Herlev Hospital

Background Initial clinical studies of pulsed field ablation (PFA) to treat atrial fibrillation (AF) indicated a >90% durability rate of pulmonary vein isolation (PVI). However, these studies were largely conducted in single centers and involved a limited number of operators. The electrophysiological findings and outcomes in patients undergoing repeat ablation after an initial PF ablation for AF are incompletely understood. Methods In the MANIFEST-REDO study, we investigated patients who underwent repeat ablation due to clinical recurrence – AF or atrial tachycardia (AT) – following first-ever PVI with a pentaspline PFA catheter (Farawave; Boston Scientific Inc). Results At 22 centers, 427 patients (age 64±11 years; 37% female) were included. Of note, the recurrent arrhythmia leading to the repeat ablation was paroxysmal AF (51%), persistent AF (30%), or AT (19%). At the repeat procedure, the PV reconnection rates were: 30% (LSPV), 28% (LIPV), 33% (RSPV) and 32% (RIPV). In 45% of patients all PVs were durably isolated at the beginning of the repeat procedure, with the previous use of any imaging or mapping modality being univariately associated with durable PVI. After a post-redo follow-up period of 284 [90-366] days, the primary effectiveness endpoint (freedom from documented AF/AT lasting ≥30s after 3-month blanking without class I/III antiarrhythmic drugs or symptoms) was achieved in 65% of patients, with significant differences between groups (PAF 65% vs. PersAF 56% vs. AT 76%; p=0.04). Persistent AF as recurrent arrhythmia after the initial PFA ablation predicted AT/AF recurrence after repeat ablation (HR 1.241 (95% CI 1.534-1.005 CI); p=0.045). The procedural complication rate was 2.8%. Conclusion In repeat procedures for AF/AT performed after an index procedure with PFA for AF, PV reconnections are not uncommon. Repeat procedures can be performed safely and with an acceptable subsequent success rate.

The ovarian oncobiome is subject to increasing scientific focus, but a potential link between bacterial dysbiosis and ovarian carcinogenesis remains controversial. Our primary aim was to characterize the bacterial microbiota in epithelial ovarian cancer samples. Secondarily, we aimed to compare results from the bacterial microbiota in formalin‐fixed, paraffin‐embedded ovarian tissue samples from 194 patients with epithelial ovarian cancer, fallopian tube tissue samples from 16 patients with serous tubal intraepithelial carcinomas and in benign fallopian tube tissue samples from 25 patients. Bacterial abundance was investigated by means of 16S rDNA Next Generation Sequencing. The 16S rDNA sequencing run produced a very low number of bacterial reads. Only seven samples displayed bacterial reads above 5000. Validation of detected bacterial reads by qPCR was negative and indicative of results being background amplification. Our results indicate no amount of bacterial biomass in the ovarian cancer, benign fallopian tube and in the samples with serous tubal intraepithelial carcinomas. The findings underline the importance of validating results from bacterial microbiota studies with additional technical assays before any conclusion may be drawn.

OBJECTIVE In the Diabetes Virus Detection and Intervention trial, antiviral treatment with pleconaril and ribavirin decreased the decline, compared with placebo, in endogenous C-peptide 1 year after diagnosis of type 1 diabetes (T1D) in children and adolescents. This article reports the results 2 and 3 years after diagnosis. RESEARCH DESIGN AND METHODS This was a multicenter, randomized, placebo-controlled (1:1) trial of 96 children and adolescents aged 6–15.9 years newly diagnosed with T1D. Antiviral treatment (pleconaril and ribavirin) or placebo was given for 6 months from diagnosis, and participants were followed for 3 years. The primary outcome was residual C-peptide secretion, reported as the area under the curve (AUC), assessed by 2-h mixed-meal tolerance test. Secondary outcomes included insulin doses and HbA1c. RESULTS At the 3-year follow-up, 75 participants attended. At 2 years, the mean ± SD AUC for C-peptide in the placebo group was 0.27 ± 0.33 compared with 0.34 ± 0.37 in the pleconaril and ribavirin group. After 3 years, the AUC had decreased to 0.17 ± 0.23 and 0.25 ± 0.34, respectively. There was no statistically significant difference between the groups. The groups were also comparable with regard to secondary end points. CONCLUSIONS The decreased reduction in C-peptide levels after antiviral treatment is no longer present after 2 or 3 years. Further investigations are needed to explore options to use antiviral treatment in the prevention and treatment of T1D.

The tumor microenvironment (TME) is integral to cancer progression, impacting metastasis and treatment response. It consists of diverse cell types, extracellular matrix components, and signaling molecules that interact to promote tumor growth and therapeutic resistance. Elucidating the intricate interactions between cancer cells and the TME is crucial in understanding cancer progression and therapeutic challenges. A critical process induced by TME signaling is the epithelial-mesenchymal transition (EMT), wherein epithelial cells acquire mesenchymal traits, which enhance their motility and invasiveness and promote metastasis and cancer progression. By targeting various components of the TME, novel investigational strategies aim to disrupt the TME’s contribution to the EMT, thereby improving treatment efficacy, addressing therapeutic resistance, and offering a nuanced approach to cancer therapy. This review scrutinizes the key players in the TME and the TME's contribution to the EMT, emphasizing avenues to therapeutically disrupt the interactions between the various TME components. Moreover, the article discusses the TME’s implications for resistance mechanisms and highlights the current therapeutic strategies toward TME modulation along with potential caveats.

Objectives To evaluate the effect of intravesical alkalinised lidocaine as an anaesthetic treatment on procedural pain during intradetrusor onabotulinumtoxinA (BTX‐A) injections for overactive bladder. Patients and Methods This single‐centre, randomised, double‐blind, placebo‐controlled two period crossover trial was conducted on women scheduled for BTX‐A injections at our outpatient urogynaecology clinic between September 2022 and May 2024. Patients were randomly assigned (1:1) to receive either alkalinised lidocaine or placebo during the first treatment period. Alkalinised lidocaine solution comprised lidocaine hydrochloride (20 mg/mL, 20 mL), sodium hydrogen carbonate (1 mmoL/mL, 10 mL), and sodium chloride (9 g/L, 10 mL). The matching placebo was sodium chloride (9 g/L, 40 mL). The primary outcome measure was procedural pain rated on a 100‐mm visual analogue scale (VAS). Secondary outcomes included adverse effects such as post‐void residual urine volumes requiring catheterisation, urinary tract infection, haematuria 1 week after treatment, and patient satisfaction measured on a 5‐point scale. During the second treatment period, patients received the alternative intervention. Results We enrolled 50 patients, of which 41 were eligible for per‐protocol analyses. The mean VAS score was significantly lower following intravesical alkalinised lidocaine (mean 21.3 mm, 95% confidence interval [CI] 14.7–27.8 mm) compared to placebo (mean 41.6 mm, 95% CI 35.0–48.1 mm) with a mean difference of −20.3 mm (95% CI −29.2 to −11.5 mm; P < 0.001). Adverse events and patient satisfaction did not significantly differ between the alkalinised lidocaine and placebo treatments (P = 0.825 and P = 0.138, respectively). Conclusions Intravesical instillation of alkalinised lidocaine before BTX‐A injections significantly reduced VAS pain scores compared to placebo (ClinicalTrials.gov identifier: NCT05415865).

Objectives Acute kidney injury (AKI) is a syndrome with high mortality and morbidity in part due to delayed recognition based on changes in creatinine. A marker for AKI based on a single measurement is needed and therefore the performance of a single measurement of plasma neutrophil gelatinase-associated lipocalin (pNGAL) to predict AKI in patients admitted to the emergency department was tested. Methods Samples from the Triage study which included 6005 consecutive adult patients admitted to the emergency department were tested for pNGAL. The optimal cutoff for pNGAL was determined by the AUC and compared to AKI based on creatinine using different estimations of the premorbid kidney function. Results In 4833 patients, two or more plasma creatinine (pCr) measurements were available allowing the detection of AKI. The highest prevalence of AKI (10%) was found when defining AKI as an increase in pCr ≥26.5 μmol/L from the prior year’s mean pCr. At these conditions the AUC for pNGAL to predict AKI was 85% giving an optimal cutoff of 142.5 ng/mL with a negative predictive value of 0.96, a positive predictive value of 0.35, a specificity of 0.87 and a sensitivity of 0.70. Conclusion The study illustrates that the value of a single measurement of pNGAL is primarily in excluding AKI whereas it`s poorer in predicting the presence of AKI. When diagnosing AKI with pCr the optimal baseline pCr level is the mean of available pCr (mb-pCr) measurements from up to a year prior to the current event.

An increasing number of autosomal recessive forms of adenomatous polyposis have been described, but some in very few cases. Here, we describe a rare case of biallelic germline pathogenic variants in the MLH3 gene, implicating it as a potential cause of early colorectal cancer. The patient, a 47‐year‐old woman, presented with rectal bleeding, leading to the discovery of a malignant rectal tumor and adenomas during colonoscopy. Histopathological examination confirmed adenocarcinoma without microsatellite instability, and genetic testing identified two likely pathogenic frameshift variants in MLH3 located in trans. These findings contribute to the expanding knowledge of MLH3‐related polyposis and colorectal cancer and underscore the need for further research into the gene's broader implications, including its potential role in cancer and infertility pathways.

Secondary hyperparathyroidism (sHPT) is a significant clinical complication of CKD leading to bone abnormalities and cardiovascular disease. Current treatment based on activating the parathyroid calcium-sensing receptor (CaSR) using calcimimetics such as Cinacalcet, aims to decrease plasma PTH levels and inhibit the progression of parathyroid hyperplasia. In the present study, we found significant diurnal rhythmicity of Casr, encoding the Cinacalcet drug target in hyperplastic parathyroid glands (p = 0.006). In rats with sHPT, Cinacalcet treatment timed prior to the acrophase of Casr expression (chronotherapy: Cina1) was compared with the usual timing of treatment early in the active phase (conventional: Cina2). Without Cinacalcet treatment, induction of sHPT resulted in a significant increase in parathyroid proliferation in terms of Ki-67⁺ cells compared to that of control rats (p = 0.001). Conventional Cinacalcet treatment (Cina2) did not significantly reduce Ki-67 index compared to untreated rats with sHPT (p = 0.09). In contrast, chronotherapy treatment (Cina1) resulted in a marked inhibition of parathyroid proliferation by Ki-67⁺ cells compared to untreated rats with sHPT (p = 0.0001). We found significantly reduced parathyroid Ki-67 index using chronotherapy compared to conventional timing of Cinacalcet (Cina1 vs. Cina2: 0.92±0.14% vs. 2.46±0.37%, p = 0.006). Transcriptomic analysis showed that the reduced proliferation of Cina1 was associated with downregulation of genes involved in mitotic activity, together with an increased adaptive response of energy metabolism, as evident from upregulated pathways of Oxidative phosphorylation and TCA cycle compared to the untreated uremic group. Conclusively, it is shown that the inhibitory effect of Cinacalcet on parathyroid cell proliferation is markedly impacted by the timing of administration, suggesting a possible benefit of using chronotherapy in Cinacalcet treatment of sHPT.

Biological datasets often consist of thousands or millions of variables, e.g. genetic variants or biomarkers, and when sample sizes are large it is common to find many associated with an outcome of interest, for example, disease risk in a GWAS, at high levels of statistical significance, but with very small effects. The False Discovery Rate (FDR) is used to identify effects of interest based on ranking variables according to their statistical significance. Here, we develop a complementary measure to the FDR, the priorityFDR, that ranks variables by a combination of effect size and significance, allowing further prioritisation among a set of variables that pass a significance or FDR threshold. Applying to the largest GWAS of type 1 diabetes to date (15,573 cases and 158,408 controls), we identified 26 independent genetic associations, including two newly‐reported loci, with qualitatively lower priorityFDRs than the remaining 175 signals. We detected putatively causal type 1 diabetes risk genes using Mendelian Randomisation, and found that these were located disproportionately close to low priorityFDR signals ( p = 0.005), as were genes in the IL‐2 pathway ( p = 0.003). Selecting variables on both effect size and significance can lead to improved prioritisation for mechanistic follow‐up studies from genetic and other large biological datasets.

Aim To describe the use of invasive mechanical ventilation core strategies, adjuvant treatments and the occurrence of barotrauma and prolonged ventilation in ICU patients with COVID‐19 in Denmark, retrospectively. Methods All ICUs admitting COVID‐19 patients in Denmark from 10 March 2020 to 2 April 2021 were invited to participate. All patients with COVID‐19 who received invasive mechanical ventilation were included and data was retrospectively collected from electronic patient records. Results A total of 774 patients were invasively ventilated during the first two waves and included; 70% were males and the median age was 69 years. 340 (51.5%) of patients never exceeded tidal volumes of 8 mL/kg. For all patients, tidal volumes under 8 mL/kg were applied in 77.6% (IQR 54.5%–96.2%) of the time on ventilator in the ICU; plateau pressure was below 30 cm H 2 O in 125 (80.6%) patients; prone positioning was used in 44.7% of patients. In ICU, 169 of 774 (21.8%) patients experienced barotrauma and 220 (28.4%) prolonged ventilation. At 90 days, 306 (39.5%) had died. Conclusions Lung protective ventilation and prone positioning were used in many of the Danish ICU patients with COVID‐19, but barotrauma, prolonged ventilation and death occurred frequently.

Understanding the molecular landscape of nonmuscle-invasive bladder cancer (NMIBC) is essential to improve risk assessment and treatment regimens. We performed a comprehensive genomic analysis of patients with NMIBC using whole-exome sequencing (n = 438), shallow whole-genome sequencing (n = 362) and total RNA sequencing (n = 414). A large genomic variation within NMIBC was observed and correlated with different molecular subtypes. Frequent loss of heterozygosity in FGFR3 and 17p (affecting TP53) was found in tumors with mutations in FGFR3 and TP53, respectively. Whole-genome doubling (WGD) was observed in 15% of the tumors and was associated with worse outcomes. Tumors with WGD were genomically unstable, with alterations in cell-cycle-related genes and an altered immune composition. Finally, integrative clustering of multi-omics data highlighted the important role of genomic instability and immune cell exhaustion in disease aggressiveness. These findings advance our understanding of genomic differences associated with disease aggressiveness in NMIBC and may ultimately improve patient stratification.

Background The 313-variant polygenic risk score (PRS313) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS313 across different European populations which could influence risk estimation has not been performed. Methods We explored the distribution of PRS313 across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank. The mean PRS was calculated by country in the BCAC dataset and by country of birth in the UK Biobank. We explored different approaches to reduce the observed heterogeneity in the mean PRS across the countries, and investigated the implications of the distribution variability in risk prediction. Results The mean PRS313 differed markedly across European countries, being highest in individuals from Greece and Italy and lowest in individuals from Ireland. Using the overall European PRS313 distribution to define risk categories, leads to overestimation and underestimation of risk in some individuals from these countries. Adjustment for principal components explained most of the observed heterogeneity in the mean PRS. The mean estimates derived when using an empirical Bayes approach were similar to the predicted means after principal component adjustment. Conclusions Our results demonstrate that PRS distribution differs even within European ancestry populations leading to underestimation or overestimation of risk in specific European countries, which could potentially influence clinical management of some individuals if is not appropriately accounted for. Population-specific PRS distributions may be used in breast cancer risk estimation to ensure predicted risks are correctly calibrated across risk categories.

Background Intermediate-high risk pulmonary embolism (PE) carries a significant risk of hemodynamic deterioration or death. Treatment should balance efficacy in reducing clot burden with the risk of complications, particularly bleeding. Previous studies on high-dose, short-term thrombolysis with alteplase (rtPA) showed a reduced risk of hemodynamic deterioration but no change in mortality and increased bleeding complications. Catheter-based techniques, including ultrasound-assisted thrombolysis (USAT), and low-dose thrombolysis may offer reasonable efficacy with lower risk. However, studies comparing these methods have been few. This trial aims to address this gap by randomizing patients to three treatment modalities. Methods Multicenter, randomized trial with 1:1:1 allocation of 210 patients with acute intermediate-high risk PE, excluding those with absolute contraindications to thrombolysis. Patients are eligible for inclusion if they are > 18 years of age, have had symptoms < 14 days, and are able to give informed consent. Patients are allocated 1:1:1 into three treatment strategies: (1) unfractionated heparin (UFH)/low molecular weight heparin (LMWH), (2) UFH/LMWH + 20 mg rtPA/6 h intravenously (IV), or (3) UFH + 20 mg rtPA/6 h via USAT. Co-primary outcomes include reduction in clot burden as assessed by refined Miller score from pre-treatment to follow-up (48–96 h) computed tomography pulmonary angiogram (CTPA) comparing low-dose rtPA (± USAT) groups to UFH/LMWH group (p < 0.01, N = 210) and reduction in refined Miller score on follow-up CT angiography comparing low-dose rtPA by USAT to intravenous rtPA, p < 0.04, N = 140). Secondary outcomes comprise bleeding complications, duration of index admission, FiO2, blood pressure, respiratory and heart rate at the time of follow-up CT angiography, mortality in the three groups, incidence of tricuspid regurgitation pressure gradient < 40 mmHg at 3 months follow-up echocardiography, 6-min walk test at 3 months comparing the three groups, and health-related quality of life at 3 months follow-up comparing the three groups. Discussion We hypothesize that in patients with intermediate-high risk PE (1) administration of 20 mg rtPA leads to a greater reduction in clot burden compared to heparins and (2) administration of 20 mg rtPA via USAT results in a greater reduction in clot burden compared to 20 mg rtPA intravenous. Trial registration ClinicalTrials.gov NCT04088292. Registered in September 2019 (retrospectively registered).

Aims In the EMPACT‐MI trial, empagliflozin reduced heart failure (HF) hospitalizations but not mortality in acute myocardial infarction (MI). Contemporary reports of clinical event rates with and without type 2 diabetes mellitus (T2DM) in acute MI trials are sparse. The treatment effect of empagliflozin in those with and without T2DM in acute MI is unknown. Methods and results A total of 6522 patients with acute MI with newly reduced left ventricular ejection fraction (LVEF) to <45%, congestion, or both, were randomized to empagliflozin 10 mg or placebo. The primary endpoint was time to first HF hospitalization or all‐cause death. Rates of endpoints with and without T2DM and the efficacy and safety of empagliflozin according to T2DM status were assessed. Overall, 32% had T2DM; 14% had pre‐diabetes; 16% were normoglycaemic; 38% had unknown glycaemic status. Patients with T2DM, compared to those without T2DM, were at higher risk of time to first HF hospitalization or all‐cause death (hazard ratio [HR] 1.44; 95% confidence interval [CI] 1.06–1.95) and all‐cause death (HR 1.70; 95% CI 1.13–2.56). T2DM did not confer a higher risk of first HF hospitalization (HR 1.22, 95% CI 0.82–1.83). Empagliflozin reduced first and total HF hospitalizations, but not all‐cause mortality, regardless of presence or absence of T2DM. The safety profile of empagliflozin was the same with and without T2DM. Conclusion Patients with acute MI, LVEF <45% and/or congestion who had T2DM were at a higher risk of mortality than those without T2DM. Empagliflozin reduced first and total HF hospitalizations regardless of the presence or absence of T2DM.

Introduction: Atopic dermatitis (AD) and related atopic diseases are among the chronic health conditions that are becoming more common in children. Children with AD may develop atopic comorbidities, which makes it more difficult to manage treatment and necessitates more precautions in the child's everyday life. The parents of chronically ill children play a key role as the children's primary carers. This article explores the experiences of parents with the everyday tasks related to their children's illnesses. Methods: Face-to-face interviews in the Capital Region of Denmark, with eleven families with children, aged between one and five years, with AD and at least one atopic comorbidity (food allergy, allergic rhinoconjunctivitis or asthma). Results: We argue that, aside from the immediate tasks directly linked to the child's treatments, there are numerous other types of tasks, both inside and outside the home, that emerge when a family adjusts to living with a child with AD and atopic comorbidities. We present three major strategies that parents use to protect their child: risk avoidance, pursuing a normal childhood, and good parenting. These strategies are closely related to the parents' wish to give their child as normal a childhood as possible. Conclusion: Based on the findings, we suggest that healthcare professionals, beside the medical examination and treatment, are sensitive and attentive towards the large amounts of invisible work that parents of children with AD and atopic comorbidities accomplish and maintain awareness that parents may downplay the workload. Knowing the patients as persons can help facilitate and strength a trusting relationship.