To Örebro University

BACKGROUND: The lack of a standardised definition of large for gestational age (LGA) complicates clinical assessments and the interpretation of research.

OBJECTIVE: The objective of this study is to assess how different definitions of LGA affect the interpretation of outcomes in a stepped wedge cluster randomised controlled trial (SW-CRT).

METHODS: Secondary analysis of the Changing Diagnostic Criteria for Gestational Diabetes (CDC4G, ISRCTN41918550) study population (n = 47,080 pregnancies), including eight delivery units in Sweden during 2018. The outcome measures were the prevalence of LGA and severe LGA before and after switching from the previous Swedish diagnostic criteria for gestational diabetes (SWE-GDM) to the World Health Organisation (WHO-2013) criteria. LGA and severe LGA were defined as birthweight > 90th and > 97th percentile, respectively, using the following reference growth charts: The new Swedish reference ranges for foetal weight (SWE-REF), the Gestation Related Optimal Weight (GROW) and the International Foetal and Newborn Growth Consortium for the 21st Century (Intergrowth-21st). Analyses were performed on a modified intention-to-treat (mITT) population and on the subgroup discordant for GDM diagnosis between new and former criteria, i.e., glucose levels between the WHO-2013 and SWE-GDM diagnostic thresholds.

RESULTS: In the mITT population, the prevalence of LGA decreased from 19.4% to 13.1% after the switch to the WHO-2013 GDM criteria, as defined by SWE-REF (adjusted relative risk [RR], 0.92; 95% confidence interval [CI] 0.86, 0.98). There was no change in severe LGA using any of the reference charts. In the subgroup, LGA defined by SWE-REF (RR 0.68, 95% CI 0.50, 0.91) and GROW (RR 0.78, 95% CI 0.63, 0.95) was reduced, but not when defined by Intergrowth-21st (RR 0.88, 95% CI 0.74, 1.06). Severe LGA was reduced only when defined by Intergrowth-21st (RR 0.73, 95% CI 0.62, 0.85).

CONCLUSIONS: The choice of LGA definition affected the interpretation of the results in the CDC4G trial.

Patients with COPD and comorbid depression/anxiety are at risk of reduced health status. This study aimed to assess health status in COPD patients with depression/anxiety, the occurrence of severely reduced health status in this group, and to investigate associations between severely reduced health status and patient-related clinical factors. This cross-sectional study included 2245 randomly selected COPD patients from primary care and hospital outpatient clinics in Sweden. The COPD Assessment Test (CAT) and the Clinical COPD Questionnaire (CCQ) were used to assess health status. Severely reduced health status was defined as CAT ≥ 20 or CCQ ≥ 2. The 524 patients (23.3%) who reported depression/anxiety had higher mean CAT scores (18.3 vs. 15.2, p < 0.001) and CCQ scores (2.37 vs. 1.83, p < 0.001) than patients without depression/anxiety. In this group, 48% had CAT ≥ 20 and 57% had CCQ ≥ 2. In patients with depression/anxiety, factors associated with CAT ≥ 20 were: onset of COPD symptoms before 60 years of age (OR = 2.62 [95% CI 1.37-5.04]), frequent symptoms of depression in the previous three months (2.59 [1.55-4.30]), one or more COPD exacerbations in the previous six months (2.37 [1.41-4.00]) and physical inactivity (1.89 [1.11-3.22]). Apart from physical inactivity, factors associated with CCQ ≥ 2 were the same as for CAT ≥ 20. Approximately half of the COPD patients with comorbid depression/anxiety reported severely reduced health status. Exacerbations, frequent depressive symptoms and physical inactivity were factors associated with severely reduced health status, and constitute important treatable and preventable traits of COPD.

If Epstein-Barr virus is essential for multiple sclerosis (MS) pathogenesis, there may be differences in MS risk for auxiliary exposures that occur before or after Epstein-Barr virus infection. Infectious mononucleosis (IM) during adolescence typically represents the primary Epstein-Barr virus infection, so can be used as a proxy marker, while concussion in adolescence is considered a separate non-essential risk factor for MS. The objective here was to examine if concussion before or after IM during adolescence is differently associated with MS risk. Using national Swedish health registers, among those born from 1980 with follow-up to 2023, we identified a cohort with IM between ages 11 and 20 years among people without a demyelinating disease diagnosis by age 20 years (n = 37 432), among whom 174 had a subsequent MS diagnosis. The median age (and interquartile range) at IM was 17.00 (15.52-18.59) years among those without MS and 16.66 (15.15-18.29) years among those with MS. In this cohort, between ages 11 and 20 years, there were 1474 episodes of concussion before IM and 1171 occurring afterwards. Associations between concussion and MS risk were estimated using Cox regression, with age as the underlying timescale and adjustment for age at IM, year of birth (both modelled as continuous measures using restricted cubic splines), sex and county. Notably, only concussion occurring before, but not after, IM was associated with increased MS risk producing adjusted hazard ratios (with 95% confidence intervals) of 2.23 (1.24-4.03; P = 0.008) for concussion before IM and 0.85 (0.35-2.09; P = 0.726) for concussion after IM. However, there is no statistically significant effect modification for MS with an interaction for concussion before and after IM of 1.60 (0.16-15.60; P = 0.685). Our findings suggest that changes in the environment of the CNS caused by concussion facilitate development of MS if present before primary Epstein-Barr virus infection.

Background: The COVID-19 pandemic compelled governments worldwide to adopt diverse public health and economic policies. However, the relative efficiency of these interventions across European countries has not been comprehensively evaluated. This study assessed the efficiency of COVID-19 policy responses in 27 European countries of the Organization for Economic Co-operation and Development (OECD), with the aim of identifying factors associated with effective pandemic management. The time period of this study is from January 1, 2020 to December 31, 2022.

Methods: A data envelopment analysis (DEA) framework was applied to evaluate the efficiency of national responses. Policy inputs, including healthcare resources, economic support, and stringency indices, were assessed against outputs reflecting adverse outcomes, namely COVID-19 cases, mortality, and virus transmission. Data were obtained from the Oxford COVID-19 Government Response Tracker and other publicly available international databases.

Results: Marked heterogeneity in policy efficiency was observed. Countries that implemented early, stringent, and adaptive measures demonstrated superior efficiency scores. Italy, Greece, and Austria consistently ranked among the most efficient, while nations with delayed or inflexible strategies performed less effectively despite comparable resource availability. Importantly, policy flexibility and dynamic adjustment to epidemiological trends emerged as critical determinants of sustained efficiency.

Conclusions: This study provides a robust comparative evaluation of COVID-19 policy efficiency across European OECD countries. The findings emphasize that timeliness of interventions, adaptability of policy measures, and judicious resource allocation were more influential than absolute resource capacity. Incorporating efficiency assessments into pandemic preparedness strategies may enhance resilience and inform evidence-based decision-making for future global health emergencies.

PURPOSE OF REVIEW: As the life expectancy of people with multiple sclerosis (PwMS) increases, the importance of recognizing and addressing specific needs and challenges faced by those undergoing age-related sex hormone changes and hypogonadism is becoming increasingly evident. We present expert-led, practical recommendations from a consensus program that address gaps in age-related sex hormone changes and hypogonadism in PwMS not sufficiently addressed in current literature and guidelines. A multidisciplinary steering committee (SC) of 15 international experts identified 18 key clinical questions across 6 themes: climacteric symptoms in women with MS; impact of MS on the climacteric stage; impact of menopause on MS disease activity and progression; treatment and management of climacteric symptoms in women with MS; late-onset hypogonadism (LOH) in men with MS; and patient-centered care. After thorough review of the evidence from a systematic literature review, the SC formulated 18 clinical recommendations to address the questions. These recommendations were voted on by the SC and an extended faculty of 23 health care professionals from 16 countries, including 2 nurses and 1 patient association representative.

RECENT FINDINGS: Consensus was reached when ≥75% of respondents expressed agreement, with a score of 7-9 on a 9-point scale. After a single voting round, all 18 recommendations reached consensus (14 reaching consensus at 90%-100% and 4 at 80%-90%). The clinical recommendations addressed the following: the potential overlap and exacerbation of MS symptoms during the climacteric stage; the need for preventive care and screening during the menopausal transition; the potential for, and a paucity of data on, differential efficacy and tolerability of MS medications in menopausal/postmenopausal women; the complex causal interplay between hormonal and/or immunologic changes and natural aging in PwMS switching to a more progressive phase of disease; consideration of behavioral/lifestyle interventions alongside pharmacologic treatments; effects of hormonal treatments on MS symptoms; and management of LOH in men with MS.

SUMMARY: These recommendations were based on a robust modified Delphi consensus approach and present a valuable framework for improved patient care. These results emphasize the need to address critical gaps in our understanding and management of PwMS undergoing age-related sex hormone changes and hypogonadism.

BACKGROUND AND AIM: Patients with COPD and concurrent depression and/or anxiety are known to have an increased risk of exacerbations, morbidity, mortality, and deteriorated quality of life. Early detection of depression/anxiety may enable early interventions. The aims of this study were to describe the occurrence of depression and anxiety in primary care patients with COPD in Sweden, and to investigate age and gender differences together with other clinical factors associated with this comorbidity.

METHODS: A cross-sectional study was performed on a cohort of patients with doctor's diagnoses of COPD. Patients were randomly selected based on the patients' contact with 98 primary healthcare centers and 13 hospitals in Sweden in 2014. Information about self-reported depression/anxiety, patient characteristics, symptoms, and comorbidity, were collected using patient self-completion questionnaires. Lung function data were extracted from medical records.

RESULTS: Of the 2245 patients recruited, 23% (n = 524) reported depression/anxiety, 29% in women and 16% in men (p <0.001). Factors associated with depression/anxiety were being a woman (OR = 2.06 [95% CI 1.56-2.72]), current smoking (1.83 [1.37-2.43]), comorbid asthma (1.77 [1.32-2.37]), dyspnea (the modified Medical Research Council dyspnea scale ≥2 points) (1.58 [1.17-2.13]) and age <65 years (1.57 [1.17-2.10]). The youngest age groups had the highest proportions of patients with depression/anxiety.

CONCLUSIONS: Healthcare professionals need to be particularly aware of depression/anxiety in patients with COPD who are younger, women, current smokers, have comorbid asthma, or dyspnea.

Introduction & Objectives: The diagnostic workup for suspected prostate cancer is often emotionally distressing and may negatively affect patients’ well-being. Considerable variability exists in waiting times across diagnostic pathways, yet evidence on how such delays influence psychological distress is limited. Objective: To assess whether a fast-track diagnostic workup reduces psychological and physiological stress among men with suspected prostate cancer.

Materials & Methods: In this randomized clinical trial, 304 men referred for suspected prostate cancer at the Urology Department, Örebro University Hospital (Sweden), were randomized to either a fast-track diagnostic workup—aiming for the shortest possible waiting time—or usual care. Primary outcomes were patient-reported symptoms of distress (anxiety, depression, perceived stress, and sleep disruption); secondary outcomes included physiological stress markers, such as diurnal salivary cortisol. Data were collected from randomization to 12 months post-enrollment.

Results: Men in the fast-track group had a significantly shorter waiting time to their first consultation (median 7 days) compared with the usual care group (median 35 days). During the first six months, participants in the fast-track arm reported lower levels of distress, anxiety, and perceived stress, and improved sleep quality. Among those undergoing prostate biopsy, the strongest intervention effect was seen one to four weeks post-procedure. For men subsequently diagnosed with prostate cancer, the effect was most pronounced one week after biopsy. Differences between groups were no longer evident at 12 months. Diurnal cortisol profiles indicated a more favorable stress pattern in th efast-track group, especially during the period surrounding diagnostic disclosure.

Conclusions: A fast-track diagnostic workup for suspected prostate cancer substantially reduces psychological and physiological stress during the diagnostic phase. These findings support the implementation of accelerated diagnostic pathways in urological practice to improve patient experience and potentially reduce stress-related health risks.

OBJECTIVES: European countries implemented highly diverse mitigation policies during the COVID-19 pandemic, ranging from strict nationwide lockdowns to more voluntary approaches. This study aims to understanding how timing, stringency, and comprehensiveness of policy responses influenced epidemic trajectories by applying machine learning-based counterfactual analysis.

METHODS: Data from 27 European OECD countries between January 2020 and December 2022 were analysed. Daily epidemiological data, including COVID-19 cases, deaths, effective reproduction number were linked with government response indicators, demographics, vaccination, testing, and mobility data. Temporal Fusion Transformer (TFT) models were applied for multi-horizon time series forecasting by capturing nonlinear relationships between policy response indicators and COVID-19 outcome variables. Simulations were conducted under eight hypothetical response scenarios, ranging from the loosest to the strictest policy bundles. The impacts of policy responses on COVID-19 outcomes were assessed by comparing the counterfactual scenarios with the factual outcomes.

RESULTS: TFT models achieved excellent predictive accuracy (percentage mean absolute error <10%). The strictest responses were associated with reduced daily COVID-19 cases by over 10% in several countries, notably Hungary, Switzerland, and Turkey, while the loosest responses were associated with increased incidence by 10-20%, with the highest value observed in Poland. Associations with mortality were smaller and heterogeneous, with potentially maximum reductions of 7-10% in Belgium, Portugal, and Switzerland under strict scenarios. Over early relaxation from the restrictions might lead to outcomes as adverse as those under continuously loose policies. Feature importance analyses highlighted restrictions on mobility and gatherings, vaccination, testing, and fiscal measures as dominant drivers, alongside country-level factors such as age structure and chronic disease burden.

CONCLUSIONS: The TFT-based machine learning framework demonstrated favourable feasibility and interpretability, reinforcing its value in guiding policy decisions. Comprehensive, multi-domain interventions outperformed partial or short-lived restrictions. Lifting measures before achieving sufficient immunity and epidemic control posed substantial risks. Stringent policies reduced transmission, but their impact on mortality was constrained, which might be due to demographic and systemic vulnerabilities. Adaptive, data-driven strategies integrating epidemiology, policy, and structural context are essential to strengthen policy responses against future pandemics.

BACKGROUND: Beta-blockers may improve outcomes in patients with chronic obstructive pulmonary disease (COPD) without cardiovascular disease, but randomized trials have been inconclusive.

METHODS: This was a multicenter, open-label, pragmatic, phase 4 randomized trial. Patients 40 years of age or older with COPD, sinus rhythm, and no cardiovascular disease were randomly assigned in a 1:1 ratio to receive metoprolol, at a target dose of 100 mg daily, in addition to standard care or to receive standard care alone. The primary end point was the time to the first occurrence of a COPD exacerbation, cardiovascular event, or death during 1 year of follow-up.

RESULTS: A total of 1695 patients underwent random assignment; their mean age was 70 years, and 62% were female. The primary end point occurred in 27% of patients assigned to receive metoprolol and in 30% assigned to receive standard care (hazard ratio, 0.87; 95% confidence interval [CI], 0.73 to 1.05; P=0.14). The corresponding hazard ratios were 0.88 (95% CI, 0.72 to 1.06) for COPD exacerbations, 0.73 (95% CI, 0.48 to 1.11) for cardiovascular events, 0.92 (95% CI, 0.48 to 1.77) for death, and 0.87 (95% CI, 0.58 to 1.28) for exacerbations requiring hospitalization. Serious adverse events occurred in 80 (9.4%) of 848 participants in the metoprolol group and 66 (7.8%) of 847 participants in the standard care group. Nonserious adverse events occurred in 293 (34.6%) of 848 patients in the metoprolol group and 247 (29.2%) of 847 in the standard care group.

CONCLUSIONS: Among patients with COPD and no cardiovascular disease, metoprolol did not significantly improve the time to a composite of exacerbations, cardiovascular events, or death. (Funded by research grants from the Swedish Research Council and others; ClinicalTrials.gov number, NCT03566667.).

BACKGROUND: We examined the association of peripubertal pregnancies with long-term health and developmental outcomes in adult offspring and strengthened causal inference using sibling-comparison methods.

METHODS: Using linked Swedish register data from 1964 to 2018, we conducted a cohort study to estimate associations of pregnancies before age 16 years compared with pregnancies between ages 16 and 25 years, with body mass index (BMI), systolic blood pressure (SBP), cognitive function, and stress resilience among 943 444 male offspring aged 17-21 years in the Military Conscription Register. We further assessed associations with type 2 diabetes (T2D), depression, and anxiety among 2 461 510 male and female offspring aged 18-73 years using population-wide registers. Linear, multinomial, and survival models were used. Sibling fixed-effect models were used to account for unmeasured confounding shared among siblings.

RESULTS: Offspring from pregnancies before age 16 years compared with pregnancies between ages 16 and 25 years had lower SBP (β - 1.12; 95% confidence interval [CI] - 1.97 to -0.26), poorer cognitive function (β  - 0.54; 95% CI -0.67 to -0.40), and poorer stress resilience (β -0.24; 95% CI -0.38, -0.10). There was no increased risk of being underweight or overweight compared with normal weight. There was a lower risk of anxiety (hazard ratio 0.87; 95% CI 0.80 to 0.95) and no increased risk of T2D or depression. Sibling-comparison analyses attenuated deleterious associations to null or reversed them and amplified associations with markers of better health.

CONCLUSION: Pregnancies before age 16 years may not be causally associated with adverse long-term health and developmental outcomes in adolescent and adult offspring. The adverse associations in conventional analyses appear attributable to shared familial characteristics.