The impact of rurality and disadvantage on the diagnostic interval for breast cancer in a large population-based study of 3202 women in Queensland, Australia

Delays in diagnosing breast cancer (BC) can lead to poorer outcomes. We investigated factors related to the diagnostic interval in a population-based cohort of 3202 women diagnosed with BC in Queensland,Australia. Interviews ascertained method of detection and dates of medical/procedural appointments,and clinical information was obtained from medical records. Time intervals were calculated from self-recognition of symptoms (symptom-detected) or mammogram (screen-detected) to diagnosis (diagnostic interval (DI)). The cohort included 1560 women with symptom-detected and 1642 with screen-detected BC. Symptom-detected women had higher odds of DI of >60 days if they were Indigenous (OR = 3.12,95% CI = 1.40,6.98); lived in outer regional (OR = 1.50,95% CI = 1.09,2.06) or remote locations (OR = 2.46,95% CI = 1.39,4.38); or presented with a “non-lump” symptom (OR = 1.84,95% CI = 1.43,2.36). For screen-detected BC,women who were Indigenous (OR = 2.36,95% CI = 1.03,5.80); lived in remote locations (OR = 2.35,95% CI = 1.24,4.44); or disadvantaged areas (OR = 1.69,95% CI = 1.17,2.43) and attended a public screening facility (OR = 2.10,95% CI = 1.40,3.17) had higher odds of DI > 30 days. Our study indicates a disadvantage in terms of DI for rural,disadvantaged and Indigenous women. Difficulties in accessing primary care and diagnostic services are evident. There is a need to identify and implement an efficient and effective model of care to minimize avoidable longer diagnostic intervals

Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors

Background: Limits on the frequency of whole blood donation exist primarily to safeguard donor health. However, there is substantial variation across blood services in the maximum frequency of donations allowed. We compared standard practice in the UK with shorter inter-donation intervals used in other countries. Methods: In this parallel group, pragmatic, randomised trial, we recruited whole blood donors aged 18 years or older from 25 centres across England, UK. By use of a computer-based algorithm, men were randomly assigned (1:1:1) to 12-week (standard) versus 10-week versus 8-week inter-donation intervals, and women were randomly assigned (1:1:1) to 16-week (standard) versus 14-week versus 12-week intervals. Participants were not masked to their allocated intervention group. The primary outcome was the number of donations over 2 years. Secondary outcomes related to safety were quality of life, symptoms potentially related to donation, physical activity, cognitive function, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin. This trial is registered with ISRCTN, number ISRCTN24760606, and is ongoing but no longer recruiting participants. Findings: 45 263 whole blood donors (22 466 men, 22 797 women) were recruited between June 11, 2012, and June 15, 2014. Data were analysed for 45 042 (99·5%) participants. Men were randomly assigned to the 12-week (n=7452) versus 10-week (n=7449) versus 8-week (n=7456) groups; and women to the 16-week (n=7550) versus 14-week (n=7567) versus 12-week (n=7568) groups. In men, compared with the 12-week group, the mean amount of blood collected per donor over 2 years increased by 1·69 units (95% CI 1·59–1·80; approximately 795 mL) in the 8-week group and by 0·79 units (0·69–0·88; approximately 370 mL) in the 10-week group (p<0·0001 for both). In women, compared with the 16-week group, it increased by 0·84 units (95% CI 0·76–0·91; approximately 395 mL) in the 12-week group and by 0·46 units (0·39–0·53; approximately 215 mL) in the 14-week group (p<0·0001 for both). No significant differences were observed in quality of life, physical activity, or cognitive function across randomised groups. However, more frequent donation resulted in more donation-related symptoms (eg, tiredness, breathlessness, feeling faint, dizziness, and restless legs, especially among men [for all listed symptoms]), lower mean haemoglobin and ferritin concentrations, and more deferrals for low haemoglobin (p<0·0001 for each) than those observed in the standard frequency groups. Interpretation: Over 2 years, more frequent donation than is standard practice in the UK collected substantially more blood without having a major effect on donors' quality of life, physical activity, or cognitive function, but resulted in more donation-related symptoms, deferrals, and iron deficiency. Funding: NHS Blood and Transplant, National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

A multilevel study of the determinants of area-level inequalities in colorectal cancer survival

Background: In Australia, associations between geographic remoteness, socioeconomic disadvantage, and colorectal cancer (CRC) survival show that survival rates are lowest among residents of geographically remote regions and those living in disadvantaged areas. At present we know very little about the reasons for these inequalities, hence our capacity to intervene to reduce the inequalities is limited. Methods/Design: This study, the first of its type in Australia, examines the association between CRC survival and key area- and individual-level factors. Specifically, we will use a multilevel framework to investigate the possible determinants of area- and individual-level inequalities in CRC survival and quantify the relative contribution of geographic remoteness, socioeconomic and demographic factors, disease stage, and access to diagnostic and treatment services, to these inequalities. The multilevel analysis will be based on survival data relating to people diagnosed with CRC in Queensland between 1996 and 2005 (n = 22,723) from the Queensland Cancer Registry (QCR), area-level data from other data custodians such as the Australian Bureau of Statistics, and individual-level data from the QCR (including extracting stage from pathology records) and Queensland Hospitals. For a subset of this period (2003 and 2004) we will utilise more detailed, individual-level data (n = 1,966) covering a greater range of risk factors from a concurrent research study. Geo-coding and spatial technology will be used to calculate road travel distances from patients’ residence to treatment centres. The analyses will be conducted using a multilevel Cox proportional hazards model with Level 1 comprising individual-level factors (e.g. occupation) and level 2 area level indicators of remoteness and area socioeconomic disadvantage. Discussion: This study focuses on the health inequalities for rural and disadvantaged populations that have often been documented but poorly understood, hence limiting our capacity to intervene. This study utilises and develops emerging statistical and spatial technologies that can then be applied to other cancers and health outcomes. The findings of this study will have direct implications for the targeting and resourcing of cancer control programs designed to reduce the burden of colorectal cancer, and for the provision of diagnostic and treatment services

The impact and significance of tephra deposition on a Holocene forest environment in the North Cascades, Washington, USA.

© 2016 Elsevier Ltd. High-resolution palaeoecological analyses (stratigraphy, tephra geochemistry, radiocarbon dating, pollen and ordination) were used to reconstruct a Holocene vegetation history of a watershed in the Pacific Northwest of America to evaluate the effects and duration of tephra deposition on a forest environment and the significance of these effects compared to long-term trends. Three tephra deposits were detected and evaluated: MLF-T158 and MLC-T324 from the climactic eruption of Mount Mazama, MLC-T480 from a Late Pleistocene eruption of Mount Mazama and MLC-T485 from a Glacier Peak eruption. Records were examined from both the centre and fringe of the basin to elucidate regional and local effects. The significance of tephra impacts independent of underlying long-term trends was confirmed using partial redundancy analysis. Tephra deposition from the climactic eruption of Mount Mazama approximately 7600 cal. years BP caused a significant local impact, reflected in the fringe location by changes to open habitat vegetation (Cyperaceae and Poaceae) and changes in aquatic macrophytes (Myriophyllum spicatum, Potamogeton, Equisetum and the alga Pediastrum). There was no significant impact of the climactic Mazama tephra or other tephras detected on the pollen record of the central core. Changes in this core are potentially climate driven. Overall, significant tephra fall was demonstrated through high resolution analyses indicating a local effect on the terrestrial and aquatic environment, but there was no significant impact on the regional forest dependent of underlying environmental changes

A multilevel investigation of inequalities in clinical and psychosocial outcomes for women after breast cancer

Background In Australia, breast cancer is the most common cancer affecting Australian women. Inequalities in clinical and psychosocial outcomes have existed for some time, affecting particularly women from rural areas and from areas of disadvantage. We have a limited understanding of how individual and area-level factors are related to each other, and their associations with survival and other clinical and psychosocial outcomes. Methods/Design This study will examine associations between breast cancer recurrence, survival and psychosocial outcomes (e.g. distress, unmet supportive care needs, quality of life). The study will use an innovative multilevel approach using area-level factors simultaneously with detailed individual-level factors to assess the relative importance of remoteness, socioeconomic and demographic factors, diagnostic and treatment pathways and processes, and supportive care utilization to clinical and psychosocial outcomes. The study will use telephone and self-administered questionnaires to collect individual-level data from approximately 3, 300 women ascertained from the Queensland Cancer Registry diagnosed with invasive breast cancer residing in 478 Statistical Local Areas Queensland in 2011 and 2012. Area-level data will be sourced from the Australian Bureau of Statistics census data. Geo-coding and spatial technology will be used to calculate road travel distances from patients' residence to diagnostic and treatment centres. Data analysis will include a combination of standard empirical procedures and multilevel modelling. Discussion The study will address the critical question of: what are the individual- or area-level factors associated with inequalities in outcomes from breast cancer? The findings will provide health care providers and policy makers with targeted information to improve the management of women with breast cancer, and inform the development of strategies to improve psychosocial care for women with breast cancer

Longer-term efficiency and safety of increasing the frequency of whole blood donation (INTERVAL): extension study of a randomised trial of 20 757 blood donors

Background: The INTERVAL trial showed that, over a 2-year period, inter-donation intervals for whole blood donation can be safely reduced to meet blood shortages. We extended the INTERVAL trial for a further 2 years to evaluate the longer-term risks and benefits of varying inter-donation intervals, and to compare routine versus more intensive reminders to help donors keep appointments. Methods: The INTERVAL trial was a parallel group, pragmatic, randomised trial that recruited blood donors aged 18 years or older from 25 static donor centres of NHS Blood and Transplant across England, UK. Here we report on the prespecified analyses after 4 years of follow-up. Participants were whole blood donors who agreed to continue trial participation on their originally allocated inter-donation intervals (men: 12, 10, and 8 weeks; women: 16, 14, and 12 weeks). They were further block-randomised (1:1) to routine versus more intensive reminders using computer-generated random sequences. The prespecified primary outcome was units of blood collected per year analysed in the intention-to-treat population. Secondary outcomes related to safety were quality of life, self-reported symptoms potentially related to donation, haemoglobin and ferritin concentrations, and deferrals because of low haemoglobin and other factors. This trial is registered with ISRCTN, number ISRCTN24760606, and has completed. Findings: Between Oct 19, 2014, and May 3, 2016, 20 757 of the 38 035 invited blood donors (10 843 [58%] men, 9914 [51%] women) participated in the extension study. 10 378 (50%) were randomly assigned to routine reminders and 10 379 (50%) were randomly assigned to more intensive reminders. Median follow-up was 1·1 years (IQR 0·7–1·3). Compared with routine reminders, more intensive reminders increased blood collection by a mean of 0·11 units per year (95% CI 0·04–0·17; p=0·0003) in men and 0·06 units per year (0·01–0·11; p=0·0094) in women. During the extension study, each week shorter inter-donation interval increased blood collection by a mean of 0·23 units per year (0·21–0·25) in men and 0·14 units per year (0·12–0·15) in women (both p<0·0001). More frequent donation resulted in more deferrals for low haemoglobin (odds ratio per week shorter inter-donation interval 1·19 [95% CI 1·15–1·22] in men and 1·10 [1·06–1·14] in women), and lower mean haemoglobin (difference per week shorter inter-donation interval −0·84 g/L [95% CI −0·99 to −0·70] in men and −0·45 g/L [–0·59 to −0·31] in women) and ferritin concentrations (percentage difference per week shorter inter-donation interval −6·5% [95% CI −7·6 to −5·5] in men and −5·3% [–6·5 to −4·2] in women; all p<0·0001). No differences were observed in quality of life, serious adverse events, or self-reported symptoms (p>0.0001 for tests of linear trend by inter-donation intervals) other than a higher reported frequency of doctor-diagnosed low iron concentrations and prescription of iron supplements in men (p<0·0001). Interpretation: During a period of up to 4 years, shorter inter-donation intervals and more intensive reminders resulted in more blood being collected without a detectable effect on donors' mental and physical wellbeing. However, donors had decreased haemoglobin concentrations and more self-reported symptoms compared with the initial 2 years of the trial. Our findings suggest that blood collection services could safely use shorter donation intervals and more intensive reminders to meet shortages, for donors who maintain adequate haemoglobin concentrations and iron stores. Funding: NHS Blood and Transplant, UK National Institute for Health Research, UK Medical Research Council, and British Heart Foundation

Lancet

BACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37.5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89.5% in Australia and 90.2% in the USA, but international differences remain very wide, with levels as low as 66.1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68.9%), colon (71.8%), and rectum (71.1%); in Japan for oesophageal cancer (36.0%); and in Taiwan for liver cancer (27.9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59.9% in South Korea, 52.1% in Taiwan, and 49.6% in China), and for both lymphoid malignancies (52.5%, 50.5%, and 38.3%) and myeloid malignancies (45.9%, 33.4%, and 24.8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49.8% in Ecuador to 95.2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28.9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms