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In this study, the impact of the apolipoprotein B mRNA-editing catalytic subunit-like (APOBEC) enzyme APOBEC3B (A3B) on epidermal growth factor receptor (EGFR)-driven lung cancer was assessed. A3B expression in EGFR mutant (EGFRmut) non-small-cell lung cancer (NSCLC) mouse models constrained tumorigenesis, while A3B expression in tumors treated with EGFR-targeted cancer therapy was associated with treatment resistance. Analyses of human NSCLC models treated with EGFR-targeted therapy showed upregulation of A3B and revealed therapy-induced activation of nuclear factor kappa B (NF-κB) as an inducer of A3B expression. Significantly reduced viability was observed with A3B deficiency, and A3B was required for the enrichment of APOBEC mutation signatures, in targeted therapy-treated human NSCLC preclinical models. Upregulation of A3B was confirmed in patients with NSCLC treated with EGFR-targeted therapy. This study uncovers the multifaceted roles of A3B in NSCLC and identifies A3B as a potential target for more durable responses to targeted cancer therapy.

Abstract The effect of past environmental changes on the demography and genetic diversity of natural populations remains a contentious issue and has rarely been investigated across multiple, phylogenetically distant species. Here, we perform comparative population genomic analyses and demographic inferences for seven widely distributed and ecologically contrasting European forest tree species based on concerted sampling of 164 populations across their natural ranges. For all seven species, the effective population size, N e , increased or remained stable over many glacial cycles and up to 15 million years in the most extreme cases. Surprisingly, the drastic environmental changes associated with the Pleistocene glacial cycles have had little impact on the level of genetic diversity of dominant forest tree species, despite major shifts in their geographic ranges. Based on their trajectories of N e over time, the seven tree species can be divided into three major groups, highlighting the importance of life history and range size in determining synchronous variation in genetic diversity over time. Altogether, our results indicate that forest trees have been able to retain their evolutionary potential over very long periods of time despite strong environmental changes.

Abstract Multiple synchronous lung cancers (MSLCs) constitute a unique subtype of lung cancer. To explore the genomic and immune heterogeneity across different pathological stages of MSLCs, we analyse 16 MSLCs from 8 patients using single-cell RNA-seq, single-cell TCR sequencing, and bulk whole-exome sequencing. Our investigation indicates clonally independent tumours with convergent evolution driven by shared driver mutations. However, tumours from the same individual exhibit few shared mutations, indicating independent origins. During the transition from pre-invasive to invasive adenocarcinoma, we observe a shift in T cell phenotypes characterized by increased Treg cells and exhausted CD8+ T cells, accompanied by diminished cytotoxicity. Additionally, invasive adenocarcinomas exhibit greater neoantigen abundance and a more diverse TCR repertoire, indicating heightened heterogeneity. In summary, despite having a common genetic background and environmental exposure, our study emphasizes the individuality of MSLCs at different stages, highlighting their unique genomic and immune characteristics.

Abstract Recirculating aquaculture systems (RAS) have become more attractive due to reduced water consumption and effluent discharge. However, intensification of production increases the risk of introducing pathogens at farming sites. The emergence of uncultivable pathogens and RAS pathobiome diversity shifts the traditional disease paradigm from “one pathogen, one disease” to complex multiple-pathogen disease cases. Piscine orthoreovirus genotype 3 (PRV-3) is an excellent example, as it is capable of inducing anemia and heart pathology resembling heart and skeletal muscle inflammation under experimental conditions, and is associated with increased mortality in association with other pathogens in the field. The aim of this study was to develop a method for detection of multiple pathogens and putative pathogens, as co-infections are common in aquaculture. To do this, in the pilot study, we mapped the pathobiome of RAS-farmed rainbow trout (Oncorhynchus mykiss) (commercial RAS, farm A) using both standard diagnostic methods and metabarcording (16S rRNA) to investigate the gill microbiome. During this study, we observed infections with multiple pathogens, and detected two putative gill pathogens Candidatus Branchiomonas cysticola and Candidatus Piscichlamydia salmonis, both of which have been linked with complex gill disease in Atlantic salmon (Salmo salar). Based on the pilot study, we developed and tested a high throughput qPCR (HT-qPCR) chip targeting 22 viral and bacterial pathogens and putative pathogens, followed by a surveillance of a fish cohort in a commercial RAS farm during production (farm B). Co-infection with PRV-3 and Ca. B. cysticola combined with stress inducing management practices may explain the severe disease outbreak observed (37% mortality). The time course study sets the base for a future screening scheme for disease prediction and addresses limitations of the method when testing environmental DNA/RNA.

Abstract Background Surfactant is a well-established therapy for preterm neonates affected by respiratory distress syndrome (RDS). The goals of different methods of surfactant administration are to reduce the duration of mechanical ventilation and the severity of bronchopulmonary dysplasia (BPD); however, the optimal administration method remains unknown. This study compares the effectiveness of the INtubate-RECruit-SURfactant-Extubate (IN-REC-SUR-E) technique with the less-invasive surfactant administration (LISA) technique, in increasing BPD-free survival of preterm infants. This is an international unblinded multicenter randomized controlled study in which preterm infants will be randomized into two groups to receive IN-REC-SUR-E or LISA surfactant administration. Methods In this study, 382 infants born at 24+0–27+6 weeks’ gestation, not intubated in the delivery room and failing nasal continuous positive airway pressure (nCPAP) or nasal intermittent positive pressure ventilation (NIPPV) during the first 24 h of life, will be randomized 1:1 to receive IN-REC-SUR-E or LISA surfactant administration. The primary outcome is a composite outcome of death or BPD at 36 weeks’ postmenstrual age. The secondary outcomes are BPD at 36 weeks’ postmenstrual age; death; pulse oximetry/fraction of inspired oxygen; severe intraventricular hemorrhage; pneumothorax; duration of respiratory support and oxygen therapy; pulmonary hemorrhage; patent ductus arteriosus undergoing treatment; percentage of infants receiving more doses of surfactant; periventricular leukomalacia, severe retinopathy of prematurity, necrotizing enterocolitis, sepsis; total in-hospital stay; systemic postnatal steroids; neurodevelopmental outcomes; and respiratory function testing at 24 months of age. Randomization will be centrally provided using both stratification and permuted blocks with random block sizes and block order. Stratification factors will include center and gestational age (24+0 to 25+6 weeks or 26+0 to 27+6 weeks). Analyses will be conducted in both intention-to-treat and per-protocol populations, utilizing a log-binomial regression model that corrects for stratification factors to estimate the adjusted relative risk (RR). Discussion This trial is designed to provide robust data on the best method of surfactant administration in spontaneously breathing preterm infants born at 24+0–27+6 weeks’ gestation affected by RDS and failing nCPAP or NIPPV during the first 24 h of life, comparing IN-REC-SUR-E to LISA technique, in increasing BPD-free survival at 36 weeks’ postmenstrual age of life. Trial registration ClinicalTrials.gov NCT05711966. Registered on February 3, 2023.

Infectious hematopoietic necrosis (IHN) is a common disease in the intensive production of salmonids. The IHN virus (IHNV) was isolated for the first time in North Macedonia in 2018. This study aimed to investigate the distribution and genotype of IHN in farmed rainbow trout and autochthonous salmonid fish in North Macedonia following the first detection. The samples were collected from 47 trout farms. Trout fry with or without clinical signs of IHN were selected as individual samples. Kidney, spleen, and heart were taken from each fish during the dissection. Three pooled samples were collected from each farm. A total of 141 pooled samples were collected: Rainbow trout (Oncorhynchus mykiss) n=127, Macedonian trout (Salmo macedonicus) n=11, and Ohrid trout (Salmo letnica) n=3. The virus was detected in 43 samples (30.50%): rainbow trout (n=40), Macedonian trout (n=2), and Ohrid trout (n=1). There were 18 (38.30%) positive fish farms. The MAKIHNV1 isolate from 2018 (MN641902) and the newly isolated virus shared a similarity of >99 and were placed in clade E-1 of European genogroup E. The IHN has spread throughout the country and is also present in the autochthonous salmonids.

The authors present a case report of a 68-year-old man evaluated at the emergency department for repeated syncope, asthenia, and general malaise, suggesting heart failure in a patient with several comorbidities. At presentation, the patient was afebrile, but he had reported a low-grade fever in the previous six months. At first glance, transthoracic echocardiography was not clear, while transesophageal echocardiography revealed an echo-free image at the level of the non-coronary sinus of the aortic root, suggestive of a pseudoaneurysm, communicating with the right atrium with continuous systo-diastolic flow, compatible with the aorto-cavitary fistula between the aortic root and the RA. Echocardiographic findings were confirmed by cardiac computed tomography. The case was discussed with the heart team and was considered suitable for surgery, but the patient suddenly died just before surgery due to impairment and friability.

Metabolic Syndrome (MetS), a multifactorial condition that increases the risk of cardio-vascular events, is frequent in Heart-transplant (HTx) candidates and worsens with immunosuppressive therapy. The aim of the study was to analyze the impact of MetS on long-term outcome of HTx patients. Since 2007, 349 HTx patients were enrolled. MetS was diagnosed if patients met revised NCEP-ATP III criteria before HTx, at 1, 5 and 10 years of follow-up. MetS was present in 35% of patients pre-HTx and 47% at 1 year follow-up. Five-year survival in patients with both pre-HTx (65% vs. 78%, p < 0.01) and 1 year follow-up MetS (78% vs 89%, p < 0.01) was worst. At the univariate analysis, risk factors for mortality were pre-HTx MetS (HR 1.86, p < 0.01), hypertension (HR 2.46, p < 0.01), hypertriglyceridemia (HR 1.50, p=0.03), chronic renal failure (HR 2.95, p < 0.01), MetS and diabetes at 1 year follow-up (HR 2.00, p < 0.01; HR 2.02, p < 0.01, respectively). MetS at 1 year follow-up determined a higher risk to develop Coronary allograft vasculopathy at 5 and 10 year follow-up (25% vs 14% and 44% vs 25%, p < 0.01). MetS is an important risk factor for both mortality and morbidity post-HTx, suggesting the need for a strict monitoring of metabolic disorders with a careful nutritional follow-up in HTx patients.

Objective: The optimal corticosteroid treatment regimen for subacute thyroiditis has not yet been established. To avoid side effects, tapering of the initial dose of corticosteroid is recommended. With reducing dose, the symptoms can recur. Design: In a prospective clinical study, a 30-day methylprednisolone (MPSL) treatment protocol with a starting dose of 24 mg/day and tapered by 4 mg every 5 days was assessed for effectiveness and safety regarding possible adrenal insufficiency. Methods: Fifty-nine patients with subacute thyroiditis were included. At visit 1, after establishing the diagnosis, a short stimulation adrenocorticotrophic hormone (ACTH) test was performed and methylprednisolone treatment was prescribed. At visit 2 (40 ± 5 days after visit 1), clinical, laboratory (including short stimulation ACTH test), and ultrasound evaluation were repeated. Results: Forty-eight patients (81.4%) were cured by the prescribed protocol, having significantly lower cortisol levels after stimulation at visit 1 than patients who were not cured (mean, 674.9 nmol/L and 764.0 nmol/L, respectively, P = 0.012). Seven patients (12.3%) developed adrenal insufficiency; this group had significantly lower cortisol levels after stimulation at visit 1 than patients without adrenal insufficiency development (mean, 561.5 nmol/L and 704.7 nmol/L, respectively, P = 0.005). Using stimulated cortisol level at visit 1 as the explanatory variable, logistic models were optimized to determine treatment efficacy (AUC = 0.745, optimal threshold 729 nmol/L, specificity 71%, sensitivity 73%) and adrenal function (AUC = 0.861, optimal threshold 629 nmol/L, specificity 73%, sensitivity 100%). Conclusions: The described protocol was efficient for more than 80% of patients. Using this protocol, the corticosteroid treatment interval is shorter than proposed in current guidelines. Significance statement: A short but effective protocol for treatment of subacute thyroiditis with methylprednisolone is presented in this article. Using this protocol, the treatment interval is shorter than proposed in current guidelines. Its safety regarding possible adrenal insufficiency is assessed.

Climate change is one of the most important challenges for mankind in the far and near future. In this regard, sustainable production of woody crops on marginal land with low water availability is a major challenge to tackle. This dataset is part of an experiment, in which we exposed three genetically differentiated genotypes of Populus nigra originating from contrasting natural habitats to gradually increasing moderate drought. RNA sequencing was performed on fine roots, developing xylem and leaves of those three genotypes under control and moderate drought conditions in order to get a comprehensive dataset on the transcriptional changes at the whole plant level under water limiting conditions. This dataset has already provided insight in the transcriptional control of saccharification potential of the three Populus genotypes under drought conditions and we suggest that our data will be valuable for further in-depth analysis regarding candidate gene identification or, on a bigger scale, for meta-transcriptome analysis.

BackgroundSurgery for type A aortic dissection (TAAD) is associated with high risk of mortality. Current risk scoring methods have a limited predictive accuracy.MethodsSubjects were patients who underwent surgery for acute TAAD at 18 European centers of cardiac surgery from the European Registry of Type A Aortic Dissection (ERTAAD).ResultsOut of 3,902 patients included in the ERTAAD, 2,477 fulfilled the inclusion criteria. In the validation dataset (2,229 patients), the rate of in-hospital mortality was 18.4%. The rate of composite outcome (in-hospital death, stroke/global ischemia, dialysis, and/or acute heart failure) was 41.2%, and 10-year mortality rate was 47.0%. Logistic regression identified the following patient-related variables associated with an increased risk of in-hospital mortality [area under the curve (AUC), 0.755, 95% confidence interval (CI), 0.729–0.780; Brier score 0.128]: age; estimated glomerular filtration rate; arterial lactate; iatrogenic dissection; left ventricular ejection fraction ≤50%; invasive mechanical ventilation; cardiopulmonary resuscitation immediately before surgery; and cerebral, mesenteric, and peripheral malperfusion. The estimated risk score was associated with an increased risk of composite outcome (AUC, 0.689, 95% CI, 0.667–0.711) and of late mortality [hazard ratio (HR), 1.035, 95% CI, 1.031–1.038; Harrell's C 0.702; Somer's D 0.403]. In the validation dataset (248 patients), the in-hospital mortality rate was 16.1%, the composite outcome rate was 41.5%, and the 10-year mortality rate was 49.1%. The estimated risk score was predictive of in-hospital mortality (AUC, 0.703, 95% CI, 0.613–0.793; Brier score 0.121; slope 0.905) and of composite outcome (AUC, 0.682, 95% CI, 0.614–0.749). The estimated risk score was predictive of late mortality (HR, 1.035, 95% CI, 1.031–1.038; Harrell's C 0.702; Somer's D 0.403), also when hospital deaths were excluded from the analysis (HR, 1.024, 95% CI, 1.018–1.031; Harrell's C 0.630; Somer's D 0.261).ConclusionsThe present analysis identified several baseline clinical risk factors, along with preoperative estimated glomerular filtration rate and arterial lactate, which are predictive of in-hospital mortality and major postoperative adverse events after surgical repair of acute TAAD. These risk factors may be valuable components for risk adjustment in the evaluation of surgical and anesthesiological strategies aiming to improve the results of surgery for TAAD.Clinical Trial Registrationhttps://clinicaltrials.gov, identifier NCT04831073.