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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.

Background: Extensive surgical resection of the thoracic aorta in patients with type A aortic dissection (TAAD) is thought to reduce the risk of late aortic wall degeneration and the need for repeat aortic operations. Objectives: We evaluated the early and late outcomes after aortic root replacement and supracoronary ascending aortic replacement in patients with TAAD involving the aortic root. Design: Retrospective, multicenter cohort study. Methods: The outcomes after aortic root replacement and supracoronary ascending aortic replacement in patients with TAAD involving the aortic root, that is dissection flap located at least in one of the Valsava segments, were herein evaluated. In-hospital mortality, neurological complications, dialysis as well as 10-year repeat proximal aortic operation, and mortality were the outcomes of this study. Results: Supracoronary ascending aortic replacement was performed in 198 patients and aortic root replacement in 215 patients. During a mean follow-up of 4.0 ± 4.0 years, 19 patients underwent 22 repeat procedures on the aortic root and/or aortic valve. No operative death occurred after these reinterventions. The risk of proximal aortic reoperation was significantly lower in patients who underwent aortic root replacement (5.5% vs 12.9%, adjusted subdistributional hazard ratio (SHR) 0.085, 95% CI 0.022–0.329). Aortic root replacement was associated with higher rates of in-hospital (14.4% vs 12.1%, adjusted odds ratio 2.192, 95% CI 1.000–4.807) and 10-year mortality (44.5% vs 30.4%, adjusted hazard ratio 2.216, 95% CI 1.338–3.671). Postoperative neurological complications and dialysis rates were comparable in the study groups. Conclusion: Among patients with TAAD involving the aortic root, its replacement was associated with a significantly lower rate of repeat proximal aortic operation of any type compared to supracoronary aortic replacement. Still, aortic root replacement seems to be associated with an increased risk of mortality in these patients. Trial registration: ClinicalTrials.gov: NCT04831073 ( https://clinicaltrials.gov/study/NCT04831073 ).

Piscine orthoreoviruses pose a significant challenge to salmonid aquaculture, as there are currently no preventive measures, like vaccines, available. Piscine orthoreovirus genotype 3 (PRV-3), now renamed Orthoreovirus piscis, has been linked to disease in rainbow trout (Oncorhynchus mykiss) farmed in recirculating aquaculture systems (RAS), and has a high prevalence in Danish RAS. Previous studies have demonstrated that functional feeds can reduce the heart inflammation caused by PRV-1 in Atlantic salmon (Salmo salar). This study aims to determine whether functional feeds have a similar effect on rainbow trout infected with PRV-3. Specifically, we investigated the impact of a krill meal enriched diet on heart inflammation, anemia, and viral RNA load in rainbow trout exposed to PRV-3. The fish were pre-fed with either a control diet or enriched diet for six weeks prior to challenge with PRV-3. The results showed no significant differences in viral RNA load, hematocrit levels or heart pathology between the diets. However, PRV-3 exposed fish fed with the enriched diet exhibited significantly higher weight gain compared to those on the control diet. These findings suggest that while krill meal enhances growth performance, it does not reduce PRV-3-induced heart pathology in rainbow trout. Further research is needed to explore the underlying mechanisms and potential benefits of dietary interventions in managing PRV-3 infections.

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.

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.

Background: Type A aortic dissection (TAAD) is a life-threatening condition which requires prompt diagnosis and surgical treatment. When TAAD involves the aortic root, aortic valve-sparing or Bentall procedures are the main surgical treatment options. Method: The subjects of this analysis were 3735 patients included in the European Registry of Type A Aortic Dissection (ERTAAD). Propensity score matching was performed by estimating a propensity score from being treated with the Bentall or the David procedure using multilevel mixed-effects logistics, considering the cluster effect of the participating hospitals. Results: A Bentall procedure was performed in 862 patients, while a David operation was performed in 139 patients. The proportion of aortic root replacement, as well as the different techniques of aortic root replacement, varied significantly between the participating hospitals (p < 0.001). After propensity score matching, we obtained two groups of 115 patients each, and no statistical differences were reported in terms of postoperative outcomes, except for the rate of dialysis, which was higher in the patients requiring a Bentall procedure (17.4% vs. 7.0%, p-value 0.016). In the unmatched cohorts, the David procedure was associated with a lower 10-year mortality rate compared to the Bentall procedure (30.1% vs. 45.6%, p-value 0.004), but no difference was observed after matching (30.0% vs. 43.9%, p-value 0.082). After 10 years, no differences were observed in terms of proximal aortic reoperation (3.9% vs. 4.1%, p-value 0.954), even after propensity score matching (2.8% vs. 1.8%, p-value 0.994). Conclusions: The David and Bentall procedures are durable treatment methods for TAAD. When feasible, it is advisable that the David procedure is performed for acute TAAD by surgeons with experience with this demanding surgical technique.

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.

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.

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.

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.

Liposuction is among the most performed plastic surgery procedures in Brazil. According to data from the International Society of Aesthetic Plastic Surgery (ISAPS), 231,604 liposuctions were performed, 15.5% of all aesthetic procedures in the country in 2019. Adopting liposuction as a single procedure or adjunct to other cosmetic procedures stimulated its technical evolution from simple fat aspiration to more sophisticated body shaping. Thus, this review aimed to systematically evaluate the published data regarding the complications found in liposuction. A review was conducted using PubMed, SciELO, LILACS, Cochrane Library, SCOPUS, Web of Science, and gray literature databases, published between 2016 and 2021, using the descriptors “Liposuction” and “Complications.” A total of 187 articles were found in the searched databases, of which 16 were selected according to the outcome “to assess safety through the prevalence of complications in liposuction as a single procedure and associated with other procedures such as abdominoplasty and fat grafting.” We found a mortality rate ranging from 0 to 0.06 among all procedures and a predominance of venous thromboembolism, hematoma, seroma, and hyperpigmentation concerning all complications, being more common when liposuction is associated with other procedures. Therefore, through this review, it was possible to verify that liposuction as a single procedure has lower complication rates when compared to liposuction combined with other procedures.

Thrombocytopenia is a common condition that recognizes an infinite number of possible causes, especially in specific settings like the one covered in this case report: the postoperative period of cardiac surgery. We report a case of an old male with multiple comorbidities who underwent a coronary angioplasty procedure and aortic valve replacement. He showed severe thrombocytopenia in the postoperative days. Differential diagnosis required a big effort, also for the experts in the field. Our goal was to aggressively treat the patient with prednisolone, platelets, and intravenous immunoglobulins to maximize the prognosis. Our patient developed no complications and was discharged successfully.

O objetivo deste estudo foi compreender como ocorre o processo de gestão de startups por meio do emprego de proxies informacionais em alternativa à ausência de mecanismos formais de controle gerencial. Para o alcance deste objetivo, adotou-se como estratégia a pesquisa qualitativa básica ou genérica. Sete entrepreneurs que apresentavam formações básicas e complementares diversas, bem como experiências profissionais variadas foram entrevistados. Em relação aos achados, observou-se que as startups realizam a adoção de proxies informacionais para serem o alicerce na construção dos discursos organizacionais. As proxies identificadas são derivadas, usualmente, de artefatos formais e que se comportam como instrumentos auxiliares aos entrepreneurs/gestores no processo de tomada de decisões e no alinhamento de suas ações com os objetivos organizacionais. Por fim, os relatos obtidos e analisados neste estudo evidenciaram que, se não todas, a maiorias das proxies identificadas contribuíram, consoante suas peculiaridades, da trajetória inicial até o momento atual do negócio.