Temporal and regional differences in the incidence of hospital-diagnosed endometriosis:a Danish population-based study

INTRODUCTION: Due to diagnostic challenges, normalization of symptoms and an overall lack of awareness among both patients and physicians, endometriosis is an underdiagnosed disease. This can result in delayed treatment and potentially worsening of the disease. Despite initiatives, such as patients' support organizations and specialized endometriosis referral centers, differences in awareness, socioeconomic factors and lifestyle, combined with varying distances to specialized referral centers, could result in regional differences in the degree of underdiagnosing. This study aims to explore temporal and regional variations in the incidence of endometriosis based on the Danish hospital discharge register, and shed light on the degree of underdiagnosing of endometriosis in Denmark. MATERIAL AND METHODS: This registry‐based cohort study included all women aged 15–55 living in Denmark from 1990–2017. Participants were identified through the Danish Civil Registration system and endometriosis diagnoses received at a hospital were obtained from the Danish National Patient Registry. Incidence rates of diagnosed endometriosis were calculated for each year of the study period and for each municipality in Denmark. A Cox regression analysis, stratified by calendar time and adjusted for ethnic origin, household composition, highest educational level and family socioeconomic status, was performed to estimate the association between residence and likelihood of receiving a hospital‐based diagnosis of endometriosis. RESULTS: The nationwide incidence rate of hospital‐diagnosed endometriosis was 7.89 (95% confidence interval [CI] 7.80–7.99) per 10 000 person‐years and the prevalence in 2017 was 1.63%. The results showed an overall increase in the incidence of diagnosed endometriosis of 46.8% (95% CI 32.9–62.2) during the study period and also displayed significant regional differences. After adjustments, women living in northern Jutland had the highest probability of receiving a hospital‐based diagnosis of endometriosis (hazard ratio 1.13, 95% CI 1.09–1.18), whereas women living in northern Zealand had the lowest probability (hazard ratio 0.63, 95% CI 0.60–0.67) compared with eastern Jutland. These regional differences have become more evident over time. CONCLUSIONS: Our results reveal significant regional differences in the incidence of hospital‐diagnosed endometriosis, suggesting that a significant number of women may be left behind without a diagnosis. Further studies are needed to assess the underlying reasons for the significant regional differences

Furosemide versus placebo for fluid overload in intensive care patients—The randomised GODIF trial second version : Statistical analysis plan

Publisher Copyright: © 2023 The Authors. Acta Anaesthesiologica Scandinavica published by John Wiley & Sons Ltd on behalf of Acta Anaesthesiologica Scandinavica Foundation.Background: Fluid overload is associated with increased mortality in intensive care unit (ICU) patients. The GODIF trial aims to assess the benefits and harms of fluid removal with furosemide versus placebo in stable adult patients with moderate to severe fluid overload in the ICU. This article describes the detailed statistical analysis plan for the primary results of the second version of the GODIF trial. Methods: The GODIF trial is an international, multi-centre, randomised, stratified, blinded, parallel-group, pragmatic clinical trial, allocating 1000 adult ICU patients with moderate to severe fluid overload 1:1 to furosemide versus placebo. The primary outcome is days alive and out of hospital within 90 days post-randomisation. With a power of 90% and an alpha level of 5%, we may reject or detect an improvement of 8%. The primary analyses of all outcomes will be performed in the intention-to-treat population. For the primary outcome, the Kryger Jensen and Lange method will be used to compare the two treatment groups adjusted for stratification variables supplemented with sensitivity analyses in the per-protocol population and with further adjustments for prognostic variables. Secondary outcomes will be analysed with multiple linear regressions, logistic regressions or the Kryger Jensen and Lange method as suitable with adjustment for stratification variables. Conclusion: The GODIF trial data will increase the certainty about the effects of fluid removal using furosemide in adult ICU patients with fluid overload. Trial Registrations: EudraCT identifier: 2019-004292-40 and ClinicalTrials.org: NCT04180397.Peer reviewe

Clinical Staphylococcus aureus inhibits human T-cell activity through interaction with the PD-1 receptor

Staphylococcus aureus (S. aureus) represents a major clinical challenge due to its explicit capacity to select mutations that increase antibiotic resistance and immune evasion. However, the molecular mechanisms are poorly defined, especially for adaptive immunity. Cancer immunotherapy targeting programmed cell death protein 1 (PD-1) enhances T-cell activity and is emerging for the treatment of certain viral infections, while its potential against bacterial infections remains elusive. We show that an S. aureus clpP mutant, selected during clinical antibiotic therapy, inhibits T-cell activity by directly interacting with PD-1 on human T cells. Specificity of the interaction was confirmed using recombinant PD-1, as well as PD-1 overexpressing and knock out cells. Moreover, the PD-1-binding S. aureus inhibited intracellular calcium mobilization, T-cell proliferation, CD25 expression, and IL-2 secretion, while the key effects were alleviated by antibody-mediated PD-1 blockade using an engineered IgG1-based anti-PD-1 antibody. Our results suggest that clpP mutant S. aureus directly targets PD-1 to evade immune activation and that therapeutic targeting of PD-1 may be used against certain staphylococcal infections. IMPORTANCE Therapies that target and aid the host immune defense to repel cancer cells or invading pathogens are rapidly emerging. Antibiotic resistance is among the largest threats to human health globally. Staphylococcus aureus (S. aureus) is the most common bacterial infection, and it poses a challenge to the healthcare system due to its significant ability to develop resistance toward current available therapies. In long-term infections, S. aureus further adapt to avoid clearance by the host immune defense. In this study, we discover a new interaction that allows S. aureus to avoid elimination by the immune system, which likely supports its persistence in the host. Moreover, we find that blocking the specific receptor (PD-1) using antibodies significantly relieves the S. aureus-imposed inhibition. Our findings suggest that therapeutically targeting PD-1 is a possible future strategy for treating certain antibiotic-resistant staphylococcal infections.</div