Effectiveness of Vortioxetine in Working Patients with Major Depressive Disorder in China: A Subgroup Analysis of the RELIEVE China Study.

Background: Major depressive disorder (MDD) causes significant functional impairments that impact on all aspects of patients' daily lives, including their ability to work, work productivity, and social life. Purpose: To assess the real-world effectiveness of the multimodal antidepressant vortioxetine in working patients with MDD in China. Patients and methods: RELIEVE China was an observational, prospective cohort study. Patients (aged ≥18 years) with MDD initiating treatment with vortioxetine in routine clinical practice settings were followed for 24 weeks. In this subgroup analysis, functioning was assessed using the Sheehan Disability Scale (SDS) in patients in full- or part-time work or education at baseline who remained on treatment at all follow-up visits (n=424). Depressive, cognitive, and anxiety symptoms were also assessed. For all endpoints, mean change from baseline at weeks 8 and 24 was analyzed using mixed models for repeated measures. Results: Clinically relevant and sustained improvements in patient functioning and measures of work productivity were observed over the 24 weeks of vortioxetine treatment. The adjusted mean (standard error) reduction in SDS total score from baseline was 5.4 (0.3) points at week 8 and 8.7 (0.3) points at week 24 (both P<0.001 vs baseline). Significant improvements were observed across all SDS domains and in levels of absenteeism and presenteeism (P<0.001 vs baseline for all endpoints at both time points). Significant improvements in depressive, cognitive, and anxiety symptoms were also observed over the study period (all P<0.001 vs baseline). The proportion of patients in remission (ie, 17-item Hamilton Depression Rating Scale score ≤7) after 24 weeks of vortioxetine treatment was 65.4%. Vortioxetine was well tolerated; nausea was the most common adverse event, reported by 18.6% of patients. Conclusion: These findings support the effectiveness and tolerability of vortioxetine in working patients with MDD receiving treatment in routine clinical practice settings in China.

Discovering Subgroups of Children With High Mortality in Urban Guinea-Bissau: Exploratory and Validation Cohort Study.

BACKGROUND: The decline in global child mortality is an important public health achievement, yet child mortality remains disproportionally high in many low-income countries like Guinea-Bissau. The persisting high mortality rates necessitate targeted research to identify vulnerable subgroups of children and formulate effective interventions. OBJECTIVE: This study aimed to discover subgroups of children at an elevated risk of mortality in the urban setting of Bissau, Guinea-Bissau, West Africa. By identifying these groups, we intend to provide a foundation for developing targeted health interventions and inform public health policy. METHODS: We used data from the health and demographic surveillance site, Bandim Health Project, covering 2003 to 2019. We identified baseline variables recorded before children reached the age of 6 weeks. The focus was on determining factors consistently linked with increased mortality up to the age of 3 years. Our multifaceted methodological approach incorporated spatial analysis for visualizing geographical variations in mortality risk, causally adjusted regression analysis to single out specific risk factors, and machine learning techniques for identifying clusters of multifactorial risk factors. To ensure robustness and validity, we divided the data set temporally, assessing the persistence of identified subgroups over different periods. The reassessment of mortality risk used the targeted maximum likelihood estimation (TMLE) method to achieve more robust causal modeling. RESULTS: We analyzed data from 21,005 children. The mortality risk (6 weeks to 3 years of age) was 5.2% (95% CI 4.8%-5.6%) for children born between 2003 and 2011, and 2.9% (95% CI 2.5%-3.3%) for children born between 2012 and 2016. Our findings revealed 3 distinct high-risk subgroups with notably higher mortality rates, children residing in a specific urban area (adjusted mortality risk difference of 3.4%, 95% CI 0.3%-6.5%), children born to mothers with no prenatal consultations (adjusted mortality risk difference of 5.8%, 95% CI 2.6%-8.9%), and children from polygamous families born during the dry season (adjusted mortality risk difference of 1.7%, 95% CI 0.4%-2.9%). These subgroups, though small, showed a consistent pattern of higher mortality risk over time. Common social and economic factors were linked to a larger share of the total child deaths. CONCLUSIONS: The study's results underscore the need for targeted interventions to address the specific risks faced by these identified high-risk subgroups. These interventions should be designed to work to complement broader public health strategies, creating a comprehensive approach to reducing child mortality. We suggest future research that focuses on developing, testing, and comparing targeted intervention strategies unraveling the proposed hypotheses found in this study. The ultimate aim is to optimize health outcomes for all children in high-mortality settings, leveraging a strategic mix of targeted and general health interventions to address the varied needs of different child subgroups.

Application of life course trajectory methods to public health data: A comparison of sequence analysis and group-based multi-trajectory modeling for modelling childhood adversity trajectories.

There is increasing awareness of the importance of modelling life course trajectories to unravel how social, economic and health factors relate to health over time. Different methods have been developed and applied in public health to classify individuals into groups based on characteristics of their life course. However, the application and results of different methods are rarely compared. We compared the application and results of two methods to classify life course trajectories of individuals, i.e. sequence analysis and group-based multi-trajectory modeling (GBTM), using public health data. We used high-resolution Danish nationwide register data on 926,160 individuals born between 1987 and 2001, including information on the yearly occurrence of 7 childhood adversities in 2 dimensions (i.e. family poverty and family dynamics). We constructed childhood adversity trajectories from 0 to 15 years by applying (1) sequence analysis using optimal matching and cluster analysis using Ward's method and (2) GBTM using logistic and zero-inflated Poisson regressions. We identified 2 to 8 cluster solutions using both methods and determined the optimal solution for both methods. Both methods generated a low adversity, a poverty, and a consistent or high adversity cluster. The 5-cluster solution using sequence analysis additionally included a household psychiatric illness and a late adversity cluster. The 4-group solution using GBTM additionally included a moderate adversity cluster. Compared with the solution obtained through sequence analysis, the solution obtained through GBTM contained fewer individuals in the low adversity cluster and more in the other clusters. We find that the two methods generate qualitatively similar solutions, but the quantitative distributions of children over the groups are different. The method of choice depends on the type of data available and the research question of interest. We provide a comprehensive overview of important considerations and benefits and drawbacks of both methods.

Early childhood adversity and body mass index in childhood and adolescence: linking registry data on adversities with school health records of 53,401 children from Copenhagen.

OBJECTIVE: We examined whether childhood adversity experienced in early childhood (0-5 years) is related to body mass index (BMI) in childhood (6-7 years) and adolescence (12-15 years). METHODS: This study combined data from the nationwide register-based DANLIFE study on childhood adversities with data on height and weight of school children in Copenhagen. Data were available for 53,401 children born in Denmark between 1980 and 1996. Children were divided into groups of early childhood adversity by applying group-based multi-trajectory modelling using their yearly count of childhood adversity in three dimensions (i.e., material deprivation, loss or threat of loss, and family dynamics) from 0-5 years. Direct and total associations between the early childhood adversity groups and BMI z-scores in childhood and adolescence were estimated using sex-stratified structural equation models. RESULTS: Five exclusive and exhaustive groups of early childhood adversity were identified, which were characterized by low adversity (51%), moderate material deprivation (30%), high material deprivation (14%), loss or threat of loss (3%) and high adversity (2%). Boys and girls exposed to moderate or high material deprivation and loss or threat of loss had a slightly higher BMI z-score, especially in adolescence, compared with those in the low adversity group, with the strongest association found for girls in the loss or threat of loss group (b (95% CI) = 0.18 (0.10, 0.26)). Additionally, boys in the high adversity group had a slightly lower BMI z-score in childhood than boys in the low adversity group (b (95% CI) = -0.12 (-0.22, -0.02)). CONCLUSIONS: Whereas associations with BMI were found for children and adolescents exposed to material deprivation, loss or threat of loss, and high adversity, the effect sizes were generally small. Contrary to prevailing hypotheses, weight changes in childhood is probably not a major explanatory mechanism linking early childhood adversity with later-life morbidity.

Childhood adversity and risk of type 2 diabetes in early adulthood: results from a population-wide cohort study of 1.2 million individuals.

AIMS/HYPOTHESIS: To examine whether childhood adversity is related to development of type 2 diabetes in early adulthood (16 to 38 years) among men and women. METHODS: We used nationwide register data of 1,277,429 individuals born in Denmark between 1 January 1980 and 31 December 2001, who were still resident in Denmark and without diabetes at age 16 years. Individuals were divided into five childhood adversity groups based on their yearly exposure to childhood adversities (from age 0-15 years) across three dimensions: material deprivation, loss or threat of loss, and family dynamics. We estimated HR and hazard differences (HD) for type 2 diabetes according to the childhood adversity groups using Cox proportional hazards and Aalen additive hazards models. RESULTS: During follow-up from age 16 to 31 December 2018, 4860 individuals developed type 2 diabetes. Compared with the low adversity group, the risk of type 2 diabetes was higher in all other childhood adversity groups among both men and women. For example, the risk was higher in the high adversity group characterised by high rates of adversity across all three dimensions among men (HR 2.41; 95% CI 2.04, 2.85) and women (1.58; 1.31, 1.91), translating into 36.2 (25.9, 46.5) additional cases of type 2 diabetes per 100,000 person-years among men and 18.6 (8.2, 29.0) among women. CONCLUSIONS/INTERPRETATION: Individuals who experienced childhood adversity are at higher risk of developing type 2 diabetes in early adulthood. Intervening upon proximal determinants of adversity may help reduce the number of type 2 diabetes cases among young adults.

Cancer burden among adolescents and young adults in relation to childhood adversity: a nationwide life-course cohort study of 1.2 million individuals.

Background: Childhood adversity such as poverty, loss of a parent, and dysfunctional family dynamics may be associated with exposure to environmental and behavioral hazards, interfere with normal biological functions, and affect cancer care and outcomes. To explore this hypothesis, we assessed the cancer burden among young men and women exposed to adversity during childhood. Methods: We undertook a population-based study using Danish nationwide register data on childhood adversity and cancer outcomes. Children who were alive and resident in Denmark until their 16th birthday were followed into young adulthood (16-38 years). Group-based multi-trajectory modelling was used to categorize individuals into five distinct groups: low adversity, early material deprivation, persistent material deprivation, loss/threat of loss, and high adversity. We assessed the association with overall cancer incidence, mortality, and five-year case fatality; and cancer specific outcomes for the four most common cancers in this age group in sex-stratified survival analyses. Findings: 1,281,334 individuals born between Jan 1, 1980, and Dec 31, 2001, were followed up until Dec 31, 2018, capturing 8229 incident cancer cases and 662 cancer deaths. Compared to low adversity, women who experienced persistent material deprivation carried a slightly lower risk of overall cancer (hazard ratio (HR) 0.90; 95% CI 0.82; 0.99), particularly due to malignant melanoma and brain and central nervous system cancers, while women who experienced high adversity carried a higher risk of breast cancer (HR 1.71; 95% CI 1.09; 2.70) and cervical cancer incidence (HR 1.82; 95% CI 1.18; 2.83). While there was no clear association between childhood adversity and cancer incidence in men, those men who had experienced persistent material deprivation (HR 1.72; 95% CI 1.29; 2.31) or high adversity (HR 2.27; 95% CI 1.38; 3.72) carried a disproportionate burden of cancer mortality during adolescence or young adulthood compared to men in the low adversity group. Interpretation: Childhood adversity is associated with a lower risk of some subtypes of cancer and a higher risk of others, particular in women. Persistent deprivation and adversity are also associated with a higher risk of adverse cancer outcomes for men. These findings may relate to a combination of biological susceptibility, health behaviors and treatment-related factors. Funding: None.

Childhood adversity and cardiovascular disease in early adulthood: a Danish cohort study.

AIMS: To examine the effect of childhood adversity on the development of cardiovascular disease (CVD) between ages 16 and 38, specifically focusing on ischaemic heart disease and cerebrovascular disease. METHODS AND RESULTS: Register data on all children born in Denmark between 1 January 1980 and 31 December 2001, who were alive and resident in Denmark without a diagnosis of CVD or congenital heart disease until age 16 were used, totalling 1 263 013 individuals. Cox proportional hazards and Aalen additive hazards models were used to estimate adjusted hazard ratios (HRs) and adjusted hazard differences of CVD from ages 16 to 38 in five trajectory groups of adversity experienced between ages 0 and 15. In total, 4118 individuals developed CVD between their 16th birthday and 31 December 2018. Compared with those who experienced low levels of adversity, those who experienced severe somatic illness and death in the family (men: adjusted HR: 1.6, 95% confidence interval: 1.4-1.8, women: 1.4, 1.2-1.6) and those who experienced very high rates of adversity across childhood and adolescence (men: 1.6, 1.3-2.0, women: 1.6, 1.3-2.0) had a higher risk of developing CVD, corresponding to 10-18 extra cases of CVD per 100 000 person-years in these groups. CONCLUSIONS: Individuals who have been exposed to childhood adversity are at higher risk of developing CVD in young adulthood compared to individuals with low adversity exposure. These findings suggest that interventions targeting the social origins of adversity and providing support for affected families may have long-term cardio-protective effects.

The effect on women's health of extending parental leave: a quasi-experimental registry-based cohort study.

BACKGROUND: Parental leave policies have been hypothesized to benefit mothers' mental health. We assessed the impact of a 6-week extension of parental leave in Denmark on maternal mental health. METHODS: We linked individual-level data from Danish national registries on maternal sociodemographic characteristics and psychiatric diagnoses. A regression discontinuity design was applied to study the increase in parental leave duration after 26 March 1984. We included women who had given birth between 1 January 1981 and 31 December 1987. Our outcome was a first psychiatric diagnosis following the child's birth, ascertained as the first day of inpatient hospital admission for any psychiatric disorder. We presented cumulative incidences for the 30-year follow-up period and reported absolute risk differences between women eligible for the reform vs not, in 5-year intervals. RESULTS: In all, 291 152 women were followed up until 2017, death, emigration or date of first psychiatric diagnosis. The median follow-up time was 29.99 years, corresponding to 10 277 547 person-years at risk. The cumulative incidence of psychiatric diagnoses at 30 years of follow-up was 59.5 (95% CI: 57.4 to 61.6) per 1000 women in the ineligible group and 57.5 (95% CI: 55.6 to 59.4) in the eligible group. Eligible women took on average 32.85 additional days of parental leave (95% CI: 29.20 to 36.49) and had a lower probability of having a psychiatric diagnosis within 5 years [risk difference (RD): 2.4 fewer diagnoses per 1000 women, 95% CI: 1.5 to 3.2] and up to 20 years after the birth (RD: 2.3, 95% CI: 0.4 to 4.2). In subgroup analyses, the risk reduction was concentrated among low-educated, low-income and single women. CONCLUSIONS: Longer parental leave may confer mental health benefits to women, in particular to those from disadvantaged backgrounds.

Causes of Outcome Learning: a causal inference-inspired machine learning approach to disentangling common combinations of potential causes of a health outcome.

Nearly all diseases are caused by different combinations of exposures. Yet, most epidemiological studies focus on estimating the effect of a single exposure on a health outcome. We present the Causes of Outcome Learning approach (CoOL), which seeks to discover combinations of exposures that lead to an increased risk of a specific outcome in parts of the population. The approach allows for exposures acting alone and in synergy with others. The road map of CoOL involves (i) a pre-computational phase used to define a causal model; (ii) a computational phase with three steps, namely (a) fitting a non-negative model on an additive scale, (b) decomposing risk contributions and (c) clustering individuals based on the risk contributions into subgroups; and (iii) a post-computational phase on hypothesis development, validation and triangulation using new data before eventually updating the causal model. The computational phase uses a tailored neural network for the non-negative model on an additive scale and layer-wise relevance propagation for the risk decomposition through this model. We demonstrate the approach on simulated and real-life data using the R package 'CoOL'. The presentation focuses on binary exposures and outcomes but can also be extended to other measurement types. This approach encourages and enables researchers to identify combinations of exposures as potential causes of the health outcome of interest. Expanding our ability to discover complex causes could eventually result in more effective, targeted and informed interventions prioritized for their public health impact.

Understanding the child mortality decline in Guinea-Bissau: the role of population-level nutritional status measured by mid-upper arm circumference.

BACKGROUND: Malnutrition is considered an important contributing factor to child mortality, and the mid-upper arm circumference (MUAC) is regarded as one of the better anthropometric predictors of child mortality. We explored whether the decline in child mortality over recent decades could be explained by changes in children's MUAC. METHODS: This prospective study analysed individual-level data from 47 731 children from the capital of Guinea-Bissau followed from 3 months until 36 months of age over 2003 to 2016. We used standardization to compare the mortality rate as if only the MUAC distribution had changed between an early period (2003-05) and a late period (2014-16). We adjusted the analyses for age, sex, socioeconomic-related possessions and maternal education. RESULTS: A total of 949 deaths were included in the analysis. The adjusted mortality rate was 18.9 [95% confidence interval (CI) 14.3-23.3] deaths per 1000 person-years (pyrs) in the early period and declined to 4.4 (95% CI 2.9-6.0) deaths per 1000 pyrs in the late period, a 77% (95% CI 71-83%) reduction in the mortality rate. At all calendar years, the MUAC distribution in the population was close to the WHO reference population. MUAC below -1 z-score was associated with increased child mortality. The change in MUAC distribution from the early period to the late period (in the early period mortality standardization) corresponded to 1.5 (95% CI 1.0-2.2) fewer deaths per 1000 pyrs, equivalent to 11% (95% CI 7-14%) of the observed change in child mortality. CONCLUSIONS: From 2003 to 2016, child mortality in urban Guinea-Bissau declined considerably but, though a low MUAC was associated with increased mortality, changes in the MUAC distribution in the population explained little of the decline. Understanding the driving factors of child mortality decline can help scope tomorrow's interventions.

Mediation of the parental education gradient in early adult mortality by childhood adversity: a population-based cohort study of more than 1 million children.

BACKGROUND: Children born into disadvantaged socioeconomic circumstances are more likely to experience both adversity during childhood and premature mortality. The aim of this study was to investigate how much of the parental education gradient in early adult mortality is explained by exposure to childhood adversity. METHODS: We used data from the nationwide register-based Danish Life Course cohort study. Our sample consisted of all individuals born between Jan 1, 1980, and Dec 31, 2001, who did not emigrate or die before age 16 years, and for whom information on parental education level was available. These individuals were followed up for mortality from age 16 years until Dec 31, 2018. Highest attained parental education level at birth was divided into low (≤9 years), medium (10-12 years), and high (>12 years) according to years in education. Individuals were assigned to one of five childhood adversity trajectory groups based on their annual exposure between age 0 and 16 years to a broad selection of adversities in three dimensions: material deprivation, loss or threat of loss in the family, and family dynamics. Childhood abuse was not included. The association between parental education level and mortality was assessed with a Cox proportional hazards model. To assess the magnitude of mediation of this association by childhood adversity, we used counterfactual mediation analysis and an Aalen additive hazards model. Analyses were unadjusted and adjusted for parental origin and parental ages at birth. FINDINGS: Our sample consisted of 1 278 156 individuals followed up from birth until age 16-38 years. The sample comprised 655 633 (51·3%) men and 622 523 (48·7%) women, and 1 243 981 (97·3%) participants were of European descent. During follow-up, 5387 deaths were registered. Compared with the high parental education group, we calculated a total effect equal to 8·7 additional deaths (95% CI 6·6-10·9) per 100 000 person-years in the medium parental education group and 31·9 (28·5 to 35·2) per 100 000 person-years in the low parental education group. Mediation through childhood adversity trajectories accounted for 41·5% (95% CI 8·0-67·5) of the additional deaths in the medium parental education group and 46·4% (32·9-58·8) of the additional deaths in the low parental education group. The results were similar when adjusting the analyses for sociodemographic factors. INTERPRETATION: The experience of childhood adversity seems to be an important mediator of the association between parental education and mortality in early adulthood. Interventions reducing the exposure to childhood adversity might thus reduce the parental education gradient in early adult mortality. FUNDING: Netherlands Organisation for Health Research and Development.

Hospitalisation patterns among children exposed to childhood adversity: a population-based cohort study of half a million children.

BACKGROUND: Children who are exposed to adversities might be more susceptible to disease development during childhood and in later life due to impaired physiological and mental development. To explore this hypothesis, we assessed hospitalisation patterns through childhood and into adult life among those exposed to different trajectories of adversities during childhood. METHODS: For this population-based cohort study, we used annually updated data from Danish nationwide registers covering more than half a million children (aged 0-15 years) born between 1994 and 2001. Children who were alive and resident in Denmark on their 16th birthday were included in the analysis. Cluster analysis was used to divide children into five distinct trajectories according to their experience of childhood adversities, including poverty and material deprivation, loss or threat of loss within the family, and aspects of family dynamics. To describe comprehensively the disease patterns experienced by these groups of children, we assessed the associations of each adversity trajectory with hospital admission patterns according to the entire spectrum of disease diagnoses in the International Classification of Diseases 10th edition, from birth to 24 years of age, using survival models. FINDINGS: 508 168 children born between Jan 1, 1994, and Dec 31, 2001, were followed up until Dec 31, 2018, capturing more than 3·8 million hospital admissions from birth to early adulthood. Hospitalisation rates were consistently higher in all four adversity groups compared with the low adversity group. The high adversity group (14 577 children, 3%), who were exposed to adversities of deprivation, family loss, and negative family dynamics, had a markedly higher rate of hospitalisations across all ages. For example, we observed 243 additional hospital admissions per 1000 person-years (95% CI 238-248) in the high versus low adversity group for those aged 16-24 years. These associations were particularly strong for diagnoses related to injuries, unspecified symptoms, and factors influencing health service contacts (eg, health screening and observation). They also covered a considerable burden of respiratory and infectious diseases, congenital malformations, diseases of the nervous system (especially in early life), mental and behavioural diagnoses, and diagnoses related to pregnancy and childbirth in early adult life. INTERPRETATION: The close linkage between childhood adversities and poor lifelong health outcomes highlights a need for public health and policy attention on improving the socioeconomic circumstances children are born into to prevent the early emergence of health inequalities. FUNDING: None.

Childhood adversity trajectories and PTSD in young adulthood: A nationwide Danish register-based cohort study of more than one million individuals.

We examine the association between trajectories of childhood adversities and Post-Traumatic Stress Disorder (PTSD) using a register-based Danish cohort. The DANish LIFE Course (DANLIFE) cohort includes and prospectively follows all individuals born in Denmark from 1980. We estimated the rate of PTSD diagnosed from age 16, according to childhood adversity trajectories from age 0 to 16 (n = 1 277 548). Trajectories were previously defined into 5 groups: Low Adversity, Early Life Material Deprivation, Persistent Material Deprivation, Loss or Threat of Loss, And High Adversity. We then estimated adjusted relative hazard ratios (aHR), and absolute hazards differences of PTSD according to childhood adversity trajectories in adjusted survival analysis. All analyses were stratified by sex. Individuals were followed for a median of 10·1 years a fter their 16th birthday, and 4966 individuals were diagnosed with PTSD. Compared with the low adversity group, children exposed to childhood adversity were more likely to be diagnosed with PTSD. The aHR for PTSD varied from 1·4 (95% CI: 1·3-1·5) in the Early Life Material Deprivation group, to 3·7 (3·3-4·1) in the High Adversity group, which corresponds to 8·3 extra cases of PTSD per 10 000 person years. The relative associations were comparable in men and women, but approximately twice as many women compared with men were affected. We report a clear association between exposure to childhood adversities and PTSD in young adulthood. The highest burden was among women in the high adversity group.

Life expectancy of HIV-infected patients followed at the largest hospital in Guinea-Bissau is one-fourth of life expectancy of the background population.

PURPOSE: To estimate the life expectancy (LE) of HIV-infected patients in the West African country Guinea-Bissau and compare it with the background population. METHODS: Using data from the largest HIV outpatient clinic at the Hospital Nacional Simão Mendes in the capital Bissau, a retrospective observational cohort study was performed. The study included patients attending the clinic between June 2005 and January 2018. A total of 8958 HIV-infected patients were included. In the analysis of the background population, a total of 109,191 people were included. LE incorporating loss to follow-up (LTFU) was estimated via Kaplan-Meier estimators using observational data on adult HIV-infected patients and background population. RESULTS: The LE of 20-year-old HIV-infected patients was 9.8 years (95% CI 8.3-11.5), corresponding to 22.3% (95% CI 18.5-26.7%) of the LE of the background population. (LE for 20-year-olds in the background population was 44.0 years [95% CI 43.0-44.9].) Patients diagnosed with CD4 cell counts below 200 cells/µL had a LE of 5.7 years (95% CI 3.6-8.2). No increase in LE with later calendar period of diagnosis was observed. CONCLUSIONS: LE was shown to be markedly lower among HIV-infected patients compared with the background population. While other settings have shown marked improvements in prognosis of HIV-infected patients in recent years, no improvement in Bissau was observed over time (9.8 years (95% CI 7.6-12.2) and 9.9 years (95% CI 7.6-12.1) for the periods 2005-2010 and 2014-2016, respectively).

Trajectories of Childhood Adversity and Type 1 Diabetes: A Nationwide Study of One Million Children.

OBJECTIVE: Experiencing adversities in childhood may increase the risk of type 1 diabetes through hyperactivation of the stress response system, but the empirical evidence is conflicting. We aim to describe the age-specific incidence of type 1 diabetes for males and females separately in five predefined groups covering the most common trajectories of adversity among Danish children. RESEARCH DESIGN AND METHODS: We included all 1,081,993 children without parental type 1 diabetes born in Denmark from 1980 to 1998. We used register data to estimate age-specific incidence rates of type 1 diabetes in five trajectory groups of adversity characterized by 1) low adversity, 2) early life material deprivation, 3) persistent material deprivation, 4) loss or threat of loss in the family, and 5) cumulative high adversity. All analyses were stratified by sex. RESULTS: In total, 5,619 people developed type 1 diabetes before 2016. We found only minor differences when comparing the incidence rates of type 1 diabetes between the trajectory groups. The only clear exceptions were in the high versus low adversity group, in which males had a higher incidence of type 1 diabetes in childhood (<11 years [incidence rate ratio (IRR) 1.78 (95% CI 1.31-2.42)]) and females had a higher incidence in early adulthood (≥16 years [IRR 2.19 (95% CI 1.57-3.07)]). CONCLUSIONS: Childhood adversities were generally not associated with age-specific incidence of type 1 diabetes except among those exposed to a very high and increasing annual rate of childhood adversities. Differences between highly exposed males and females seem to depend on age at onset of type 1 diabetes.

Determinants of Bacille Calmette-Guérin scarification in Danish children.

BACKGROUND: Studies in low-income countries have shown that among Bacille Calmette-Guérin (BCG) vaccinated children, those who develop a BCG-scar have significantly better survival than those who do not develop a scar. In a Danish multicenter randomized clinical trial we assessed determinants for developing a BCG-scar and for BCG scar size following neonatal BCG vaccination. METHODS: At three Danish hospitals, newborns were randomized 1:1 to BCG vaccination or no BCG vaccination. The infants were invited for a clinical examination at the ages of 3 and 13 months. At 13 months, the scar site was inspected and scar size measured. We investigated three groups of determinants; external, parental, and individual-level determinants on relative scar prevalence and differences in median scar sizes. RESULTS: Among 2118 BCG vaccinated infants, 2039 (96 %) were examined at 13 months; 1857 of these (91 %) had developed a BCG-scar. Compared with Copenhagen University Hospital, Hvidovre (85 %), Copenhagen University Hospital, Rigshospitalet had a scar prevalence of 95 % (adjusted Prevalence ratio (aPR) = 1.24 [CI 95 %: 1.18 to 1.30]); it was 93 % at Kolding Hospital (aPR 1.27 [CI 95 %: 1.19 to 1.35]). Increasing vaccine experience was positively associated with developing a scar and with scar size. CONCLUSION: Across multiple potential determinants of BCG scaring and size, logistical factors dominated. The results support that injection technique is an important determinant of developing a scar. Given the strong link between having a BCG scar and subsequent health, improved BCG vaccination technique could play a major role for child health.

Timeliness of DTaP-IPV-Hib Vaccination and Development of Atopic Dermatitis Between 4 Months and 1 Year of Age-Register-Based Cohort Study.

BACKGROUND: An Australian study including 4433 children found that delayed Diphtheria-Tetanus-acellular Pertussis-containing vaccination was associated with reduced risk of developing atopic dermatitis (AD) before age 1 year. OBJECTIVE: We assessed whether delayed vaccination against diphtheria, tetanus, acellular pertussis, polio, and Haemophilus influenzae type b (Diphtheria, Tetanus, acellular Pertussis - Inactivated Polio vaccine - Haemophilus influenzae type b [DTaP]) was associated with a reduced risk of new cases of AD before age 1 year in Denmark. METHODS: We used nationwide registers to follow 883,160 children born in Denmark from 1997 to 2012. Binary regression models adjusting for potential confounding factors were applied to estimate relative risks (adjusted relative risks [aRRs]) of developing AD among children with delayed DTaP vaccination (defined as given 1 month or more after the recommended age) compared with timely vaccinated children. RESULTS: Among 143,429 children with a delayed first dose of DTaP, 4,847 (3.4%) developed AD between age 4 months and 1 year, compared with 27,628 (3.7%) among 739,731 children not having delayed DTaP (aRR 0.94; 95% CI, 0.91-0.97). The aRR was 0.94 (95% CI, 0.90-0.99) for children with a delayed second dose, and the aRR was 0.88 (95% CI, 0.82-0.93) when comparing children with delayed first and second doses with all timely vaccinated children. CONCLUSIONS: The results support the hypothesis that delayed vaccination with DTaP is associated with reduced risk of developing new cases of AD after age 4 months. The dose-dependent relationship strengthens the evidence of a causal relationship. Some countries are introducing maternal pertussis vaccination and delaying the first dose of DTaP, providing a possibility for further testing the hypothesis.

Diphtheria-Tetanus-Pertussis (DTP) Vaccine Is Associated With Increased female-Male Mortality. Studies of DTP administered before and after measles vaccine.

BACKGROUND: The third dose of diphtheria-tetanus-pertussis vaccine (DTP3) is used to monitor immunization programs. DTP has been associated with higher female mortality. METHODS: We updated previous literature searches for DTP studies of mortality by sex. We examined the female/male (F/M) mortality rate ratio (MRR) with increasing number of doses of DTP and for subsequent doses of measles vaccine (MV) after DTP and of DTP after MV. RESULTS: Eight studies had information on both DTP1 and DTP3. The F/M MRR was 1.17 (95% confidence interval [CI], .88-1.57) after DTP1 and increased to 1.66 (95% CI, 1.32-2.09) after DTP3. Following receipt of MV, the F/M MRR declined to 0.63 (95% CI, .42-.96). In 11 studies the F/M MRR increased to 1.73 (95% CI, 1.33-2.27) when DTP-containing vaccine was administered after MV. CONCLUSIONS: F/M MRR increased with increasing doses of DTP. After MV, girls had lower mortality than boys. With DTP after MV, mortality increased again for girls relative to boys. No bias can explain these changes in F/M MRR. DTP does not improve male survival substantially in situations with herd immunity to pertussis and higher F/M MRR after DTP may therefore reflects an absolute increase in female mortality.

Trajectories of childhood adversity and mortality in early adulthood: a population-based cohort study.

BACKGROUND: Childhood is a sensitive period with rapid brain development and physiological growth, and adverse events in childhood might interfere with these processes and have long-lasting effects on health. In this study, we aimed to describe trajectories of adverse childhood experiences and relate these to overall and cause-specific mortality in early adult life. METHODS: For this population-based cohort study, we used unselected annually updated data from Danish nationwide registers covering more than 1 million children born between 1980 and 1998. We distinguished between three different dimensions of childhood adversities: poverty and material deprivation, loss or threat of loss within the family, and aspects of family dynamics such as maternal separation. We used a group-based multi-trajectory clustering model to define the different trajectories of children aged between 0 and 16 years. We assessed the associations between these trajectories and mortality rates between 16 and 34 years of age using a Cox proportional hazards model and an Aalen hazards difference model. FINDINGS: Between Jan 1, 1980 and Dec 31, 2015, 2 223 927 children were included in the Danish Life Course cohort. We excluded 1 064 864 children born after 1998, 50 274 children who emigrated before their 16th birthday, and 11 161 children who died before their 16th birthday, resulting in a final sample of 1 097 628 children. We identified five distinct trajectories of childhood adversities. Compared with children with a low adversity trajectory, those who had early-life material deprivation (hazard ratio 1·38, 95% CI 1·27-1·51), persistent deprivation (1·77, 1·62-1·93), or loss or threat of loss (1·80, 1·61-2·00) had a moderately higher risk of premature mortality. A small proportion of children (36 081 [3%]) had multiple adversities within all dimensions and throughout the entire childhood. This group had a 4·54 times higher all-cause mortality risk (95% CI 4·07-5·06) than that of children with a low adversity trajectory, corresponding to 10·30 (95% CI 9·03-11·60) additional deaths per 10 000 person-years. Accidents, suicides, and cancer were the most common causes of death in this high adversity population. INTERPRETATION: Almost half of Danish children in our study experienced some degree of adversity, and this was associated with a moderately higher risk of mortality in adulthood. Among these, a small group of children had multiple adversities across social, health, and family-related dimensions. This group had a markedly higher mortality risk in early adulthood than that of other children, which requires public health attention. FUNDING: None.

Vaccinology: time to change the paradigm?

The existing vaccine paradigm assumes that vaccines only protect against the target infection, that effective vaccines reduce mortality corresponding to the target infection's share of total mortality, and that the effects of vaccines are similar for males and females. However, epidemiological vaccine research has generated observations that contradict these assumptions and suggest that vaccines have important non-specific effects on overall health in populations. These include the observations that several live vaccines reduce the incidence of all-cause mortality in vaccinated compared with unvaccinated populations far more than can be explained by protection against the target infections, and that several non-live vaccines are associated with increased all-cause mortality in females. In this Personal View we describe current observations and contradictions and define six emerging principles that might explain them. First, that live vaccines enhance resistance towards unrelated infections. Second, non-live vaccines enhance the susceptibility of girls to unrelated infections. Third, the most recently administered vaccination has the strongest non-specific effects. Fourth, combinations of live and non-live vaccines given together have variable non-specific health effects. Fifth, vaccinating children with live vaccines in the presence of maternal immunity enhances beneficial non-specific effects and reduces mortality. Finally, vaccines might interact with other co-administered health interventions, for example vitamin A supplementation. The potential implications for child health are substantial. For example, if BCG vaccination was given to children at birth, if higher measles vaccination coverage could be obtained, if diphtheria, tetanus, and pertussis-containing vaccines were not given with or after measles vaccine, or if the BCG strain with the best non-specific effects could be used consistently, then child mortality could be considerably lower. Pursuing these emerging principles could improve our understanding and use of vaccines globally.