Temporal clustering of neuroblastic tumours in children and young adults from Ontario, Canada.

BACKGROUND: The aetiology of neuroblastic tumours is likely to involve both genetic and environmental factors. A number of possible environmental risk factors have been suggested, including infection. If an irregular temporal pattern in incidence is found, this might suggest that a transient agent, such as an infection, is implicated. Previous work has found evidence for temporal clustering in children and young adults living in northern England. METHODS: We examined data from a second population-based registry from Ontario, Canada to determine whether there was evidence of temporal clustering of neuroblastic tumours. Cases diagnosed in children and young adults aged 0-19 years between 1985 and 2016 were extracted from the population-based Pediatric Oncology Group of Ontario Networked Information System (POGONIS). A modified version of the Potthoff-Whittinghill method was used to test for temporal clustering. Estimates of extra-Poisson variation (EPV) and standard errors (SE) were obtained. RESULTS: Eight hundred seventy-six cases of neuroblastic tumours were diagnosed during the study period. Overall, no evidence of temporal clustering was found between fortnights, between months or between quarters within years. However, significant EPV was found between years within the full study period (EPV = 1.05, SE = 0.25; P = 0.005). CONCLUSIONS: The findings are consistent with the possibility that a transient agent, such as an infection that is characterised by 'peaks and troughs' in its occurrence, might be implicated in the aetiology of neuroblastic tumours. However, this pattern may also reflect a long-term increase in the numbers of cases, rather than peaks and troughs.

Behavior Change Techniques Used in Digital Behavior Change Interventions to Reduce Excessive Alcohol Consumption: A Meta-regression.

Background: Digital behavior change interventions (DBCIs) appear to reduce alcohol consumption, but greater understanding is needed of their mechanisms of action. Purpose: To describe the behavior change techniques (BCTs) used in DBCIs and examine whether individual BCTs, the inclusion of more BCTs or more Control Theory congruent BCTs is associated with increased effectiveness. Methods: Forty-one randomized control trials were extracted from a Cochrane review of alcohol reduction DBCIs and coded for up to 93 BCTs using an established and reliable method. Random effects unadjusted and adjusted meta-regression models were performed to assess associations between BCTs and intervention effectiveness. Results: Interventions used a mean of 9.1 BCTs (range 1-22), 23 different BCTs were used in four or more trials. Trials that used "Behavior substitution" (-95.112 grams per week [gpw], 95% CI: -162.90, -27.34), "Problem solving" (-45.92 gpw, 95% CI: -90.97, -0.87) and "Credible source" (-32.09 gpw, 95% CI: -60.64, -3.55) were significantly associated with greater alcohol reduction than trials without these BCTs. The "Behavior substitution" result should be treated as preliminary because it was reported in only four trials, three of which were conducted by the same research group. "Feedback" was used in 98% of trials (n = 41); other Control Theory congruent BCTs were used less frequently: for example, "Goal setting" 43% (n = 18) and "Self-monitoring" 29%, (n = 12). Conclusions: "Behavior substitution," "Problem solving," and "Credible source" were associated with greater alcohol reduction. Many BCTs were used infrequently in DBCIs, including BCTs with evidence of effectiveness in other domains, such as "Self-monitoring" and "Goal setting."

A restatement of the natural science evidence base concerning the health effects of low-level ionizing radiation.

Exposure to ionizing radiation is ubiquitous, and it is well established that moderate and high doses cause ill-health and can be lethal. The health effects of low doses or low dose-rates of ionizing radiation are not so clear. This paper describes a project which sets out to summarize, as a restatement, the natural science evidence base concerning the human health effects of exposure to low-level ionizing radiation. A novel feature, compared to other reviews, is that a series of statements are listed and categorized according to the nature and strength of the evidence that underpins them. The purpose of this restatement is to provide a concise entrée into this vibrant field, pointing the interested reader deeper into the literature when more detail is needed. It is not our purpose to reach conclusions on whether the legal limits on radiation exposures are too high, too low or just right. Our aim is to provide an introduction so that non-specialist individuals in this area (be they policy-makers, disputers of policy, health professionals or students) have a straightforward place to start. The summary restatement of the evidence and an extensively annotated bibliography are provided as appendices in the electronic supplementary material.

What helps or hinders midwives to implement physical activity guidelines for obese pregnant women? A questionnaire survey using the Theoretical Domains Framework.

OBJECTIVE: to investigate barriers and facilitators to physical activity (PA) guideline implementation for midwives when advising obese pregnant women. DESIGN: a cross-sectional, self-completion, anonymous questionnaire was designed using the Theoretical Domains Framework. this framework was developed to evaluate the implementation of guidelines by health care professionals. A total of 40 questions were included. These were informed by previous research on pregnant women's and midwives views, knowledge and attitudes to PA, and supported by national evidence based guidelines. Demographic information and free text comments were also collected. SETTING: three diverse NHS Trusts in the North East of England. PARTICIPANTS: all midwives employed by two hospital Trusts and the community midwives from the third Trust (n=375) were invited to participate. MEASUREMENTS: mean domain scores were calculated. Factor and regression analysis were performed to describe which theoretical domains may be influencing practice. Free text comments were analysed thematically. FINDINGS: 192 (53%) questionnaires were returned. Mean domain scores were highest for social professional role and knowledge, and lowest for skills, beliefs about capabilities and behaviour regulation. Regression analysis indicated that skills and memory/attention/decision domains had a statistically significant influence on midwives discussing PA with obese pregnant women and advising them accordingly. Midwives comments indicated that they felt it was part of their role to discuss PA with all pregnant women but felt they lacked the skills and resources to do so effectively. KEY CONCLUSIONS: midwives seem to have the necessary knowledge about the need/importance of PA advice for obese women and believe it is part of their role, but perceive they lack necessary skills and resources, and do not plan or prioritise the discussion regarding PA with obese pregnant woman. IMPLICATIONS FOR PRACTICE: designing interventions that improve skills, promote routine enquiry regarding PA and provide resources (eg. information, referral pathways) may help improve midwives' PA advice.

Treatments for Hyperemesis Gravidarum and Nausea and Vomiting in Pregnancy: A Systematic Review.

Importance: Nausea and vomiting affects approximately 85% of pregnant women. The most severe form, hyperemesis gravidarum, affects up to 3% of women and can have significant adverse physical and psychological sequelae. Objective: To summarize current evidence on effective treatments for nausea and vomiting in pregnancy and hyperemesis gravidarum. Evidence Review: Databases were searched to June 8, 2016. Relevant websites and bibliographies were also searched. Titles and abstracts were assessed independently by 2 reviewers. Results were narratively synthesized; planned meta-analysis was not possible because of heterogeneity and incomplete reporting of findings. Findings: Seventy-eight studies (n = 8930 participants) were included: 67 randomized clinical trials (RCTs) and 11 nonrandomized studies. Evidence from 35 RCTs at low risk of bias indicated that ginger, vitamin B6, antihistamines, metoclopramide (for mild symptoms), pyridoxine-doxylamine, and ondansetron (for moderate symptoms) were associated with improved symptoms compared with placebo. One RCT (n = 86) reported greater improvements in moderate symptoms following psychotherapy (change in Rhodes score [range, 0 {no symptoms} to 40 {worst possible symptoms}], 18.76 [SD, 5.48] to 7.06 [SD, 5.79] for intervention vs 19.18 [SD, 5.63] to 12.81 [SD, 6.88] for comparator [P < .001]). For moderate-severe symptoms, 1 RCT (n = 60) suggested that pyridoxine-doxylamine combination taken preemptively reduced risk of recurrence of moderate-severe symptoms compared with treatment once symptoms begin (15.4% vs 39.1% [P < .04]). One RCT (n = 83) found that ondansetron was associated with lower nausea scores on day 4 than metoclopramide (mean visual analog scale [VAS] score, 4.1 [SD, 2.9] for ondansetron vs 5.7 [SD, 2.3] for metoclopramide [P = .023]) but not episodes of emesis (5.0 [SD, 3.1] vs 3.3 [SD, 3], respectively [P = .013]). Although there was no difference in trend in nausea scores over the 14-day study period, trend in vomiting scores was better in the ondansetron group (P = .042). One RCT (n = 159) found no difference between metoclopramide and promethazine after 24 hours (episodes of vomiting, 1 [IQR, 0-5] for metoclopramide vs 2 [IQR, 0-3] for promethazine [P = .81], VAS [0-10 scale] for nausea, 2 [IQR, 1-5] vs 2 [IQR, 1-4], respectively [P = .99]). Three RCTs compared corticosteroids with placebo or promethazine or metoclopramide in women with severe symptoms. Improvements were seen in all corticosteroid groups, but only a significant difference between corticosteroids vs metoclopramide was reported (emesis reduction, 40.9% vs 16.5% at day 2; 71.6% vs 51.2% at day 3; 95.8% vs 76.6% at day 7 [n = 40, P < .001]). For other interventions, evidence was limited. Conclusions and Relevance: For mild symptoms of nausea and emesis of pregnancy, ginger, pyridoxine, antihistamines, and metoclopramide were associated with greater benefit than placebo. For moderate symptoms, pyridoxine-doxylamine, promethazine, and metoclopramide were associated with greater benefit than placebo. Ondansetron was associated with improvement for a range of symptom severity. Corticosteroids may be associated with benefit in severe cases. Overall the quality of evidence was low.

Critical care admission trends and outcomes in individuals with bronchiectasis in the UK.

BACKGROUND: There are limited data on admission trends and outcomes of individuals with bronchiectasis admitted to intensive care (ICU). Using national critical care data, we analysed admissions to ICU and estimated outcomes in terms of mortality in individuals with bronchiectasis and chronic obstructive pulmonary disease (COPD) admitted to ICU. METHODS: Using data from the Intensive Care National Audit and Research Centre, admissions from bronchiectasis and COPD from 1 January 2009 to 31 December 2013 were extracted. Crude admission rates for bronchiectasis and COPD were calculated and Poisson regression was used to estimate unadjusted annual admission rate ratios. We investigated changes to length of stay on ICU, ICU mortality and in-hospital mortality during the study period. We also compared mortality rates in people with bronchiectasis and COPD aged 70 or above. RESULTS: We found an annual increase of 8% (95% Confidence Interval [CI] 2-15) in the number of ICU admissions from bronchiectasis, whilst the yearly increase in ICU admissions from COPD was 1% (95% CI 0.3-2). ICU and in-hospital mortality was higher in individuals with bronchiectasis compared with those with COPD, especially in people aged 70 years or above. CONCLUSION: Admission to ICU in people with bronchiectasis are uncommon, but are increasing in frequency over time, and carries a substantial mortality rate. This needs to be considered allocating health care resources and planning respiratory services.

Does primary biliary cirrhosis cluster in time?

The aetiology of primary biliary cirrhosis (PBC) is not well established. Previously we found evidence of space-time clustering and seasonal variation in the date of diagnosis, suggesting a possible role for a transient or seasonally varying environmental factor. We examined whether a temporally varying environmental agent may be involved by analysing population-based PBC data from northeast England over 1987-2003. Using an adaptation of a method proposed by Potthoff and Whittinghill, we found significant temporal variation by date of diagnosis at the level of aggregation of one year. However, there was no evidence for general irregular (non-seasonal) temporal clustering within periods less than a year. These results provide little support for the involvement of agents occurring in geographically widespread mini-epidemics, but--taken together with studies of spatial and spatio-temporal clustering--do not preclude the role of more localised sporadic mini-epidemics. Future research should seek to elicit putative environmental agents.

Temporal clustering of neuroblastic tumours in children and young adults from Northern England.

BACKGROUND: The aetiology of neuroblastic tumours is unclear with both genetic and environmental factors implicated. The possibility that an infectious agent may be involved has been suggested. 'Temporal clustering' occurs if cases display an irregular temporal distribution and may indicate the involvement of an agent that exhibits epidemicity. We tested for the presence and nature of temporal clustering using population-based data from northern England. METHODS: We extracted all cases of neuroblastic tumours diagnosed in children and young adults aged 0-24 years during 1968-2011 from the Northern Region Young Persons' Malignant Disease Registry. This is a population-based registry, covering a population of approximately 900,000 young persons, and includes all cases resident in northern England at the time of diagnosis. Tests for temporal clustering were applied using a modified version of the Potthoff-Whittinghill method. Estimates of extra-Poisson variation (ß) and standard errors (SEs) were obtained. RESULTS: 227 cases of neuroblastic tumours were diagnosed during the study period. All the analyses between fortnights and between months found significant extra-Poisson variation, with ß = 0.846 (SE = 0.310, P = 0.004) for the analysis between fortnights within months. Restricting the analyses to the 76 cases diagnosed at ages less than 18 months showed significant extra-Poisson variation between fortnights within months (ß = 1.532, SE = 0.866, P = 0.038), but not between months. In contrast, analyses of cases aged 18 months to 24 years showed significant extra-Poisson variation between quarters within years, as well as over shorter timescales. CONCLUSIONS: Transient environmental agents may be involved in the aetiology of neuroblastic tumours. The initiating factor might be a geographically-widespread agent that occurs in 'mini-epidemics'.

Calculation of lifetime lung cancer risks associated with radon exposure, based on various models and exposure scenarios.

The risk of lung cancer mortality up to 75 years of age due to radon exposure has been estimated for both male and female continuing, ex- and never-smokers, based on various radon risk models and exposure scenarios. We used risk models derived from (i) the BEIR VI analysis of cohorts of radon-exposed miners, (ii) cohort and nested case-control analyses of a European cohort of uranium miners and (iii) the joint analysis of European residential radon case-control studies. Estimates of the lifetime lung cancer risk due to radon varied between these models by just over a factor of 2 and risk estimates based on models from analyses of European uranium miners exposed at comparatively low rates and of people exposed to radon in homes were broadly compatible. For a given smoking category, there was not much difference in lifetime lung cancer risk between males and females. The estimated lifetime risk of radon-induced lung cancer for exposure to a concentration of 200 Bq m(-3) was in the range 2.98-6.55% for male continuing smokers and 0.19-0.42% for male never-smokers, depending on the model used and assuming a multiplicative relationship for the joint effect of radon and smoking. Stopping smoking at age 50 years decreases the lifetime risk due to radon by around a half relative to continuing smoking, but the risk for ex-smokers remains about a factor of 5-7 higher than that for never-smokers. Under a sub-multiplicative model for the joint effect of radon and smoking, the lifetime risk of radon-induced lung cancer was still estimated to be substantially higher for continuing smokers than for never smokers. Radon mitigation-used to reduce radon concentrations at homes-can also have a substantial impact on lung cancer risk, even for persons in their 50 s; for each of continuing smokers, ex-smokers and never-smokers, radon mitigation at age 50 would lower the lifetime risk of radon-induced lung cancer by about one-third. To maximise risk reductions, smokers in high-radon homes should both stop smoking and remediate their homes.

How do childhood diagnoses of type 1 diabetes cluster in time?

BACKGROUND: Previous studies have indicated that type 1 diabetes may have an infectious origin. The presence of temporal clustering-an irregular temporal distribution of cases--would provide additional evidence that occurrence may be linked with an agent that displays epidemicity. We tested for the presence and form of temporal clustering using population- based data from northeast England. MATERIALS AND METHODS: The study analysed data on children aged 0-14 years diagnosed with type 1 diabetes during the period 1990-2007 and resident in a defined geographical region of northeast England (Northumberland, Newcastle upon Tyne, and North Tyneside). Tests for temporal clustering by time of diagnosis were applied using a modified version of the Potthoff-Whittinghill method. RESULTS: The study analysed 468 cases of children diagnosed with type 1 diabetes. There was highly statistically significant evidence of temporal clustering over periods of a few months and over longer time intervals (p<0.001). The clustering within years did not show a consistent seasonal pattern. CONCLUSIONS: The study adds to the growing body of literature that supports the involvement of infectious agents in the aetiology of type 1 diabetes in children. Specifically it suggests that the precipitating agent or agents involved might be an infection that occurs in "mini-epidemics".

Joint analysis of three European nested case-control studies of lung cancer among radon exposed miners: exposure restricted to below 300 WLM.

Analyses of lung cancer risk were carried out using restrictions to nested case-control data on uranium miners in the Czech Republic, France, and Germany. With the data restricted to cumulative exposures below 300 working-level-months (WLM) and adjustment for smoking status, the excess relative risk (ERR) per WLM was 0.0174 (95% CI: 0.009-0.035), compared to the estimate of 0.008 (95% CI: 0.004-0.014) using the unrestricted data. Analysis of both the restricted and unrestricted data showed that time since exposure windows had a major effect; the ERR/WLM was six times higher for more recent exposures (5-24 y) than for more distant exposures (25 y or more). Based on a linear model fitted to data on exposures <300 WLM, the ERR WLM of lung cancer at 30 y after exposure was estimated to be 0.021 (95% CI: 0.011-0.040), and the risks decreased by 47% per decade increase in time since exposure. The results from analyzing the joint effects of radon and smoking were consistent with a sub-multiplicative interaction; the ERR WLM was greater for non-smokers compared with current or ex-smokers, although there was no statistically significant variation in the ERR WLM by smoking status. The patterns of risk with radon exposure from the combined European nested case-control miner analysis were generally consistent with those based on the BEIR VI Exposure-Age-Concentration model. Based on conversions from WLM to time weighted averaged radon concentration (expressed per 100 Bq m), the results from this analysis of miner data were in agreement with those from the joint analysis of the European residential radon studies.

Development of a decision framework for establishing a health register following a major incident.

INTRODUCTION: Health registers have been established in the United Kingdom (UK) and elsewhere following mass exposure to novel agents or known agents, but there is no consensus on the criteria for establishing such registers. OBJECTIVE: This study aimed to develop a decision framework to assess the need for establishing a health register for major chemical, biological, radiological, and nuclear (CBRN) incidents. METHODS: The study comprised three stages. In the first stage, the study team prepared a list of potential criteria that may be used to assess the need for setting up a health register based on literature review and personal experiences in previous incidents. In the second stage, the potential criteria were evaluated in two Delphi rounds involving experts and key decision makers from the UK Health Protection Agency (HPA) and academic organizations. In the final stage, the criteria were converted into a decision framework, and its utility was tested using four fictional scenarios. RESULTS: A total of 11 statements were proposed by the study group. These criteria were revised following feedback from 16 experts in the first Delphi round. All 11 statements achieved consensus at the end of the second Delphi round. Pilot testing of the agreed criteria on four fictional scenarios confirmed validity and reliability for use in the decision process. CONCLUSIONS: A decision framework to assess the need for setting up a health register after a major incident was agreed upon and tested using fictional scenarios. Further areas of work for practical implementation of the criteria and related planning for systems and protocols have been identified.

Ischemic heart disease in nuclear workers first employed at the Mayak PA in 1948-1972.

Following an earlier study of incidence and mortality of ischemic heart disease (IHD) published in 2010, a second analysis has been conducted based on an extended cohort and five additional years of follow-up. The cohort includes 18,763 workers, of whom 25% were females, first employed at the Mayak PA in 1948-1972 and followed up to the end of 2005. Some of these workers were exposed to external gamma rays only, and others were exposed to a mixture of external gamma-rays and internal alpha-particle radiation. A total of 6,134 cases and 2,629 deaths from IHD were identified in the study cohort. A statistically significant increasing trend was found with total external gamma-ray dose in IHD incidence (ERR/Gy 0.099; 95% CI: 0.045-0.153) after adjusting for non-radiation factors. This value reduced slightly when adjusting for internal liver dose. There was no statistically significant increase trend for internal liver dose in IHD incidence. These findings were consistent with an earlier study. New findings in IHD incidence revealed a statistically significant decrease in IHD incidence among workers exposed to external gamma-rays doses of 0.2-0.5 Gy in relation to the external doses below 0.2 Gy. This decreased risk is heavily influenced by female workers. This finding has never been reported in other studies, and the results should be treated with caution. The findings for IHD mortality are similar to those results in the earlier analysis; there was no statistically significant trend with external gamma-ray dose or for internal liver dose after adjustment for external dose. The risk estimates obtained from these analyses of IHD incidence and mortality in relation to external gamma-rays in the cohort of Mayak workers are generally compatible with those from other large occupational radiation worker studies and the Japanese atomic bomb survivors.

Cerebrovascular diseases in nuclear workers first employed at the Mayak PA in 1948-1972.

Incidence and mortality from cerebrovascular diseases (CVD) (430-438 ICD-9 codes) have been studied in a cohort of 18,763 workers first employed at the Mayak Production Association (Mayak PA) in 1948-1972 and followed up to the end of 2005. Some of the workers were exposed to external gamma-rays only while others were exposed to a mixture of external gamma-rays and internal alpha-particle radiation due to incorporated (239)Pu. After adjusting for non-radiation factors, there were significantly increasing trends in CVD incidence with total absorbed dose from external gamma-rays and total absorbed dose to liver from internal alpha radiation. The CVD incidence was statistically significantly higher among workers with total absorbed external gamma-ray doses greater than 0.20 Gy compared to those exposed to lower doses; the data were consistent with a linear trend in risk with external dose. The CVD incidence was statistically significantly higher among workers with total absorbed internal alpha-radiation doses to liver from incorporated (239)Pu greater than 0.025 Gy compared to those exposed to lower doses. There was no statistically significant trend in CVD mortality risk with either external gamma-ray dose or internal alpha-radiation dose to liver. The risk estimates obtained are generally compatible with those from other large occupational studies, although the incidence data point to higher risk estimates compared to those from the Japanese A-bomb survivors. Further studies of the unique cohort of Mayak workers chronically exposed to external and internal radiation will allow improving the reliability and validating the radiation safety standards for occupational and public exposure.

Two error components model for measurement error: application to radon in homes.

In this paper, a simple model for analysing variability in radon concentrations in homes is tested. The approach used here involves two error components, representing additive and multiplicative errors, together with variation between-houses. We use a Bayesian approach for our analysis and apply this model to two datasets of repeat radon measurements in homes; one based on 3-month long measurements for which the original measurements were close to the current UK Radon Action Level (200 Bq m(-3)), and the other based on 6-month measurement data (from regional and national surveys), for which the original measurements cover a wide range of radon concentrations, down to very low levels. The model with two error components provides a better fit to these datasets than does a model based on solely multiplicative errors.

Second malignancies in breast cancer patients following radiotherapy: a study in Florence, Italy.

INTRODUCTION: Patients diagnosed with breast cancer are often treated with surgery followed by radiation therapy. In this paper, we evaluate the effect that radiotherapy may have had on the subsequent risk of second malignancies, including the possible influences of age at treatment and menopausal status. METHODS: In order to evaluate the long-term consequences of radiotherapy, a cohort study was conducted based on clinical records for 5,248 women treated for breast cancer in Florence (Italy), with continuous follow-up from 1965 to 1994. The Cox proportional hazards model for ungrouped survival data was used to estimate the relative risk for second cancer after radiotherapy. RESULTS: This study indicated an increased relative risk of all second cancers combined following radiotherapy (1.22, 95% CI: 0.88 to 1.69). The increased relative risk appeared five or more years after radiotherapy and appeared to be highest amongst women treated after the menopause (1.61, 95% CI: 1.13 to 2.29). Increased relative risks were observed specifically for leukaemia (8.13, 95% CI: 0.96 to 69.1) and other solid cancers (1.84, 95% CI: 1.06 to 3.16), excluding contralateral breast cancer. For contralateral breast cancer, no raised relative risk was observed during the period more than five years after radiotherapy. CONCLUSIONS: The study indicated a raised risk of second malignancies associated with radiotherapy for breast cancer, particularly for women treated after the menopause.

Uncertainties in radon related to house-specific factors and proximity to geological boundaries in England.

Data collected as a part of a survey on radon concentrations from about 40 000 dwellings in England for six contrasting geological units were analysed to evaluate the impact of house-specific factors (building characteristics and construction dates) and of proximity to geological boundaries. After adjusting for temperature and outdoor radon, geological unit, house type, double glazing and date of building were found to have a statistically significant influence on indoor radon concentrations and explained about 29 % of the total variation between dwellings in logarithmically transformed radon values. In addition, there were statistically significant differences in radon concentrations according to proximity to geological boundaries categories for most of the geological units, but no consistent pattern could be detected.