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BACKGROUND: The association between assisted reproductive technologies (ARTs) and the body mass index (BMI) of children remains controversial. Confounding by morbidity and other factors associated with parental infertility may have biased studies comparing children born after ART with children born after no treatment. We investigated the associations between different fertility treatments and BMI in children at age 5 to 8 years, adjusting for and stratifying by causes of parental infertility. METHODS AND FINDINGS: This Danish cohort study included 327,301 children born between 2007 and 2012 (51% males, median age at follow-up 7 years). Of these, 13,675 were born after ART, 7,728 were born after ovulation induction with or without intrauterine insemination [OI/IUI], and 305,898 were born after no fertility treatments. Using the International Obesity Task Force (IOTF) standards, we defined overweight (BMI ≥ IOTF-25) and obesity (BMI ≥ IOTF-30). We compared children born after ART versus OI/IUI; intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilization (IVF); and frozen-thawed versus fresh embryo transfer and estimated crude and adjusted prevalences of children with overweight or obesity at age 5 to 8 years, prevalence odds ratios (PORs), and differences in mean BMI z-scores. Adjustment was performed using stabilized inverse probability of treatment weights, including parity, year of conception, parental causes of infertility, age, educational level, comorbidities, maternal country of origin, BMI, and smoking as covariates. The crude prevalence of obesity was 1.9% in children born after ART, 2.0% in those born after OI/IUI, and 2.7% in those born after no fertility treatment. After adjustment, children born after ART and OI/IUI had the same prevalence of being overweight (11%; POR 1.00, 95% confidence interval [CI] 0.91 to 1.11; p = 0.95) or obese (1.9%; POR 1.01, 95% CI 0.79 to 1.29; p = 0.94). Comparison of ICSI with conventional IVF yielded similar pattern (POR 0.95, 95% CI 0.83 to 1.07; p = 0.39 for overweight and POR 1.16, 95% CI 0.84 to 1.61; p = 0.36 for obesity). Obesity was more prevalent after frozen-thawed (2.7%) than fresh embryo transfer (1.8%) (POR 1.54, 95% CI 1.09 to 2.17; p = 0.01). The associations between fertility treatments and BMI were only modestly different in subgroups defined by the cause of infertility. Study limitations include potential residual confounding, restriction to live births, and lack of detailed technical information about the IVF procedures. CONCLUSIONS: We found no association with BMI at age 5 to 8 years when comparing ART versus OI/IUI or when comparing ICSI versus conventional IVF. However, use of frozen-thawed embryo transfer was associated with a 1.5-fold increased risk of obesity compared to fresh embryo transfer. Despite an elevated relative risk, the absolute risk difference was low.

PURPOSE: Refugees are vulnerable to psychiatric disorders because of risk factors linked to migration. Limited evidence exist on the impact of the neighbourhood in which refugee resettle. We examined whether resettling in a socioeconomically disadvantaged neighbourhood increased refugees risk of psychiatric disorders. METHODS: This register-based cohort study included 42,067 adults aged 18 years and older who came to Denmark as refugees during 1986-1998. Resettlement policies in those years assigned refugees in a quasi-random fashion to neighbourhoods across the country. A neighbourhood disadvantage index was constructed using neighbourhood-level data on income, education, unemployment, and welfare receipt. Main outcomes were psychiatric diagnoses and psychiatric medication usage ascertained from nationwide patient and prescription drug registers, with up to 30-year follow-up. Associations of neighbourhood disadvantage with post-migration risk of psychiatric disorders were examined using Cox proportional hazards and linear probability models adjusted for individual, family, and municipality characteristics. RESULTS: The cumulative risk of psychiatric diagnoses and medication was 13.7% and 46.1%, respectively. Refugees risk of psychiatric diagnoses and psychiatric medication usage was higher among individuals assigned to high-disadvantage compared with low-disadvantage neighbourhoods in analyses including fixed effects for assigned municipality (psychiatric diagnoses: hazard ratio (HR) = 1.14, 95% CI 1.04, 1.25; psychiatric medication: HR = 1.05, 95% CI 1.00, 1.11). Consistent results were found using linear probability models. Results for diagnostic categories and subclasses of medications suggested that the associations were driven by neurotic and stress-related disorders and use of anxiolytic medications. CONCLUSION: Resettlement in highly disadvantaged neighbourhoods was associated with an increase in refugees risk of psychiatric disorders, suggesting that targeted placement of newly arrived refugees could benefit refugee mental health. The results contribute quasi-experimental evidence to support links between neighbourhood characteristics and health.

ObjectivesNeighborhood disadvantage may increase the risk of adverse health outcomes among older refugees. Yet few studies rigorously estimate the effects of place-based factors on later-life health, particularly dementia and mortality. Evidence about refugees is especially sparse.MethodsThis study leveraged a natural experiment in the form of a Danish policy (1986-1998) that dispersed refugees quasi-randomly across neighborhoods upon arrival. We used longitudinal registers allowing 30 years of follow-up among refugees aged 40+ years upon arrival in Denmark (N = 9,854). Cox models assessed the association between neighborhood disadvantage and risk of dementia and mortality. We examined heterogeneous effects by sex, age, and family size. We also examined associations among non-refugee immigrants and native-born Danes.ResultsNeighborhood disadvantage was not associated with dementia in any group. One unit increase in neighborhood disadvantage index (ranges -8 to 5.7) was associated with greater mortality risk among non-refugee immigrants (HR 1.06, 95%CI: 1.02, 1.10) and native-born Danes (HR 1.11, 95%CI: 1.06, 1.17). In contrast, neighborhood disadvantage was associated with lower mortality risk among refugees (HR 0.96, 95%CI: 0.93, 0.99). Neighborhood disadvantage remained negatively associated with mortality risk in subgroups: refugees who are female (on moderate-disadvantage compared to low-disadvantage), aged 60+, and who arrived with families.DiscussionWhile neighborhood disadvantage was associated with lower mortality risk among refugees, it was associated with greater mortality risk among non-refugee immigrants and native-born Danes, perhaps due to confounding in the latter groups or different place-based experiences by immigration status. Future research is warranted to explain the reasons for contrasting findings.

BackgroundMost medical educational programs emphasize clinical observation or clinical skill acquisition, fewer focus upon research. The Danish-American Research Exchange (DARE) program, sponsored by the Lundbeck Foundation, is unique in that the medical student initiates biomedical research collaboration between Danish and US medical institutions. To achieve this, Danish medical students (DARE students) conduct binational mentored research projects while based in the United States for 10 months. In addition, DARE students are introduced to interdisciplinary thinking about how to develop ultra-low-cost healthcare interventions through the '$10 Challenge'.MethodsWe conducted a cross-sectional study of DARE alumni over five consecutive years (2015-2020, n = 24). Research metrics included completion of a research project, primary authorship, and co-authorship of publications. The number of publications, prior to and after the DARE program were enumerated. For the first four cohorts, graduation from medical school and acceptance or intention to enter a joint MD-PhD program also were assessed. Two focus groups were conducted using constructivist grounded theory. Discussions were transcribed, redacted, and coded using Dedoose software.ResultsDARE Medical students were 31.2 years (range 24-35), the majority were women (67%;16/24). The majority (17/24;71%) completed a first author publication in a peer-reviewed journal with a median of 3.9 per DARE alumnus. DARE alumnus reported increased proficiency in biostatistics, epidemiology, coding and public speaking as well as stronger research qualities in creativity, critical thinking, comfort in approaching scientist in both the US and Denmark (p

Background Preclinical animal studies have suggested that myeloid cell-synthesized coagulation factor X dampens antitumor immunity and that rivaroxaban, a direct factor Xa inhibitor, can be used to promote tumor immunity. This study was aimed at assessing whether patients with atrial fibrillation taking direct factor Xa inhibitors have lower risk of cancer and cancer-related mortality than patients taking the direct thrombin inhibitor dabigatran. Methods and findings This nationwide population-based cohort study in Denmark included adult patients with atrial fibrillation and without a history of cancer, who started taking a factor Xa inhibitor or dabigatran between 2011 and 2015. Data on medical history, outcomes, and drug use were acquired through Danish healthcare registries. The primary outcome was any cancer. Secondary outcomes were cancer-related mortality and all-cause mortality. Outcome events were assessed during 5 years of follow-up in an intention-to-treat analysis. The propensity score-based inverse probability of treatment weighting was used to compute cumulative incidence and subdistribution hazard ratios (SHRs) and corresponding 95% confidence intervals (CIs), with death as a competing event. Propensity scores were estimated using logistic regression and including in the model sex, age group at index date, comorbidities, and use of comedications. A total of 11,742 patients with atrial fibrillation starting a factor Xa inhibitor and 11,970 patients starting dabigatran were included. Mean age was 75.2 years (standard deviation [SD] 11.2) in the factor Xa cohort and 71.7 years (SD 11.1) in the dabigatran cohort. On the basis of the propensity score-weighted models, after 5 years of follow-up, no substantial difference in the cumulative incidence of cancer was observed between the factor Xa inhibitor (2,157/23,711; 9.11%, 95% CI [8.61%,9.63%]) and dabigatran (2,294/23,715; 9.68%, 95% CI [9.14%,10.25%]) groups (SHR 0.94, 95% CI [0.89,1.00], P value 0.0357). We observed no difference in cancer-related mortality (factor Xa inhibitors cohort 1,028/23,711; 4.33%, 95% CI [4.02%,4.68%]. Dabigatran cohort 1,001/23,715; 4.22%, 95% CI [3.83%,4.66%]; SHR 1.03, 95% CI [0.94,1.12]), but all-cause mortality was higher in the factor Xa inhibitor cohort (factor Xa inhibitors cohort 7,416/23,711; 31.31%, 95% CI [30.37%,32.29%]. Dabigatran cohort 6,531/23,715; 27.56%, 95% CI [26.69%,28.45%]; HR 1.17, 95% CI [1.13,1.21]). The main limitations of the study were the possibility of residual confounding and the short follow-up period. Conclusions In this population based cohort study, factor Xa inhibitor use was not associated with an overall lower incidence of cancer or cancer-related mortality when compared to dabigatran. We did observe an increase in all-cause mortality in the factor Xa inhibitor cohort., Author(s): Floris Bosch 1,2,3,*, Erzsébet Horváth-Puhó 4, Suzanne C. Cannegieter 5,6, Nick van Es 2,3, Henrik T. Sørensen 4 Introduction Cancer activates the hemostatic system, thereby promoting tumor growth and [...]

ObjectiveTo evaluate associations between gestational diabetes mellitus (GDM) and various incident cardiovascular disease (CVD) end points, considering the effects of the mediating role of type 2 diabetes and shared environmental/familial factors.Research design and methodsThis population-based cohort study included 10,02,486 parous women in Denmark during 1978-2016. We used Cox regression to 1) examine the associations of GDM with overall and type-specific CVDs using full-cohort and sibling-matched analysis, 2) quantify the impact of type 2 diabetes after GDM using mediation analysis, and 3) assess whether these associations were modified by prepregnancy obesity or maternal history of CVD.ResultsWomen with a history of GDM had a 40% increased overall CVD risk (hazard ratio [HR] 1.40, 95% CI 1.35-1.45). Sibling-matched analyses yielded similar results (HR 1.44, 95% CI 1.28-1.62). The proportion of association between GDM and overall CVD explained by subsequent type 2 diabetes was 23.3% (15.4-32.8%). We observed increased risks of specific CVDs, including 65% increased stroke risk and more than twofold risks for myocardial infarction, heart failure, and peripheral artery disease. The elevated overall risks were more pronounced among women with GDM and prepregnancy obesity or maternal history of CVD.ConclusionsA history of GDM was associated with increased risks of overall and specific CVDs. Increased risks were partly explained by subsequent type 2 diabetes, and the need to identify other pathways remains important. Continuous monitoring of women with a history of GDM, especially those with prepregnancy obesity or maternal history of CVD, may provide better opportunities to reduce their cardiovascular risk.

Author(s): Cecilia Hvitfeldt Fuglsang, Lars Pedersen, Morten Schmidt, Jan P. Vandenbroucke, Hans Erik Bøtker, Henrik Toft Sørensen The first author's name is indexed incorrectly. The correct citation is: Fuglsang CH, [...]

BackgroundPosttraumatic stress disorder is a well-documented risk factor for cardiovascular disease. Whether non-specific stress-related psychopathology also increases risk is less well known.MethodsIn a cohort of adult Danish-born residents of Denmark with an incident diagnosis of unspecified reaction to severe stress ("unspecified stress reaction") between 1995 and 2011 (N = 24,534), we assessed incidence of seven arterial and venous cardiovascular events/conditions between 1996 and 2013. We calculated standardized incidence ratios (SIRs) comparing incidence of each outcome among the cohort to expected incidence based on sex-, age-, and calendar-time-specific national rates. We conducted stratified analyses by demographic characteristics, comorbidities, and length of follow-up time.ResultsIncidence over the study period ranged from 1.1% for provoked VTE to 5.7% for stroke, adjusting for competing risk of death. Unspecified stress reaction was associated with all outcomes (SIRs ranging from 1.3, 95% confidence interval (CI): 1.1-1.4 for atrial fibrillation/flutter to 1.9, 95% CI: 1.7-2.2 for unprovoked VTE and 1.9, 95% CI: 1.6-2.3 for provoked VTE). Associations persisted, but were attenuated, when restricting to persons without alcohol use disorder and to persons without physical health comorbidities.LimitationsUnspecified stress reaction has less precise criteria than other stress-related diagnoses, and we could not adjust for some potential confounders.ConclusionsOur results augment literature on stress disorders and cardiovascular disease by highlighting the additional importance of unspecified stress disorders. Further research on this diagnostic category, which may represent subsyndromal psychopathology, is warranted. These findings support considering persons with non-specific stress-related psychopathology in treatment and tertiary prevention activities.

The recently discovered lytic polysaccharide monooxygenases (LPMOs), which cleave polysaccharides by oxidation, have been associated with bacterial virulence, but supporting functional data is scarce. Here we show that CbpD, the LPMO of Pseudomonas aeruginosa, is a chitin-oxidizing virulence factor that promotes survival of the bacterium in human blood. The catalytic activity of CbpD was promoted by azurin and pyocyanin, two redox-active virulence factors also secreted by P. aeruginosa. Homology modeling, molecular dynamics simulations, and small angle X-ray scattering indicated that CbpD is a monomeric tri-modular enzyme with flexible linkers. Deletion of cbpD rendered P. aeruginosa unable to establish a lethal systemic infection, associated with enhanced bacterial clearance in vivo. CbpD-dependent survival of the wild-type bacterium was not attributable to dampening of pro-inflammatory responses by CbpD ex vivo or in vivo. Rather, we found that CbpD attenuates the terminal complement cascade in human serum. Studies with an active site mutant of CbpD indicated that catalytic activity is crucial for virulence function. Finally, profiling of the bacterial and splenic proteomes showed that the lack of this single enzyme resulted in substantial re-organization of the bacterial and host proteomes. LPMOs similar to CbpD occur in other pathogens and may have similar immune evasive functions.

ObjectiveThis population-based, matched cohort study aimed to evaluate utilization of health care services by mothers of children with major congenital anomalies (MCAs), compared to mothers of children without MCAs over a 20-year post-birth time horizon in Denmark.MethodsOur analytic sample included mothers who gave birth to an infant with a MCA (n = 23,927) and a cohort of mothers matched to them by maternal age, parity and infant's year of birth (n = 239,076). Primary outcomes were period prevalence and mothers' quantity of health care utilization (primary, inpatient, outpatient, surgical, and psychiatric services) stratified by their child's age (i.e., ages 0-6 = before school, ages 7-13 = pre-school + primary education, and ages 14-18 = secondary education or higher). The secondary outcome measure was length of hospital stays. Outcome measures were adjusted for maternal age at delivery, parity, marital status, income quartile, level of education in the year prior to the index birth, previous spontaneous abortions, maternal pregnancy complications, maternal diabetes, hypertension, alcohol-related diseases, and maternal smoking.ResultsIn both cohorts the majority of mothers were between 26 and 35 years of age, married, and employed, and 47% were primiparous. Mothers of infants with anomalies had greater utilization of outpatient, inpatient, surgical, and psychiatric services, compared with mothers in the matched cohort. Inpatient service utilization was greater in the exposed cohort up to 13 years after a child's birth, with the highest risk in the first six years after birth [adjusted risk ratio, 1.13; 95% confidence interval (CI), 1.12-1.14], with a decrease over time. Regarding the quantity of health care utilization, the greatest difference between the two groups was in inpatient service utilization, with a 39% increased rate in the exposed cohort during the first six years after birth (adjusted rate ratio, 1.39; 95% CI, 1.37-1.42). During the first 6 years after birth, mothers of children with anomalies stayed a median of 6 days (interquartile range [IQR], 3-13) in hospital overall, while the comparison cohort stayed a median of 4 days (IQR, 2-7) in hospital overall. Rates of utilization of outpatient clinics (adjusted rate ratio, 1.36; 95% CI, 1.29-1.42), as well as inpatient (adjusted rate ratio, 1.77; 95% CI, 1.68-1.87), and surgical services (adjusted rate ratio, 1.33; 95% CI, 1.26-1.41) was higher in mothers of children with multiple-organ MCAs during 0 to 6 years after birth. Among mothers at the lowest income levels, utilization of psychiatric clinic services increased to 59% and when their child was 7 to 13 years of age (adjusted rate ratio, 1.59; 95% CI, 1.24-2.03).ConclusionMothers of infants with a major congenital anomaly had greater health care utilization across services. Health care utilization decreased over time or remained stable for outpatient, inpatient, and surgical care services, whereas psychiatric utilization increased for up to 13 years after an affected child's birth. Healthcare utilization was significantly elevated among mothers of children with multiple MCAs and among those at the lowest income levels.