Little is known about how parental socioeconomic status affects offspring asthma risk in the general population, or its relation to healthcare and medication use among diagnosed children.This register-based cohort study included 211,520 children born between April 2006 and December 2008 followed until December 2010. Asthma diagnoses were retrieved from the National Patient Register, and dispensed asthma medications from the Prescribed Drug Register. Parental socioeconomic status (income and education) were retrieved from Statistics Sweden. The associations between parental socioeconomic status and outcomes were estimated by Cox proportional hazard regression.Compared to the highest parental income level, children exposed to all other levels had increased risk of asthma during their first year of life  and the risk was decreased after the first year, especially among children from the lowest parental income quintile . Further, compared to children with college-educated parents, those whose parents had lower education had increased risk of childhood asthma regardless of age. Children with the lowest parental education had increased risk of an inpatient  and outpatient  asthma diagnosis. Among diagnosed children, those from families with lower education used fewer controller medications than those whose parents were college graduates.Our findings indicate an age-varying association between parental income and childhood asthma and consistent inverse association regardless of age between parental education and asthma incidence, dispensed controller medications and inpatient care which should be further investigated and remedied. Asthma is the most prevalent chronic disease among children and is associated with morbidity, substantial healthcare resource use and parental absence from work Current global and national treatment guidelines emphasize use of controller medications such as inhaled corticosteroids (ICS) or leukotriene receptor antagonists (LTRA) for asthma control In this study we investigated whether parental income and education were associated with the risk of childhood asthma in a nationwide register-based cohort of preschool children. We also investigated whether parental income and education were associated with an inpatient or outpatient diagnosis and use of controller medications among all diagnosed children identified from the cohort.The Swedish National Board of Health and Welfare holds a number of registers covering health information. The universal use of the Personal Identity Number (PIN), a unique identifier for each resident, enables unambiguous linkage between these registers and those covering socioeconomic information held by Statistics Sweden. We conducted a prospective population-based cohort study among children aged 0–4 years in Sweden, using data from the Medical Birth Register (MBR), the Multi-Generation Register (MGR), the National Patient Register (NPR), the Prescribed Drug Register (PDR), and the longitudinal integration database for health insurance and labour market studies (LISA by Swedish acronym), linked through each individual’s unique PIN. The regional ethical review board in Stockholm, Sweden granted permission for the study and all individual’s information was anonymized and de-identified prior to analysis.From the MBR  data were obtained from the LISA database at yearly intervals from the child’s birth year. LISA includes all individuals 16 years and older living in Sweden and integrates labour market, educational and social sector data from several nationwide, annually updated registers. Firstly, parental SES was measured by annual disposable income, which includes individual net benefits after deduction of debits such as taxes, repaid study allowance, and paid maintenance support. The household level disposable incomes were summed up and adjusted for consumption weights th version of the International Classification of Diseases (ICD-10)). The level of healthcare resource used at diagnosis was categorized as inpatient or outpatient care. Time to the next visit at inpatient care after the first diagnosis was measured as time from the first visit at inpatient (discharge date) or outpatient (visit date) care to the date of the next admission to in-patient care with an asthma diagnosis. From the PDR, incidence date of asthma medication was defined as the date of the first dispensed medication followed by at least one more record of any of the four anti-asthma medications within 24 months: ICS, β2 agonists, combination products or LTRA  codes R03AC, R03AK, R03BA, and R03DC, respectively). The average daily dose was defined and categorized in each of three groups: ICS, β2-agonists, and LTRA. The combination products (R03AK) were split into both ICS and β2-agonists according to corresponding proportion of active ingredients. The daily dose of each type of medication was calculated as the total amount of active ingredients across all dispensed packages of this medication divided by number of days from the date of first asthma diagnosis to end of follow-up.There are two common care-seeking pathways for asthma conditions, one of which is a primary care physician occasionally followed by referral to a hospital specialist and the other contact with a specialist directly depending on symptoms and availability. Incident asthma was defined either by diagnosis from the NPR, which covers more than 99% of all hospital discharges and about 80% of all outpatient specialist visits, or by filling two prescriptions for asthma medication from the PDR, which contains data on all prescribed medication dispensed in Swedish pharmacies since 1 July 2005. Both asthma measures have been previously validated in population-based analyses Other independent variables included were the child’s age, gender, number of children born in the family during the study period, metropolitan areas  and healthcare regions based on residential addresses at birth year , to account for shared healthcare resources between counties and regional differences of asthma prevalence. Maternal characteristics included were age at first antenatal care visit, marital status , maternal smoking during pregnancy . Delivery characteristics included were preterm birth , low birth weight  and parity (first child or not first child). Maternal and delivery characteristics were retrieved from the MBR.Cox proportional hazards regression was used for the following (yes/no) endpoints: asthma diagnosis, at least two dispensed asthma medications (since the first active prescription), an inpatient asthma diagnosis, and an outpatient asthma diagnosis. Observations were censored at the date of death, migration, or end of follow-up (31 Dec 2010). Parental income and education were modelled as time-dependent variables, with yearly updates. Cumulative hazards for childhood-onset asthma and SES indicators were estimated with the Nelson–Aalen method. In order to examine the independent and joint effects of each SES indicator on asthma outcomes, we performed all analyses with adjustment for one single indicator, mutual adjustment (education in models of income and income in models of education) and interaction terms for education and income. Wald test was used to test for interaction between education and income and between SES measures and preterm birth. Attained age was the underlying analysis time scale. The proportional hazards assumption was checked with a test based on the Schoenfeld residuals as well as graphical examination. When the proportional hazards assumption was violated for the exposure variables, time (age) dependent hazard ratios (HR) were estimated. In the sub-cohort of children with at least one asthma diagnosis from NPR or at least 2 dispensed asthma medications regardless of diagnosis, the associations between parental income and education at the time of first diagnosis/medication and medication dosage, were analysed using linear regression with logarithmic transformed daily average dose of medication as outcome variables (among those with the corresponding medication). Children with at least one asthma diagnosis from NPR were further analysed using Cox regression model with parental income and education as time-dependent variables for the risk of a visit at inpatient care after a first diagnosis, with time from first inpatient/outpatient diagnosis as analysis time scale. Directed acyclic graph was used to determine potential confounders for different models The cumulative hazards curves for asthma defined as ≥1 diagnosis and as ≥2 prescriptions by income groups  a–b showIn this population-based cohort of 211,520 pre-school children, the study results support our hypotheses that there is an association between parental SES and childhood asthma occurrence, level of healthcare use at diagnosis and pattern of medication usage. Interestingly, parental income and education seem to affect asthma outcomes in different ways. Firstly, children from families with lower income or education had higher incidence rates of asthma measured by specialist diagnosis or medication. However, there was a lower incidence in the lowest income group after one year of age, to such an extent that there was a catch-up by the other groups. Secondly, those in families from the lowest education group had an increased risk of in- and outpatient asthma diagnosis and asthma medication. Finally, lower amounts of controller medications were dispensed for children from families with lower parental education.Although the effect of SES on the development of childhood asthma has been observed in hospital-based and other epidemiological studies Based on our finding on the association between different SES indicators and incident asthma, one possibility is that parental healthcare seeking behaviour, i.e. the income gradient of parents’ request for diagnosis and treatment, differs between the first year of life and later in childhood. Halldórsson et al. found no difference in using primary healthcare for children above 2 years of age, but less specialist care and more inpatient care for those from the lowest income group Furthermore, as consistent with previous literature Our results also indicated an effect of lower parental income and education on level of healthcare use at asthma diagnosis. This may reflect a tendency for less advantaged groups to seek care at emergency units due to parental stress and need of healthcare services Among children with diagnosed asthma, we found that parental income did not have any influence on average daily doses of all types of medications, which was in contrast to previous findings The present study is the first to show an association between parental SES and asthma medication purchases for children in a general population. By using register based information on filled prescriptions in pharmacy and diagnosis records from inpatient and outpatient care, we obtained objective measurements on childhood asthma occurrence, healthcare resource usage, and quantities of medication consumption The current study also has limitations. Firstly, using the NPR for ascertainment of asthma diagnoses has its drawback on differentiating asthma from transient wheezing in preschool children and missing information on children diagnosed in the primary care setting. Instead, we added the alternative definition on dispensed asthma medication as an additional proxy of asthma In conclusion, our population-based study shows that there is an increased risk of early childhood asthma diagnosis among families with lower income and education. Even though it appears that liberal prescription drug benefits in Sweden promote equal use of total medications between lower and higher SES families, the fact that lower SES families dispense fewer of the controller medications and are more often hospitalized at first diagnosis suggests obstacles more subtle than simply cost. The findings call for improved clinical measures to reach all young children in early stage of asthma development. Such approaches might include information and well maintained surveillance of asthma control therapy, asthma severity assessment and improved adherence to international guidelines targeted especially towards groups with lower SES over a long period.


Radiation overexposure accidents are rare but can have severe long-term health consequences. Although underreporting can be an issue, some extensive literature reviews of reported radiation overexposures have been performed and constitute a sound basis for conclusions on general trends. Building further on this work, we performed a systematic review that completes previous reviews and provides new information on characteristics and trends of reported radiation accidents.We searched publications and reports from MEDLINE, EMBASE, the International Atomic Energy Agency, the International Radiation Protection Association, the United Nations Scientific Committee on the Effects of Atomic Radiation, the United States Nuclear Regulatory Commission, and the Radiation Emergency Assistance Center/Training Site radiation accident registry over 1980-2013. We retrieved the reported overexposure cases, systematically extracted selected information, and performed a descriptive analysis.297 out of 5189 publications and reports and 194 records from the REAC/TS registry met our eligibility criteria. From these, 634 reported radiation accidents were retrieved, involving 2390 overexposed people, of whom 190 died from their overexposure. The number of reported cases has decreased for all types of radiation use, but the medical one. 64% of retrieved overexposure cases occurred with the use of radiation therapy and fluoroscopy. Additionally, the types of reported accidents differed significantly across regions.This review provides an updated and broader view of reported radiation overexposures. It suggests an overall decline in reported radiation overexposures over 1980-2013. The greatest share of reported overexposures occurred in the medical fields using radiation therapy and fluoroscopy; this larger number of reported overexposures accidents indicates the potential need for enhanced quality assurance programs. Our data also highlights variations in characteristics of reported accidents by region. The main limitation of this study is the likely underreporting of radiation overexposures. Ensuring a comprehensive monitoring and reporting of radiation overexposures is paramount to inform and tailor prevention interventions to local needs. Radiation overexposure accidents are uncommon, but can have severe long-term health consequences. Radiation is used in various settings. Major sectors include industrial, medical, and military. Some key applications are electricity production, sterilization of material equipment or food, development of nuclear weapons, radiography imaging techniques for welds inspection, radiation therapy, and radiology imaging techniques . These last decades, the medical sector in particular experienced a fast growth in the use of ionizing radiation that allowed better diagnostics and treatments –2. In orRadiation-related harms have been reported over the years in all sectors, along with those resulting from orphan sources. Harmful effects of radiation overexposure include deterministic effects  and stochastic effects (e.g. cancer). These effects can take from weeks to years to manifest, with severity depending upon multiple parameters including the total radiation absorbed dose, the radiation dose rate, the volume of body exposed, the parts of the body and tissues involved, the radiation source at stake, as well as personal characteristics of overexposed people  .Furthermore, local and global overexposures to the body translate into different health outcomes and therefore different treatment needs. Global overexposure of 1 Gray (Gy) or above induces acute radiation syndrome (ARS) characterized by consecutive hematopoietic, gastrointestinal, and neurovascular syndromes . Local sIn order to decrease the risk of harm associated with ionizing radiation, its use is often regulated at the country level. At the international level, the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), the International Atomic Energy Agency (IAEA), and the International Commission on Radiological Protection (ICRP) play a central role. They evaluate radiation risks, provide recommendations, and promote safe use of radiation technologies, which evolve rapidly and gain in complexity. Yet, in an era where resources are scarce, it is essential to identify the most pressing issues in order to better target prevention actions such as training, which can lead to dramatic improvements in the safe use of radiation .Several non-systematic reviews of radiation overexposure accidents have been published in the literature. The UNSCEAR organization performed the most extensive review, which it considers "a sound basis for conclusions regarding the number of significant radiation accidents that have occurred, the corresponding levels of radiation exposures and number of deaths and injuries, and the general trends for various practices", despite unavoidable underreporting . AdditioTo build further on the existing work and provide new information on characteristics and trends of reported radiation accidents worldwide, we performed a systematic review of reports published between 1980 and 2013 by querying the peer-reviewed literature, national and international reports, and the REAC/TS registry. Our objective was to evaluate the impact of past prevention programs and potential remaining needs for prevention planning. In this report, we present the search strategy and results of our review, and a descriptive analysis of the retrieved radiation overexposure accidents.A protocol was developed for the conduct of this systematic review and is detailed in Reported radiation overexposure accidents from 1980 to present were searched using MEDLINE, EMBASE, the IAEA publications, the congress proceedings of the International Radiation Protection Association (IRPA), the collection of UNSCEAR reports, the United States Nuclear Regulatory Commission (US NRC) reports on abnormal occurrences, and the REAC/TS registry.For the purposes of this review, we elected to use the IAEA definition of accident, which is "Any unintended event, including operating errors, equipment failures or other mishaps, the consequences or potential consequences of which are not negligible from the point of view of protection or safety" . Our stust 1980, in the English or French languages. The MEDLINE search strategy included a first keyword search in titles using: cause of overexposure  AND type of injury .We conducted an electronic search in MEDLINE and EMBASE on March 27th 2014 for all relevant articles published since January 1A second keyword search in titles was performed as follows: cause of interventional radiology overexposure  AND type of injury  NOT (erythematosus or lupus).The third search was based on the following Mesh terms:  OR  OR "Radiotherapy, Image-Guided"[Mesh] OR "Whole-Body Irradiation/adverse effects"[Mesh] OR "Fluoroscopy/adverse effects"[Mesh])) AND ("case reports"[Publication Type] OR "review"[Publication Type]) AND "humans"[Mesh].The EMBASE search strategy used the following words of major interest: 'radiation accident'/exp/mj OR 'radiation injury'/exp/mj OR 'acute radiation syndrome'/exp/mj OR 'radiation dermatitis'/exp/mj OR 'radiation sickness'/exp/mj OR 'radiation necrosis'/exp/mj AND [humans]/lim AND ([english]/lim OR [french]/lim) AND [1980–2014]/py AND [embase]/lim NOT .Reference titles and summaries were screened manually and discarded if not relevant. Selected publications were read in full text for data extraction. Cross-referencing was used to retrieve additional relevant articles.The IAEA publications , the IRPA congress proceedings(1980–2008), the UNSCEAR reports (1980–2013) and the US NRC reports to congress on abnormal occurrences (1980–2012) were systematically read in full text and extracted when relevant.st, 1980 and reported in the REAC/TS registry were retrieved using filters against our inclusion criteria. Full reports were read for retrieved cases and extracted if relevant.Finally, radiation overexposure accidents that occurred on or after January 1A case of radiation overexposure was defined as presenting at least one of the following criteria: (i) unintended global overexposure of 1 Gy or more, (ii) unintended local skin overexposure of 3 Gy or more, (iii) unintended local organ overexposure  of 5 Gy or more, or (iv) description of clinical presentation providing reasonable index of suspicion for unintended ionizing radiation overexposure . The thresholds used in this review are based on the literature, keeping in mind that these thresholds are not absolute boundaries , 12–18]–1812–18]For cases without occurrence date, we used date of first symptoms as first proxy and date of report as second proxy.Finally, similar cases issued from different reports but with insufficient information to decipher whether they were different or not, were not integrated in the database to prevent duplicates.Two independent researchers screened and reviewed data sources against the inclusion criteria. For selected reports, full-text documents were evaluated and extracted manually by one reviewer and double-checked by a second reviewer. Any divergence between reviewers regarding selection process was resolved through discussion.For each accident, select information was extracted into a data sheet. Selected data included date and place of occurrence, number of overexposed people and number of people dying from their overexposure, days between exposure and death, type of overexposed people , estimated global and local dose received, type of source, type of overexposure , and documents in which the accident was reported. Reported symptoms, course of treatment, and treatment outcomes were also recorded when available. Finally, accidents were categorized by sector of occurrence: "industrial" including industrial irradiator, production, and radiography; "radiation therapy" including teletherapy, brachytherapy, and therapeutic nuclear medicine; "fluoroscopy" used to support diagnostic and interventional radiology; "military" , and "orphan sources" for overexposures caused by sources fallen outside of regulatory control . A categOnly cases published in peer-reviewed journals or reported by official experts in radiation management  were considered, to ensure the quality of the study. Furthermore, all sources selected for data extraction addressed our review question, which was to understand the characteristics of reported radiation overexposure accidents worldwide and their evolution between 1980 and 2013. Among these, only sources showing evidence of radiation overexposure, as defined in our inclusion criteria, were considered for extraction.Our extraction sheet was used to assess the distribution of reported radiation overexposure accidents along recorded items and over time.Out of 5189 articles and reports identified, 296 met our eligibility criteria and were extracted . In addiExtracted cases were categorized by sector in which the accident occurred and by type of overexposure .Among the 634 reported radiation accidents identified, most of them occurred in the industrial sector (27%) and in the medical sector through the use of radiation therapy (32%) or fluoroscopy (31%) . ReporteOver the 1980–2009 period, the number of reported radiation accidents and the number of overexposed people by decade exhibited an overall downward trend . The samAmong reported overexposed people, patients represented the largest share . AdditioFinally, the types of overexposure in reported accidents also changed . Among rThe number of cases retrieved varied greatly across geographic regions . AltogetThis review explored a wide array of information sources. It included the assessment of peer-reviewed literature, reports from key national and international organizations in radiation management, and the review of the largest international radiation accidents registry, REAC/TS, for the period 1980–2013.This review showed that a limited and decreasing number of worldwide radiation accidents have been reported by decade since 1980 and that these accidents can be dramatic, as observed previously . FurtherOur results indicated that the number of reported radiation accidents and overexposed people have decreased over the 1980–2013 period. This likely reflects the impact of continuous efforts in radiation protection. Along the years, the IAEA in conjunction with new ICRP recommendations, has updated safety standards . In 1989This review suggested that the medical sector accounted for most reported radiation overexposures along 1980–2013. Consistently, most reported cases involved patients and a local skin overexposure component.Unlike other sectors, reported radiation therapy accidents increased along the three last decades, while the number of reported overexposed people tended to decrease. Still, for each decade, radiation therapy accidents represented the highest share of overexposed people.This upward trend in reported radiation therapy accidents could result from improved reporting or growing use of radiation therapy. UNSCEAR estimated that 5.1 million of radiation therapy treatments were delivered annually worldwide over the 1997–2007 period compared to 4.7 million annually for the period 1991–1996 . The intFurthermore, the average number of people involved per reported accident decreased from the 1980’s to the 2000–09 decade. This figure typically varies according to the cause of the accident. While some errors such as errors in treatment site or dose administered, affect a single patient, other errors such as software issue, calibration or treatment programming errors, can affect multiple patients before the issue comes to light. Error reporting systems such as ROSIS allow learning from the past through knowledge of near-misses, incidents or accidents and constitute essential prevention tools .As the use of radiation therapy is expected to grow even more in the future, it is crucial to ensure high quality assurance standards in order to avoid the multiple possible errors in the course of treatment and thus optimize all benefits of radiation therapy –311.This review also brings attention to medical fluoroscopy, which ranked second in number of reported accidents for 1980–2013. Corresponding reported radiation accidents increased significantly from the 1980s to the 1990s, and then decreased. This was consistent with the literature –18, 312312. ThisOf note, the increase in number of reported overexposed people through fluoroscopy from 1990–1999 to 2000–2009 despite the decrease in reported accidents over the same period, is primarily due to a single accident involving 206 patients. Its cause was an error in resetting a CT scan, which went undetected for 18 months . This acOur exploratory analysis suggests that the causes of reported radiation overexposure accidents differ across regions. One possible explanation relates to variations in radiation equipment and radiation use across countries. The review conducted by UNSCEAR for the period 1991–2007 emphasized that the level of X-ray equipment, radiological examinations, and radiation therapy differ greatly from one country to another and tend to be concentrated in a limited set of countries . For exaAdditionally, differences in reporting by country could also account for the observed differences in causes of overexposure. For example, Baeza highlighted the lack of reports from developing countries when going through ROSIS .Thus, these geographic differences should be monitored and accounted for in prevention strategies. Identifying specific needs and practical challenges in the implementation of the safety standards is cornerstone to adjust prevention efforts adequately and efficiently reduce the incidence of radiation injuries.The reporting of radiation overexposure injuries faces unique challenges even when a well-established regulation and a solid reporting system network are in place. Indeed, the latency period before the appearance of radiation-related adverse effects varies from days to years . Thus, pAnother major difficulty rises for radiation overexposure accidents resulting from orphan sources or medical fluoroscopy. In these contexts, the exposed subjects often cannot directly relate their injuries to their radiation exposure as they are not aware that they have been exposed to radiation. Even among medical professionals performing procedures assisted by fluoroscopy, a lack of awareness of risks associated with radiation imaging can still exist , 244], , 244], . AdditioThis review offers a solid basis of reported radiation overexposure accidents to inform radiation protection planning. Still, it has several limitations.Our literature search only included publications written in English and French languages, which might introduce some publication bias. Moreover, our review was limited to sources of information that were publicly available, with the exception of the REAC/TS registry, which has limited public access. Hence, our review does not capture cases that are exclusively reported in private databases . Thus, our review likely underestimates the number of reported radiation accidents. Additionally, when the date of overexposure was not reported (125 cases out of 2390), date of first symptoms was used as first proxy (11 cases) and date of report as second proxy (114 cases). This might introduce some bias as symptoms can appear months or years following the overexposure. Finally, reporting country was also used as a proxy for country of occurrence when not mentioned explicitly .Despite these limitations, this review captured reported radiation accidents in systematic and consistent way, enabling valuable analysis to support future prevention actions.This systematic study updates and broadens the view of reported radiation overexposure accidents. It indicates that reported radiation overexposure accidents are rare and decreased from 1980–1989 to 2000–2009. However, their potential dramatic outcomes stress the importance of radiation protection regulations. This review suggests the greater share of the medical sector in reported overexposures, for which the use of radiation has become central and is expected to grow even more in the future. Thereby, it confirms the importance of quality assurance programs in radiation therapy and medical fluoroscopy.Finally, this review suggests that the characteristics of reported accidents vary by geography and over time, and are thereby likely to require different interventions. A close reporting and monitoring of radiation overexposure accidents is of great value to inform and prioritize prevention interventions adequately and ultimately reducing further the incidence of these accidents.S1 PRISMA Checklist(PDF)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.


Background. Chronic or persistent pain and disability following noncatastrophic “musculoskeletal” (MSK) trauma is a pervasive public health problem. Recent intervention trials have provided little evidence of benefit from several specific treatments for preventing chronic problems. Such findings may appear to argue against formal targeted intervention for MSK traumas. However, these negative findings may reflect a lack of understanding of the causal mechanisms underlying the transition from acute to chronic pain, rendering informed and objective treatment decisions difficult. The Canadian Institutes of Health Research (CIHR) Institute of Musculoskeletal Health and Arthritis (IMHA) has recently identified better understanding of causal mechanisms as one of three priority foci of their most recent strategic plan. Objectives. A 2-day invitation-only active participation workshop was held in March 2015 that included 30 academics, clinicians, and consumers with the purpose of identifying consensus research priorities in the field of trauma-related MSK pain and disability, prediction, and prevention. Methods. Conversations were recorded, explored thematically, and member-checked for accuracy. Results. From the discussions, 13 themes were generated that ranged from a focus on identifying causal mechanisms and models to challenges with funding and patient engagement. Discussion. Novel priorities included the inclusion of consumer groups in research from the early conceptualization and design stages and interdisciplinary longitudinal studies that include evaluation of integrated phenotypes and mechanisms. Millions of musculoskeletal (MSK) injuries occur daily in diverse settings, ranging from those that are highly distressing  to those that are relatively benign . Despite these different contexts, many individuals with injuries classified as “noncatastrophic” or “soft-tissue” type disorders will develop persistent pain or other symptoms that can rarely be attributed to obvious structural lesions on diagnostic imaging . For somMany experts have suggested that the best method to address the epidemic of chronic pain and the high rate of chronicity following acute injury is to identify pathophysiologic mechanisms in the acute stage of injury and intervene accordingly , 7. The The exploration and development of clinical tools and prediction rules have provided an opportunity for clinicians to confidently stratify acutely injured patients by level of risk  –17. Whildeveloping a better understanding of the complex causes and clinical manifestations of chronic pain and fatigue” and “prevention of chronic musculoskeletal, skin, and oral health disorders through the identification and management of common risk factors.” IMHA recognizes that rigorous, collaborative, transdisciplinary research is required to address these foci and that integrating research into practice must be a priority. These strategic directions guided a 2-day interactive CIHR-funded workshop held at Western University in London, Ontario, Canada, in March 2015 with the theme of “developing a stakeholder-driven research and knowledge exchange agenda to improve outcomes of injury-related pain and disability.” This workshop brought together researchers, clinicians, and consumers to develop integrated, transdisciplinary research priorities in this field. The purpose of this paper is to report and thematically describe the outcomes and research priorities generated at that meeting.The Institute of Musculoskeletal Health and Arthritis (IMHA), one of the Canadian Institutes of Health Research (CIHR), recognized this need in its 2014–2018 Strategic Plan that describes three areas of priority: (i) chronic pain and fatigue; (ii) inflammation and tissue repair; and (iii) disability, mobility, and health [N = 25 in attendance and input from 5 additional individuals who were not able to attend in person) were (i) recognized academic experts in the field of trauma-related pain and injury; (ii) experts in fields not traditionally associated with trauma-related pain and disability but that held potential for expanding the breadth of trauma research; or (iii) consumer group opinion leaders. Academic backgrounds of participants included biochemistry, microbiology, proteomics, biomechanics, kinesiology, imaging physics, neurophysiology, neuroimaging, rehabilitation, genomics, pharmacology, psychology, measurement, traumatology, and epidemiology. Knowledge-user representation included physical medicine, emergency medicine, physical therapy, chiropractic, personal injury law, and patient advocacy. Geographic representation was from the Canadian provinces Ontario, Quebec, British Columbia, and Alberta as well as the United States  and Australia .Workshop participants , followed by 45 minutes of small group discussion (4–8 participants each) focused on potential points of convergence emerging from the short talks, integration, and collaboration opportunities and barriers, with a subsequent 25-minute large group discussion to “harvest” key topics identified by the small groups. A professional facilitator with no stake in the outcome ensured that the sessions kept to time were productive and that each participant had an adequate voice. A seventh large group discussion was reserved for identifying emergent themes, short- and long-term priorities, and champions for each priority.The event was sponsored by CIHR, the Orthopedic Division of the Canadian Physiotherapy Association (OD-CPA), the London Orthopedic Unit , Gordon Good Law Offices, the Cluster of Research Excellence in Cognitive Neuroscience at Western University, the Cluster of Research Excellence in Musculoskeletal Health at Western University, the Schulich School of Medicine & Dentistry, and the Faculty of Health Sciences at Western University. With the exception of CIHR, each sponsor had representation at the workshop, but sponsorship did not depend on the outcomes. Participant travel and meals, where required, were paid through the funders and sponsors of this event, as were the professional facilitator, room rental, and a team-building event.Ideas were generated and key conversation points were hand-recorded in each small breakout group. Following completion of the 2-day workshop, all recordings were collected and collated, and a thematic analysis was conducted by two authors following an established protocol . The emeEmergent Themes Arising from Thematic Analysis of Recordings of 2-Day Active Participation Workshop. Consider the following:The complex nature of acute and chronic pain.Cause-and-effect longitudinal modeling rather than correlation.Recovery starting immediately following injury.Biological markers, from broad to focused using novel experimental pain paradigms in humans and animals.Leveraging new technologies to solve old problems.Judicious dissemination: the consumer perspective of new research findings.Broad, population-based longitudinal cohort research starting from the premorbid period.Respecting context.The need for integration and convergence of knowledge and direction across disciplines.Meaningful outcomes.Struggles with patient recruitment and engagement.Public awareness and shifting paradigms.Sources of funding for research in posttrauma pain and disability.(1) The Complex Nature of Acute and Chronic Pain. All participants agreed that reducing the experience of acute or chronic pain to purely anatomical or biomechanical causes was overly simplistic and ineffective. Pain is a multifactor experience, with established models describing biological, psychological, and socioenvironmental influences. Disability, defined here as a limitation in person-specific normal daily functioning, is a separate but related construct that requires alternative modes of exploration. The experience of trauma itself, with or without tissue damage, leads to a cascade of cellular processes that, under ideal conditions, are highly coordinated and interdependent. These include activation of ATP/purinergic signaling, locus coeruleus/norepinephrine pathways, immune signaling, and the hypothalamic-pituitary-adrenal axis among many others. Activity in these pathways is not consistent across individuals and is influenced by genetic and transcriptomic profiles, the microbial environment, nutrition, psychological distress, and the social environment. Despite this complexity, participants were confident that key pathways and processes could be identified and pointed to the human genome (https://www.genome.gov/), proteome (http://www.thehpp.org/), and metabolome (http://www.hmdb.ca/) projects as evidence that complex systems biology can be successfully quantified and understood when the required resources are committed. Suggestions for future priorities included (i) integration of psychological and biomarker quantification within biomechanics research and (ii) genomic, transcriptomic, proteomic, and metabolomic (omics) research that can now be conducted with relatively low burden to the patient .(2) Cause-and-Effect and Longitudinal Modeling rather than Correlation. Risk stratification and identification research is dominated by largely correlational analyses showing an association between a variable collected in the acute stage of injury and outcomes measured 3, 6, or 12 months later. Few, if any, of these associations can be confidently considered truly causative. Certain demographic variables, such as female sex, older age, and lower socioeconomic status (SES), have demonstrated consistent associations with outcome [ cause chronic pain? The participants largely agreed that there are likely independent, overlapping, proxy, mediating, or moderating variables present that have either not been captured in such research or have not been adequately modeled. Understanding the precise mechanisms responsible for identified associations will result in the identification of more meaningful, and potentially modifiable, causes of chronic problems. outcome . However prior to the event. Indeed, in many such cohort studies, inception occurs within some time frame following an injurious event, ranging from hours to 4 weeks or longer [The group was largely in agreement with Bradford-Hill's criteria for cause-and-effect : strengtr longer –27. The (3) Recovery Starts Immediately following Injury. The participants, especially front-line clinicians who routinely receive and stabilize acute patients, appreciated the importance of their treatment in the subsequent genesis of persistent pain or disability. Reactions to trauma, including stress and inflammatory and psychological responses, are immediate and should therefore be included as part of acute posttrauma evaluation. Participants heard that the wording used, behavior demonstrated, and messages delivered by the acute trauma team (including first responders and emergency room staff) “set the stage” for the postinjury trajectory. Participants were sensitive to the effects  of spending hours immobilized on a spinal board while waiting for the clinician, undergoing multiple diagnostic tests, and well-meaning but potentially misinterpreted advice given to a patient at the point of acute care. To this end, the participants identified a priority area around more informed management of acutely injured patients through translatable research and efficient clinical pathways.(4) Biological Markers—from Broad to Focused Using Novel Experimental Pain Paradigms in Humans and Animals. Although “omics” explorations are novel and emerging, the team recognized the need to balance broad association studies with hypothesis-driven research. While genomic approaches have provided some consistent findings in the chronic pain transition literature , thwhiplash  and may (5) Leveraging New Technologies to Solve Old Problems. New and advancing technologies are offering the ability for rigorous data collection with unique contrast and better resolution than previous attempts while minimizing patient burden. Clinical MRI systems at field strengths of 3 T are commonplace in most tertiary centres while the emergence of ultrahigh field MRI at 7 T is becoming available for research investigations and is providing considerably improved resolution and novel contrast for both neuroimaging and MSK applications. Recent reports using novel applications of Magnetization Transfer Ratios (MTR) and Magnetic Resonance Spectroscopy (MRS) have revealed new mechanisms of posttrauma pain, including subclinical spinal tract damage and muscle fatty infiltration [μL sample of saliva [ltration , 32. Nucltration . Mass spf saliva . Hair isf saliva , 36. Thif saliva . These e(6) Judicious Dissemination—The Consumer Perspective of New Research Findings. Well-intentioned and useful new knowledge can lead to problems if not translated and disseminated prudently. The group was reminded that research findings describing primarily psychological causes of chronic pain  can add stigma to a patient population that already struggles for validation. As well, neuroimaging research, which has propelled the field of chronic MSK pain rapidly forward, can negatively affect a patient's sense of self-control and security. Rote reporting of findings such as “reduced cortical thickness” or “advanced brain aging” may implicitly or explicitly attempt to generalize from patients with longstanding severe pain and disability from tertiary care clinics to all patients with pain. Doing so can easily lead to considerable distress in consumer populations if not presented with appropriate interpretation. In this light, the group agreed that consumer participation at all stages of research, from conceptualization through interpretation and dissemination of results, should be an important priority in the field.(7) Broad, Population-Based Longitudinal Cohort Research Starting from the Premorbid Period. The vast majority of prospective research on traumatic pain enrolled patients after the inciting event and, therefore, it is difficult to establish changes in key biological or psychological markers. Participants pointed to the Framingham study [am study  and rela(8) Respecting Context. Injury does not occur in a vacuum; rather, a host of social influences interact with the biological and psychological effects of trauma to create the overall “response to trauma.” Participants identified a research priority around identifying social or contextual influences on the experience of pain and disability after trauma. Examples of such influences include access to and availability of care; the compensation/litigation environment; waiting times to be seen by a healthcare provider; waiting times to see medical specialists; adversarial interactions with the other party in the case of two-party trauma; workplace environment and availability of accommodations; and support from spouses, employers, colleagues, coaches, insurers, health providers, or others. Other more macrolevel influences, including prevailing cultural beliefs about injury outcomes, geographically or culturally influenced nutrition, physical activity, health promotion/prevention practices, and geographically determined weather and accessibility issues, could also influence outcomes. The status of such variables as either direct causative factors or mediators or moderators of other variables in the transition from acute to chronic pain is a particular priority for future studies.(9) The Need for Integration and Convergence of Knowledge and Direction across Disciplines. Research in trauma, pain, and disability is advancing rapidly and in many directions. Several aspects of system function— biological and psychological—are currently being explored, but rarely in the same cohort. Anecdotally, some participants described interactions with large public funding bodies who expressed disinterest in supporting intervention trials for conditions such as acute WAD or oLBP until the mechanisms underlying these conditions and their transition to chronicity are clarified. Therefore, a priority is to actively establish productive transdisciplinary research teams with members from a breadth of academic disciplines. In this way, both basic and clinical research can be conducted simultaneously and in the same patient population, offering the potential to link biological parameters with clinical signs and symptoms. Aligning an entire field of research may not be feasible and risks stifling innovation. On the other hand, having a general field-wide direction with desired outcomes such as improved quality of life or faster symptom resolution would foster cross-fertilization. As well, it would encourage basic scientists to consider the long-term clinical translatability of their findings and clinical scientists to consider potential mechanistic explanations for their clinical observations.(10) Meaningful Outcomes. Acute and chronic pain and disability are nebulous constructs that require valid and meaningful outcomes that can be applied to both research and clinical practice. The IMMPACT group [CT group  has prop(11) Struggles with Patient Recruitment and Engagement. Some workshop participants described the difficulty of enrolling patients with acute MSK injuries into research studies focused on long-term outcomes. It was largely recognized by both academics and patient advocates that many people with chronic pain are intrinsically motivated to participate in studies that may lead to a change in their condition. However, it is inappropriate to assume that those with acute injuries possess the same level of intrinsic motivation or engagement in research. Subject attrition or “loss to follow-up” was also identified as a challenge to successful longitudinal studies. The group recognized the need to “sell” the value of such research to those with acute injuries and that effective strategies for retaining subjects include appropriate compensation and frequent contact [ contact .Treating clinicians, often the first point of contact for injured patients, were identified as either a facilitator or barrier to recruitment. Emergency medicine is correctly and necessarily focused on ensuring that patients are stabilized and out of immediate threat. This busy environment leaves little time for identification and enrollment of potential study participants. However, this environment is also key for setting up smooth recovery; hence these clinicians are important stakeholders in posttrauma rehabilitation and recovery. Engaging clinicians in research design and respecting their time spent recruiting patients for research are additional priorities. assembly in research design. Although not a fatal threat to internal validity, such assembly biases should be recognized in publications arising from such research, which should include the limitations of generalizing the findings between litigating and nonlitigating cohorts.Finally, it was proposed that injured individuals involved in compensation or litigation related to their injuries appear to be less receptive to research participation. Whether this is due to cynicism/skepticism  or the added time and stress of active litigation, this barrier to recruitment represents a potential bias of(12) Public Awareness and Shifting Paradigms. Patient recruitment and engagement may also be linked to cultural beliefs or access to care, both of which may also affect the transition to recovery/chronicity. The group identified that public education campaigns are a valuable priority for addressing this factor and pointed to success of such awareness campaigns in regions like Queensland, Australia [Depression Hurts” campaign, http://www.depressionhurts.ca/), may have value as an intervention strategy. Even before employing such practices for prevention or intervention, workshop participants identified public awareness of the magnitude of the chronic pain problem as a potential tool for facilitating engagement. Print and social media were acknowledged as potential avenues for promotion and publicity as were links with existing advocacy and/or special interest groups such as the Canadian Pain Coalition or Canadian/American Pain Societies that have experience and success in large public education campaigns.ustralia . A well-(13) Sources of Funding for Research in Posttrauma Pain and Disability. It has been reported that public funding for clinical health research, especially in the field of MSK pain, has been stable or decreasing in recent years in Canada [n Canada . In contThis paper reports the results of a 2-day interactive workshop informed by thirty academics, clinicians, and consumer representatives to establish a series of consensus priorities in the field of “soft-tissue”-type acute and chronic MSK trauma-related pain and disability. In total, 13 priority themes emerged that ranged from issues around funding and patient engagement to evaluating cause-and-effect at both the micro- and macrolevels. All participants, regardless of field or discipline, agreed that simple bivariate correlational research in a single domain needed to be phased out in favour of transdisciplinary explanatory modeling using a mix of hypothesis-generating and hypothesis-driven strategies.The concept of molecular and neurobiological studies, from preinjury through to several postinjury periods, was a consistent theme that was endorsed as a highly promising way forward in the search for causal mechanisms. However, such work requires considerable financial and infrastructure resources and, therefore, represents a long-term priority. Consequently, other shorter-term priorities were generated that endorsed the use of animal models or novel experimental pain protocols in humans; these offer the potential for more focused measurement and quantification in a larger prospective study. New and advancing technologies mean that a wide spectrum of genomic, transcriptomic, proteomic, and metabolomic factors through to systems-based neural, endocrine, and biomechanical factors can be captured feasibly in a short period of time using non- or minimally invasive techniques. hypothesis-driven research is appropriate for areas where current evidence is clearly pointing towards specific physiologic systems . In contrast, more hypothesis-generating approaches related to identifying potential mediators/moderators of chronic pain development are appropriate where current evidence is insufficient and/or additional factors and mechanisms are being sought.The contrasting approaches between “fishing” for associations and the need for innovative exploratory research were recognized and discussed. For example, we identified thatRegardless of their current academic or clinical alignments, each participant endorsed research in this field as a high priority. Concern was apparent over rehabilitation funding paradigms for both clinical practice and research that appear to be diminishing based on inconsistent clinical outcomes and a handful of well-designed clinical trials showing little or no effectiveness of active rehabilitation for preventing chronic problems such as WAD , 19. TheThis report represents a summarized, factual description of targeted priorities, generating meeting, and as such limitations to interpretation are largely with respect to the perspectives of the invitees and the authors responsible for thematically summarizing the discussion. It is recognized that not all relevant disciplines could logically be invited; notably there was little or no representation from fields such as occupational health or vocational rehabilitation. This limitation will be addressed at a planned 2-year follow-up meeting to review and revise these initial priorities.The results of this workshop are a transdisciplinary research agenda focused on identifying the cause(s), prevention, diagnosis, prognosis, and cure for chronic pain following injury. Hopefully, this agenda will facilitate the allocation of research resources to areas of high yield and impact. Given IMHA's expressed focus on improving understanding of mechanisms to explain the transition from acute to chronic pain and continued pressures on medical and rehabilitation funding for many MSK injuries, the priorities identified by this workshop appear timely and feasible with recent advances in technology and growing public awareness. Improved outcomes, reduced cost, and decreased burden of chronic pain for the individual and society are goals that we believe all stakeholders can endorse.


The MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communication of such findings.Genome sequencing was performed on the Illumina HiSeq platform. Variants were filtered, interpreted, and validated according to methods developed by the Laboratory for Molecular Medicine and consistent with current professional guidelines. The GeneInsight software suite, which is integrated with the Partners HealthCare electronic health record, was used for variant curation, report drafting, and delivery.We developed a concise 5–6 page Genome Report (GR) featuring a single-page summary of results of potential medical relevance with additional pages containing structured variant, gene, and disease information along with supporting evidence for reported variants and brief descriptions of associated diseases and clinical implications. The GR is formatted to provide a succinct summary of genomic findings, enabling physicians to take appropriate steps for disease diagnosis, prevention, and management in their patients.Our experience highlights important considerations for the reporting of results of potential medical relevance and provides a framework for interpretation and reporting practices in clinical genome sequencing.The online version of this article (doi:10.1186/s12881-014-0134-1) contains supplementary material, which is available to authorized users. Whole exome and genome sequencing, hereafter referred to as genomic sequencing (GS) are rapidly expanding into the clinical arena ,2. As thWhile the expansion of GS into clinical care is promising for the diagnosis and treatment of patients with genetic disorders, and eventually the screening of healthy individuals, GS produces an extensive amount of sequencing data which must be analyzed, filtered, interpreted, and reported upon by the clinical laboratory. In contrast to traditional genetic tests which typically report back a limited set of variants conditioned on prior clinical or family data and with relatively clearly defined supporting evidence, clinical reports resulting from GS analyses contain many variants each with disparate supporting evidence associated with a broad range of diseases, and a wide set of pretest probabilities. Physicians receiving GS reports must digest this complex information and determine the relevant inferences for the care of their patient. This requires a nuanced understanding of the underlying rationale for GS, technical aspects of the testing and its primary interpretation, and knowledge of how to define (or refine) the probabilistic nature of the genotype in the context of the individual patient or family. In many instances, this understanding is also dependent on mechanistic insight into the relevant human biology. Unfortunately, many physicians in non-genetic specialties lack fundamental genetic knowledge and are uncomfortable interpreting genetic test results, which may result in misinterpretation and inaccurate patient counseling -10. SimiIn order to facilitate the communication of results of potential medical relevance to a broad range of physicians, laboratories must decide upon the level of evidence required for variants to be returned on the report. Some laboratories may choose to report all classified variants, even variants of uncertain significance with little evidence supporting pathogenicity, resulting in massive reports. In this situation, physicians may be overwhelmed by lengthy reports and experience difficulty identifying which variants are most important with respect to the care of their patient. In contrast, laboratories may restrict reports to pathogenic variants with a definitive association with disease and a narrow definition of actionability. However few variants meet this level of evidence and this approach risks the omission of many variants whose relevance is dependent on the clinical context. Indeed, some variants may turn out to be clinically relevant as further clinical data are gathered. Thus, an intermediate approach may be required to facilitate the communication of results of potential medical relevance to a broad range of physicians. Moreover, it will be vital to communicate the requisite information on potential disease or risk associations for each reported variant to allow physicians to interpret GS test results in the relevant clinical context, to orchestrate additional phenotyping, or to refer the patient to an appropriate specialist.To promote the understanding and utility of GS data, we have developed a Genome Report (GR) for the return of findings of potential medical relevance for individuals participating in the MedSeq Project, a randomized clinical trial assessing the impact of GS in two patient populations — healthy primary care patients and patients with cardiomyopathy of suspected genetic etiology. The GR is a concise 5–6 page genome-scale report featuring a succinct front page summary of findings of potential medical relevance with additional pages containing structured variant, gene, and disease information as well as supporting evidence and disease and health impact summaries.The MedSeq Project is a randomized clinical trial that is testing approaches for evaluating and reporting of GS data and assessing the impact of integrating GS into primary care and cardiology settings. To achieve these goals, the MedSeq Project is recruiting 10 primary care physicians, each with 10 of their generally healthy patients and 10 cardiologists, each with 10 of their cardiomyopathy patients, for total of 200 participants. Half of the participants are being randomized to the GS arm. The physicians of each patient enrolled in the GS arm receive a GR communicating genetic findings of potential medical relevance. Interviews and survey instruments for both physicians and patients are being used to determine the impact of GS on attitudes, behaviors, healthcare utilization, and decision-making. A detailed report of the goals, protocol, and methods in the MedSeq Project is summarized elsewhere .GS is performed by the CLIA-certified, CAP-accredited Illumina Clinical Services Laboratory  using paired-end 100 base pair reads on the Illumina HiSeq platform . Genomeshttp://evs.gs.washington.edu/EVS/) classified as disease causing (DM) or possible disease causing mutations (DM?) in the Human Gene Mutation Database [http://www.iccg.org/iccg-member-toolbox/databases-tools/medial-exome-gene-list) and (3) pharmacogenomic variants for metformin (C11orf65 rs11212617), clopidogrel , warfarin , simvastatin (SLCO1B1 rs4149056), and digoxin (ABCB1 rs1045642) metabolism. The disease-associated gene list is iteratively refined as gene-disease association information is curated. In addition, blood group antigens are predicted through a parallel pipeline as noted below.Lossless BAM files are converted to FASTQ format to obtain sequence read data and reads are realigned to the NCBI reference sequence (GRCh37) using the Burrows-Wheeler Aligner 0.6.1-r104 . VariantDatabase  or as PaSeveral variants required deliberation by MedSeq Project team members  in order to assign a final classification. The LMM uses a five tier classification system which includes the following classifications: benign, likely benign, uncertain significance, likely pathogenic, and pathogenic. In addition, a subset of uncertain significance variants are further subclassified into “uncertain significance: favor benign” or “uncertain significance: favor pathogenic”. With the exception of pharmacogenomic alleles and blood group antigens, only those variants with substantial evidence for causing or contributing to Mendelian genetic disease are reported. This includes all pathogenic, likely pathogenic, and uncertain significance: favor pathogenic variants. All reported disease-associated variants are confirmed via Sanger sequencing before reporting. Variants are fully reassessed when identified in a new case and the last assessment was completed over 1 year ago for pathogenic variants or over 6 months ago for likely pathogenic variants and variants of uncertain significance. Likely benign and benign variants are not fully reassessed unless requested by a clinician. However, all variants in the categories of likely pathogenic, uncertain significance, and likely benign are briefly reevaluated before each reporting through a quick search of online variant databases  to ensure no new data has been reported.The principles we follow for the classification of potential Mendelian disease-causing variants have been previously described  and invoA set of 18 variants associated with the metabolism of 5 drugs (see above) commonly used in the treatment of primary care and cardiology patients were selected for inclusion in the GR from PharmGKB Clinical Annotation Levels of Evidence Class I and Class II variants  and confRed blood cell (RBC) and human platelet antigens (HPAs) are predicted using GS data. For all 45 RBC and 6 HPA genes, GATK is used to genotype each exon along with the first and last 10 bases of each intron. A custom prediction algorithm is then used to semi-automatically predict RBC and platelet antigens, followed by manual verification in the BAM alignment files for all antigens listed on the GR .Variant information, including classifications, interpretations, and associated references are stored in an internal laboratory knowledge base using the GeneInsight software suite . ApproveThe GR presented herein was developed by a team of MedSeq Project investigators including physicians from genetic and non-genetic specialties, genetic counselors, molecular geneticists, and bioinformaticians. Prior to implementation with physicians and patients, the GR was evaluated by a multi-disciplinary advisory committee also consisting of physicians from genetic and non-genetic specialties, genetic counselors, molecular geneticists, bioinformaticians, bioethicists, patient advocates, and biotechnology industry leaders. Revised versions of the GR were subsequently reviewed with primary care physicians who were considering participation in MedSeq Project and underwent further changes intended to maximize clarity and utility  , we haveA total of 381 unique variants were manually assessed and classified for the first 20 MedSeq Project cases . After assessment, 168 (44%) of these variants were classified as benign or likely benign, 168 (44%) were classified as uncertain significance (including 5 classified as uncertain significance: favor pathogenic), and 45 (12%) were classified as likely pathogenic or pathogenic  were confirmed, 1 (1%) was confirmed but with differing zygosity, and 11 (14%) were determined to be false positive. All false positive variants were either indels with low genotyping quality scores, or variants residing next to repetitive polynucleotide stretches. After final deliberation by the MedSeq Project team, 48/69 (69%) of the unique Sanger-confirmed variants were returned to the first 20 MedSeq Project participants (Table WFS1) gene, may exhibit low frequency sensorineural hearing loss and/or diabetes mellitus [In order to communicate findings of potential medical relevance to MedSeq Project physicians, we developed a GR designed to convey complex genomic data in a succinct and effective manner to the non-genetic specialist physician Figure . The firmellitus -28. A suDue to the vast array of diseases, genes, and variant types that could be returned from GS, we sought to balance the need for a high level summary that enables quick viewing, with the importance of providing sufficient detail and evidence to support reported results. Therefore, we expand upon the single page GR summary with a detailed variant information section featuring structured tables with RefSeq transcript, variant frequency, disease prevalence, and if applicable, carrier frequency , GeneReviews, PubMed, and disease-specific resources. Future iterations may include the addition of ancestry information and common disease risk alleles. In addition, the scope of genome analysis for each patient may evolve as an individual patient’s medical history and clinical situation develop. For example, additional pharmacogenomic results may be added and reinterpretation of genome data may be warranted if new symptoms arise or previously unappreciated familial risk is uncovered.In the current genetic testing paradigm, clinical laboratories provide physicians with genetic results and physicians are in turn responsible for incorporating these results into care plans for their patients. One of the greatest barriers to integrating GS into clinical care is the limited amount of objective data regarding the best course of action for almost any genetic finding in the context of sequence from an entire genome. Physicians may grapple with ordering additional diagnostic tests for their patients to uncover potential disease-related phenotypes, and whether additional family members should be evaluated . While tIn order to advance the incorporation of GS data into clinical care, we have created a concise clinical GR that outlines findings of potential medical relevance, enabling physicians to counsel patients regarding the health and reproductive implications of their genome sequences. Our experience highlights important considerations in the reporting of findings of potential medical relevance and provides a framework for evolving interpretation and reporting practices in clinical GS.


Health-related quality of life (HRQOL) is an important predictor of morbidity and mortality; however, its geographical variation in older adults in the United States has not been characterized. We compared HRQOL among older adults in the 50 US states and the District of Columbia using the Health and Activities Limitation Index (HALex). We also compared the HRQOL of 4 regions: South, West, Midwest, and Northeast.We analyzed pooled data from 1997 through 2010 from the National Health Interview Survey for participants aged 65 or older. HALex scores  were calculated by combining data on participants’ perceived health and activity limitations. We ranked states by mean HALex score and performed multivariable logistic regression analyses to compare low scores (defined as scores in the lowest quintile) among US regions after adjustment for sociodemographics, health behaviors, and survey design.Older residents of Alaska, Alabama, Arkansas, Mississippi, and West Virginia had the lowest mean HALex scores ; residents of Arizona, Delaware, Nevada, New Hampshire, and Vermont had the highest mean scores . Residents in the Northeast  and the Midwest  were less likely than residents in the South to have scores in the lowest quintile after adjustment for sociodemographics, health behaviors, and survey design.Significant regional differences exist in HRQOL of older Americans. Future research could provide policy makers with information on improving HRQOL of older Americans. Healthy People 2020  is predictive of mortality in older adults , and it ple 2020 , and an ple 2020 ,5 and obple 2020 ,7 has beStudies show a regional variation in the health behaviors of older adults. For example, 1 study found state variations in smoking, drinking, and physical activity levels among older adults . A studyWe pooled data from 1997 through 2010 from the National Health Interview Survey (NHIS), an annual multistage probability household survey of the US civilian noninstitutionalized population. We included participants aged 65 or older . HALex scores were calculated according to methods described by Livingston and Ko ; scores We ranked states by calculated mean HALex score and sorted states by mean score. We used multivariable logistic regression to compare low HALex scores (defined as scores in the lowest quintile) among US regions ; we used the South as the reference group. States were assigned to regions according to the 2010 US Census classification  Figure)Figure). The mean HALex score for older US adults was 0.735  to 0.79 (Delaware), the former score representing on average an inability to perform a major activity (such as an activity of daily living) and the latter representing a partial limitation in a nonessential activity . Older aThe pattern of low HALex scores in the South and higher scores in other regions is not totally consistent. For example, Delaware (included as a southern state in this study) ranked the highest of all states, and Florida ranked 14th, far above all other southern states. In other studies, Florida showed evidence of not being similar to other southern states — older residents of Florida have a higher life expectancy , a lowerAmong the potential explanations for the inconsistent rankings of Delaware and Alaska is the HALex calculation. The index includes measures of functional limitations, and therefore it depends on the individual’s physical limitations as well as the individual’s access to transportation, services, and assistive devices. HALex tends to give more biased  measures for people with disabilities than some other HRQOL scores ,27. A stOur state rankings differed from a previous Behavioral Risk Factor Surveillance System (BRFSS)–based study of the general adult population , especiaSignificant regional variation exists in the HRQOL of older individuals in the United States. Measures aimed at improving the HRQOL of older adults are warranted in southern states and in Alaska.


This study examines the associations between lifecourse adversity and physical performance in old age in different societies of North and South America and Europe.We used data from the baseline survey of the International Study of Mobility in Aging, conducted in: Kingston (Canada), Saint-Hyacinthe (Canada), Natal (Brazil), Manizales (Colombia) and Tirana (Albania). The study population was composed of community dwelling people between 65 and 74 years of age, recruiting 200 men and 200 women at each site. Physical Performance was assessed with the Short Physical Performance Battery (SPPB). Economic and social adversity was estimated from childhood adverse events, low education, semi-skilled occupations during adulthood and living alone and insufficient income in old age.A total of 1995 people were assessed. Low physical performance was associated with childhood social and economic adversity, semi-skilled occupations, living alone and insufficient income. Physical performance was lower in participants living in Colombia, Brazil and Albania than in Canada counterparts, despite adjustment for lifecourse adversity, age and sex.We show evidence of the early origins of social and economic inequalities in physical performance during old age in distinct populations and for the independent and cumulative disadvantage of low socioeconomic status during adulthood and poverty and living alone in later life. Knowledge of lifecourse conditions and aging across diverse societies is needed to promote healthy aging Birnie et al reported that the associations of childhood socioeconomic position (SEP) with physical performance were maintained after adjustment by adult SEP, suggesting that the accumulation of adverse exposures over a lifetime may be a better model of the associations than one which considers only adult factors and concluded that the associations of childhood socioeconomic position with physical capability vary by study context including geographical location and birth period, whereby SEP in early life may play a more important role in some contexts than others After reviewing nineteen studies, Studies conducted in European countries, United States, United Kingdom, South America and Korea have focused on social economic position (SEP) to examine associations between lifecourse adversities with physical health outcomes in later life Our research uses baseline data from the International Mobility in Aging Study (IMIAS) to examine associations between lifecourse conditions and physical function in old age in five cities with very different socioeconomic contexts and cultural norms.The IMIAS is a multicenter and multidisciplinary project, conducted in: Natal (Brazil), Manizales (Colombia), Tirana (Albania), Saint-Hyacinthe  and Kingston . These population differ widely in living conditions and health outcomes, therefore provides an opportunity to examine the associations of life course in old age at different settings.Natal is a coastal and flat city of 817,590 inhabitants in Northeast Brazil. Manizales is in the coffee-growing zone of the Colombia Andes, with steep terrain . Tirana (Albania), in a central valley, has approximately 700,000 inhabitants. Saint-Hyacinthe is a francophone city , near Montreal, Quebec. Kingston is predominantly Anglophone  and in the province of Ontario. The socioeconomic and cultural characteristics of these cities differ substantially although each is relatively homogeneous, and their elderly populations have resided locally for all or most of their lives.These sites show considerable variation on the Human Development Index (HDI) and the Gender Inequality Index (GII), published in 2013 by the United Nation Development Program The IMIAS study provides an important chance to investigate the life course influence on health and function in old people, because it investigates five distinct societies. We aim to identify whether social and economic adversity in early life and during adulthood and old age predict poor physical function in older populations analyzing diverse populations with different social, economic and cultural conditions.Our research asks whether, among older adults aged 65–74: 1) Does childhood adversity predicts physical performance? 2) Does adulthood adversity predicts physical performance, independent of childhood adversity? 3) Does adversity in old age predicts physical performance independent of earlier adversities in life? This evidence will deepen knowledge on the nature of lifecourse effects on physical function in old age.All of the IMIAS participants gave written informed consent and the study was approved by the ethics committee of each site.Cross-sectional epidemiological study using baseline data from the IMIAS  project, a population-based prospective cohort study was collected in five sites: Natal (Brazil), Manizales (Colombia), Tirana (Albania), Saint-Hyacinthe  and Kingston .The study population was composed of community-dwelling men and women aged between 65 to 74 years. Stratification by sex occurred at the enrollment stage with the aim of recruiting 200 men and 200 women at each site.Participants were recruited in 2012 through neighborhood primary care center registers in Tirana, Manizales and Natal. At these sites a random sample of older, community-dwelling adults registered at the neighborhood health center was selected and participants were visited in their homes by our interviewers to invite them to participate. In Kingston and Saint-Hyacinthe, potential participants received a letter from their primary care physicians inviting them to contact our field coordinator. Two different recruitment methods were needed because of Canadian ethics requirements that precluded direct contact with potential participants.Participants who made 4 or more errors in the orientation scale of the Leganes Cognitive Test (LCT), a screening test for dementia in populations with little education, were excluded Data collection used assessment tools with known validity among international aging populations. Physical performance tests were conducted at the interview site  everywhere except Manizales, where tests were done at the hospital. Interviewer training was standardized following instructions contained in the IMIAS manual (available upon request). Piloting occurred at each site to estimate response rates and establish logistics of interviews, exams, and blood and saliva collection. A more detailed description of research sites and procedures has been submitted for publication.Short Physical Performance Battery (SPPB) is a timed test to assess impairment in gait, balance and muscular strength Childhood adversity was measured via the following questions on events occurring during the first fifteen years of life: death of parents, abuse of alcohol or drugs by either parent, parental divorce, witnessing physical violence in the family, having been physically abused, low economic status, having been hungry, parent unemployment Adversity in adulthood was indicated by less than secondary education (compared to secondary or post secondary education) and semi-skilled occupation . The nature of longest held occupation was measured with open questions and recoded according to the International Standard Classification of Occupations in 10 major groups then further classified into three groups: 1. Non manual; 2. Skilled manual: machine operators and assemblers and crafts and related trades; 3. Semi-skilled manual: farm work, services, elementary occupations or housewife.Adversity in old age was indicated by insufficiency of monthly income for basic needs (compared to very sufficient and sufficient income) and living alone .Potential confounders considered were: age, sex, research site.2) test to identify a possible association between life course adversity and low physical performance (SPPB<8). Using ANOVA, means of SPPB were compared across indicators of life course adversity.Data were analyzed using SPSS  20.0. Bivariate analyses were as performed via Pearson’s chi square  was greatest in Natal . Using cAs hypothesized, greater childhood social and economic adversity was associated with low physical performance (p<0.001). Adulthood and old age adversity showed similar associations (p<0.001).Multivariate models were fitted according to exposure to adversity in childhood, adulthood and old age. Three models addressed our research questions and all controlled for sex, age and site , 4, 5. TThe second to fifth columns , 4 and 5In the meta-analyses, comparing subjects who had experienced childhood social adversity in childhood with those that had not, and adjusting for childhood economic adversity, age and sex, the pooled odds ratio was OR = 2.02 ; the corresponding figures for childhood economic adversity were OR = 1.43 . The overall association of low education with low SPPB, adjusting for childhood disadvantage, age and sex was not significant OR = 1.25 . The overall association of manual occupation with low SPPB was not significant OR = 1.37 . Lastly, income insufficiency had an overall effect of OR = 1.55  and living alone or with other than the spouse had an overall OR = 1.59 . See Figure S1 to Figure S6 in We explored whether low physical performance in old age is related to exposure to social and economic adversity during the lifecourse and how that relationship varies across societies. Although SES in early life has been previously associated with adverse health and functional outcomes in later life, including poor physical performance Both childhood social and economic adversity independently predicted lower physical performance decades later. Previous research has shown that economic disadvantage in childhood is associated with a range of adverse outcomes in adulthood, often independent of adulthood socioeconomic status Both income and education have been studied extensively in the literature on health inequalities in older populations. Occupation is often the most common SES measure used as the basis for social class comparisons in studies conducted in the United Kingdom In our study, semi-skilled occupations and insufficient income were associated with poor physical performance independent of childhood adversity and after adjustment for sex, age and site. However, education was not independently associated with physical performance, suggesting that occupation and income are the stronger socioeconomic determinants of function in the studied populations. An alternative explanation could be that education categories were too wide to assess whether differences exist. The vast majority of Latin American participants had less than secondary education, and this category includes those that are illiterate, who have completed primary school and those having initiated secondary school. These wide categories are appropriate for cross-country analyses; however we acknowledge their SES meaning is not equivalent across sites.Living alone was an independent risk factor for low physical function among our populations. Living alone may be a proxy for weak social networks and it is widely accepted that social networks protect for physical function in old age Independent of lifecourse adversities, there were specific effects of the research site and sex on functional outcomes in old age, which reflect differences in conditions of aging between countries with high socioeconomic inequalities or a former communist economy, in health and social protection systems, in human development and in gender equality. More international research on conditions for active aging is needed to better understand these specific gender and site effects. Several studies on lifecourse adversity and physical function in old age have been conducted in Europe, USA, UK, South America and Korea Nevertheless, there are some potential sources of bias and lack of precision. Recruitment procedures in Canada were indirect, as required by ethics review boards, with a response rate of 30% of the original target sample. A comparison of the study samples with the 2006 Canadian census shows that the percentages of the population with college education in the 65 to 74 age group were 55% (Kingston) and 46% (Saint-Hyacinthe). Thus, participants in our Kingston cohort have higher education than the reference population surveyed in the 2006 census, whereas differences were smaller in Saint-Hyacinthe. This suggests that our findings regarding physical function and adversity in Kingston may give an overoptimistic view of the reality of older adults living in Kingston.As mentioned before, life expectancy at birth for a cohort born in 1950–1954 varied across sites, suggesting that those surviving to age 65 and able to participate in IMIAS in Natal, Manizales and Tirana belong to the fittest of their birth cohorts. Differential survival might arise from variation in childhood adversity and may produce an underestimate of the effect of social and economic adversity on physical function in these sites. This mortality selection may explain the attenuated associations between social and economic adversity and low physical performance in the non-Canadian study sites. In addition, under-reporting of adversity exposure may be more frequent in non-Canadian sites where poverty and violence are more widespread and tolerated. This argument is supported by our finding of similar frequencies in reporting hunger and violence across research sites.Confidence intervals for the odds ratio estimated in site-specific analyses are sometimes wide leading to imprecision. Sample size at each research site (n = 400) may be insufficient to test associations in models with a large number of co-variables. Lastly, 25 people from Manizales had missing SPPB scores and were, therefore, excluded from analyses, however, the difference in self-reported mobility between those 25 people and the remainder of the Manizales sample was not significant.Despite these limitations, meta-analysis results show consistency of associations across societies, although there is some heterogeneity that could be related to stronger relationships in Canadian sites due to the differential survival of those subject to early adversity and particularly to their lower survival in the Latin American contexts.This study confirms the independent and cumulative associations of lifecourse adversity at each stage of the lifecourse with physical function in older adults. We provide new evidence for the independent effects of childhood experiences of conflict and violence, beyond the already known effects of childhood poverty, on physical function in old age across several distinct populations. This research supports the increasing body of literature showing that early social and economic inequalities continue to do harm years later and also, the cumulative disadvantage in physical function among those exposed to social and economic adversity in adulthood and old age. Promotion of healthy aging requires considering policies and practices that increase social and economic wellbeing for children and youth as well as adults, as early adversity has an ongoing and negative effect well into old age.File S1This file contains Figures S1–S6. Figure S1, Odds ratio for childhood social adversity adjusting for childhood economic adversity, age and sex. Figure S2, Odds ratio for childhood economic adversity adjusting for childhood social adversity, age and sex. Figure S3, Odds ratio for income adjusting for childhood adversity, education, living arrangement, age and sex. Figure S4, Odds ratio for living alone or with someone other than the spouse, adjusting for childhood adversity, education, insufficient income, age and sex. Figure S5, Odds ratio for secondary education adjusting for childhood adversity, age and sex. Figure S6, Odds ratio for manual occupation adjusting for childhood adversity, education, age and sex.(DOCX)Click here for additional data file.


Hydraulic fracturing technologies, developed over the last 65 years, have only recently been combined with horizontal drilling to unlock oil and gas reserves previously deemed inaccessible. Although these technologies have dramatically increased domestic oil and natural gas production, they have also raised concerns for the potential contamination of local water supplies with the approximately 1,000 chemicals that are used throughout the process, including many known or suspected endocrine-disrupting chemicals.We discuss the need for an endocrine component to health assessments for drilling-dense regions in the context of hormonal and antihormonal activities for chemicals used.a) surface and groundwater contamination by oil and gas extraction operations, and b) potential human exposure, particularly in the context of the total hormonal and antihormonal activities present in surface and groundwater from natural and anthropogenic sources; we also discuss initial analytical results and critical knowledge gaps.We discuss the literature on In light of the potential for environmental release of oil and gas chemicals that can disrupt hormone receptor systems, we recommend methods for assessing complex hormonally active environmental mixtures.We describe a need for an endocrine-centric component for overall health assessments and provide information supporting the idea that using such a component will help explain reported adverse health trends as well as help develop recommendations for environmental impact assessments and monitoring programs.http://dx.doi.org/10.1289/ehp.1409535Kassotis CD, Tillitt DE, Lin CH, McElroy JA, Nagel SC. 2016. Endocrine-disrupting chemicals and oil and natural gas operations: potential environmental contamination and recommendations to assess complex environmental mixtures. Environ Health Perspect 124:256–264;  A novel source of human and animal exposure to endocrine-disrupting chemicals (EDCs) is through their use in oil and gas drilling operations. EDCs are exogenous compounds that can disrupt both development and normal hormone action either directly, by interacting with hormone receptors as agonists/antagonists, or indirectly by, for example, altering endogenous hormone concentrations, delivery to receptors, modulation of endogenous hormone responses, enzyme activities, or other mechanisms . ImportaIn hydraulic fracturing, millions of gallons of water, tens of thousands of gallons of chemicals, and millions of kilograms of suspended solids are injected into the ground under high pressure. Hydraulic fracturing serves to fracture the shale or coal bed layer and release trapped natural gas or oil, allowing for increased well production. Although hydraulic fracturing technologies have been developed over the last 65 years, they have only recently been combined with horizontal drilling to unlock vast new oil and gas reserves around the world that were previously deemed either inaccessible or unprofitable . ChemicaFollowing the initial injection into the well to generate fractures, a portion of the injected volume returns to the surface immediately; this fluid is known as “flow-back.” The remaining fluids either permeate the shale or coal bed formation and/or return to the surface over the life of the producing well; this fluid is known as “produced water.” Both types of wastewater can contain fracturing fluids, naturally occurring salts, radioactive materials, heavy metals, and other chemicals from the shale formation such as polycyclic aromatic hydrocarbons, alkenes, alkanes, and other volatile and semi-volatile organic compounds . WastewaWater. Oil and natural gas operations can lead to the contamination of surface and groundwater, both of which are sources of drinking water , and it has been estimated that 50% of surface spills contaminate groundwater on the basis of data from Weld County, Colorado . An analWastewater is commonly sent to wastewater treatment plants in many regions  that areGroundwater contamination associated with oil and gas operations has also been reported . This coAir. Oil and natural gas production processes also contribute contaminants to the air, creating another potential route of exposure for humans and animals  or inhibition of positive control–induced expression (antagonist). We found 1 estrogen receptor agonist, 11 estrogen receptor antagonists, and 10 androgen receptor antagonists; several chemicals exhibited multiple receptor activities  numbers . ImportaEDC activity in water near oil and natural gas operations. We assessed the estrogen and androgen receptor activities of water samples collected from five sites in a drilling-dense region of Garfield County, Colorado, that had experienced industry-related spills or preventable discharges relative to surface and groundwater collected immediately outside of the drilling-dense region , with total dissolved organic carbon as high as 5.5 g/L, and many individual compounds present at > 500 mg/L and up to grams per liter concentrations (http://www.fracfocus.org/), and reported benzene ≤ 4.1% and naphthalene and ethylbenzene ≤ 0.45% of total fracturing fluid volume, resulting in milligrams per liter concentrations for these and other chemicals  has published two studies for the oil and natural gas extraction industry: one about work crew exposures to respirable crystalline silica, and the other about work crew exposures to VOCs .erations , is assoAdverse pregnancy outcomes.Cancer. In a health impact assessment, Limitations and data gaps. Limitations of the above-mentioned studies are the lack of both direct exposure assessment and information on residential mobility of study participants. To date, no longitudinal study has enrolled a cohort of residents in a community that has an active oil and natural gas extraction industry so that biomarkers can be obtained in a timely manner. Known and suspected risk factors need to be collected to fully model the exposure risk. The critical route/timing of exposure for hazardous chemicals associated with oil and natural gas operations has yet to be established. Drilling wells release different amounts of air pollutants at different stages of the development and production processes  integrate endocrine-centric end points into human health assessments in areas of unconventional drilling operations; b) perform biomonitoring studies for chemicals and their metabolites in humans; c) develop an effect-directed screening approach to assess endocrine-related effects of mixtures; d) perform controlled laboratory animal studies of exposure to complex mixtures of oil and natural gas chemicals to assess adverse health outcomes; and e) perform in vitro bioassays to assess receptor interactions with complex mixtures.Based on the hypothesis that exposure to oil and natural gas chemicals contributes to negative health outcomes, we offer the following recommendations to evaluate the risks posed to humans and wildlife: a) reproductive effects , b) developmental irregularities , and c) cancer, particularly hormone-responsive types such as testicular, breast, prostate, and brain cancers . One of the major limitations in human risk assessment of oil and natural gas operations is the paucity of chemical exposure information, considering the number of chemicals used and the proprietary disclosure rules. Until now, most research has focused on airborne emissions  for chemical fractionation and testing. These procedures should include orthogonal separations and screening of the resulting fractions in bioassays to refine and isolate bioactive chemicals. Refined fractions can then be analyzed using the mass spectrometry (MS) tools described below and recently reported  to help EDC-centric laboratory animal health assessments. Laboratory animal models can and should be used to test for causal relationships between exposure and negative health outcomes that might be expected in drilling-dense regions. Humans and wildlife living in these regions are likely exposed to oil and gas operation chemicals during different developmental windows, and known critical periods such as prenatal, perinatal, childhood, and puberty should be targeted. Studies of adult exposure should also be performed to assess occupational exposure and chronic exposure at environmentally relevant levels encountered by nearby residents. We further recommend that the route of exposure remain as relevant as possible. Likely exposure to chemicals may occur through oral, dermal, and/or inhalation routes, and parameters such as volatility and partition coefficients will help determine which exposure routes are of the highest concern for individual chemicals. Route of exposure is crucial to understanding health effects because varying routes of exposure can result in very different bioavailability of EDCs, as has recently been described for bisphenol A . Adversein vivo can often be the result of disruption of several hormone receptor systems by single chemicals or by mixtures. Statistical modeling , reproduction/infertility, metabolic diseases, and developmental abnormalities, suggest that EDC exposures account for an estimated 1.8% to 40% of societal health care costs . More reHerein, we have provided a series of recommendations that will allow scientifically defensible, accurate assessments of the potential endocrine-related risks from chemical exposure associated with oil and natural gas operations. We present these recommendations in light of the growing body of information regarding both chemical concentrations in the environment and adverse health outcomes reported in humans and in wildlife. We suggest that these approaches will lead to improved information for resource management decisions and will ultimately protect and improve human health.