Educational, labour market and relationship outcomes in people with acne.

BACKGROUND: Although acne is associated with scarring, mental health comorbidities and bullying, little is known about its impact on socio-economic outcomes. OBJECTIVES: To examine the association between acne and educational, labour market and relationship outcomes. METHODS: We conducted a nationwide registry-based cohort study in Denmark. We included birth cohorts from 1982 to 1988 and compared those with and without acne identified using hospital diagnosis codes and redeemed prescriptions. Our main educational outcome was educational attainment. The main labour market outcomes were earned income at age 30 and long-term unemployment at any time before age 30. The main relationship outcomes were single partnership and childlessness by age 30. Outcomes were assessed using Poisson regression for binary outcomes and linear regression for continuous outcomes, adjusted for sex, calendar year, mother's socio-economic position and hormonal contraception use. RESULTS: Those with acne had a lower risk of not completing upper secondary education (relative risk (RR): 0.79; 95% confidence interval [CI]: 0.76-0.83) and higher education (RR: 0.90; 95% CI: 0.88-0.91), with absolute differences up to 4 percentage points. Persons with acne had slightly higher income (mean percentile difference: 2.6%, 95% CI: 2.2-2.9) and lower risk of long-term unemployment than those without acne (9.8% vs. 11.4%; RR: 0.90; 95% CI: 0.87-0.93). The prevalence of being single until age 30 was similar (19.7% vs. 20.1%; adjusted RR: 0.96; 95% CI: 0.94-0.98) but childlessness was slightly more prevalent (60.5% vs. 57.5%; adjusted RR: 1.03; 95% CI: 1.02-1.04). However, all associations were attenuated or lost in secondary analysis restricted to exposure-discordant siblings to address confounding from family-related factors. CONCLUSIONS: Acne during adolescence does not seem to affect long-term educational, labour market or relationship outcomes. However, there is a need for additional studies to validate the findings in untreated patients and different health and social systems.

Associations between physical diseases and subsequent mental disorders: a longitudinal study in a population-based cohort.

People with physical diseases are reported to be at elevated risk of subsequent mental disorders. However, previous studies have considered only a few pairs of conditions, or have reported only relative risks. This study aimed to systematically explore the associations between physical diseases and subsequent mental disorders. It examined a population-based cohort of 7,673,978 people living in Denmark between 2000 and 2021, and followed them for a total of 119.3 million person-years. The study assessed nine broad categories of physical diseases (cardiovascular, endocrine, respiratory, gastrointestinal, urogenital, musculoskeletal, hematological and neurological diseases, and cancers), encompassing 31 specific diseases, and the subsequent risk of mental disorder diagnoses, encompassing the ten ICD-10 groupings (organic, including symptomatic, mental disorders; mental disorders due to psychoactive substance use; schizophrenia and related disorders; mood disorders; neurotic, stress-related and somatoform disorders; eating disorders; personality disorders; intellectual disabilities; pervasive developmental disorders; and behavioral and emotional disorders with onset usually occurring in childhood and adolescence). Using Poisson regression, the overall and time-dependent incidence rate ratios (IRRs) for pairs of physical diseases and mental disorders were calculated, adjusting for age, sex and calendar time. Absolute risks were estimated with the Aalen-Johansen estimator. In total, 646,171 people (8.4%) were identified as having any mental disorder during follow-up. All physical diseases except cancers were associated with an elevated risk of any mental disorder. For the nine broad pairs of physical diseases and mental disorders, the median point estimate of IRR was 1.51 (range: 0.99-1.84; interquartile range: 1.29-1.59). The IRRs ranged from 0.99 (95% CI: 0.98-1.01) after cancers to 1.84 (95% CI: 1.83-1.85) after musculoskeletal diseases. Risks varied over time after the diagnosis of physical diseases. The cumulative mental disorder incidence within 15 years after diagnosis of a physical disease varied from 3.73% (95% CI: 3.67-3.80) for cancers to 10.19% (95% CI: 10.13-10.25) for respiratory diseases. These data document that most physical diseases are associated with an elevated risk of subsequent mental disorders. Clinicians treating physical diseases should constantly be alert to the possible development of secondary mental disorders.

The Population-level Effect of Adjuvant Therapies on Breast Cancer Recurrence: Application of the Trend-in-Trend Design.

PURPOSE: Breast cancer has an average 10-year relative survival reaching 84%. This favorable survival is due, in part, to the introduction of biomarker-guided therapies. We estimated the population-level effect of the introduction of two adjuvant therapies-tamoxifen and trastuzumab-on recurrence using the trend-in-trend pharmacoepidemiologic study design. METHODS: We ascertained data on women diagnosed with nonmetastatic breast cancer who were registered in the Danish Breast Cancer Group clinical database. We used the trend-in-trend design to estimate the population-level effect of the introduction of (1) tamoxifen for postmenopausal women with estrogen receptor (ER)-positive breast cancer in 1982, (2) tamoxifen for premenopausal women diagnosed with ER-positive breast cancer in 1999, and (3) trastuzumab for women <60 years diagnosed with human epidermal growth factor receptor 2-positive breast cancer in 2007. RESULTS: For the population-level effect of the introduction of tamoxifen among premenopausal women diagnosed with ER-positive breast cancer in 1999, the risk of recurrence decreased by nearly one-half (OR = 0.52), consistent with evidence from clinical trials; however, the estimate was imprecise (95% confidence interval [CI] = 0.25, 1.85). We observed an imprecise association between tamoxifen use and recurrence from the time it was introduced in 1982 (OR = 1.24 95% CI = 0.46, 5.11), inconsistent with prior knowledge from clinical trials. For the introduction of trastuzumab in 2007, the estimate was also consistent with trial evidence, though imprecise (OR = 0.51; 95% CI = 0.21, 22.4). CONCLUSIONS: We demonstrated how novel pharmacoepidemiologic analytic designs can be used to evaluate the routine clinical care and effectiveness of therapeutic advancements in a population-based setting while considering some limitations of the approach.

The impact of comorbidity burden on cardiac arrest mortality: A population-based cohort study.

AIM: Patients experiencing cardiac arrest are often burdened with comorbidities that increase mortality. This study examined the impact of comorbidity burden on cardiac arrest mortality by quantifying biological interaction. METHODS: Nationwide population-based Danish cohort study of adult patients hospitalized for cardiac arrest during 1996-2021 and 5:1 matched comparisons from the general population (matched on age, sex, calendar year, and all Charlson Comorbidity Index comorbidities). Mortality rates and hazard ratios for the association between cardiac arrest and mortality was calculated according to comorbidity burden (none, low, moderate, severe). Biological interaction was examined by calculating interaction contrasts (difference in rate differences). RESULTS: For no comorbidity burden, the 30-day mortality rate per 1,000 person-years was 18,110 in the cardiac arrest cohort and 24 in the comparison cohort (hazard ratio = 1,435). For low comorbidity burden, the 30-day mortality rate increased to 20,272 in the cardiac arrest cohort and 41 in the comparison cohort (hazard ratio = 504). The corresponding interaction contrast of 2,145 indicated that 11% of the mortality rate in patients with cardiac arrest and low comorbidity burden was explained by interaction between the two. This percentage increased to 20% for moderate and to 28% for severe comorbidity burden. Within 31-365-day follow-up, the percentage of the mortality rate explained by interaction was 28% for low, 38% for moderate, and 41% for severe comorbidity burden. The interaction effect was present for both out-of-hospital and in-hospital cardiac arrest. CONCLUSIONS: Comorbidity burden interacted with cardiac arrest to increase mortality beyond that explained by their separate effects.

Recurrent ischemic stroke/transient ischemic attack after patent foramen ovale closure: A cohort study.

BACKGROUND: Patent foramen ovale (PFO) has been associated with ischemic stroke and transient ischemic attack (TIA). Guidelines recommend PFO closure for stroke prevention in selected patients, but the risk of recurrent stroke remains high compared to the background population. We aimed to evaluate the causes of recurrent stroke/TIA and post-interventional complications in patients after PFO closure. METHODS: Patients from the Central Denmark Region who underwent PFO closure at Aarhus University Hospital between November 5, 2018, and May 12, 2023, following an ischemic stroke, TIA, amaurosis fugax, or retinal emboli were included. Data on patient demographics, risk factors, procedural details, post-interventional complications, and recurrent stroke/TIA were collected from electronic medical records. RESULTS: PFO closure was performed in 310 patients (median age: 49 years). During a median follow-up of 2.6 years (interquartile range: 1.5-3.6, 814 total patient-years), recurrent stroke/TIA was observed in 8 patients (2.6%), or 0.98 recurrent strokes per 100 patient-years. Recurrent stroke/TIA was more frequent in patients with hypertension (50.0% vs. 16.9%, p = 0.039). Recurrent stroke/TIA was related to thrombophilia or hematologic conditions entailing hypercoagulability in 62.5% of patients. New-onset atrial fibrillation was observed in 9.4% of patients within 45 days after the procedure. None of these patients subsequently developed an ischemic event. Other adverse outcomes were uncommon. CONCLUSION: Rates of recurrent ischemic stroke/TIA after PFO closure were comparable to findings in previous trials. Pre-existing vascular risk factors (hypertension), and a hypercoagulable state were associated with recurrent ischemic stroke/TIA.

The association between the use of fertility indicators and fecundability in a Danish preconception cohort.

BACKGROUND: The use of fertility indicators to predict ovulation has largely been studied for contraceptive purposes, while less so as fertility-promoting tools. OBJECTIVE: To investigate the association between fertility indicators and fecundability in Danish women trying to conceive. METHODS: Web-based preconception cohort study. We analysed data from 11,328 females aged 18-49 years trying to conceive without fertility treatment for ≤6 menstrual cycles, from the Danish SnartGravid.dk and SnartForældre.dk cohorts (2007-2023). Participants reported the use of fertility indicators (counting days since the last menstrual period, cervical fluid monitoring, urinary ovulation testing, feeling ovulation, using a smartphone fertility app and measuring basal body temperature [BBT]). Time to pregnancy was measured in menstrual cycles ascertained by self-reported pregnancy status. We estimated fecundability ratios (FR) and 95% confidence intervals (CIs) using proportional probabilities regression models adjusted for age, socio-economic position, health indicators, reproductive history and gynaecological factors. RESULTS: Fertility indicators were used by 63.3% of participants at study entry. Counting days was the most common (46.9%), while measuring BBT was the least (3.0%). Other indicators ranged from 17.0% to 23.6%, with 69.7% using more than one indicator. Compared with non-use, use of any fertility indicator was associated with greater fecundability (adjusted FR 1.14, 95% CI 1.08, 1.19). Cervical fluid monitoring showed the strongest association (aFR 1.46, 95% CI 1.03, 2.07), followed by urinary ovulation testing (aFR 1.35, 95% CI 1.16, 1.58) and counting days (aFR 1.18, 95% CI 1.09, 1.29). Feeling ovulation and fertility apps were modestly associated with fecundability, while measuring BBT was not associated. Sensitivity analysis restricting to ≤2 cycles of attempt time and two cycles of follow-up showed an aFR for any indicator use of 1.21 (95% CI 1.13, 1.31). CONCLUSION: In this Danish preconception cohort, use of fertility indicators was associated with a higher fecundability, varying by type of indicator.

The combined impact of migraine and gestational diabetes on long-term risk of premature myocardial infarction and stroke: A population-based cohort study.

OBJECTIVE: To examine the combined impact of migraine and gestational diabetes mellitus (GDM) on the risks of premature (persons aged ≤60 years) major adverse cardiovascular and cerebrovascular events (MACCE) based on a composite endpoint of fatal and non-fatal myocardial infarction (MI) and stroke. BACKGROUND: Migraine and GDM are risk factors for cardiovascular disease. It is unknown how the combination of migraine and GDM may affect cardiovascular disease risk. METHODS: In a Danish population-based cohort longitudinal study, we established four cohorts among women with at least one pregnancy during 1996-2018: women with migraine, women with GDM, women with both migraine and GDM, and women free of migraine and free of GDM. Risks of premature MACCE and component endpoints were assessed for each cohort. RESULTS: We included 1,307,456 women free of migraine and free of GDM, 56,811 women with migraine, 24,700 women with GDM, and 1484 women with migraine and GDM. The 20-year absolute risk of MACCE was 1.3% (MI: 0.4%, ischemic stroke: 0.6%, hemorrhagic stroke: 0.3%) among women free of migraine and free of GDM, 2.3% (MI: 0.8%, ischemic stroke: 1.2%, hemorrhagic stroke: 0.5%) among women with migraine, 2.2% (MI: 1.0%, ischemic stroke: 1.0%, hemorrhagic stroke: 0.4%) among women with GDM, and 3.7% (MI: 1.7%, ischemic stroke: 1.7%, hemorrhagic stroke: 0.3%) among women with both migraine and GDM. The 20-year adjusted hazard ratio of premature MACCE was 1.65 (95% confidence interval [CI] 1.49-1.82) for women with migraine; 1.64 (95% CI 1.37-1.96) for women with GDM; and 2.35 (95% CI 1.03-5.36) for women with both GDM and migraine when compared with women free of migraine and free of GDM. CONCLUSIONS: Migraine and GDM were each independently associated with an increased risk of MACCE. Risk of premature MACCE was greatest among women with both migraine and GDM, although this risk estimate was imprecise.

Platelet response to romiplostim amongst patients with newly diagnosed, persistent, and chronic immune thrombocytopenia in routine clinical practice in Denmark, Sweden, and Norway.

Patient characteristics and platelet responses at romiplostim initiation according to the duration of immune thrombocytopenia (ITP) are poorly understood. Amongst romiplostim-exposed adults with ITP lasting ≥6 months during 2009-2018 in Denmark, Sweden, and Norway, we examined characteristics at romiplostim initiation, romiplostim dosage, and durable platelet response (≥75% of measurements ≥50 × 109/L at 14-24 weeks) for subcohorts with newly diagnosed (duration <3 months), persistent (3-12 months), or chronic (>12 months) ITP initiating romiplostim. The 285 romiplostim initiators comprised 81 (28%) with newly diagnosed, 47 (16%) with persistent, and 157 (55%) with chronic ITP. More patients with newly diagnosed ITP than longer ITP duration, had low comorbidity levels, two or more prior ITP therapies, and previous bleeding requiring hospitalisation. The median romiplostim doses were similar across subcohorts. During treatment, median platelet counts were similar across subcohorts (75-76 × 109/L), and the durable platelet response was 64.6%, 52.9%, and 52.7% for newly diagnosed, persistent, and chronic ITP, respectively. After treatment cessation, the median platelet count was 138 × 109/L, 68 × 109/L, and 71 × 109/L, respectively. In conclusion, newly diagnosed patients, compared with romiplostim initiators with longer disease duration, had more severe ITP, higher frequency of durable platelet response, and higher median platelet count after cessation.

Confounding and Negative Control Methods in Observational Study of SARS-CoV-2 Vaccine Effectiveness: A Nationwide, Population-Based Danish Health Registry Study.

Background: Observational studies of SARS-CoV-2 vaccine effectiveness are prone to confounding, which can be illustrated using negative control methods. Methods: Nationwide population-based cohort study including two cohorts of Danish residents 60-90 years of age matched 1:1 on age and sex: A vaccinated and a non-vaccinated cohort, including 61052 SARS-CoV-2 vaccinated individuals between 1 March and 1 July 2021 and 61052 individuals not vaccinated preceding 1 July 2021. From these two cohorts, we constructed negative control cohorts of individuals diagnosed with SARS-CoV-2 infection or acute myocardial infarction, stroke, cancer, low energy fracture, or head-trauma. Outcomes were SARS-CoV-2 infection, negative control outcomes (eg, mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear), and death. We used Cox regression to calculate adjusted incidence and mortality rate ratios (aIRR and aMRR). Results: Risks of SARS-CoV2 infection and all negative control outcomes were elevated in the vaccinated population, ranging from an aIRR of 1.15 (95% CI: 1.09-1.21) for eye examinations to 3.05 (95% CI: 2.24-4.14) for malignant melanoma. Conversely, the risk of death in the SARS-CoV-2 infected cohort and in all negative control cohorts was lower in vaccinated individuals, ranging from an aMRR of 0.23 (95% CI: 0.19-0.26) after SARS-CoV-2 infection to 0.50 (95% CI: 0.37-0.67) after stroke. Conclusion: Our findings indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be subject to substantial confounding. Therefore, randomized trials are essential to establish vaccine efficacy after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.

Why was this study done: : After the emergence of new SARS-CoV-2 variants and the rollout of multiple booster SARS-CoV-2 vaccines, the impact of vaccination on risk of SARS-CoV-2 infection and death after the infection has mainly been explored in observational studies. We used negative control methods to investigate whether confounding affects the results of observational SARS-CoV-2 vaccine effectiveness studies. Findings: : We used Danish registry data obtained during the SARS-CoV-2 vaccine roll-out to conduct a nationwide, matched population-based cohort study of Danish residents 60­90 years in which we compared vaccinated individuals with non-vaccinated individuals. Compared with unvaccinated individuals, vaccinated individuals had increased risks of SARS-CoV2 infection but also had increased risks of all negative control outcomes (mammography, prostate biopsy, operation for cataract, malignant melanoma, examination of eye and ear). The risk of death after SARS-CoV2 infection was lower in the vaccinated cohort, as was the risk of death after acute myocardial infarction, stroke, cancer, low energy fracture, and head-trauma. Meaning: : The negative control methods indicate that observational studies of SARS-CoV-2 vaccine effectiveness may be prone to substantial confounding which may impact the observed associations. This bias may both lead to underestimation of vaccine effectiveness (increased risk of SARS-CoV2 infection among vaccinated individuals) and overestimation of the vaccine effectiveness (decreased risk of death after of SARS-CoV2 infection among vaccinated individuals). Our results highlight the need for randomized vaccine efficacy studies after the emergence of new SARS-CoV-2 variants and the rollout of multiple booster vaccines.

Risk and Prognosis of Cancer in Patients with Obstructive Uropathy Compared with the General Danish Population.

BACKGROUND: To examine whether obstructive uropathy is associated with increased risk of cancer and whether mortality differs between patients with cancer with and without obstructive uropathy. METHODS: In a nationwide population-based Danish cohort study including 37,275 adult patients with a first-time hospital-related diagnosis of obstructive uropathy in 1996 to 2022, we assessed cumulative cancer incidence (risk) and standardized incidence ratios (SIR). Furthermore, we compared the mortality of 7,485 patients diagnosed with cancer after obstructive uropathy diagnosis with that of 69,785 patients with cancer without obstructive uropathy matched by age, sex, cancer site, stage, and calendar year of cancer diagnosis. RESULTS: The 3-month risk of cancer after an obstructive uropathy diagnosis was 9.6%. The 3-month SIR was 34.2 [95% confidence interval (CI), 33.1-35.4] while the 1 to <5 year SIR was 1.2 (95% CI, 1.1-1.3). The 3-month SIRs were 82.7 (95% CI, 79.3-86.2) for urological cancer, 88.8 (95% CI, 79.8-98.5) for gynecological cancer, and 13.9 (95% CI, 12.0-15.9) for colorectal cancer. After 1 year of follow-up, the excess number of urological cancers decreased to 0.1 per 100 person-years, whereas we observed no excess risk of gynecological and colorectal cancers. The 5-year all-cause mortality following cancer was 64.1% (95% CI, 62.9-65.2) in patients with an obstructive uropathy diagnosis before cancer diagnosis and 53.2% (95% CI, 52.9-53.6) in those without. CONCLUSIONS: A first-time diagnosis of obstructive uropathy can be a clinical marker of underlying undiagnosed cancer and elevated mortality in relation to any cancer diagnosed after obstructive uropathy. IMPACT: These findings can inform the follow-up recommendations for obstructive uropathy.

Direct factor Xa inhibitors and the risk of cancer and cancer mortality: A Danish population-based cohort study.

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.

Stillbirth risk by fetal size among 126.5 million births in 15 countries from 2000 to 2020: A fetuses-at-risk approach.

OBJECTIVE: To compare stillbirth rates and risks for small for gestational age (SGA), large for gestational age (LGA) and appropriate for gestational age (AGA) pregnancies at 24-44 completed weeks of gestation using a birth-based and fetuses-at-risk approachs. DESIGN: Population-based, multi-country study. SETTING: National data systems in 15 high- and middle-income countries. POPULATION: Live births and stillbirths. METHODS: A total of 151 country-years of data, including 126 543 070 births across 15 countries from 2000 to 2020, were compiled. Births were categorised into SGA, AGA and LGA using INTERGROWTH-21st standards. Gestation-specific stillbirth rates, with total births as the denominator, and gestation-specific stillbirth risks, with fetuses still in utero as the denominator, were calculated from 24 to 44 weeks of gestation. MAIN OUTCOME MEASURES: Gestation-specific stillbirth rates and risks according to size at birth. RESULTS: The overall stillbirth rate was 4.22 per 1000 total births (95% CI 4.22-4.23) across all gestations. Applying the birth-based approach, the stillbirth rates were highest at 24 weeks of gestation, with 621.6 per 1000 total births (95% CI 620.9-622.2) for SGA pregnancies, 298.4 per 1000 total births (95% CI 298.1-298.7) for AGA pregnancies and 338.5 per 1000 total births (95% CI 337.9-339.0) for LGA pregnancies. Applying the fetuses-at-risk approach, the gestation-specific stillbirth risk was highest for SGA pregnancies (1.3-1.4 per 1000 fetuses at risk) prior to 29 weeks of gestation. The risk remained stable between 30 and 34 weeks of gestation, and then increased gradually from 35 weeks of gestation to the highest rate of 8.4 per 1000 fetuses at risk (95% CI 8.3-8.4) at ≥42 weeks of gestation. The stillbirth risk ratio (RR) was consistently high for SGA compared with AGA pregnancies, with the highest RR observed at ≥42 weeks of gestation (RR 9.2, 95% CI 15.2-13.2), and with the lowest RR observed at 24 weeks of gestation (RR 3.1, 95% CI 1.9-4.3). The stillbirth RR was also consistently high for SGA compared with AGA pregnancies across all countries, with national variability ranging from RR 0.70 (95% CI 0.43-0.97) in Mexico to RR 8.6 (95% CI 8.1-9.1) in Uruguay. No increased risk for LGA pregnancies was observed. CONCLUSIONS: Small for gestational age (SGA) was strongly associated with stillbirth risk in this study based on high-quality data from high- and middle-income countries. The highest RRs were seen in preterm gestations, with two-thirds of the stillbirths born as preterm births. To advance our understanding of stillbirth, further analyses should be conducted using high-quality data sets from low-income settings, particularly those with relatively high rates of SGA.

Cervical intraepithelial neoplasia and fecundability: a prospective cohort study.

STUDY QUESTION: Is cervical intraepithelial neoplasia (CIN) associated with reduced fecundability, defined as the probability of conceiving per menstrual cycle? SUMMARY ANSWER: Overall, we observed no meaningful association between CIN and fecundability, regardless of surgical status, although a recent diagnosis of moderate or severe CIN might be associated with slightly reduced fecundability for 2 years after diagnosis. WHAT IS KNOWN ALREADY: About 15% of couples experience infertility. Few studies have examined the influence of CIN on fertility, and the results have been inconsistent. No study has investigated the association between fecundability and pathologist-reported CIN diagnoses, particularly with respect to the recency of the specific CIN diagnoses. STUDY DESIGN, SIZE, DURATION: This prospective cohort study included 9586 women trying to conceive. The women were enrolled from 1 June 2007 to 3 February 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women were invited to complete a baseline questionnaire and bimonthly follow-up questionnaires for up to 12 months or until pregnancy occurred. Data on cervical cytologies and biopsies were retrieved from The National Pathology Registry (DNPR), which holds records of all cervical specimens examined in Denmark. Women were categorized based on their most severe diagnosis of CIN: no lesion, other cervical changes, mild CIN (CIN1), or moderate/severe CIN (CIN2+) with or without surgery. To investigate the association between CIN and fecundability, we computed fecundability ratios (FR) and 95% confidence intervals (CI) using a proportional probabilities regression model. We adjusted for age at study entry, partner age, body mass index, smoking status, timing of intercourse, parity, education, number of sexual partners, and household income. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with no lesion, the adjusted FRs (95% CI) for the association between CIN and fecundability were: other cervical lesions, 0.97 (0.91-1.04); CIN1, 1.04 (0.96-1.13); CIN2+ no surgery, 1.00 (0.82-1.22); and CIN2+ with surgery 0.99 (0.89-1.10). The FRs (95% CI) for a recent diagnosis (<2 years) of CIN were 0.98 (0.86-1.11) for other cervical lesions; 1.13 (0.99-1.29) for CIN1; 0.89 (0.62-1.26) for CIN2+ no surgery and 0.91 (0.75-1.10) for CIN2+ with surgery compared with the no lesion group. LIMITATIONS, REASONS FOR CAUTION: In the analyses, we adjusted for several covariates related to the women. However, we had little information on the male partners which could lead to unmeasured confounding as fecundability is a couple-based measure of fertility. Furthermore, a CIN diagnosis may not be constant as it may regress or progress spontaneously; therefore, it is possible that we have misclassified some women, especially women categorized as having normal cells or CIN1. WIDER IMPLICATIONS OF THE FINDINGS: Our results contribute important knowledge to women who are concerned about their future fertility after receiving a CIN diagnosis. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by The Danish Cancer Society (R167-A11036-17-S2). The overall cohorts were funded by the National Institute of Child Health and Human Development (R01-HD086742 and R03-HD094117). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Characterization of genetic variants of GIPR reveals a contribution of ß-arrestin to metabolic phenotypes.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of ß-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and ß-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and ß-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a ß-arrestin dependency and genetic ablation of ß-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of ß-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Urticaria and the risk of cancer: a Danish population-based cohort study.

BACKGROUND: Urticaria has been tentatively linked to cancer, but epidemiological evidence supporting this link is sparse and conflicting. We therefore conducted a population-based cohort study using healthcare databases of the Danish population (January 1980-December 2022). We followed 87,507 people for a median of 10.1 years after first hospital contact for urticaria. OBJECTIVES: To examine associations of a hospital diagnosis of urticaria with incident cancer. METHODS: We computed absolute risk of cancer and standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) standardized to Danish national cancer rates. In a cross-sectional analysis, we examined whether the extent of cancer spread differed between people with vs. without a previous urticaria diagnosis. RESULTS: The overall SIR for all types of cancer was 1.09 (95% CI, 1.06-1.11) based on 7,788 observed vs. 7,161 expected cases. The risk for any cancer was 0.7% (95% CI, 0.6-0.7) for the first year of follow-up. Cancer was diagnosed in 588 people with urticaria during the first year of follow-up (SIR 1.49, 95% CI, 1.38-1.62) and in 7,200 people thereafter (SIR 1.06, 95% CI, 1.04-1.09). During the first year of follow-up, we found strong associations with hematological cancers (e.g., non-Hodgkin lymphoma SIR 2.91, 95% CI, 1.92-4.23). Cancer stage was similar in people with vs. without previous urticaria diagnosis. CONCLUSIONS: At the time of urticaria diagnosis, or in the first year afterwards, we found a large increase in the risk for cancer. In subsequent years, a persistent 6% increase in risk remained. Diagnostic efforts may partly explain the elevated short-term risk, but occult cancer may promote urticaria, or cancer and urticaria share common risk factors.

Mediating pathways between neighborhood disadvantage and cardiovascular risk: Quasi-experimental evidence from a Danish refugee dispersal policy.

Research has documented that neighborhood disadvantage is associated with increased cardiovascular disease risk, but it is unclear which mechanistic pathways mediate this association across the life course. Leveraging a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998 and using 30 years of follow-up data from population and health registers, we assessed whether and how individual-level poverty, unstable employment, and poor mental health mediate the relation between neighborhood disadvantage and the risk of hypertension, hyperlipidemia, and type 2 diabetes among Danish refugees (N= 40,811). Linear probability models using the discrete time-survival framework showed that neighborhood disadvantage was associated with increased risk of hypertension (0.05 percentage points [pp] per year [95%CI -0.00, 0.10]); hyperlipidemia (0.03 pp per year [95%CI -0.01, 0.07]), and diabetes (0.01 pp per year (95%CI -0.02, 0.03)). The Baron-Kenny product-of-coefficients method for counterfactual mediation analysis indicated that cumulative income mediated 6%-28% of the disadvantage effect on these outcomes. We find limited evidence of mediation by unstable employment and poor mental health. This study informs our theoretical understanding of the pathways linking neighborhood disadvantage with cardiovascular disease risk and identifies income security as a promising point of intervention in future research.

Association of Autoimmune Diseases With Coronary Atherosclerosis Severity and Ischemic Events.

BACKGROUND: Some autoimmune diseases carry elevated risk for atherosclerotic cardiovascular disease (ASCVD), yet the underlying mechanism and the influence of traditional risk factors remain unclear. OBJECTIVES: This study sought to determine whether autoimmune diseases independently correlate with coronary atherosclerosis and ASCVD risk and whether traditional cardiovascular risk factors modulate the risk. METHODS: The study included 85,512 patients from the Western Denmark Heart Registry undergoing coronary computed tomography angiography. A diagnosis of 1 of 18 autoimmune diseases was assessed. Adjusted OR (aOR) for any plaque, any coronary artery calcification (CAC), CAC of >90th percentile, and obstructive coronary artery disease as well as adjusted HR (aHR) for ASCVD were calculated. RESULTS: During 5.3 years (Q1-Q3: 2.8-8.2 years) of follow-up, 3,832 ASCVD events occurred. A total of 4,064 patients had a diagnosis of autoimmune disease, which was associated with both presence of any plaque (aOR: 1.29; 95% CI: 1.20-1.40), any CAC (aOR: 1.28; 95% CI: 1.19-1.37), and severe CAC of >90th percentile (aOR: 1.53; 95% CI: 1.39-1.68), but not with having obstructive coronary artery disease (aOR: 1.04; 95% CI: 0.91-1.17). Patients with autoimmune diseases had a 46% higher risk (aHR: 1.46; 95% CI: 1.29-1.65) for ASCVD. Traditional cardiovascular risk factors were strongly associated with future ASCVD events, and a favorable cardiovascular risk factor profile in autoimmune patients was associated with ∼54% lower risk compared to patients with presence of risk factors (aHR: 0.46; 95% CI: 0.27-0.81). CONCLUSIONS: Autoimmune diseases were independently associated with higher burden of coronary atherosclerosis and higher risk for future ASCVD events, with risk accentuated by traditional cardiovascular risk factors. These findings suggest that autoimmune diseases increase risk through accelerated atherogenesis and that cardiovascular risk factor control is key for improving prognosis in patients with autoimmune diseases.

Risk of mortality and recurrence after first-time stroke among patients with type 2 diabetes: A Danish nationwide cohort study.

INTRODUCTION: The prognosis for stroke patients with type 2 diabetes mellitus (T2DM) remains poorly understood. We examined the risk of mortality and stroke recurrence in stroke patients with T2DM and stroke patients without diabetes. PATIENTS AND METHODS: We conducted a population-based cohort study including all patients diagnosed with a first-time ischemic stroke (n = 131,594) or intracerebral hemorrhage (ICH, n = 15,492) in Denmark, 2005-2021. Patients with T2DM were identified using hospital diagnosis codes and glucose-lowering drug prescriptions. We calculated risks, risk differences, and risk ratios, standardized by age, sex, and calendar year of stroke admission. RESULTS: Following ischemic stroke, the 5-year standardized mortality was 46.1% for patients with T2DM and 35.4% for patients without diabetes (standardized risk difference: 10.7% [95% CI 9.9-11.6]; risk ratio: 1.3 [95% CI 1.3-1.3]). The 5-year risk of recurrence following ischemic stroke was 12.7% for patients with T2DM and 11.3% for those without diabetes (risk difference: 1.4% [95% CI 0.9-2.0]; risk ratio: 1.1 [95% CI 1.1-1.2]). Following ICH, the 5-year mortality was 62.8% for patients with T2DM and 53.0% for patients without diabetes (risk difference: 9.8% [95% CI 7.2-12.4)]; risk ratio: 1.2 [95% CI 1.1-1.2]). The 5-year risk of recurrence after ICH was 9.1% for patients with T2DM and 9.7% for patients without diabetes. DISCUSSION AND CONCLUSION: Stroke patients with T2DM were at increased risk of mortality. The risk of stroke recurrence was slightly higher for ischemic stroke patients with T2DM than patients without diabetes, while no difference was observed among ICH patients.