Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios.We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias.TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects .TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient’s care, while reducing the potential for bias.When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias.ISRCTN85757829. Registered 26 July 2012.TRIGGER: ISRCTN47845793. Registered 28 May 2012.TAPPS:  The main goal of a randomised controlled trial (RCT) is to ensure that, apart from the intervention, there are no systematic differences between treatment groups under study, thereby ensuring an unbiased estimate of treatment effect. However, randomisation alone does not preclude the possibility of systematic differences. If patients, clinicians, or assessors are aware of treatment assignments, this may influence reporting or measurement of the outcome and introduce bias . For exaIt is therefore recommended that trials be blinded (or masked) as far as possible to limit bias , 3. HoweFor objective outcomes, such as all-cause mortality, unblinded assessment is unlikely to bias the trial results . HoweverDeveloping methods to reduce bias when blinding is not possible has recently been identified as a research priority following a Delphi process involving all UK registered clinical trials units . This arThe goal of blinded outcome assessment is to ensure that bias is not introduced due to knowledge of the patient’s treatment group. However, blinded outcome assessment alone is not sufficient to prevent bias; it is also necessary to ensure that the information upon which the assessment is based is not subject to bias.For example, consider a trial where a blinded adjudication committee determines whether an adverse event has occurred based on a description of the event prepared by an unblinded researcher. Knowledge of the patient’s treatment arm may influence how the event summary was prepared by the researcher , which could in turn affect the assessment of the adjudication committee.Therefore, prevention of outcome assessment bias requires two components. The first is that those making the assessment are blinded to which treatment arm the patient is in. The second is that the information upon which the assessment is made cannot have been influenced by knowledge of the treatment assignment.Two common methods of blinded outcome assessment are to have a blinded clinician directly assess the patient to determine the outcome, or to have a blinded adjudication committee assess the outcome based on information provided about the patient. We discuss some scenarios below where these methods of blinded assessment may be difficult or impossible to achieve.Blinded assessment may not be feasible in trials where all clinicians or researchers in a centre are aware of treatment assignment by necessity . In some trials, it may be logistically impossible to ensure a blinded clinician is always available to assess the patient; this is a particular issue when the timings of assessment occur randomly, for example if patients need to be assessed when symptoms occur, rather than at fixed time points.The use of a blinded adjudication committee may be impractical when the relevant information is not available to send to the committee, or when the information provided to the committee may have been influenced by knowledge of the treatment allocation. For example, a photo or a video may be required for the committee to make an informed assessment; however, the technology may not be routinely available for this. In other cases, the committee may require a narrative of the event or symptoms for their assessment. However, if it is only feasible for an unblinded person to prepare this narrative, this could introduce bias despite the use of a blinded adjudication committee.Some outcomes may be subject to bias due to lack of blinding, but are not formally assessed (making it impossible for a blinded adjudication committee to eliminate bias). An example of this type of outcome is whether a patient received ancillary interventions or supplemental care (that is a co-intervention) during the follow-up period . This ouTRIGGER was conducted according to the declaration of Helsinki, and received ethical approval from the Scotland A Research Ethics Committee (Reference 12/SS/0023) and the NRES Committee South Central - Oxford C (Reference 12/SC/0062). Consent was obtained for data collection on all enrolled patients.TAPPS was conducted according to the declaration of Helsinki, and received ethical approval from the NRES Committee North West - Preston (Reference 12/NW/0467). All patients provided consent to take part in the trial.Using two recent UK multi-centred trials as examples, we highlight the methods that were used to reduce the potential for bias where blinded outcome assessment was not feasible.TRIGGER  was a cluster randomised feasibility trial comparing two different red blood cell transfusion policies  in patients presenting to emergency departments in UK hospitals with acute upper gastrointestinal bleeding (AUGIB) , 17. AUGDue to the nature of the intervention (administering a blood transfusion), and the fact that the intervention was implemented hospital wide, it was necessary for all clinicians and study personnel in a centre to be aware of the randomised transfusion policy. The primary clinical outcome was further bleeding up to 28 days from presentation.A direct assessment by a blinded clinician was not feasible for TRIGGER, as all clinicians in a hospital were aware of the allocated treatment and so would be unsuitable. Asking clinicians from another hospital to assess outcomes would have been unrealistic, as further bleeding requires assessment when it is suspected. As this could happen at any time, it would be logistically impossible for a clinician from another hospital to always be available to assess patients.Using a blinded adjudication committee to determine the presence of further bleeding was also not feasible. Whilst it is possible to take photos of the bleeding lesion during an endoscopy , this facility is not always routinely available, particularly when procedures are performed ‘out of hours’ in an emergency setting, which is likely to occur frequently for a condition like AUGIB. Therefore, the adjudication committee would need to base their decision on a composite of clinical parameters  which may be a poor surrogate marker of further bleeding, or from a review of case notes or descriptive information prepared by an unblinded clinician, in which case the advantages of a blinded assessor are lost.Because blinded assessment is not feasible, further bleeding was determined by an unblinded clinician. In order to limit the potential for bias due to unblinded assessment, the clinically accepted definition of further bleeding was modified to ensure it was as objective as possible, thus reducing the potential impact of unblinded assessment.Further bleeding was defined as either ongoing bleeding at the end of the first endoscopy, or bleeding that restarted after initially stopping. Unlike in standard practice, where further bleeding is often defined purely on the basis of surrogate markers including a combination of patient symptoms  and clinical parameters  count), assessment of bleeding in TRIGGER was via inspection of the patient’s upper gastrointestinal tract to determine whether there was an active bleed; this must have been performed using endoscopy, surgery, or radiology. The outcome assessment was therefore based simply on the presence of blood versus absence of blood, which was unlikely to have been affected by whether the assessor was aware of the treatment allocation.TAPPS was a randomised trial assessing the management of patients with malignant pleural effusions (fluid in the chest cavity), which often leads to breathlessness and chest pain. Patients were randomised to one of two methods of fluid drainage and administration of talc : (a) talc slurry pleurodesis, which involves inserting a chest drain into the pleural space, and inserting talc slurry  through the drain; or (b) thoracoscopic talc poudrage, which involves inserting a thoracoscope  into the pleural space, and inserting talc using a dry spray technique.The two interventions used different medical instruments and different techniques of reaching the pleural space, and so blinding of patients or study personnel was impossible. The primary outcome was whether the patient received a further procedure for pleural drainage within 90 days of randomisation.Clinicians who were not directly involved in the care of a specific patient were unaware of the treatment allocation, and could therefore be used as blinded assessors to determine whether the patient should undergo further intervention, making direct assessment by a blinded assessor feasible. However, this option was not acceptable practically, as a large proportion of clinicians may feel it is unacceptable for treatment decisions for their patients to be made without their input, and may therefore not be willing to take part in the trial, jeopardising recruitment.should have undergone further pleural drainage, rather than whether they did undergo a further procedure. This could be based on a combination of clinical parameters  and a description of the patient’s symptoms prepared by a blinded clinician. However, an adjudicated outcome of whether the patient should have undergone further pleural drainage could be regarded as a less pragmatic outcome, and thus the treatment effect from such an outcome may not reflect what is likely to occur in usual practice [A blinded adjudication committee could assess whether a patient practice . Additiopractice , and couTo limit bias, the decision to refer patients for further drainage was made using a combination of clinical parameters, and blinded and unblinded assessment:If a chest x-ray showed that a third or more of the patient’s pleural space was filled with fluid, then the unblinded clinician in charge of patient care could refer the patient for further drainage. There is no need for a blinded assessment in this scenario as it is clear that fluid recurrence has occurred, and further intervention is indicated.If less than a third of the pleural space was filled with fluid, then the unblinded clinician in charge of patient care discussed whether further pleural drainage was required (taking care not to unblind them). If the two clinicians disagreed, they discussed the case with the (blinded) chief investigator who made the final decision.This strategy (a) led to the outcome being based on results from the patient’s chest x-ray when clearly indicated; (b) allowed the unblinded clinician responsible for the patient to be involved in their management; and (c) attempted to mitigate any potential bias from the unblinded clinician by introducing a second, blinded assessor into the process.Many trial designs do not permit blinding, and are therefore designed as open-label, with patients, clinicians, and other study investigators aware of treatment allocation. Research has suggested that these trials should use blinded outcome assessment to avoid bias in estimated treatment effects –10. BlinHowever, in some scenarios both of these methods of blinded assessment may be unfeasible. A direct blinded assessment of the patient may be difficult in scenarios where most or all of the staff in a centre are aware of the patient’s treatment, or when assessments occur randomly . Likewise, the use of a blinded adjudication committee may be complicated in situations where it is difficult to compile information to send to the committee , or when it is necessary for the information to be prepared by unblinded personnel, which could bias results despite the use of a blinded committee. Additionally, some outcomes do not require assessment , but may nonetheless be biased by knowledge of the treatment arm.When blinded outcome assessment is not feasible, it is important to ensure that outcomes are as robust as possible to the lack of blinding. We have demonstrated with both the TAPPS and the TRIGGER trials that outcome definitions or the methods of assessment can be modified to reduce the risk of bias. This has been highlighted as a trial methodology priority, yet there are few examples in the literature to guide clinicians planning trials.This strategy is particularly important given the shift away from surrogate outcome measures towards outcomes that are directly relevant to patients. For example, previous trials in patients with malignant pleural effusion have often used the amount of fluid on a patient’s chest x-ray as a surrogate for pleurodesis failure . This caThe TAPPS and TRIGGER trials both used patient-relevant outcome measures, which has the benefit of measuring treatment effects which are more relevant to patients. However, the drawback of this approach is that these outcome measure are often more difficult to blind. We have described in this paper the strategies used to reduce this risk of bias, leading to patient-relevant outcomes with minimal risks of bias. In the TRIGGER trial, the outcome definition for further bleeding was modified to exclude the subjective aspects of the definition , leaving only the most objective aspects . In the TAPPS trial, the outcome was modified so that the unblinded clinician could only refer the patient for a further procedure when clearly indicated based on the patient’s chest x-ray; otherwise, they needed to reach consensus with a blinded clinician.Although these strategies should reduce the risk of bias, they are not without limitations. The requirement in TAPPS to use a second (blinded) clinician to assess the patient added extra complexity to the trial, as it required more effort to ensure that clinicians who were not directly involved with the patient were kept blinded, that these clinicians were available to assess the patient when needed, and that this assessment procedure was being followed as specified. The requirement in TRIGGER for all episodes of further bleeding to be confirmed via a procedure  meant that a very small number of bleeding episodes may have been missed in patients who were too unwell to receive a procedure. However, in both cases the benefits of the outcome modification far outweigh the limitations.Developments in multimedia technology have made blinded assessment for outcomes based on visual inspection (such as further bleeding in TRIGGER) more feasible, as there are often affordable ways of taking high-quality pictures, videos, or other digital recordings, which can be given to an independent adjudicator for assessment. This type of technology has been used in other gastrointestinal trials, for example in the assessment of degree of colonic inflammation in trials of ulcerative colitis . It was Outcome assessment should be blinded when possible. In scenarios where this is not feasible, it may be beneficial to modify the outcome definition or method of assessment to minimise the subjective elements, to ensure that results are as robust as possible to the lack of blinding.


Background and aims: While the relationships between video game use and negative consequences are debated, the relationships between video game addiction and negative consequences are fairly well established. However, previous studies suffer from methodological weaknesses that may have caused biased results. There is need for further investigation that benefits from the use of methods that avoid omitted variable bias. Methods: Two wave panel data was used from two surveys of 1,928 Norwegian adolescents aged 13 to 17 years. The surveys included measures of video game use, video game addiction, depression, heavy episodic drinking, academic achievement, and conduct problems. The data was analyzed using first-differencing, a regression method that is unbiased by time invariant individual factors. Results: Video game addiction was related to depression, lower academic achievement, and conduct problems, but time spent on video games was not related to any of the studied negative outcomes. Discussion: The findings were in line with a growing number of studies that have failed to find relationships between time spent on video games and negative outcomes. The current study is also consistent with previous studies in that video game addiction was related to other negative outcomes, but it made the added contribution that the relationships are unbiased by time invariant individual effects. However, future research should aim at establishing the temporal order of the supposed causal effects. Conclusions: Spending time playing video games does not involve negative consequences, but adolescents who experience problems related to video games are likely to also experience problems in other facets of life. The current study is the first to use FD to investigate the relationship between video game use and associated problems. Therefore, our study is the first to control for all possible time invariant individual variables when investigating the negative outcomes of video gaming.This study used data from the surveys “Young in Norway 2010” and “Young in Norway 2012”, where the goal was to collect the same information from the same individuals at two time points separated by two years. In 2010 (t1), the survey was administered at a total of 89 schools in Norway. The sample of schools were drawn in order to gain a representative sample of Norwegian adolescents, and included elementary schools , junior high schools (age range 12 to 16 years), and senior high schools (age range 16 to 19 years). A total of 11,487 students were invited to participate in the survey. Of these, 8,356 students participated, which equals a response rate of 72.7%. The questionnaires were completed in one school hour, and students not present at the time of the data collection were given the chance to complete the survey at a later occasion.n = 2,021), and 2) contact information was missing . Among those invited, 2,450 participated, which equals a response rate of 53.7%, however, the proportion who participated in 2012 of those who participated in 2010 was 29.3%.In 2012 (t2), 4,561 of the adolescents who took part in the 2010 survey were invited to take part in a follow-up survey. There were two reasons why not all respondents from the 2010 survey were invited, 1) they had not consented to be invited for the follow-up , with an age range of 13 to 17 years in 2010.Video game use. Responses to two questions were used to estimate time spent gaming in the last four weeks. One question asked about the duration of a typical gaming session . Time spent gaming was the product of the quantity and frequency questions. Scores ranged from 0 to 210.Video game addiction. The seven-item version of the “Game Addiction Scale for Adolescents” . The first category was “serious conduct problems” and comprised the following question items: “stolen things worth more than NOK 1000”,Age, gender and grades predicted attrition between t1 and t2. In the analysis, this was corrected for by applying inverse probability weights. The distributions of scores on all measures apart from academic achievement were heavily skewed to the right. To avoid violation of the assumption of homoscedasticity in linear regression analysis, the natural logarithms of the scores were used in the analysis. Since there is no natural logarithm of zero, 0.1 was added to all values before conversion. The regression analysis was conducted using data from t1 and t2, and FD models, which may be explained as follows: The formula for OLS regression of a dependent variable on an independent variable at one time point is:DVi1 = β1 * IVi1 + β2 * iC + ei1,i at time 1. iC denotes other possible causes for DV that are time-invariant (i.e. they do not change over time). Similarly, the formula for OLS regression of a dependent variable on an independent variable at a second time point is:where DV is the dependent variable and IV is the independent variable for individual DVi2 = β1 * IVi2 + β2 * iC + ei2.1 will be biased if IVi1 and iC are correlated. However, with FD, the second formula is subtracted from the first, which eliminates Ci. This yields an estimate of β that is not biased by time-invariant individual factors, since these are cancelled out from the regression analysis. In practice, FD simply involves regressing change from t1 to t2 in the dependent variable on change from t1 to t2 in the independent variable.Using OLS, the regression coefficient bUsing FD in the current study, depression, academic achievement, heavy episodic drinking and conduct problems were regressed on time spent gaming. In addition, depression, academic achievement, heavy episodic drinking and conduct problems were regressed on video game addiction.The study procedures were carried out in accordance with the Declaration of Helsinki. The survey procedures were approved by the Norwegian Social Science Data Services. All students were informed of the purpose of the survey, and consented after having received this information. In addition, written consent was given by the parents of all students attending elementary school and junior high school.The results from the FD models are presented in The level of gaming addiction in the current study was comparable with previous studies using the same measurement instrument. The mean score in our sample  was similar to what was reported for two samples of adolescent gamers in the Netherlands (1.52 and 1.54) . It was The current study showed that video game addiction was associated with higher level of depression, poorer academic achievement, and more conduct problems. This is in line with several other studies that have investigated the possible detrimental effects over time of experiencing problems with video games . Howevervariant omitted variables. Therefore, it is possible that the observed effects are indirect and biased by unknown intermediate variables. Thirdly, all the information used in the study was self-reported and is therefore vulnerable to self-report bias. Fourth, we did not differentiate between different kinds of video games. It may be the case that some games may be more closely related to negative outcomes, while the opposite is true for other types of games. Therefore future research may benefit from differentiating between different types of games. Fifth, because our study lacks experimental design, it is not possible to be conclusive about the directionality of causation. It could be the case that for instance depression causes problems with video games rather than the opposite. It can also be the case that the relationship is reciprocal with an elusive starting point, and constitutes a downward spiral where video game addiction causes depression which in turn causes video game addiction. This form of relationship may also be true for those between academic achievement, conduct problems and video game addiction.Despite the strengths of the current study, there are several limitations that need to be addressed. Although the sample size was large compared to other studies in this field, there was high attrition between t1 and t2, and the subsample that did participate at both time points may not be representative of the Norwegian adolescent population. Some correction was made for this issue by weighting the data for gender, age and academic achievement, but care should be taken in generalizing the findings beyond the study sample. Secondly, while the first differencing method avoids omitted variable bias resulting from time-invariant individual effects, it does not control for the possible effect of time Despite these limitations that should be addressed in future research, the implications of the current study are firstly that the research in this field may benefit from continuing to differentiate between time spent on games and video game addiction. Our results indicate relatively strong relationships between gaming addiction and negative outcomes, and that these relationships are not spurious. This has implications for future studies that aim at establishing causal links between video game addiction and negative outcomes. The current study also contributes to fulfilling the proposed requirements for establishing causation in epidemiological studies , but seeIn summary, the results from current study showed that video game addiction is associated with depression, decreased academic achievement, and with conduct problems, but it is not associated with heavy episodic drinking. However, the study also showed that the amount of time spent gaming is only negligibly associated with the same outcomes. These findings have implications for future research that aims at establishing causal links between video game addiction and negative outcomes.


Long-term employment trajectories of young problem drinkers are poorly understood.th birthday, we extracted information from the records of Statistics Finland on educational attainment, main type of economic activity, months in employment, and months in unemployment for a minimum of seven years (range 7–16 years). We used information on the timing of alcohol-related hospitalizations and deaths in the same period to define problem drinkers with early onset limited course, early onset persistent course, and late onset problem drinking.We constructed retrospective labour market participation histories at ages 18–34 of 64 342 persons born in 1969–1982. Beginning from the year of each subject’s 18Early onset limited course problem drinkers improved their employment considerably by age, whereas early onset persistent problem drinkers experienced a constant decline in their employment by age. From the age of 18 to 34, early onset persistent problem drinkers were in employment merely 12% of the time, in comparison with 39% among the early onset limited course problem drinkers, and 58% among the general population.These results indicate that young adults who were retrospectively defined as having early onset persistent course problem drinking were extensively marginalized from the labour market early on during their life course, and that their employment trajectory was significantly worse compared to other problem drinkers. Problem drinking –4 has thMany of those with an early onset problem drinking experience their highest level of symptoms of problem drinking in their early twenties , and theth birthday for a minimum of seven years and up to 16 years. Comparison with the general population will give us an idea of the differences in relation to the normative trajectory of labour market participation. Using this novel design, we do not aim to establish the causal role of problem drinking in determining labour market participation but we aim to provide an insight to the typical group-level employment trajectories of persons among whom alcohol plays a substantial negative role in their life course. This information could be used in developing more effective interventions aimed to promote employability among individuals who are particularly vulnerable to the severe and persistent negative life course effects of problem drinking.Because severe forms of problem drinking among young adults are relatively rare in the general population, prospective population-based cohort studies are often not feasible for studying long-term trajectories of labour market participation among these persons. The purpose of this register-based retrospective cohort study is therefore to establish how young adults aged 18–34 years, who were hospitalized or died due to alcohol-related causes, participated in the labour market after they had completed their compulsory basic education. We used the alcohol-related diagnoses recorded in the Hospital Discharge Register and the Cause of Death Register as proxy measures for a severe form of problem drinking. This operationalization is in accordance with the definition of a problem drinker provided by the World Health Organization . In lineThe sampling and data linkage was approved by the ethics committee of Statistics Finland.The original register-based study data consists of an 11% random sample of all persons who were living in Finland during the years 1987–2007. For the purpose of this study we selected those who were aged 18 at entry, and followed them up for a minimum of seven years . An additional sample of all deaths that occurred during the study period was drawn so that 80% of the persons who died during the study period were identified. This was the maximum representation of deaths retrievable from the records of Statistics Finland due to data protection rules. Information from the nation-wide registers of Statistics Finland  and the National Institute for Health and Welfare  were linked to the data. Statistics Finland carried out the sampling and data linkage using a unique personal identity code issued to all Finnish residents and available in all registers used in this study. All data were anonymized and de-identified by Statistics Finland prior to analyses.We constructed retrospective cohorts of persons born in 1969–1982 who remained in Finland after the age of 17 (N = 76 609). Persons who immigrated or emigrated during the study period were excluded from the data (n = 7721). To ensure that all participants had the opportunity to experience comparable age-related transitions in their life course regarding educational and occupational attainment, persons who died before the age of 25 were also excluded (n = 4546). All deaths, therefore, occurred in 1994–2007 at ages 25–34. Hospitalizations were not used in determining eligibility and were thus allowed to occur at any time up to the age of 34. The final study data consisted of 64 342 persons.We used the alcohol-related diagnoses recorded in the Hospital Discharge Register and the Cause of Death Register as surrogate/proxy measures for problem drinking. Alcohol-related hospitalizations and deaths were identified using the International Classification of Diseases, Finnish modification, ninth (ICD-9) and tenth revisions (ICD–10) codes. For ICD-9 we used the following codes: 291, 303, 3050, mental and behavioural disorders due to use of alcohol; 3575, alcoholic polyneuropathy; 4255, alcoholic cardiomyopathy; 5353, alcoholic gastritis; 5710–5713, alcoholic liver disease; 5770D–5770F, 5771C–5771D, alcoholic pancreatitis; 980, toxic effect of alcohol; E851, accidental poisoning by alcohol. For ICD-10 we used the following codes: F10, mental and behavioural disorders due to use of alcohol; G312, degeneration of nervous system due to alcohol; G4051, epileptic seizures related to alcohol; G621, alcoholic polyneuropathy; G721, alcoholic myopathy; I426, alcoholic cardiomyopathy; E244, alcohol-induced pseudo-Cushing syndrome; K292, alcoholic gastritis; K70, alcoholic liver disease; K852, alcohol-induced acute pancreatitis; T51, toxic effects of alcohol; X45, accidental poisoning by and exposure to alcohol. We used primary and secondary diagnoses in identifying alcohol-related hospitalizations, and underlying and contributory causes of death in identifying alcohol-related deaths in order to improve the coverage in identifying problem drinkers. By using secondary diagnoses of hospitalizations and contributory causes of deaths, we identified e.g. persons who had alcohol intoxication or alcohol dependence recorded as a contributing factor. A total of 2600 persons were retrospectively defined as problem drinkers based on the above criteria.Alcohol-related hospitalizations occurring before the age of 25 were considered as indicators of early onset problem drinking . Early oth birthday, we extracted information from the records of Statistics Finland on indicators relevant to labour market participation; educational attainment, main type of economic activity, months in employment, and months in unemployment. The highest level of education attained after the compulsory basic education was recorded according to the International Standard Classification of Education (ISCED) coding. Among those who were not educated beyond the compulsory basic education, the ISCED coding was lower secondary education (level 2). In Finland, this typically corresponds to 9–10 years of schooling. Information on main type of economic activity indicated whether the person was employed, unemployed, student, pensioner, conscript, or other outside the labour force at the end of a given year. This is later referred to as labour market participation. Persons not in employment, education or training, “NEETs” were defined as those whose main activity at the end of a given year was not one of: employed, student, or conscript. Time outside the labour force was defined as months not being employed or unemployed. We used information on living arrangement and household composition to determine whether the person lived alone or not. Leaving parental home and living alone at an early age, particularly if not because of attending school, is potentially an indicator of various negative life course characteristics, e.g. in the childhood family environment [Beginning from the year of each subject’s 18ironment , 33, andThe main results are based on comparisons across the three groups reflecting retrospectively defined time-ordered patterns of problem drinking, in particular in terms of contrasting early onset limited course with early onset persistent course of problem drinking. Comparisons against the general population provide a quantification of the overall disadvantage in relation to the normative life course trajectories.We used generalized estimating equations (GEE) in analyzing the average time in employment, unemployment, and time outside labour force, while adjusting for the effects of sex, cohort, and age at death/end of follow-up. By using GEE we estimated the group-level employment trajectories. This method adjusts the standard errors for the within-subject clustering of data over repeated measurements (7–16 measurement points). We used an autoregressive correlation structure on the assumption that within subject measurements closer in time are more highly correlated than measurements further apart. The results from these models are presented as estimated marginal means with their 95% confidence intervals. Analysis weight variable was used in all the analyses to correct for the different sampling probability between survivors (11%) and the deceased (80%). SAS/STAT software's GENMOD procedure was used to perform the GEE analyses.Men were overrepresented among those who were hospitalized or died due to alcohol-related causes (80%). Among men and women, the first alcohol-related hospitalization before the age of 25 occurred at a mean age of 19.6 years , the mean age for the first alcohol-related hospitalization between ages 25 and 34 was 28.5 years (SD = 3.0), and the mean age for alcohol-related death was 28.9 years . The majority (77%) of alcohol-related hospitalizations were related to diagnoses of mental and behavioural disorders, and the second largest diagnostic group was injuries/external causes (14%). The relative contribution of alcohol-related injuries/external causes was largest among early onset limited course problem drinkers (30%) and lowest among late onset problem drinkers (6%). Of the alcohol-related deaths, 82% were related either to suicide (40%), poisoning (14%), or injuries/other external causes (28%).The proportion of persons living alone at the age of 18 was around three-fold higher among retrospectively defined problem drinkers, compared to the general population. Women were more frequently living alone than men. Among retrospectively defined problem drinkers, the proportion of persons living alone at the age of 18 was lowest among those who were defined as having late onset problem drinking, and highest among those defined as having early onset persistent course problem drinking.At the age of 18, around one in three (31%) of the men and women who were retrospectively defined as problem drinkers were not in employment or in education (NEETs), in comparison with around one in ten among the general population (10%). By the age of 24, the proportion of NEET men and women among problem drinkers had increased to around one in two (52%), in comparison with one in five among the general population (20%). In all three problem drinking groups, the rate of moving outside the labour force was higher than the rate of moving to unemployment. For example, of the male early onset persistent course problem drinkers, 30% were unemployed at the age of 18, and this proportion increased to 44% by the age of 24 (1.5-fold increase), whereas the proportion outside the labour force increased in the same period from 13% to 32% (2.5-fold increase).The results suggest that the transition from formal education to employment was markedly less successful among problem drinkers compared to the general population. Even if the proportion on persons in education decreased between ages 18 and 24 in a comparable fashion in the various groups, the parallel increase in the proportion of persons in employment was markedly lower among those who were retrospectively defined as problem drinkers (1.3-fold increase from 26% to 33%) than among the general population (2.6-fold increase from 22% to 58%).All in all, the early onset persistent course problem drinkers were employed 12% (2.0/16), unemployed 34% (5.5/16), and outside the labour force 53% (8.5/16) of the time between ages 18 and 34. The early onset limited course problem drinkers were employed 39%, unemployed 22%, and outside the labour force 39% of the time between ages 18 and 34. The respective proportions among the general population were 58%, 8%, and 34%. It should be noted here that being outside the labour force among the general population was mainly related to being in formal education, whereas among those who were retrospectively defined as problem drinkers, being in education contributed much less to the time outside the labour force, as shown in The employment trajectory of the early onset limited course problem drinkers, and the late onset problem drinkers followed a comparable trajectory up to the age of 25, after which the trajectories diverged statistically significantly. By the age of 26, the increasing employment trajectory of the late onset problem drinkers had levelled off, whereas the employment trajectory of the early onset limited course problem drinkers continued to increase. By the age of 32, the difference in the average level of employment between these groups had increased to two-fold .In contrast with the other two retrospectively defined problem drinking groups, the early onset persistent course problem drinkers showed a declining employment trajectory. Their average level of employment was one-third at the age of 24 and at the age of 32 one-sixth, compared to the level of employment of the early onset limited course problem drinkers.We established how young adults aged 18–34 who were retrospectively defined as problem drinkers based on the alcohol-related harm they experienced, participated in the labour market after completing their compulsory basic education. All models were adjusted for the effects of cohort, sex, and age at the time of death/end of follow-up. About half of these young problem drinkers were disengaged from formal education at the age of 18. As a result, the proportion of persons with compulsory basic education as the highest educational attainment was four-fold higher among them compared to the general population. Furthermore, compared to the general population, their transition from formal education to employment was significantly less successful, which was evidenced e.g. by a disproportionately high level of unemployment already at the age of 18, and the markedly lower rate of gaining employment after the age of 18. During the age period 18–34, the early onset persistent course problem drinkers were in employment merely 12% (i.e. two years of the 16-year follow-up period) of the time, in comparison with 39% of the time in employment among the early onset limited course problem drinkers, and 58% among the general population.Despite being disadvantaged in relation to the general population, those who belonged to the early onset limited course problem drinking group improved their employment considerably by age, whereas those in the early onset persistent problem drinking group experienced a constant decline in their employment. In particular, young persons who were retrospectively defined as persistent problem drinkers were, therefore, markedly disadvantaged in the labour market in terms of their ability to gain employment, compared to other problem drinkers and the general population.Severe forms of problem drinking are relatively rare among young adults in the general population. For example in 2007, of all the alcohol-related hospitalization in the general population 3.9% were among persons under 25 and 9.7% among persons under 35 years . Our regHowever, because the definition of problem drinking was based on alcohol-related hospitalizations and deaths, the results apply only to those problem drinkers who are at risk of experiencing similar alcohol-related health outcomes. On the continuum of harm, hospitalizations and deaths represent the most severe end of the continuum, and therefore those who are at risk of experiencing less severe alcohol-related harm, such as outcomes leading only to ambulatory care, could have different trajectories of labour market participation. A limitation is that we did not have information on actual alcohol consumption, which could have been used in establishing the timing and level of harmful alcohol use more accurately. Our time-ordered patterns of problem drinking, however, enabled us to control at least some of the issues related to timing between problem drinking and trajectories of labour market participation. For example, the first alcohol-related hospitalization in our data occurred at a mean age of 19.6 years for those who were defined as having an early onset problem drinking, which means that the first alcohol-related hospitalization occurred on average at the beginning of the follow-up period for labour market participation.We excluded those who died before the age of 25 because persons who died at very young age had very limited opportunity to gain high educational attainment and participate in the labour market. The non-employment estimates for the retrospectively defined problem drinkers are therefore likely underestimates rather than overestimates. We controlled cohort effects statistically in the GEE models by adjusting for birth year but the potential effects of residual confounding should still be kept in mind when interpreting the results because birth year is only a proxy for e.g. the differences in the societal context affecting the success of different birth cohorts entering labour market.Our finding of the low educational level and high level of unemployment among retrospectively defined problem drinkers is in line with findings in other populations using different criteria for problem drinking –15, 19. The worst employment trajectory was seen among the early onset persistent course problem drinkers. In this group, the role of problem drinking is more strongly indicated than among early onset limited course problem drinkers or late onset problem drinkers. It is therefore probable that alcohol played a substantial negative causal role in the life course of these persons. However, particularly those who progress rapidly to problem drinking after drinking initiation and who present persistent problem drinking over their life course –10 are fThe employment trajectory among the early onset limited course problem drinkers in comparison with the other two problem drinking groups suggested that persons who are able to desist from a severe form of problem drinking are capable of improving their employment considerably over their life course. However, the employment trajectories deviated between the early onset limited course problem drinkers and the late onset problem drinkers only after the age of 25. An important unanswered question, therefore, is why the employment trajectories did not differ for the favour of the late onset group during the age period before the age of 25, in comparison with the early onset limited course problem drinking group. Comparison with the general population shows that the late onset problem drinking group could have had much potential for improvement in their level of employment before the age of 25. One possible explanation for the non-significant difference between these two problem drinking groups is that below the age of 25, the various correlates of problem drinking are relatively more important in determining the success in competing for the limited employment opportunities available for low skilled youth than problem drinking in itself. Another possible explanation is that those defined as having late onset problem drinking were already consuming alcohol in excessive and disruptive manner, but without severe health outcomes and were thus not captured in the early onset group by using our definition of problem drinking based on alcohol-related hospitalizations. Future studies with more detailed measurement of problem drinking and its correlates should aim to shed more light on these differences.An earlier Finnish study found that the majority of older retrospectively defined problem drinkers, i.e. of persons who died due to alcohol-related causes aged 45–64, were in employment up to ten years before death . This in


Recent technological advances have made airway management safer. Because difficult intubation remains challenging to predict, having tools readily available that can be used to manage a difficult airway in any setting is critical. Fortunately, video technology has resulted in improvements for intubation performance while using laryngoscopy by various means. These technologies have been applied to rigid optical stylets, flexible intubation scopes, and, most notably, rigid laryngoscopes. These tools have proven effective for the anticipated difficult airway as well as the unanticipated difficult airway. Airway management remains a difficult skill to master. Competency requires didactic instruction as well as hands-on training with simulators and human patients. To augment challenges with training, airway management is burdened with poor prediction models for difficulty or failure. Indeed, most studies of bedside tests may only marginally predict that direct laryngoscopy fails to achieve an adequate laryngeal view. These tests have very limited application to actual intubation success rates and tools other than direct laryngoscopy with a Macintosh blade. Fortunately, recent advances in airway management have facilitated easier intubation by augmenting the laryngeal view with video technologies. Application of light-emitting diode (LED) light, liquid crystal display (LCD) screens, and complementary metal–oxide–semiconductor (CMOS) video chip technology has made video augmentation more portable, easier to use, and feasible in today’s economic climate. This review will briefly discuss how video technology has changed optical stylets and flexible intubation scopes. Further emphasis will be placed on newer-generation rigid video laryngoscopes.1. Other newer optical stylets have also incorporated technologies with flexible tips2. These attached video screens have overcome a classic barrier to optical stylets—that the head and eye of the provider need to follow a moving target as the scope is advanced through the pharynx and redirected toward the trachea. Instead, a screen that swivels allows the provider to remain in a neutral position to facilitate laryngoscopy. Furthermore, the use of a video camera provides a much wider field of view than the narrow field of view provided by fiberoptic devices.Older optical stylets used fiberoptic bundles and thus required an eyepiece that the provider would have to place their eye on. Today’s optical stylets use video chips and thus can incorporate an easy-to-view video screen on the handle itself. This simplicity and ease of use result in improvements in intubation performance, especially when the neck is mobilizedFlexible intubation scopes have done away with an old name of “flexible fiberoptic” as the optical component no longer utilizes fiberoptic bundles. Today’s technologies also use a video chip carried on the distal end of the bronchoscope. As flexible intubation remains the standard tool for the anticipated difficult airway, better optics and fewer degradation problems related to fiberoptic bundle fracture stand to improve the reliability of awake flexible bronchoscopic airway management. The literature has yet to offer comparisons of video bronchoscopic techniques with older fiberoptic techniques. However, these technologies have allowed them to become more portable. They do not require a large cart with a light source and video processor.4.In recent years, bronchoscopes have become more portable and have even come in disposable forms. A disposable approach permits availability of this gold-standard airway management tool in areas where difficult airways are managed less frequently, such as an ambulatory surgery center. Although the technology is not quite as robust as a traditional platform bronchoscopic system, it can be effectively used for difficult airway management6. However, evidence has made it clear that video laryngoscopy eases intubation difficulty and increases first-attempt success rates in the airway predicted to be difficult to intubate by direct laryngoscopy10. These benefits are seen for patients who are obese, have a raised Mallampati score, or have reduced cervical motion from pathology or cervical spine precautions.Video laryngoscopy made its introduction to airway management many years ago with the introduction of the GlideScope video laryngoscope . Since that time, we have learned much about the utility of the devices and have generated questions to guide future investigation. These tools have been shown to consistently provide an improved view of the larynx compared with direct laryngoscopy. Research has attempted to identify whether these benefits translate to an improvement in actual intubation difficulty or success rate, or both. As success rates for tracheal intubation using direct laryngoscopy in experienced hands are very high, there does not seem to be added benefit beyond improvement of laryngeal view for the undifferentiated airway across age spectrums12. These benefits come both with devices that are video-assisted direct laryngoscopes and with those with acutely curved indirect laryngoscopes. An instructor-guided laryngoscopy with a video device appears to accelerate even direct laryngoscopy skills13.Video laryngoscopy offers significant benefits for the provider who is less experienced with airway management. Compared with direct laryngoscopy, intubation success rates are higher with video laryngoscopy in the hands of novice providers14. Findings demonstrated similar performance with both techniques. However, validity of the study findings is limited by sedation of study patients, exclusion of those with neck pathologies, and inappropriate post-randomization exclusions15. In another study of awake nasal intubation with flexible bronchoscopy versus video laryngoscopy, techniques performed similarly16. In this study, patients in both groups were sufficiently sedated to avoid recall of the procedure. As such, findings may not apply to the true “awake” intubation. Despite these limitations, awake video laryngoscopy may be a tool that is easier to learn and master than flexible bronchoscopic intubation and likely has a future role in awake airway management.Compared with awake fiberoptic intubation, awake video laryngoscopy has been evaluated in the potential difficult airwayOne of the potential benefits of video technology is the capacity to record and archive still images or video clips from the laryngoscopy. These recordings can be used to confirm tracheal tube placement, document laryngeal view, document absence of trauma, and teach future laryngoscopists. Today’s anesthesia record contains a narrative describing the device, laryngeal view on the Cormack and Lehane scale, absence of trauma, and confirmation of tube placement with various tools. The future electronic record could feasibly store a single picture or video clip that tells the airway management story. To date, anesthesia information management systems have not incorporated archiving of digital airway images as part of the anesthesia record, but this future seems feasible. This advancement is poised to change how we define difficult airway management. Instead of describing a laryngeal view by Cormack-Lehane grading, a video recording may better tell the story and also better describe challenges related to tube passage that may be difficult to describe in a narrative.19. There is one randomized trial to confirm benefit of video laryngoscopy in the critical care environment20. The findings are impressive, but interpretation of the results is limited by a select patient and provider population. In the setting of trauma, the use of video laryngoscopy was associated merely with longer intubation times21. In the obstetric environment, video laryngoscopy has been used for emergency airway management, potential difficult intubations, and rescue of failure of direct laryngoscopy22. Finally, in prehospital emergency medicine, video laryngoscopy is associated with a reduction in the number of intubation attempts and shorter laryngoscopy time than direct laryngoscopy24. However, these studies are observational in nature and interpretation of the results deserves some caution because of the possibility of confounding factors. Prospective randomized studies are much more difficult to perform in these dynamic and emergent environments. Clinical care appears to be transitioning to primary use of video laryngoscopy in these environments, but the literature has not yet confirmed that this practice should be standard in these environments. Prospective randomized controlled trials are still needed to confirm the potential benefit for all airway management within each of these environments.Early investigations in various clinical environments outside of the operating room suggest potential benefit. These environments contain both difficult airway scenarios and providers with less airway management experience than is often found in the operating room. In critical care and emergency medicine environments, video laryngoscopy was associated with a higher intubation success rate in patients with predictors of difficult direct laryngoscopy25. Current intubation rescue techniques include video laryngoscopy, flexible bronchoscopic intubation, use of a lighted stylet, or insertion of a supraglottic airway as a conduit to tracheal intubation. One study across two centers demonstrated that rescue using the GlideScope video laryngoscope was successful in 94% of cases (224/239) after failed direct laryngoscopy26. The Pentax AWS  was found to achieve successful intubation in 99% of cases (268/270) in which direct laryngoscopy failed to achieve an adequate laryngeal view for intubation27. In a large observational study of a new algorithm involving a small group of providers and select group of patients, failed direct laryngoscopy was rescued by using the Airtraq system  in 27 out of 28 cases28. Others reported that when mask ventilation and intubation are both difficult, supraglottic airways restore ventilation in 94% of cases (16/17)29. In summary, video laryngoscopy appears to have a promising role in the management of failed direct laryngoscopy as a rescue technique with a high success rate.When direct laryngoscopy fails, it is unclear how to proceed with airway management. The American Society of Anesthesiologists’ difficult airway algorithm calls for transitioning to alternate airway management techniques, but it is not clear which techniques are optimal26. The strongest predictor for failure is neck pathology from tumor, radiation, or surgical scar. This evidence suggests that flexible techniques remain an important tool to master and maintain competency with. Indeed, awake airway management with flexible techniques remains the gold standard for difficult airway management in the cooperative patient for experienced providers. The key challenge is to maintain this competency.Despite these many benefits for the difficult airway, video laryngoscopy can fail. One source of failure is an inability to achieve a laryngeal view. However, a frequent and more perplexing scenario is that of an adequate laryngeal view but inability to pass the tube into the trachea. This difficulty may occur with acutely curved indirect laryngoscopes, channeled video laryngoscopes, or even video-assisted direct laryngoscopes. A recent study identified predictors of failure with the GlideScope video laryngoscopeOne potential cause of difficult tube passage results when an acutely curved video laryngoscope is inserted too deep.30.Many authors believe that video laryngoscopy causes less patient stress than direct laryngoscopy. Indeed, less suspension pressure and extension of the cervical spine may be necessary to achieve an adequate laryngeal view. However, well-designed clinical trials have been inconsistent in demonstrating that video laryngoscopy is associated with less cervical traction than direct laryngoscopy when manual in-line stabilization is applied31. In fact, the operator, not the device, is responsible for this injury. However, despite more widespread knowledge of this potential problem, this complication occurs even in experienced clinical hands. Caution is warranted when advancing a tracheal tube through the pharynx during video laryngoscopy, especially when visual attention may be distracted from the patient. Specifically, the provider needs to watch the tube pass into the mouth and make the turn toward the larynx prior to focusing further attention on the video screen.Video laryngoscopy appears to expose the patient to different kinds of iatrogenic trauma compared with direct laryngoscopy. Reports continue to warn that pharyngeal injury is a problem with video laryngoscopy, although the incidence appears to be low. In particular, there are reports of tracheal tubes passing through the pharynx during video laryngoscopy32. Furthermore, questions surrounding blade design continue to arise. For example, video-assisted direct laryngoscopes (i.e. Macintosh blade design) have the potential benefit of familiarity, simple tube passage, and narrow blade profile. On the other hand, acutely curved blade designs may further augment laryngeal view for the anterior airway beyond what may be achieved with a video-assisted direct laryngoscope. Thus far, studies have not shown a clear difference in success rate between various blade design types34.Future research is poised to address some new questions. In particular, very few studies have compared video laryngoscope types and designs to determine the ideal device characteristics. Some limited data suggest that devices with channeled components (i.e. with a preloaded tube) result in faster and easier intubation than non-channeled devicesIn summary, video laryngoscopy has established a permanent role in difficult airway management. Future investigations will help guide the clinical scenarios for use, algorithm approaches, and device designs. It is less clear whether video laryngoscopy will one day replace direct laryngoscopy. Currently, cost remains a barrier to such transitions for routine clinical care in the operating room. In other environments, that transition has occurred already on the basis of observational data, suggesting a reduction in intubation attempts.


In higher education binge drinking is an important problem. To target binge drinking in students, studying the social context of students is necessary. Faculties are social contexts in which students behave, but little is known about how faculty binge drinking norms relate to monthly binge drinking. In this study, this relationship is investigated in addition to known personal determinants.Data were collected from 7,181 students in 22 faculty-level units, using an anonymous online survey. Multilevel analyses were used to investigate the relationship of both individual-level determinants  and faculty-level binge drinking norms, with monthly binge drinking.Almost two-third (62.2%) of the sample was female and the mean age was 21.06 (SD = 2.85) years. In males, significant faculty-level variance in monthly binge drinking was found. At faculty-level only faculty binge drinking norms about male students showed a positive relationship . At individual level both perceived binge drinking norms about male and female students, and social drinking motives positively related to monthly binge drinking. In females no significant faculty-level variance was found. Only individual-level determinants  positively related to monthly binge drinking. No cross-level interactions were found.Faculties are especially in men relevant environmental structures and networks to take into account besides individual determinants when targeting binge drinking in higher education.


IKZF2 rs12619285 polymorphism is associated with the eosinophil count, which has multidimensional functions in the pathogenesis of coronary heart disease (CHD). The aim of the present study was to investigate the contribution of the IKZF2 rs12619285 polymorphism to the risk of CHD in a Han Chinese population. In total, 721 CHD cases and 631 non-CHD controls were recruited for an association study of the IKZF2 rs12619285 polymorphism. Genotyping was performed using the melting temperature-shift polymerase chain reaction method. No statistically significant association was observed between the IKZF2 rs12619285 polymorphism and CHD . In addition, subgroup analyses by gender or age were unable to identify any association between IKZF2 rs12619285 and CHD (P>0.05), and there was no significant correlation between IKZF2 rs12619285 and the severity of CHD (P>0.05). The power of the case-control study was determined to be 63.3%. In addition, the G allele frequency was calculated as 63.6% in the Han Chinese population, which was similar to the 59.3% recorded for the HapMap Chinese population of Han Chinese individuals living in Beijing, compared with 24.3% in European descendents (HapMap-CEU). Therefore, the results indicated that the IKZF2 rs12619285 polymorphism was not associated with CHD in a Han Chinese population. The discrepancy in the association between rs12619285 and CHD may be due to the ethnic differences between Han Chinese and European populations.The  Coronary heart disease (CHD) is a major cause of mortality and disability worldwide . The gloIKZF2 gene is located on chromosome 2q13 and encodes the zinc-finger protein, Helios, which is a member of the Ikaros family of zinc-finger proteins. IKZF2 protein is a functional component in lymphocyte differentiation  polymorphism in European populations  and East Asian populations  was significantly associated with CHD , 1.38, 95% confidence interval (CI), 0.97–1.98], with no departure from the Hardy-Weinberg equilibrium (HWE) in the controls (IKZF2 rs12619285 and CHD (162 cases and 113 controls); however, the statistical power was only 45.2%  and Ningbo Yinzhou People’s Hospital . CHD cases were confirmed with angiographic evidence that showed vascular stenosis of >50% in at least one major coronary artery. In addition, participants with a history of angioplasty or coronary artery bypass surgeries were classified as CHD cases. Control samples comprised patients whose vascular stenosis was <50% in each of the major coronary arteries . The sevIKZF2-g forward, 5′-GCGGGCAGGGCGGCA CCAAGGAAAATGGAGCTTCTG-3′; IKZF2-a forward, 5′-GATTACCGACCAAGGAAAATGGAGCTTCTA-3′); and IKZF2 reverse, 5′-GCCTCTTTAGGTAGGGAAGAG AGAACACA-3′. The PCR amplification program consisted of an initial denaturation at 95°C for 30 sec, followed by denaturation at 95°C for 30 sec, annealing at 59°C for 30 sec and extension at 72°C for 30 sec for 40 cycles, and a final extension at 72°C for 30 sec. PCR was performed using the ABI GeneAmp® PCR System 9700 with the 96-Well Sample Block Module . Subsequently, melting curve analysis was performed using a Roche LightCycler 480® fluorescence quantitative PCR instrument . The melting curve analysis program was 95°C for 15 sec, 60°C for 30 sec, followed by increasing the temperature by 0.11°C per sec, until a temperature of 95°C was reached. As shown in Genomic DNA from the peripheral blood was extracted using a nucleic acid automatic extractor  and all the DNA samples were stored in Tris-EDTA buffer. Genotyping was performed using the melting temperature-shift polymerase chain reaction (PCR) method ,25. The http://faculty.vassar.edu/lowry/odds2x2.html). The Cochran-Mantel-Haenszel (CMH) test was performed using SAS 9.2 software , while power analysis was conducted using the software of Power and Sample Size Calculation   . DiffereTN, USA) . A two-tIKZF2 rs12619285 polymorphism to CHD. Genotype distributions of the IKZF2 rs12619285 polymorphism were shown to not deviate from the HWE in the CHD cases, non-CHD controls and additional subgroups divided by gender or age . The case-control study included 1,352 individuals that comprised 721 CHD cases and 631 controls. However, the current study was relatively small compared with a previous genome-wide association study that included 12,118 European and 5,212 East Asian individuals  population (59.3%). In addition, the G allele frequency was 63.6% in the controls of the present study, which was similar to that of the HapMap-CHB (59.3%) population (IKZF2 rs12619285 polymorphism and CHD in the Han Chinese population.Further analysis indicated that there was an ethnic difference in the allele frequency of the pulation . The disIKZF2 gene. The current study only focused on one polymorphism of the IKZF2 gene; thus, the function of the IKZF2 gene may not be fully demonstrated. Future studies should investigate a greater number of polymorphisms in order to improve the understanding of the role of the IKZF2 gene in the susceptibility of CHD.Genetic heterogeneity may be an additional explanation for the negative results. A total of 3,355 polymorphisms have been identified in the IKZF2 has been demonstrated to be involved in the earliest hematopoietic differentiation of human embryonic stem cells (IKZF2 gene may play a role in the pathogenesis of CHD.IKZF2 protein has been identified at an early phase of development in thymocytes; thus, IKZF2 has been regarded as a key regulator in lymphocyte differentiation . In addiem cells , and neuem cells . Eosinopem cells , which mem cells ,35. ThusIKZF2 rs12619285 polymorphism and CHD in the Han Chinese population. This observation indicated that other IKZF2 polymorphisms or different genes can affect the variation in blood eosinophil numbers, which may further the understanding into the contribution of inflammatory pathways in CHD.In conclusion, the present case-control study demonstrated a lack of association between the


In this paper, a smoothing algorithm for compensating inertial sensor saturation is proposed. The sensor saturation happens when a sensor measures a value that is larger than its dynamic range. This can lead to a considerable accumulated error. To compensate the lost information in saturated sensor data, we propose a smoothing algorithm in which the saturation compensation is formulated as an optimization problem. Based on a standard smoothing algorithm with zero velocity intervals, two saturation estimation methods were proposed. Simulation and experiments prove that the proposed methods are effective in compensating the sensor saturation. In ∈R4 be a quaternion representing the rotation relationship between the navigation coordinate frame and the body coordinate frame. Let C(q) ∈ R3×3 be the rotation matrix corresponding to the quaternion q T is the body angular rate.Our goal is to estimate attitude (expressed using the quaternion), position and velocity of the object from the sensor data. Let ernion q , and r ∈quations :(1)q˙=1gy ∈ R3 be the gyroscope output and ay ∈ R3 be the accelerometer output. They satisfy the following relationship [gn and an are zero mean white Gaussian sensor noises with covariances ḡ=[0 0 g]T The symbol g denotes the gravitational acceleration. It is assumed the sensor bias is already compensated using the standard calibration algorithm T∈R3. Assuming eq̄ is small, C(eq) can be approximated by the following [p×] (p=[p1p2p3]T ∈ R3) is defined by:The heading in or in q̂ . A smallollowing :(6)C is estimated using a smoother. To do that, we derive a differential equation for x(t). From the assumption that eq̄ and ω−gy is small, we obtain the follow T) and Since the sensor sampling period is T, T :(9)xk+1v,kn is added in the following equation:Since no external sensors other than the inertial sensor are used, there is no physical measurement during the motion. However, the fact that the velocity is zero during the not moving period can be used as a virtual measurement. In motion analysis, it is assumed that the object is not moving when the gyroscope and the variation of the accelerometer are smaller than threshold values for some specified time. Thus there will be a chance that a moving interval is detected as a zero velocity interval. To reflect this fact, a small noise v,kn at time k is modeled as a Gaussian white noise with the covariance k:kz=[0−kv̂] and kH=[03 03I3]. The noise mZ which consist of the discrete time indices belonging to the zero velocity intervals. That is, if k∈mZ, then we can use the We introduce a set k can be formulated as the following optimization problem [A smoother problem to estimate x problem ,11:kx and kw for 0≤k≤N that minimize:k+x1=d,kxkA+kw. It is assumed that the initial value x̂0 and the initial covariance error P0 are given. The method to choose these initial values will be discussed Section 5. The x0 and w0,…,k+w1 conditioned on x̂0,y1,…,ky is proportional to exp(−J), which implies that minimizing J means maximizing this probability density.Find k+x1=d,kxkA+kw into kw from the optimization problem:By inserting the constraint x̄ be defined by M1∈R9(N+1)×9(N+1),M2∈R1×9(N+1),M3∈R can be computed from x̄, which can be computed efficiently using the quadratic optimization method [q̂,v̂ and r̂ can be updated using Let the optimization variable n method . MinimizJ*. Note that J* depends on g,ky, a,ky(0≤k≤N), q̂0, r̂0, v̂0 and 0P. For later use, we denote J* by a function f as follows:Let the minimum solution to the problem. xy plane of the local navigation coordinate frame, we can make use of zero z axis position as following:z axis position is given by:In 4.gn and an in The sensor saturation occurs when the measured values are over the sensors' dynamic ranges . While iEach sensor has its own range of measurement. When the measured values are larger than the measurement limit, the saturation happens. Even if the saturation happens in a short time, it could lead to a large accumulated error since the lost information is in a large magnitude data area. The data loss due to the saturation has a considerable influence to the result, especially when the integration is used in data processing.The saturation can be avoided by using large dynamic range sensors. Usually, large measuring range (with the same sensor resolution) sensors tend to be expensive. Instead of using an expensive large range sensor, we can use a low cost one with smaller measuring limit along with applying a saturation compensation algorithm.g,x,ky,g,y,ky, g,z,ky are used to denote three elements in g,ky∈R3. Similarly, a,x,ky,a,y,ky and a,z,ky are used for a,ky∈R3. We use the fact that the value of the sensor output is smaller than the saturation value outside the saturation interval. In the saturation interval, we assume that the sensor output is equal to the saturation value. Let g,saty be the saturation value of a gyroscope and g,xS be the set of gyroscope x saturation inertial indexes:The saturation can happen in gyroscopes and accelerometers in three axes. Symbols Sg,y, Sg,z, ya,sat , Sa,x, Sa,y and Sa,z. Denote gδ,x,k, gδ,y,k, gδ,z,k, aδ,x,k, aδ,y,k, aδ,z,k, the compensation values of gyroscopes and accelerations in x,y,z axes at the time k, respectively. The compensated sensor value  is the sum of sensor output value and compensation value. For example, the compensated x axis gyroscope value is given by:Similarly, we can define δ be set of g,x,kδ, g,y,kδ, g,z,kδ, a,x,kδ, a,y,kδ and a,z,kδ variables. For example, if g,xS={5,6,7}, a,yS={8,9,10}, and g,yS= g,zS= a,xS= a,zS=⊘ then δ is given by:Let g,kȳ and a,kȳ. The flowchart of the algorithm is given in δ which is explained in Sections 4.1 and 4.2. Given δ values, the standard smoother algorithm (steps B and C) is applied to compute the smoother. This standard algorithm (given in Section 3) can be formulated as the quadratic optimization algorithm. How good the computed smoother is can be evaluated using the computed J value in δ values. The algorithm finishes if the minimum value of J is found. We note that δ optimization can be formulated as a constrained nonlinear optimization problem. Once the minimization process is done, we can compute the saturation compensated smoother values (step E).Now the standard smoother algorithm in Section 3 is modified using Consider the following function from :(18)f are larger than saturation value . The initial value of δ can be chosen as a set of 0 and varies in a range which satisfies the condition in δ, one value of x̄ is obtained. The minimum value of δ which makes x̄ minimizes the quadratic problem In 1,087°/s ; in gaiting case . Therefo4.2.kx−2, kx−1,kx in l1 starting from kx with the slope ξ'(k) is generated. With the same procedure (quadratic function g(t) for hx,h+1x,h+2x), we generate a line l2. l1 and l2 are the reconstruction part of sensor saturation. The intersection point of 1l and l2 (at the time mt) is the maximum value (mx) for compensation. Now consider l1 is created based on  and  points, l2 is created based on  and  points. Changing the height of the intersection from saturation value to maximum compensation value mx we can generate several sets of basic lines l1,l2 which contain compensation values. The intersection point is defined as following:In this method, the saturated sensor data region is approximated by a triangle see  and quadThe other compensation value is defined by:δ can be generated by changing the intersection point's value from saturation value to maximum compensation value. In this case, δ only depends on intersection point. Denote I the intersection point. Once I is created, the rest compensation data will be obtained based on l1 and l2 lines using δ value which relates to the intersection point.Using this method, sets of sensor's compensation values t) is formed up based on , and  points. In saturation parts, the compensation value at time kt is χ(kt).With the same idea, a quadratic approximation can be used to generate the lost information . The smoothing results  is applied. In In this simulation, smoother  and the In In g,y,saty value is changed. For example, if we set g,y,saty=12 in g,y,saty value, the sensor saturation increases. With the method 1, when the bδ is fixed and the saturation value is changed, the accuracy of the proposed smoother may be affected (if the bδ is chosen not large enough). As can be seen from bδ is chosen as 2.5, the accuracy will decrease when the compensation value that is used to compensate the saturated data is larger than. bδ However, this effect can be avoided since the saturation value is known for each sensor. Therefore, we can choose bδ as a large number compared with the sensor's saturation value.In order to verify the robustness of the proposed algorithms to the saturation, a simulation is done by checking the position norm errors while bδSections 4.1 and 4.2 showed that the accuracy of the method 2 only depends on the saturation value while the accuracy of the method 1 is affected by the saturation value and the. bδ may affect the accuracy. In some applications, the bδ is known from doing statistical experiments. In the case where bδ is unknown, we can choose an arbitrarily large value. This does not affect the result as shown in bδ is chosen smaller than the compensation value that is used to compensate the saturated data, the error could be large. If we increase, bδ the error decreases since a larger saturation can be compensated. However, it could lead to more computations for solving the optimization As mentioned above, how to choose x axis of the IMU coincides with direction of movement. In this case, there exists saturation in the sensor's accelerometer in the x axis . The trajectory of the object is estimated by the forward-backward smoother and our proposed compensation smoother using two methods. a,x,ky data was compensated using the proposed compensation smoothers.In the first experiment, an object, which is attached with an IMU on the top, moved in a straight line of 0.95 m so that the The estimated position errors are given in g,z,ky data. The estimated trajectories are compared with the true trajectory of the digitizer in Another experiment has been done to verify the compensation feasibility of the proposed algorithm. In this experiment, an IMU is attached at the tip of a digitizer see . The tipIn the last experiment, we verify the compensation smoother application in multiple zero velocity intervals movement (in Section 5). In this experiment, an IMU is attached on a human foot. The volunteer was asked to walk along a straight corridor. A pen is also attached on the volunteer's shoe to mark the steps' positions on the floor. The obtained data from IMU is used to estimate the trajectory of the foot. A comparison of proposed and forward-backward smoothers trajectories is given in 7.This paper has proposed some approaches to compensate for sensor saturation. Saturation is a common problem with IMU sensors in tracking a moving object. The lost data in the saturated parts could be important due to the accumulated errors. In the paper, the authors used a standard smoothing algorithm with zero velocity intervals to compensate sensor saturation. The considered motion includes a moving interval between two zero velocity intervals. Two methods were proposed. The first method directly estimates the saturation compensation while the second one uses a geometric form to estimate the saturation. The proposed smoothing algorithm can be applied in some motions which contain many moving intervals separated by zero velocity intervals. In this case, the motion is divided into segments based on zero-velocity intervals so that between two zero velocity intervals there is one moving interval. The saturation estimation algorithm is applied in each segment from the first to the last one. To verify the feasibility of the two methods, some experiments have been done. The experiments showed that the proposed smoothing algorithm can compensate the sensor saturation and provides a smaller error than a conventional smoother (forward-backward filter). In practical applications, the sensor saturation compensation methods proposed in this paper can be used to improve the accuracy of small dynamic range sensors instead of using a large dynamic range one which usually tends to be more expensive.


Learning from adverse events and near misses may reduce the incidence of preventable errors. Current literature on adverse events and near misses in the ICU focuses on errors reported by nurses and intensivists. ICU near misses identified by anesthesia providers may reveal critical events, causal mechanisms and system weaknesses not identified by other providers, and may differ in character and causality from near misses in other anesthesia locations.We analyzed events reported to our anesthesia near miss reporting system from 2009 to 2011. We compared causative mechanisms of ICU near misses with near misses in other anesthesia locations.p = 0.001), and were more likely to be associated with airway management . ICU near misses were less likely to be associated with equipment issues .A total of 1,811 near misses were reported, of which 22 (1.2 %) originated in the ICU. Five causal mechanisms explained over half of ICU near misses. Compared to near misses from other locations, near misses from the ICU were more likely to occur while on call (45 % vs. 19 %, A limited number of causal mechanisms explained the majority of ICU near misses, providing targets for quality improvement. Errors associated with airway management in the ICU may be underappreciated. Specialist consultants can identify systems weaknesses not identified by critical care providers, and should be engaged in the ICU patient safety movement. Preventable errors are estimated to cause nearly 100,000 deaths in the United States each year, and cost the healthcare system $9 billion annually . IncidenCurrent literature on adverse events and near misses in the ICU primarily relies on events reported by critical care nurses and intensivist physicians –9. AnestWe hypothesized that analysis of patient safety events in the ICU identified by anesthesia providers may reveal critical events, causal mechanisms, and system weaknesses not identified in previous literature on the topic. Furthermore, patient safety events in the ICU may differ in character and causal mechanisms from events identified by anesthesia providers in other locations in the hospital, underscoring the important and unique role of the anesthesiologist in care of the critically ill. Thus, we sought to characterize near miss reports submitted by anesthesia providers in the ICU to our department’s near miss reporting system and compare them to reports submitted by anesthesia providers in other hospital locations in order to highlight unidentified weaknesses in the provision of critical care and provide targets for quality improvement.The University of California, San Francisco (UCSF) Medical Center is a 560-bed academic quaternary care hospital with 77 adult ICU beds  and 76 pediatric ICU beds . The adult medical/surgical ICUs are closed for malignant hematology patients and patients of surgical subspecialists, such that the ICU team takes primary care of approximately one-third of ICU admissions. For all other patients, the adult medical/surgical ICU is semi-closed—primary care of the patient is the responsibility of the admitting service, but intensivist consultation is mandatory. In the adult neuroscience and cardiology/cardiothoracic ICUs, there is mandatory intensivist consultation only for patients requiring mechanical ventilation; intensivist consultation for other patients occurs at the discretion of the primary team. The typical adult critical care team includes residents from the departments of medicine, anesthesia, and emergency medicine; a critical care fellow from the department of medicine, surgery, anesthesia, emergency medicine, or neurology; and a board-certified or board-eligible intensivist from the department of medicine, surgery, or anesthesia. Intensivist coverage is provided by anesthesia intensivists 60 % of the time. All of the pediatric and neonatal ICUs are closed, with care provided by critical care trained pediatric intensivists in conjunction with pediatric critical care fellows, neonatology fellows, and pediatric residents.The UCSF Department of Anesthesia and Perioperative Care provides anesthesia services at six sites in San Francisco: a 560-bed tertiary care academic medical center , a 564-bed hospital and trauma center owned and operated by the city and county of San Francisco, a 90-bed academic hospital and comprehensive cancer center, a 104-bed Veteran’s Affairs Hospital, a six-operating room outpatient surgery center associated with UCSF Medical Center, and a four-operating room stand alone orthopedic surgery center. The department is housed at the UCSF Medical Center and the majority of clinical care occurs there, in the operating rooms, preoperative and postoperative areas, labor and delivery, remote locations, and the ICU. The department includes 24 board-certified intensivists, who attend in the adult medical/surgical ICUs as well as the adult subspecialty ICUs at UCSF Medical Center. Anesthesia residents and anesthesia critical care fellows rotate through the adult ICUs during their training. Anesthesia providers do not staff the pediatric ICUs. In addition to the role of anesthesia providers on the adult critical care team described above, anesthesia providers may also be involved in adult or pediatric ICU patient care during patient handoffs (transport to or from procedures), provision of anesthesia for procedures performed in the ICU, airway emergencies, and code blues.On January 1, 2009, the department instituted a near miss reporting system in order to capture and study potential incidents that occur during the provision of anesthesia. Near miss reports are submitted by anesthesia providers  via a voluntary, anonymous, self-reporting, internet-based near miss reporting system .We retrospectively analyzed near miss reports submitted from January 1, 2009 to December 31, 2011 from the UCSF Medical Center. Near miss reports from other UCSF anesthesia sites were excluded from this analysis since these other sites also have their own internal near miss reporting system such that reports submitted to the departmental near miss system may not be representative of all near misses, and/or the sites do not have intensive care units. Descriptive statistics are stated as frequency and percentage. We characterized the near misses based on the causal mechanisms associated with each report. Using the Joint Commission patient safety event taxonomy,  we categA total of 15,704 patients were admitted to the adult ICU and 7,672 were admitted to the pediatric ICU during the study period, for a total of 64,307 adult ICU patient days and 62,151 pediatric ICU patient days. There were 63,818 anesthesia cases over the same time period, of which 44,465 (69.7 %) took place in the main operating room, and 811 (1.27 %) occurred in the ICU. Near miss reports totaled 1,811, of which 1,529 (84.4 %) originated in the main operating room and 22 (1.2 %) originated in the ICU. Of the ICU near misses, 18 (82 %) were from the adult ICUs and 4 (18 %) were from the pediatric ICUs. Near miss reports were generated from 2.8 % of non-ICU anesthesia cases, 2.7 % of ICU anesthesia cases, and 0.09 % of ICU admissions. There were 0.17 near misses reported per 1,000 ICU patient days.p = 0.001), and were more likely to be associated with airway management . ICU near misses were less likely than near misses from other locations to be associated with equipment issues . ICU and non-ICU near misses were equally likely to be associated with human errors , systems errors , technical errors , and a poor culture of safety  , poor communication 12 %), failure to perform a routine task (12 %), poor culture of safety (8 %), and equipment malfunction (8 %)  and more likely to be associated with airway management  than near misses occurring in the preoperative area or PACU. In a post-hoc analysis, airway-related near misses from the ICU did not differ from airway-related near misses occurring outside the ICU in terms of association with human errors, systems errors, technical errors, equipment errors or a poor culture of safety. Airway-related ICU near misses were more likely to have occurred on call than airway-related near misses occurring outside the ICU .In a pre-planned subgroup analysis, ICU near misses were more likely to occur on call  performed by the anesthesia provider in the ICU as compared to other anesthesia locations. However, airway-related events warrant attention since they are frequently associated with physical injury, increased hospital length of stay, and family dissatisfaction, and may be mitigated by adequate ICU staffing and the use of skilled assistants . The useThird, ICU near misses were less likely than near misses in other anesthesia locations to be associated with equipment errors. Despite this difference, equipment errors remain an important priority given they may be easily addressed by interventions at the systems-level.Finally, the rate of near misses reported in the ICU and OR was similar. Although this may be due to a bias in the type of reporting system used, it also suggests anesthesiologist involvement in the ICU may result in lower event rates.et al., a larger proportion of near misses from our study occurred at night or on the weekend, [Existing literature on adverse events and near misses in the ICU is primarily based on incident reports submitted by critical care nurses and intensivists –9. To ouweekend,  which coweekend,  the propOur study has several limitations. First, we are limited by our small sample size. The number of events reported per 1,000 ICU patient days is markedly lower than that reported in previous studies , 15, 16.Second, our near miss system captures limited information in order to minimize the time required to report an event. As such, additional data that could enhance our analysis, such as the provider’s role in the care of the patient, or the patient’s age and comorbidities are not available.Additionally, the differences observed between ICU near misses and near misses from other anesthesia locations may simply be due to differences in the nature of care in the ICU as compared to other locations where anesthesia is provided. And, differences between the causal mechanisms associated with our near misses and those previously published in the literature may be confounded by heterogeneity in the definitions of the mechanisms being studied. Furthermore, since our near miss system collects reports solely from providers within the department of anesthesia, it is not possible to compare reports submitted by anesthesia providers to those submitted by other specialists.Finally, since our data were collected from a single academic anesthesia department with a large number of critical care trained faculty, our findings may not be generalizable to other institutions.To our knowledge, this is the first analysis of near miss reports associated with ICU care from the perspective of the anesthesia provider. A few causal mechanisms explained the majority of ICU near misses, providing targets for quality improvement. Errors associated with airway management may be more common in the ICU than other anesthesia locations; further efforts to understand the dangers of airway management in the ICU are needed. Specialist consultants may be able to identify systems weaknesses not identified by critical care providers, and should be engaged in the ICU patient safety movement.