Copenhagen University Hospital

There is limited data regarding the rare and aggressive colorectal neuroendocrine carcinoma (CR-NEC). In this large prospective study, molecular-clinical characteristics and treatment outcomes following palliative chemotherapy are reported for 163 metastatic CR-NEC patients, with a comparison to a population-based prospective cohort of 263 metastatic colorectal adenocarcinoma (CR-AC) patients. Eighty-three percent of CR-NEC received first-line platinum-etoposide, while 98% of CR-AC patients received first-line fluorouracil-based chemotherapy. Disease control rate across all first-line regimens in CR-NEC and CR-AC was 43% vs. 74%, immediate progressive disease 46% vs. 15%, progression-free survival 2.4 months (m) (95% CI 2.1-3.3) vs. 7.7 m (95% CI 6.9-8.5), and overall survival 6.7 m (95% CI 5.6-8.8) vs. 16.8 m (95% CI 13.7-20.3), all, p < .001. CR-NEC more often had synchronous metastases, worse performance status, and symptom burden at treatment initiation than CR-AC (all, p < .001). Two-year survival was 9% vs. 37% in CR-NEC and CR-AC (p < .001). BRAF mutations were frequent in CR-NEC and CR-AC (26% vs. 20%, p = .153) and associated with shorter OS in CR-NEC and CR-AC (p = .025 and p = .003). KRAS mutations were less frequent in CR-NEC than CR-AC (34% vs. 45%, p = .041), but only associated with shorter OS in rectal NEC (p = .04). The frequencies of APC and TP53 mutations were similar between the cohorts and did not impact survival. Metastatic CR-NEC and CR-AC are clinically distinct, with NEC demonstrating more aggressive features, limited treatment effect, and worse prognosis. Although they share important driver mutations, the underlying reason for their marked clinical differences remains unclear.

Virtual reality-based cognitive remediation therapy (VR-CRT) offers an ecologically valid approach to enhance real-world cognitive functioning in mood disorders (MD) or schizophrenia spectrum disorders (SSD). This study investigated baseline cognitive, clinical, and neural predictors of VR-CRT response in MD and SSD. Sixty-two MD and SSD participants were randomized to receive four-week VR-CRT or control with assessments at baseline, treatment completion (week 5), and follow-up (week 17). Univariate general linear models examined predictors of VR-CRT improvement on daily-life cognitive skills, assessed using the Cognition Assessment in Virtual Reality (CAVIR). Predictors included age, diagnosis, baseline cognition, IQ-cognition discrepancy, dorsal prefrontal cortex (dPFC) activation during a working memory task, functional connectivity within the dorsal attention (DAN) and salience (SAL) networks, subjective cognition, and technological acceptance. Higher IQ-cognition discrepancy at baseline (i.e., better cognitive performance than expected from premorbid IQ) predicted greater treatment efficacy at treatment completion (β=0.17, p=0.045) and follow-up (β=0.21, p=0.008), while baseline cognition was not associated with treatment response (ps≥0.15). Higher baseline dPFC activity predicted more improvements at both times (β=2.27 p=0.03; β=1.82; p=0.048, respectively). Higher DAN-SAL connectivity predicted improvements at treatment completion (β=2.81 p=0.047), but not at follow-up (p=0.38). Age, sex, diagnosis, subjective cognition, and technological acceptance were not associated with cognitive change. Better cognitive performance than expected based on IQ, possibly reflecting higher cognitive fitness, and greater task-related engagement of dPFC may enhance VR-CRT responsiveness. This profile may indicate greater readiness for change and propensity to translate cognitive strategies into daily life.

Integrated genomic surveillance, combining whole genome sequencing (WGS) of bacterial isolates with patient movement data, promises improved detection and prevention of pathogen transmission. However, evidence on its cost-effectiveness and clinical utility remains limited, not least because the full extent of transmission in hospital settings is difficult to capture. We conducted a 28-month observational study at Rigshospitalet, Copenhagen, collecting patient movement data and sequencing 18 438 bacterial isolates from 7398 patients across diverse species, infection sites, and resistance profiles. We estimated the hypothetical benefits of implementing integrative WGS surveillance, assuming that continued transmission could be prevented when WGS information was acted upon immediately. We found that 1975 of 7398 of culture-positive hospitalized patients (26.7%) harboured a pathogen genetically related to another patient's isolate. Of those, 1359 (68.8%) had an epidemiological link in the hospital, with Enterococcus faecium by far being the most prevalent bacteria involved in transmissions. WGS-informed prevention could hypothetically generate a net savings of €1.35 million annually if transmission was stopped once a clonal isolate was detected in a second patient. Furthermore, this approach could potentially have prevented an estimated 1284 hospital-acquired infections over the 28-month study period, including 94 cases characterized by the recovery of bloodstream isolates. Our integrated genomic surveillance approach reveals previously unexplored transmission landscapes. We discovered that transmission is widespread, varies between species, and is not limited to resistant isolates. Our results emphasize the potential of integrated genomic surveillance, the identification of local transmission hotspots, potential for greater savings by including susceptible isolates, and an incremental cost-effectiveness ratio classification by pathogen species.

The systematic review evaluates the impact of indocyanine green fluorescence angiography (ICG-FA) on surgical decisions, postoperative complications, and mortality in acute bowel ischemia. Studies were included if they met the following criteria: patients ≥18 y undergoing ICG-FA for perfusion assessment in all-cause acute bowel ischemia; if they were human clinical studies with original data (n ≥ 5); and if they were published in English, Latin, or Nordic languages. The primary outcome was change of strategy; secondary outcomes included postoperative complications and mortality. Studies were excluded if they were reviews or meta-analyses, animal studies, or papers without original empirical data. Risk of bias was assessed with the Risk of Bias In Non-randomized Studies - of Interventions (ROBINS-I Tool). Outcomes were presented narratively, given the high clinical and methodological heterogeneity across studies. Seven studies met the following inclusion criteria: five retrospective cohort studies and two case series. No randomized trials were identified. A total of 356 patients undergoing fluorescence-guided surgery for suspected or confirmed acute bowel ischemia were included. Across studies, the reported change in surgical strategy ranged from 29% to 67%, postoperative complications from 0% to 24%, and mortality from 0% to 64%. Our findings suggest that ICG-FA may influence surgical decision-making in acute bowel ischemia by guiding resection strategy, but no clinical benefit in regard to postoperative outcomes was shown. However, the evidence is limited to small, retrospective studies with significant risk of bias and low quality of evidence.

People with schizophrenia experience markedly reduced health-related quality of life (QoL), partly driven by obesity and metabolic dysregulation. Glucagon-like peptide-1 receptor agonists such as semaglutide induce substantial weight loss in the general population and in patients receiving antipsychotic medication. However, the extent to which semaglutide-associated weight loss mediates changes in QoL and symptom severity in schizophrenia remains unclear. This secondary analysis of a randomized, double-blind, placebo-controlled trial included 154 adults with schizophrenia spectrum disorder, prediabetes, and overweight or obesity. Participants were randomized 1:1 to once-weekly semaglutide or placebo for 30weeks. Outcomes were the SF-36v2 Physical and Mental Component Summary scores (PCS, MCS) and the Positive and Negative Syndrome Scale, 6-item version (PANSS-6). Causal mediation analyses estimated natural direct and indirect effects of semaglutide via weight loss at weeks 15 and 30. Semaglutide improved PCS at weeks 15 and 30, with effect sizes exceeding the minimally important difference. Indirect effects via weight loss were positive but not statistically significant, although at week 30 approximately half of the total PCS effect was estimated to be mediated through weight change. No total or mediated effects were found for MCS. For PANSS-6, no meaningful mediation was observed. Semaglutide improved physical QoL in patients with schizophrenia, and weight loss may partially contribute to this effect. Longer-term studies are needed to determine whether mental QoL or symptom effects emerge beyond 30weeks.

The continuous re-emergence of yellow fever virus (YFV) poses a serious public health threat, with no approved specific antiviral drugs for treatment. Sofosbuvir and uprifosbuvir, developed for treatment of chronic hepatitis C, are nucleotide analogs with anti-YFV activity in vitro, and sofosbuvir has been used off-label in YFV-infected individuals. To study the barrier to resistance of these drugs, escape experiments were performed with the YFV 17D vaccine strain in human hepatoma Huh7.5cells. Compared to the original virus, sofosbuvir and uprifosbuvir escape variants exhibited 8.6- to 10.7-fold increased 50% effective concentration (EC50) values. Escape viruses developed putative resistance-associated-substitutions (RAS) M478K and A482G in the NS5 RNA-dependent RNA polymerase domain. Reverse-engineered YFV 17D mutants demonstrated that A482G was the primary determinant of drug resistance, resulting in 5.3- to 5.7-fold increased EC50; however, the substitutions acted synergistically when combined, leading to 12.3- and 11.1-fold increased EC50. A482G conferred slight cross-resistance to bemnifosbuvir, while no cross-resistance was observed for remdesivir, galidesivir, or NITD008. Escape and mutant viruses had slight delays in growth kinetics in Huh7.5cells and were viable in C6/36 and Aag2-AF5 mosquito cells. Structural analysis of a predicted AlphaFold3 YFV NS5-RNA structure suggests that M478K and A482G induce conformational changes in RdRp motif F, which may reduce sofosbuvir and uprifosbuvir affinities. Sofosbuvir RAS described for other orthoflaviviruses did not substantially affect drug susceptibility in reverse-engineered YFV 17D. This study demonstrates that YFV can develop resistance to sofosbuvir and uprifosbuvir with only two NS5 substitutions that have slight impact on viral fitness.

The efficacy and safety of monopolar biphasic focal pulsed field ablation (F-PFA) in close proximity to the atrioventricular (AV) node remain unknown. This study aimed to describe the effect of direct or indirect F-PFA application at the AV junction. In pigs, F-PFA (Centauri, CardioFocus) was applied directly at the AV junction (n = 3) and indirectly from within the aortic noncoronary cusp (NCC) (n = 5), followed by macroscopic gross and histologic analysis. In 5 patients planned for a pace-and-ablate strategy, F-PFA was applied at the AV junction. In 1 patient with recurrent para-Hisian atrial tachycardia and previously failed ablation, F-PFA was applied from within the NCC. In pigs, direct F-PFA applications at the AV junction were associated with junctional beats and resulted in complete AV block after 2-3 F-PFA applications. Tissue histology revealed a lesion depth of approximately 8 mm with minor hemorrhage and leukocyte infiltration. F-PFA from within the NCC resulted in a transient increase in the AV node's Wenckebach cycle length and 1 pig had transient AV block, which recovered within 10 minutes. In 5 patients undergoing pace-and-ablate strategy, F-PFA applications at the AV junction resulted in sustained AV block. In 1 patient, application of F-PFA from within the NCC resulted in termination and noninducibility of a recurrent incessant para-Hisian atrial tachycardia without AV block. There were no immediate or long-term complications. F-PFA directly at the AV junction results in nonreversible AV block. F-PFA from within the NCC may represent a promising strategy for treating para-Hisian arrhythmias while preserving AV conduction.