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Objective To identify modifiable risk factors for miscarriage and to estimate the preventable proportion of miscarriages that could be attributed to these. Design Nationwide observational follow-up study. Setting Denmark. Population Ninety-one thousand four hundred and twenty seven pregnancies included in the Danish National Birth Cohort between 1996 and 2002. Methods Information on potentially modifiable risk factors before and during pregnancy was collected by means of computer-assisted telephone interviews and linkage with Danish registers, ensuring almost complete follow-up of pregnancy outcome. Modifiable risk factors for miscarriage were identified by multiple Cox regression analysis, which provided the background for our estimations of population attributable fractions. In all, 88 373 pregnancies had full information on all covariates and were included in this analysis. Main outcome measures Miscarriage before 22 completed weeks of gestation. Results The potentially modifiable pre-pregnant risk factors associated with increased miscarriage risk were: age of 30 years or more at conception, underweight, and obesity. During pregnancy the modifiable risk factors were: alcohol consumption, lifting of >20 kg daily, and night work. We estimated that 25.2% of the miscarriages might be prevented by reduction of all these risk factors to low risk levels. Modification of risk factors acting before and during pregnancy could lead to prevention of 14.7 and 12.5%, respectively, of the miscarriages. Maternal age at conception and alcohol consumption were the most important risk factors. Conclusions Miscarriage risk is increased by multiple potentially modifiable risk factors and a considerable proportion of miscarriages may be preventable. [ABSTRACT FROM AUTHOR]

In survival analysis with competing risks, the transformation model allows different functions between the outcome and explanatory variables. However, the model's prediction accuracy and the interpretation of parameters may be sensitive to the choice of link function. We review the practical implications of different link functions for regression of the absolute risk (or cumulative incidence) of an event. Specifically, we consider models in which the regression coefficients β have the following interpretation: The probability of dying from cause D during the next t years changes with a factor exp(β) for a one unit change of the corresponding predictor variable, given fixed values for the other predictor variables. The models have a direct interpretation for the predictive ability of the risk factors. We propose some tools to justify the models in comparison with traditional approaches that combine a series of cause-specific Cox regression models or use the Fine-Gray model. We illustrate the methods with the use of bone marrow transplant data. [ABSTRACT FROM AUTHOR]

BACKGROUND: Patients with alcoholic cirrhosis are at higher risk for hepatocellular carcinoma (HCC). The role of HCC surveillance for these patients is undefined. OBJECTIVE: To provide population-based estimates of HCC incidence and comparisons of HCC-related mortality and total mortality among patients with alcoholic cirrhosis as a basis for assessing the role of HCC surveillance. DESIGN: Nationwide, registry-based, historical cohort study. SETTING: Denmark. PATIENTS: All Danish citizens with a first-time hospital diagnosis of alcoholic cirrhosis from 1993 to 2005. MEASUREMENTS: Hepatocellular carcinoma incidence and mortality starting 1 year after diagnosis of alcoholic cirrhosis through 2009; ratio of HCC-related mortality to total mortality. RESULTS: Among 8482 patients, 169 developed HCC. A total of 5734 patients died, 151 of whom had developed HCC. Five-year cumulative HCC risk was 1.0% (95% CI, 0.8% to 1.3%), and 5-year cumulative mortality was 43.7% (CI, 42.6% to 44.7%). Only 1.8% of all deaths were HCC-related. In sensitivity analyses that included all possible HCC diagnoses and a subpopulation of patients who were followed by hepatologists, the highest 5-year HCC risk was 1.9% (CI, 0.8% to 3.9%). These patients did not have higher mortality than patients in the nationwide cohort. LIMITATION: Cirrhosis and HCC diagnoses were made by hospital physicians without uniform clinical criteria, and use of registry data precluded detailed information on clinical care of patients, including HCC surveillance. CONCLUSION: Danish patients with alcoholic cirrhosis have a low risk for HCC, and HCC contributes little to their high mortality. On the basis of these data, HCC surveillance would be expected to have a minimal effect on mortality and is unlikely to be cost-effective. PRIMARY FUNDING SOURCE: None. [ABSTRACT FROM AUTHOR]

We review sources of bias which can affect non-randomized cohort studies of non-specific effects of vaccines on child mortality. Using examples from the literature on non-specific effects, we describe different sources of selection and information bias, and, where possible, outline analysis strategies to mitigate or eliminate such biases. [ABSTRACT FROM AUTHOR]

Objective To examine whether late and very-late first-contact schizophrenia carry a risk for later development of dementia. Methods By linkage of the psychiatric and the somatic nation-wide registers of all out- and in-patients with hospital contact in Denmark, we identified all patients with first ever contact during the period from January 1994 to December 2001 with one of the index main diagnoses: late (age >=40) and very-late first-contact (age >=60) schizophrenia. First contact osteoarthritis patients as well as data on the general population were used as controls. The first diagnosis of dementia for each individual at discharge or at out-patient contact was established. The probability of getting a dementia diagnosis is estimated using Poisson regression models with dementia as the outcome of interest. Results Twelve thousand six hundred and sixteen and 7,712 individuals were included in the late and very-late sample, respectively. Follow-up time was between 3.00 and 4.58 years. The rate ratio (RR) of developing dementia in late and very-late first-contact schizophrenia compared to osteoarthritis patients were 3.47 (95%CI: 2.19-5.50) and 3.15 (95%CI: 1.93-5.14), respectively. Compared to the general population the RR were 2.36 (95%CI: 1.54-3.62) and 2.21 (95%CI: 1.39-3.50), respectively. Conclusion schizophrenic patients with late- and very-late first-contact with the psychiatric hospital system are at two to three times higher risk of subsequently getting a diagnosis of dementia compared to patients with osteoarthritis and compared to the general population. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Objective: To examine whether very late first-contact delusional disorder carries a risk for later development of dementia.Methods: By linkage of the psychiatric and the somatic nationwide registers of all out- and in-patients with hospital contact in Denmark, we included all 60þ patients with first ever from 1 January 1994 to 31 December 2001 with the index main diagnosis: delusional disorder. First contact osteoarthritis patients as well as the general population were used as controls. A total of 1437 patients with persistent delusional disorder and 7302 patients with osteoarthritis were included. Median follow-up time until first diagnosis of dementia at discharge was 1.87 and 4.40 years, respectively. The probability of getting a dementia diagnosis was estimated using Poissonregression models with dementia as the outcome of interest.Results: Patients with very late first-contact delusional disorder had an 8.14 (95% CI, 6.51; 10.19) times increased rate of subsequently developing dementia compared with very late first contact osteoarthritis patients. Compared with the general population the rate ratio was 5.49 (95% CI, 4.81; 6.26).Conclusion: Very late first-contact delusional disorder increases the risk of subsequently getting a diagnosis of dementia 5-8 times compared with osteoarthritis patients and the general population. [ABSTRACT FROM AUTHOR]

Background: Depression and anxiety is prevalent among patients with dementia but the extent to which these conditions are treated with antidepressants has not previously been investigated.Methods: Nationwide register-based data in Denmark were used to identify all patients diagnosed with dementia or osteoarthritis at hospital admission or at first outpatient contact during the period 1995-2000. Rates of subsequent purchase of antidepressants from pharmacies were then calculated. Further, the rate of antidepressant use for patients with dementia was compared with the rate in a gender-, age-, and calendar-matched sample of the general population.Results: In total, 24,137 patients with a main diagnosis of dementia and 100,378 patients with a main first diagnosis of osteoarthritis were incorporated in the study. A total of 43.2% of patients with dementia received antidepressants during follow-up compared to 16.0% of patients with osteoarthritis. Among patients with a diagnosis of dementia, the rate of subsequently purchasing antidepressants was 4.17 times higher (95% CI = 4.05-4.29) than that of patients with a first diagnosis of osteoarthritis, and 8.85 times higher (95% CI = 8.68-9.03) than that of a gender-, age- and calendar-matched sample of the general population. The rate was increased in all subgroups of patients regardless of gender, age, socio-economic group and time since diagnosis.Conclusions: The findings challenge the widely held contention that depression and anxiety in patients with dementia is underdiagnosed and undertreated in clinical practice. [ABSTRACT FROM AUTHOR]

The authors investigated the shape, sex- and age-dependency, and possible confounding of the association between birth weight and systolic blood pressure (SBP) in 197,954 adults from 20 Nordic cohorts (birth years 1910-1987), one of which included 166,249 Swedish male conscripts. Random-effects meta-regression analyses were performed on estimates obtained from age- and sex-stratified analyses within each of the cohorts. There was an inverse association between birth weight and SBP, irrespective of adjustment for concurrent body mass index. The association was linear for males, but for females with a birth weight greater than 4 kg, SBP increased with birth weight (p < 0.01). The association was stronger in the older age groups (p < 0.05), although this could have been a birth cohort effect. The association was stronger among females than among males (p = 0.005) when birth weight was less than or equal to 4 kg. The estimated effect of birth weight on SBP at age 50 years was -1.52 mmHg/kg (95% confidence interval: -2.27, -0.77) in men and -2.80 mmHg/kg (95% confidence interval: -3.85, -1.76) in women. Exclusion of the Swedish conscripts produced nearly identical results. This meta-analysis supports the evidence of an inverse birth weight-SBP association, regardless of adjustment for concurrent body size. It also reveals important heterogeneity in the shape and strength of the association by sex and age. [ABSTRACT FROM AUTHOR]

The association between treatment with Selective serotonin reuptake inhibitors (SSRIs) and suicide in children and adolescents on the individual and ecological level were examined in a nationwide Danish pharmacoepidemiological register-linkage study including all persons aged 10-17 years treated with antidepressants during the period 1995-1999 (n=2,569) and a randomly selected control population (n=50,000). A tripartite approach was used. In Part 1, changes in youth suicide and use of antidepressants were examined. In Part 2, we made an assessment of youth suicide characteristics. In Part 3, we analysed the relative risk (RR) of suicide according to antidepressant treatment corrected for psychiatric hospital contact to minimize the problem of confounding by indication. The use of SSRIs among children and adolescents increased substantially during the study period, but the suicide rate remained stable (Part 1). Among 42 suicides nationally aged 10-17 years at death, none was treated with SSRIs within 2 weeks prior to suicide (Part 2). There was an increased rate of suicide associated with SSRIs (RR=4.47), however, not quite significant (95% CI: 0.95-20.96), when adjusted for severity of illness (Part 3). Conclusively, we were not able to identify an association between treatment with SSRIs and completed suicide among children and adolescents. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The sparse knowledge of the aetiology of pelvic pain in pregnancy makes evidence based prevention a limited option. The aim of this study was to examine the relation between pelvic pain in pregnancy and physical and psychosocial working conditions. METHODS: This study used self reported data on working conditions for 1219 cases and 1539 controls, sampled as a nested case-control study within the Danish national birth cohort. Cases and controls were selected on the basis of self reported pelvic pain intensity, pain localisation, and pain impact on daily living activities. Exposure data were collected prospectively; early in pregnancy and before the onset of pelvic pain. Main outcome measures were odds ratios for pelvic pain in pregnancy as a function of physical and psychosocial working conditions. RESULTS: Pregnant women with fixed evening work and with rotating shifts (without night shift) had odds ratios for pelvic pain in pregnancy of 1.76 (95% confidence intervals 1.04 to 2.96) and 1.65 (1.22 to 2.24), respectively, compared with women with day work. Physically strenuous work was associated with an almost 50% increased risk of pelvic pain in pregnancy (1.47; 1.17 to 1.84). In women who were under high psychosocial strain at work odds ratio was 1.39 (1.12 to 1.74) compared with women with low job strain. CONCLUSION: Both physically and psychosocially demanding working conditions, measured by physically strenuous work, rotating shifts, and high job strain, are associated with an increased reporting of pelvic pain in pregnancy. [ABSTRACT FROM AUTHOR]

BACKGROUND: It has been suggested that the level of high-density lipoprotein cholesterol (HDL-C) in the blood can be used as a marker of recent alcohol intake. However, before using HDL-C as a predictor of alcoholism, the relation between alcohol intake and HDL-C in the entire range of consumption must be explored. Most studies model the relation between alcohol intake and HDL-C linearly, although a threshold effect is expected. The objective of this study was to evaluate the shape of the relation between intake of alcohol and HDL-C and to determine whether there are differential effects of beer, wine, and spirits on HDL-C and whether they remain after adjusting for total alcohol. METHOD: The relation between alcohol intake and HDL-C was investigated by means of generalized additive models using data from the Copenhagen City Heart Study. RESULTS: A nonlinear effect of alcohol improved the model fit significantly, and the nonlinearity of alcohol was highly significant in both men and women. The relation was concave: HDL-C was stable in men and women who drank more than approximately 35 and 20 drinks per week, respectively. We found a significant nonlinear term of wine on HDL-C in men after adjustment for total alcohol intake. CONCLUSIONS: There was a concave relation between alcohol intake and HDL-C, indicating a threshold effect of alcohol on HDL-C. The association between wine and HDL-C in men after adjusting for total alcohol intake may be due to residual lifestyle confounding. [ABSTRACT FROM AUTHOR]

This paper deals with the competing risks model as a special case of a multi-state model. The properties of the model are reviewed and contrasted to the so-called latent failure time approach. The relation between the competing risks model and right-censoring is discussed and regression analysis of the cumulative incidence function briefly reviewed. Two real data examples are presented and a guide to the practitioner is given. [ABSTRACT FROM AUTHOR]

An introduction to event history analysis via multi-state models is given. Examples include the two-state model for survival analysis, the competing risks and illness–death models, and models for bone marrow transplantation. Statistical model specification via transition intensities and likelihood inference is introduced. Consequences of observational patterns are discussed, and a real example concerning mortality and bleeding episodes in a liver cirrhosis trial is discussed. [ABSTRACT FROM AUTHOR]

Background: Mortality from smoking-related diseases in women is increasing worldwide. Studies comparing hazards associated with smoking in women and men based on a sufficient number of heavy smokers of both genders are lacking.Methods: We used pooled data from three prospective population studies conducted in Copenhagen to compare total and cause-specific mortality in relation to smoking habits. A total of 30917 subjects, 44% women, with initial examinations between 1964 and 1992 were followed until 1994 for date and cause of death.Results: During follow up, 2900 women and 5744 men died. Smoking characteristics differed considerably with gender, particularly in the older subjects. Overall mortality rates in smokers were approximately twice those in people who never smoked. Positive associations with smoking in both men and women were confirmed for all-cause mortality as well as mortality from respiratory disease, vascular disease, lung cancer, and other tobacco-related cancers. Despite large gender differences in age at smoking debut, total and cause-specific relative mortality in smokers was similar in men and women. After excluding non-inhalers, relative risks associated with smoking for respiratory and vascular disease were higher for women than men whereas there were no gender differences in smoking related risk of cancers.Conclusions: The relative risks suggest that women may be more sensitive than men to some of the deleterious effects of smoking. However, because of lower baseline mortality rates in women, rate differences may be similar and results should be interpreted with caution. [ABSTRACT FROM AUTHOR]

Background: Two recent much cited publications have raised the concern that risk associated with cigarette smoking has so far been underestimated. In this study we wish to determine whether excess all-cause mortality associated with smoking has increased during the last 20-30 years in a study population representative of the general Danish population and whether any such changes relate to changes in smoking behaviour.Methods: Pooled data from three prospective population studies conducted in Copenhagen with detailed information on smoking habits. A total of 31,194 subjects, 17,669 males and 13,525 females, initially examined between 1964 and 1992 with examinations repeated at intervals from 1-10 years, were followed until 1995 for all-cause mortality. Relative mortality risk in smokers versus never-smokers was calculated within periods of five calendar years and compared throughout the study period.Results: Male smokers' exposure did not change during the study period whereas female smokers' exposure to tobacco increased in terms of age at smoking onset, quantity smoked and depth of inhalation. During follow-up 5744 males and 2900 females died. In males, death rate ratios (comparing continuous smokers with never-smokers) did not change in the study period. In females, ratios increased from 1964-1978 to 1979-1994 by a factor of 1.3 (95% confidence interval 1.0-1.8).Conclusions: In agreement with the observed changes in smoking habits, excess mortality in male smokers did not increase whereas excess mortality in female smokers increased slightly. [ABSTRACT FROM AUTHOR]

Editorial. Comments on the development of the field of survival analysis as an independent statistical discipline. Introduction of the framework for counting processes, martingales and stochastic integrals; Emphasis of the multistate models on medical and epidemiological applications; Evaluation of the handling of competing risks in a disease course.

Objective: To determine the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) compared with contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), and Fluorine-18-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for diagnosing suspected liver metastases in patients with newly diagnosed colorectal cancer (CRC)., Methods: The meta-analysis using the bivariate model included studies on patients with newly diagnosed CRC only and excluded patients with non-CRC liver metastases, known liver metastases, patients treated with chemotherapy and local treatments, e.g. hepatic resection or radiofrequency ablation. We used QUADAS-2 to assess the methodological quality of the studies., Results: We included 32 studies, 6 studies evaluated the accuracy of CEUS ( n  = 937 participants), 26 studies evaluated CECT ( n  = 2,582), 8 studies evaluated MRI ( n  = 564) and 6 studies evaluated FDG-PET/CT ( n  = 813). Sensitivity: FDG-PET/CT 94.4% [95% CI: 90.7-98.1%], MRI 92.9% [95% CI: 88.8-97.0%], CEUS 86.1% [95% CI: 78.0-94.3%] and CECT 84.6% [95% CI: 79.3-89.9%]. Specificity FDG-PET/CT 97.9% [95% CI: 95.9-99.9%], CEUS 96.1% [95% CI: 93.6-98.6%], MRI 94.4% [95% CI: 90.5-98.3%], and CECT 94.3% [95% CI: 91.8-96.8%]., Conclusion: FDG-PET/CT had significantly higher sensitivity and specificity than CECT, and significantly higher sensitivity than CEUS. MRI had a significantly higher sensitivity than CEUS, but a lower non-significant specificity. CECT had the lowest sensitivity and specificity., Prospero Registration Details: CRD42017055015 and CRD42017082996.

Objectives: The risk of suicidal behavior after discharge from psychiatric admission is high. The aim of this study was to examine whether the SAFE intervention, an implementation of a systematic safer discharge procedure, was associated with a reduction in suicidal behavior after discharge., Methods: The SAFE intervention was implemented at Mental Health Center Copenhagen in March 2018 and consisted of three systematic discharge procedures: (1) A face-to-face meeting between patient and outpatient staff prior to discharge, (2) A face-to-face meeting within the first week after discharge, and (3) Involvement of relatives. Risk of suicide attempt at six-month post-discharge among patients discharged from the SAFE intervention was compared with patients discharged from comparison mental health centers using propensity score matching., Results: 7604 discharges took place at the intervention site, which were 1:1 matched with discharges from comparison sites. During the six months of follow-up, a total of 570 suicide attempts and 25 suicides occurred. The rate of suicide attempt was 11,652 per 100,000 person-years at the SAFE site, while it was 10,530 at comparisons sites. No observable difference in suicide attempt 1.10 (95% CI: 0.89-1.35) or death by suicide (OR = 1.27; 95% CI:0.58-2.81) was found between sites at 6-month follow-up., Conclusion: No difference in suicidal behavior between the sites was found in this pragmatic study. High rates of suicidal behavior were found during the 6-months discharge period, which could suggest that a preventive intervention should include support over a longer post-discharge period than the one-week follow-up offered in the SAFE intervention., (© 2023. The Author(s).)

Importance: All-cause mortality and the risk for age-related medical disease is increased in individuals with psychiatric illness, but the underlying biological mechanisms are not known. Oxidative stress on nucleic acids (DNA and RNA; NA-OXS) is a molecular driver of aging and a potential pathophysiological mechanism in a range of age-related disorders., Objective: To study the levels of markers of NA-OXS in a large cohort of community-dwelling individuals with and without psychiatric illness and to evaluate their association with prospective all-cause mortality., Design, Setting, and Participants: This cohort study used a combined cohort of participants from 2 population-based health studies: the Danish General Suburban Population Study (January 2010 to October 2013) and nondiabetic control participants from the Vejle Diabetes Biobank study (March 2007 to May 2010). Individual history of psychiatric illness was characterized using register data on psychiatric diagnoses and use of psychotropic drugs before baseline examination. Urinary markers of systemic RNA (8-oxo-7,8-dihydroguanosine [8-oxoGuo]) and DNA (8-oxo-7,8-dihydro-2'-deoxyguanosine [8-oxodG]) damage from oxidation were measured by ultraperformance liquid chromatography-tandem mass spectrometry. Cox proportional hazard regression models were applied for survival analyses, using register-based all-cause mortality updated to May 2023. The follow-up time was up to 16.0 years., Exposures: History of psychiatric illness., Main Outcomes and Measures: Mortality risk according to psychiatric illness status and 8-oxoGuo or 8-oxodG excretion level., Results: A total of 7728 individuals were included (3983 [51.5%] female; mean [SD] age, 58.6 [11.9] years), 3095 of whom (40.0%) had a history of psychiatric illness. Mean (SD) baseline 8-oxoGuo was statistically significantly higher in individuals with psychiatric illness than in those without (2.4 [1.2] nmol/mmol vs 2.2 [0.9] nmol/mmol; P < .001), whereas 8-oxodG was not. All-cause mortality was higher in the psychiatric illness group vs the no psychiatric illness group (hazard ratio [HR], 1.44; 95% CI, 1.27-1.64; P < .001) and increased sequentially with each increasing tertile of 8-oxoGuo excretion in both groups to an almost doubled risk in the psychiatric illness/high 8-oxoGuo group compared to the no psychiatric illness/low 8-oxoGuo reference group (HR, 1.99; 95% CI, 1.58-2.52; P < .001). These results persisted after adjustment for a range of potential confounders and in a sensitivity analysis stratified for sex., Conclusions and Relevance: This study establishes systemic oxidative stress-induced damage to RNA as a potential mechanism in the accelerated aging observed in psychiatric disorders and urinary 8-oxoGuo as a potentially useful marker of mortality risk in individuals with psychiatric illness.

In randomised controlled trials, the outcome of interest could be recurrent events, such as hospitalisations for heart failure. If mortality rates are non-negligible, both recurrent events and competing terminal events need to be addressed when formulating the estimand and statistical analysis is no longer trivial. In order to design future trials with primary recurrent event endpoints with competing risks, it is necessary to be able to perform power calculations to determine sample sizes. This paper introduces a simulation-based approach for power estimation based on a proportional means model for recurrent events and a proportional hazards model for terminal events. The simulation procedure is presented along with a discussion of what the user needs to specify to use the approach. The method is flexible and based on marginal quantities which are easy to specify. However, the method introduces a lack of a certain type of dependence. This is explored in a sensitivity analysis which suggests that the power is robust in spite of that. Data from a randomised controlled trial, LEADER, is used as the basis for generating data for a future trial. Finally, potential power gains of recurrent event methods as opposed to first event methods are discussed., (© 2024 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Objectives: To investigate how body height and trajectories of height from infancy through childhood and adolescence were associated with spinal pain in pre- and late adolescence., Methods: This prospective study included 43,765 individuals born into The Danish National Birth Cohort (DNBC) from 1996 to 2003. DNBC-data were linked with health and social data identified from Statistics Denmark registers. Spinal pain was self-reported in both the 11-year- and 18-year follow-up of DNBC and classified according to severity. Body height was measured from birth and onwards and further modelled as distinct developmental height trajectories by using latent growth curve modelling. Associations were estimated by using multinomial logistic regression models., Results: Taller body height in childhood and adolescence was associated with approximately 20% increased likelihood of spinal pain in pre- and late adolescence among girls compared to their peers in the normal height group. For boys, taller body height was associated with spinal pain by late adolescence only. Spinal pain in pre-adolescence almost doubled the likelihood of spinal pain in late adolescence regardless of body height at age 18. Height trajectories confirmed the relationship for girls with the tall individuals being most likely to have spinal pain in both pre- and late adolescence., Conclusion: Tall body height during childhood and adolescence predisposes to spinal pain among girls in both pre-and late adolescence, and among boys in late adolescence. Body height is a contributing factor to the pathogenesis of spinal pain in adolescence; however, the mechanisms may be related to growth velocity, but for now uncertain., (© 2023. The Author(s).)

Background: Multiple reviews have been conducted on the associations between residential mold and dampness and respiratory outcomes in children, with few specifically investigating respiratory tract infections (RTIs)., Objective: We aimed to review and synthesize the available epidemiological literature on mold and dampness and risk of RTIs and respiratory symptoms compatible with RTIs in children living in high-income countries., Method: We performed a systematic search of literature available from MEDLINE, Embase, and Web of Science for observational studies. We conducted meta-analyses using two-level random effects (RE) and multi-level random effects (ML) models for contrasts of three exposure and three outcome categories, including multiple estimates reported by single studies. We report central estimates for pooled odds ratios (OR) and 95 % confidence intervals (CI).We conducted a risk of bias assessment using the Joanna Briggs Initiative (JBI) checklists for cross-sectional, case-control, and cohort studies. We additionally report on cumulative meta-analyses, leave-one-out analyses of single estimates, subgroup analyses by study quality and study design and inclusion of all effect estimates., Results: Of the 932 studies initially screened by title and abstract, we included 30 studies with 267 effect estimates that met the inclusion criteria. Most were cross-sectional (n = 22), with fewer cohort (n = 5) and case-control (n = 3) studies. Most of the studies were according to the bias assessment of poor or fair quality (n = 24). The main meta-analyses generally provided similar results regardless of statistical model and central estimates ranged from OR 1.28 (95 % CI; 1.08, 1.53) for dampness and RTIs to OR 1.76 (95 % CI; 1.64, 1.88) for mold and respiratory symptoms. Most analyses were of moderate heterogeneity. Funnel plots did not indicate strong publication bias., Conclusion: Our results are compatible with a weak to moderate effect of residential mold and or dampness on risk of RTIs in children in high-income countries. However, these results are based primarily on cross-sectional studies., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Importance: Few studies have estimated the lifetime incidence of mental health disorders and the association with socioeconomic functioning., Objective: To investigate whether the lifetime incidence of treated mental health disorders is substantially higher than previously reported and estimate associations with long-term socioeconomic difficulties., Design, Setting, and Participants: This nationwide population-based register linkage study includes a randomly selected sample of 1.5 million individuals from the population of Denmark from 1995 to 2018. Data were analyzed from May 2022 to March 2023., Main Outcomes and Measures: Lifetime incidence of any treated mental health disorder in the general population was estimated from birth to age 100 years taking into account the competing risk of all-cause death and associations with socioeconomic functioning. Register measures were (1) from hospitals, a diagnosis of any mental health disorder at an inpatient/outpatient hospital contact; (2) from hospitals and prescription statistics, any mental health disorder/psychotropic prescription, including a hospital-contact diagnosis, or any psychotropic medication prescribed by physicians, including general practitioners or private psychiatrists; and (3) socioeconomic functioning as indicated by highest educational achievement, employment, income, residential status, and marital status., Results: Among a sample of 462 864 individuals with any mental health disorder, the median (IQR) age was 36.6 years (21.0-53.6 years), 233 747 (50.5%) were male, and 229 117 (49.5%) were female. Of these, 112 641 were registered with a hospital-contact mental health disorder diagnosis and 422 080 with a prescription of psychotropic medication. The cumulative incidence of a hospital-contact mental health disorder diagnosis was 29.0% (95% CI, 28.8-29.1), 31.8% (95% CI, 31.6-32.0) for females, and 26.1% (95% CI, 25.9-26.3) for males. When also considering psychotropic prescriptions, the cumulative incidence of any mental health disorder/psychotropic prescription was 82.6% (95% CI, 82.4-82.6), 87.5% (95% CI, 87.4-87.7) for females, and 76.7% (95% CI, 76.5-76.8) for males. Socioeconomic difficulties were associated with mental health disorder/psychotropic prescriptions, including lower income (hazard ratio [HR], 1.55; 95% CI, 1.53-1.56), increased unemployment or disability benefit (HR, 2.50; 95% CI, 2.47-2.53), and a greater likelihood of living alone (HR, 1.78; 95% CI, 1.76-1.80) and being unmarried (HR, 2.02; 95% CI, 2.01-2.04) during long-term follow-up. These rates were confirmed in 4 sensitivity analyses with the lowest being 74.8% (95% CI, 74.7-75.0) (1) by using varying exclusion periods, (2) by excluding prescriptions of anxiolytics and quetiapine that may be used for off-label indications, (3) by defining any mental health disorder/psychotropic prescription as any hospital-contact mental health disorder diagnosis or any psychotropic medication prescribed at least 2 times, and (4) by excluding individuals with somatic diagnoses for which psychotropics may be prescribed off-label., Conclusions and Relevance: This registry study of data from a large representative sample of the Danish population showed that the majority of individuals either received a diagnosis of a mental health disorder or were prescribed psychotropic medication during their lifetime, which was associated with subsequent socioeconomic difficulties. These findings may help change our understanding of normalcy and mental illness, reduce stigmatization, and further prompt rethinking the primary prevention of mental illness and future mental health clinical resources.

Jack-knife pseudo-observations have in recent decades gained popularity in regression analysis for various aspects of time-to-event data. A limitation of the jack-knife pseudo-observations is that their computation is time consuming, as the base estimate needs to be recalculated when leaving out each observation. We show that jack-knife pseudo-observations can be closely approximated using the idea of the infinitesimal jack-knife residuals. The infinitesimal jack-knife pseudo-observations are much faster to compute than jack-knife pseudo-observations. A key assumption of the unbiasedness of the jack-knife pseudo-observation approach is on the influence function of the base estimate. We reiterate why the condition on the influence function is needed for unbiased inference and show that the condition is not satisfied for the Kaplan-Meier base estimate in a left-truncated cohort. We present a modification of the infinitesimal jack-knife pseudo-observations that provide unbiased estimates in a left-truncated cohort. The computational speed and medium and large sample properties of the jack-knife pseudo-observations and infinitesimal jack-knife pseudo-observation are compared and we present an application of the modified infinitesimal jack-knife pseudo-observations in a left-truncated cohort of Danish patients with diabetes., (© 2023. The Author(s).)

Discussion on "A formal causal interpretation of the case-crossover design" by Zach Shahn, Miguel A. Hernan, and James M. Robins., (© 2022 The Authors. Biometrics published by Wiley Periodicals LLC on behalf of International Biometric Society.)

Modifications of nucleic acids (DNA and RNA) from oxidative stress is a potential driver of aging per se and of mortality in age-associated medical disorders such as type 2 diabetes (T2D). In a human cohort, we found a strong prediction of all-cause mortality by a marker of systemic oxidation of RNA in patients with T2D (n = 2672) and in nondiabetic control subjects (n = 4079). The finding persisted after the adjustment of established modifiers of oxidative stress (including BMI, smoking, and glycated hemoglobin). In contrast, systemic levels of DNA damage from oxidation, which traditionally has been causally linked to both T2D and aging, failed to predict mortality. Strikingly, these findings were subsequently replicated in an independent general population study (n = 3649). The data demonstrate a specific importance of RNA damage from oxidation in T2D and general aging., (© 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.)

The analysis of recurrent events in the presence of terminal events requires special attention. Several approaches have been suggested for such analyses either using intensity models or marginal models. When analysing treatment effects on recurrent events in controlled trials, special attention should be paid to competing deaths and their impact on interpretation. This paper proposes a method that formulates a marginal model for recurrent events and terminal events simultaneously. Estimation is based on pseudo-observations for both the expected number of events and survival probabilities. Various relevant hypothesis tests in the framework are explored. Theoretical derivations and simulation studies are conducted to investigate the behaviour of the method. The method is applied to two real data examples. The bivariate marginal pseudo-observation model carries the strength of a two-dimensional modelling procedure and performs well in comparison with available models. Finally, an extension to a three-dimensional model, which decomposes the terminal event per death cause, is proposed and exemplified., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

For cohorts with long-term follow-up, the number of years lost due to a certain disease yields a measure with a simple and appealing interpretation. Recently, an overview of the methodology used for this goal has been published, and two measures have been proposed. In this work, we consider a third option that may be useful in settings in which the other two are inappropriate. In all three measures, the survival of the given dataset is compared to the expected survival in the general population which is calculated using external mortality tables. We thoroughly analyze the differences between the three measures, their assumptions, interpretation, and the corresponding estimators. The first measure is defined in a competing risk setting and assumes an excess hazard compared to the population, while the other two measures also allow estimation for groups that live better than the general population. In this case, the observed survival of the patients is compared to that in the population. The starting point of this comparison depends on whether the entry into the study is a hazard changing event (e.g., disease diagnosis or the age at which the inclusion criteria were met). Focusing on the newly defined life years difference measure, we study the estimation of the variance and consider the possible challenges (e.g., extrapolation) that occur in practice. We illustrate its use with a dataset of French Olympic athletes. Finally, an efficient R implementation has been developed for all three measures which make this work easily available to subsequent users., (© 2023 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

An aggravation in mental health during the COVID-19 lockdown has been suggested but the impact on self-injury, suicidality and eating disorders (EDs) are less elucidated. Using linear regression in different data set-ups that is longitudinal (n = 7,579) and repeated cross-sectional data (n = 24,625) from the Danish National Birth Cohort, we compared self-reported self-injury, suicidality and symptoms of EDs from before through different pandemic periods until spring 2021. The longitudinal data indicate a reduction in the proportion of self-injury in men (-3.2% points, 95% confidence interval (CI) = -4.3%; -2.2%, P < 0.001, d.f. = 2) and women (5.7% points, 95% CI = -6.6%; -4.8%, P < 0.001, d.f. = 2) and of suicide ideation in men (-3.0% points, 95% CI = -4.6%; -1.4%, P = 0.002, d.f. = 2) and women (-7.4% points, 95% CI = -8.7%; -6.0%, P < 0.001, d.f. = 2), as well as symptoms of EDs in women (-2.3% points, 95% CI = -3.2%; -1.4%, P < 0.001, d.f. = 2). For suicide attempt, indication of an increase was observed in men only (0.4% points, 95% CI = 0.1%; 0.7%, P = 0.019, d.f. = 2). In the repeated cross-sectional data, we observed no changes in any of the outcomes. Our findings provide no support for the increase in self-injury, suicidality and symptoms of EDs after the lockdowns. Key limitations are differential attrition and varying age in pre- and post-lockdown measures in the longitudinal data., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Few studies have reported real-life data on socio-economic functioning in patients with bipolar disorder and their unaffected first-degree relatives., Methods: We used Danish nation-wide population-based longitudinal register linkage to investigate socio-economic functioning in 19 955 patients with bipolar disorder, their 13 923 siblings and 20 sex, age and calendar-matched control individuals from the general population. Follow-up was from 1995 to 2017., Results: Patients with a diagnosis of bipolar disorder had lower odds of having achieved the highest educational level [OR 0.75 (95% confidence interval (CI) 0.73-0.77)], being employed [OR 0.16 (95% CI 0.159-0.168)], having achieved the 80% highest quartile of income [OR 0.33 (95% CI 0.32-0.35)], cohabitating [OR 0.44 (95% CI 0.43-0.46)] and being married [OR 0.54 (95% CI 0.52-0.55)] at first contact to hospital psychiatry as inpatient or outpatient compared with control individuals from the general population. Similarly, siblings to patients with bipolar disorder had a lower functioning within all five socio-economic areas than control individuals. Furthermore, patients and partly siblings showed substantially decreased ability to enhance their socio-economic functioning during the 23 years follow-up compared to controls., Conclusions: Socio-economic functioning is substantially decreased in patients with bipolar disorder and their siblings and does not improve during long-term follow-up after the initial hospital contact, highlighting a severe and overlooked treatment gap.

Background: Preterm birth is one of the most important contributors to neonatal mortality and morbidity. Experiencing stress during pregnancy may increase the risk of adverse birth outcomes, including preterm birth. This association has been observed in previous studies, but differences in measures used limit comparability., Objective: The objective of the study was to investigate the association between two measures of maternal stress during pregnancy, life stress and emotional distress, and gestation duration., Methods: Women recruited in the Danish National Birth Cohort from 1996 to 2002, who provided information on their stress level during pregnancy and expecting a singleton baby, were included in the study. We assessed the associations between the level of life stress and emotional distress in quartiles, both collected at 31 weeks of pregnancy on average, and the rate of giving birth using Cox regression within intervals of the gestational period., Results: A total of 80,991 pregnancies were included. Women reporting moderate or high levels of life stress vs no stress had a higher rate of giving birth earlier within all intervals of gestational age (e.g. high level: 27-33 weeks: hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.04, 1.84; 34-36 weeks: 1.10, 95% CI 0.97, 1.25; 37-38 weeks: 1.21, 95% CI 1.15, 1.28). These associations between life stress and preterm birth were mainly driven by pregnancy worries. For emotional distress, a high level of distress was associated with shorter length of gestation in the preterm (27-33 weeks: 1.38, 95% CI 1.02, 1.86; 34-36 weeks: 1.05, 95% CI 0.91, 1.19) and early term (1.11, 95% CI 1.04, 1.17) intervals., Conclusions: Emotional distress and life stress were shown to be associated with gestational age at birth, with pregnancy-related stress being the single stressor driving the association. This suggests that reverse causality may, at least in parts, explain the earlier findings of stress as a risk factor for preterm birth., (© 2022 The Authors. Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

SARS-CoV-2 is the pathogen responsible for COVID-19 that has claimed over six million lives as of July 2022. The severity of COVID-19 motivates a need to understand how it could evolve to escape potential treatments and to find ways to strengthen existing treatments. Here, we used the molecular modeling methods MD + FoldX and PyRosetta to study the SARS-CoV-2 spike receptor binding domain (S-RBD) bound to two neutralizing antibodies, B38 and CB6 and generated lists of antibody escape and antibody strengthening mutations. Our resulting watchlist contains potential antibody escape mutations against B38/CB6 and consists of 211/186 mutations across 35/22 S-RBD sites. Some of these mutations have been identified in previous studies as being significant in human populations (e.g., N501Y). The list of potential antibody strengthening mutations that are predicted to improve binding of B38/CB6 to S-RBD consists of 116/45 mutations across 29/13 sites. These mutations could be used to improve the therapeutic value of these antibodies., (© 2022. The Author(s).)

The interaction between the HIV-1 capsid and human nucleoporin 153 (NUP153) is vital for delivering the HIV-1 preintegration complex into the nucleus via the nuclear pore complex. The interaction with the capsid requires a phenylalanine/glycine-containing motif in the C-terminus of NUP153 (NUP153C). This study used molecular modeling and biochemical assays to comprehensively determine the amino acids in NUP153 that are important for capsid interaction. Molecular dynamics, FoldX, and PyRosetta simulations delineated the minimal capsid binding motif of NUP153 based on the known structure of NUP153 bound to the HIV-1 capsid hexamer. Computational predictions were experimentally validated by testing the interaction of NUP153 with capsid using an in vitro binding assay and a cell-based TRIM-NUP153C restriction assay. This work identified eight amino acids from P1411 to G1418 that stably engage with capsid, with significant correlations between the interactions predicted by molecular models and empirical experiments. This validated the usefulness of this multidisciplinary approach to rapidly characterize the interaction between human proteins and the HIV-1 capsid. IMPORTANCE The human immunodeficiency virus (HIV) can infect nondividing cells by interacting with the host nuclear pore complex. The host nuclear pore protein NUP153 directly interacts with the HIV capsid to promote viral nuclear entry. This study used a multidisciplinary approach combining computational and experimental techniques to comprehensively map the effect of mutating the amino acids of NUP153 on HIV capsid interaction. This work showed a significant correlation between computational and empirical data sets, revealing that the HIV capsid interacted specifically with only six amino acids of NUP153. The simplicity of the interaction motif suggested other FG-containing motifs could also interact with the HIV-1 capsid. Furthermore, it was predicted that naturally occurring polymorphisms in human and nonhuman primates would disrupt NUP153 interaction with capsid, potentially protecting certain populations from HIV-1 infection.

Multi-state models are frequently used when data come from subjects observed over time and where focus is on the occurrence of events that the subjects may experience. A convenient modeling assumption is that the multi-state stochastic process is Markovian, in which case a number of methods are available when doing inference for both transition intensities and transition probabilities. The Markov assumption, however, is quite strict and may not fit actual data in a satisfactory way. Therefore, inference methods for non-Markov models are needed. In this paper, we review methods for estimating transition probabilities in such models and suggest ways of doing regression analysis based on pseudo observations. In particular, we will compare methods using land-marking with methods using plug-in. The methods are illustrated using simulations and practical examples from medical research., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Importance: Nucleic acid damage from oxidative stress (NA-OXS) may be a molecular mechanism driving the severely increased morbidity and mortality from somatic causes in adults with psychiatric disorders., Objective: To systematically retrieve and analyze data on NA-OXS across the psychiatric disorder diagnostic spectrum., Data Sources: The PubMed, Embase, and PsycINFO databases were searched from inception to November 16, 2021. A hand search of reference lists of relevant articles was also performed., Study Selection: Key study inclusion criteria in this meta-analysis were as follows: adult human study population, measurement of any marker of DNA or RNA damage from oxidative stress, and either a (1) cross-sectional design comparing patients with psychiatric disorders (any diagnosis) with a control group or (2) prospective intervention. Two authors screened the studies, and 2 senior authors read the relevant articles in full and assessed them for eligibility., Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two authors performed data extraction independently, and a senior coauthor was consulted in cases of disagreement. Data were synthesized with random-effects and multilevel meta-analyses., Main Outcomes and Measures: The predefined hypothesis was that individuals with psychiatric disorders have increased NA-OXS levels. The main outcome was the standardized mean differences (SMDs) among patients and controls in nucleic acid oxidation markers compared across diagnostic groups. Analyses were divided into combinations of biological matrices and nucleic acids., Results: Eighty-two studies fulfilled the inclusion criteria, comprising 205 patient vs control group comparisons and a total of 10 151 patient and 10 532 control observations. Overall, the data showed that patients with psychiatric disorders had higher NA-OXS levels vs controls across matrices and molecules. Pooled effect sizes ranged from moderate for urinary DNA markers (SMD = 0.44 [95% CI, 0.20-0.68]; P < .001) to very large for blood cell DNA markers (SMD = 1.12 [95% CI, 0.69-1.55; P < .001). Higher NA-OXS levels were observed among patients with dementias followed by psychotic and bipolar disorders. Sensitivity analyses excluding low-quality studies did not materially alter the results. Intervention studies were few and too heterogenous for meaningful meta-analysis., Conclusions and Relevance: The results of this meta-analysis suggest that there is an association with increased NA-OXS levels in individuals across the psychiatric disorder diagnostic spectrum. NA-OXS may play a role in the somatic morbidity and mortality observed among individuals with psychiatric disorders.

Background: Observational studies determining the effect of red blood cell (RBC) donor sex on recipient mortality have been inconsistent. Emulating hypothetical randomized target trials using large real-world data and targeted learning may clarify potential adverse effects., Methods: In this retrospective cohort study, a RBC transfusion database from the Capital Region of Denmark comprising more than 900,000 transfusion events defined the observational data. Eligible patients were minimum 18 years, had received a leukocyte-reduced RBC transfusion, and had no history of RBC transfusions within the past year at baseline. The doubly robust targeted maximum likelihood estimation method coupled with ensembled machine learning was used to emulate sex-stratified target trials determining the comparative effectiveness of exclusively transfusing RBC units from either male or female donors. The outcome was all-cause mortality within 28 days of the baseline-transfusion. Estimates were adjusted for the total number of transfusions received on each day k, hospital of transfusion, calendar period, patient age and sex, ABO/RhD blood group of the patient, Charlson comorbidity score, the total number of transfusions received prior to day k , and the number of RBC units received on each day k from donors younger than 40 years of age., Findings: Among 98,167 adult patients who were transfused between Jan. 1, 2008, and Apr. 10, 2018, a total of 90,917 patients (54.6% female) were eligible. For male patients, the 28-day survival was 2.06 percentage points (pp) (95 % confidence interval [CI]: 1.81-2.32, P< 0.0001) higher under treatment with RBC units exclusively from male donors compared with exclusively from female donors. In female patients, exclusively transfusing RBC units from either male or female donors increased the 28-day survival with 0.64pp (0.52-0.76, P< 0.0001), and 0.62pp (0.49-0.75, P< 0.0001) compared with the current practice, respectively. No evidence of a sex-specific donor effect was found for female patients (0.02pp [-0.18-0.22]). The sensitivity analyses showed that a large unknown causal bias would have to be present to affect the conclusions., Interpretation: The results suggest that a sex-matched transfusion policy may benefit patients. However, a causal interpretation of the findings relies on the assumption of no unmeasured confounding, treatment consistency, positivity, and minimal model misspecifications., Funding: Novo Nordisk Foundation and the Innovation Fund Denmark., Competing Interests: P.B.-R, P.K.A., and K.B, declares no potential conflicts of interest. P.I.J reports ownership of stocks in Trial-Lab AB, Endothel Pharma ApS, TissueLink ApS, and MoxieLab ApS. S.B. owns stocks in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, and Lundbeck A/S, ALK A/S. S.B. is compensated for managing board memberships in Proscion A/S and Intomics A/S. S.B. is member of the Scientific Advisory Board of Biocenter Finland, the Scientific Advisory Board, Health Data UK, the Scientific Advisory Board of the Finnish Center of Excellence in Complex Disease Genetics (CoECDG), the Academy of Finland, the Scientific Advisory Board of the ELIXIR node in Luxembourg, the Scientific Advisory Board of Lund University Diabetes Centre, Lund University, Sweden, the Scientific Advisory Board, SciLifeLab in Sweden, and is chair of the Advisory Board for the Deep Medicine programme Oxford Martin School, University of Oxford, UK. P.I.J and S.B. declare that the financial interests listed have no impact on the submitted work., (© 2022 The Author(s).)