-strong associations were found between the NWQ-CS and log-of-walks variables. The NWQ-CS yielded statistically significantly lower mean values of total walking, weekly minutes of walking for transportation and weekly frequency of walking for transportation outside the neighborhood than the log-of-walks. Conclusions : The NWQ-CS showed measurement invariance across types of neighborhoods. It is a valid measure of walking for recreation and frequency of walking for transport. However, it may systematically underestimate the duration of walking for transport in samples that engage in high levels of this type of walking

Temozolomide and cisplatin in relapsed/refractory acute leukemia

Cisplatin depletes MGMT and increases the sensitivity of leukemia cells to temozolomide. We performed a phase I study of cisplatin and temozolomide in patients with relapsed and refractory acute leukemia. Fifteen patients had AML, 3 had ALL, and 2 had biphenotypic leukemia. The median number of prior chemotherapy regimens was 3 (1–5). Treatment was well tolerated up to the maximal doses of temozolomide 200 mg/m2/d times 7 days and cisplatin 100 mg/m2 on day 1. There was one complete remission in this heavily pretreated patient population. Five of 20 (25%) patients demonstrated a significant reduction in bone marrow blasts

Systems Biology of the qa Gene Cluster in Neurospora crassa

An ensemble of genetic networks that describe how the model fungal system, Neurospora crassa, utilizes quinic acid (QA) as a sole carbon source has been identified previously. A genetic network for QA metabolism involves the genes, qa-1F and qa-1S, that encode a transcriptional activator and repressor, respectively and structural genes, qa-2, qa-3, qa-4, qa-x, and qa-y. By a series of 4 separate and independent, model-guided, microarray experiments a total of 50 genes are identified as QA-responsive and hypothesized to be under QA-1F control and/or the control of a second QA-responsive transcription factor (NCU03643) both in the fungal binuclear Zn(II)2Cys6 cluster family. QA-1F regulation is not sufficient to explain the quantitative variation in expression profiles of the 50 QA-responsive genes. QA-responsive genes include genes with products in 8 mutually connected metabolic pathways with 7 of them one step removed from the tricarboxylic (TCA) Cycle and with 7 of them one step removed from glycolysis: (1) starch and sucrose metabolism; (2) glycolysis/glucanogenesis; (3) TCA Cycle; (4) butanoate metabolism; (5) pyruvate metabolism; (6) aromatic amino acid and QA metabolism; (7) valine, leucine, and isoleucine degradation; and (8) transport of sugars and amino acids. Gene products both in aromatic amino acid and QA metabolism and transport show an immediate response to shift to QA, while genes with products in the remaining 7 metabolic modules generally show a delayed response to shift to QA. The additional QA-responsive cutinase transcription factor-1β (NCU03643) is found to have a delayed response to shift to QA. The series of microarray experiments are used to expand the previously identified genetic network describing the qa gene cluster to include all 50 QA-responsive genes including the second transcription factor (NCU03643). These studies illustrate new methodologies from systems biology to guide model-driven discoveries about a core metabolic network involving carbon and amino acid metabolism in N. crassa

JAK2 Exon 14 Deletion in Patients with Chronic Myeloproliferative Neoplasms

BACKGROUND: The JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs); deletion of the entire exon 14 is rarely detected. In our previous study of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by reverse transcription-PCR (RT-PCR) with direct sequencing, complete deletion of exon 14 (Deltaexon14) constituted <1% of JAK2 mutations. This appears to be an alternative splicing mutation, not detectable with DNA-based testing. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the possibility that MPN patients may express the JAK2 Deltaexon14 at low levels (<15% of total transcript) not routinely detectable by RT-PCR with direct sequencing. Using a sensitive RT-PCR-based fluorescent fragment analysis method to quantify JAK2 Deltaexon14 mRNA expression relative to wild-type, we tested 61 patients with confirmed MPNs, 183 with suspected MPNs (93 V617F-positive, 90 V617F-negative), and 46 healthy control subjects. The Deltaexon14 variant was detected in 9 of the 61 (15%) confirmed MPN patients, accounting for 3.96% to 33.85% (mean = 12.04%) of total JAK2 transcript. This variant was also detected in 51 of the 183 patients with suspected MPNs (27%), including 20 of the 93 (22%) with V617F (mean [range] expression = 5.41% [2.13%-26.22%]) and 31 of the 90 (34%) without V617F (mean [range] expression = 3.88% [2.08%-12.22%]). Immunoprecipitation studies demonstrated that patients expressing Deltaexon14 mRNA expressed a corresponding truncated JAK2 protein. The Deltaexon14 variant was not detected in the 46 control subjects. CONCLUSIONS/SIGNIFICANCE: These data suggest that expression of the JAK2 Deltaexon14 splice variant, leading to a truncated JAK2 protein, is common in patients with MPNs. This alternatively spliced transcript appears to be more frequent in MPN patients without V617F mutation, in whom it might contribute to leukemogenesis. This mutation is missed if DNA rather than RNA is used for testing

Towards translation of environmental determinants of physical activity in children into multi-sector policy measures: study design of a Dutch project

Transport, and Safety) were screened for their content on physical activity in children. In addition, semi-structured interviews were conducted with policy makers of each of these sectors to identify critical success factors in the development and realization of multi-sector policy plans aimed at stimulating physical activity in children. The results of all these research activities will be discussed with local policy makers during interactive workshop sessions in order to identify clear cut multi-sector policy measures that stimulate physical activity in children. DISCUSSION: This paper describes the study design of a project that focuses on multi-sector policy measures that stimulate physical activity in children. Next to extensive research into the environmental determinants of physical activity in children, much emphasis is placed on the translation of the research outcomes into concrete and feasible policy plan