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Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. This is particularly true for interactions mediated by short linear motifs occurring in disordered regions of proteins. We find that AlphaFold-Multimer predicts with high sensitivity but limited specificity structures of domain-motif interactions when using small protein fragments as input. Sensitivity decreased substantially when using long protein fragments or full length proteins. We delineated a protein fragmentation strategy particularly suited for the prediction of domain-motif interfaces and applied it to interactions between human proteins associated with neurodevelopmental disorders. This enabled the prediction of highly confident and likely disease-related novel interfaces, which we further experimentally corroborated for FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions. Synopsis Based on thorough benchmarking of AlphaFold-Multimer a strategy for structure prediction was developed and applied to 62 protein interactions linked to neurological disease. Six novel protein interfaces were further experimentally corroborated. AlphaFold-Multimer (AF) largely fails to predict structures of interacting proteins involving short linear motifs when using full length sequences. A prediction strategy was developed based on protein fragmentation, which boosts AF sensitivity at costs of specificity. Application of this strategy to 62 protein interactions linked to neurological disease resulted in 18 correct or likely correct structural models. Six novel protein interfaces were further supported by experiments. Based on thorough benchmarking of AlphaFold-Multimer a strategy for structure prediction was developed and applied to 62 protein interactions linked to neurological disease. Six novel protein interfaces were further experimentally corroborated.

Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. We thoroughly assessed AlphaFold-Multimer accuracy for structure prediction of interactions involving folded domains binding to short linear motifs from the ELM database. The structure predictions were highly sensitive but not very specific when using small protein fragments. Sensitivity decreased substantially when using long protein fragments or full length proteins with intrinsically disordered regions. We delineated a fragmentation strategy to optimize sensitivity and applied it to interactions between proteins associated with neurodevelopmental disorders. This enabled prediction of highly confident and likely disease-related novel interfaces, but also resulted in many high scoring false positive predictions. Experiments supported predicted interfaces between CREBZF-HCFC1, FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.

This multicenter retrospective study analyzed 336 patients (236 adults, 100 children) who underwent liver transplantation (LT) for acute liver failure (ALF) between 2002 and 2019 across 14 centers in Türkiye. The aim was to evaluate pretransplant factors influencing short-term posttransplant survival. Median MELD and PELD scores were 31 and 30, respectively. The most common ALF etiologies were viral, indeterminate, and drug-induced causes. Living donor liver transplantation (LDLT) was more common in children (86.0%) than adults (57.2%). Mean posttransplant survival was 166±9 months in children and 117±6 months in adults. In adults, LDLT significantly improved survival compared to deceased donor LT (DDLT), with survival of 135 vs. 89 months ( p =0.0012). Although pediatric LDLT recipients had longer mean survival than DDLT recipients (167 vs. 132 months), this difference was not statistically significant ( p =0.5959). Three-month mortality was associated with low albumin and grade 4 hepatic encephalopathy (HE) in children. In adults, independent predictors of early mortality included DDLT, serum sodium >140 mEq/L, MELD >35, pH <7.3, and grade 4 HE. Our data suggest that LDLT may offer a survival advantage, particularly in adults with ALF. Identifying pretransplant risk factors is essential for improving early outcomes and guiding clinical decision-making.

Acute kidney injury (AKI) is common in coronavirus disease-2019 (COVID-19) and the severity of AKI is linked to adverse outcomes. In this study, we investigated the factors associated with in-hospital outcomes among hospitalized patients with COVID-19 and AKI. In this multicenter retrospective observational study, we evaluated the characteristics and in-hospital renal and patient outcomes of 578 patients with confirmed COVID-19 and AKI. Data were collected from 34 hospitals in Turkey from March 11 to June 30, 2020. AKI definition and staging were based on the Kidney Disease Improving Global Outcomes criteria. Patients with end-stage kidney disease or with a kidney transplant were excluded. Renal outcomes were identified only in discharged patients. The median age of the patients was 69 years, and 60.9% were males. The most frequent comorbid conditions were hypertension (70.5%), diabetes mellitus (43.8%), and chronic kidney disease (CKD) (37.6%). The proportions of AKI stages 1, 2, and 3 were 54.0%, 24.7%, and 21.3%, respectively. 291 patients (50.3%) were admitted to the intensive care unit. Renal improvement was complete in 81.7% and partial in 17.2% of the patients who were discharged. Renal outcomes were worse in patients with AKI stage 3 or baseline CKD. The overall in-hospital mortality in patients with AKI was 38.9%. In-hospital mortality rate was not different in patients with preexisting non-dialysis CKD compared to patients without CKD (34.4 versus 34.0%, p = 0.924). By multivariate Cox regression analysis, age (hazard ratio [HR] [95% confidence interval (95%CI)]: 1.01 [1.0-1.03], p = 0.035], male gender (HR [95%CI]: 1.47 [1.04-2.09], p = 0.029), diabetes mellitus (HR [95%CI]: 1.51 [1.06-2.17], p = 0.022) and cerebrovascular disease (HR [95%CI]: 1.82 [1.08-3.07], p = 0.023), serum lactate dehydrogenase (greater than two-fold increase) (HR [95%CI]: 1.55 [1.05-2.30], p = 0.027) and AKI stage 2 (HR [95%CI]: 1.98 [1.25-3.14], p = 0.003) and stage 3 (HR [95%CI]: 2.25 [1.44-3.51], p = 0.0001) were independent predictors of in-hospital mortality. Advanced-stage AKI is associated with extremely high mortality among hospitalized COVID-19 patients. Age, male gender, comorbidities, which are risk factors for mortality in patients with COVID-19 in the general population, are also related to in-hospital mortality in patients with AKI. However, preexisting non-dialysis CKD did not increase in-hospital mortality rate among AKI patients. Renal problems continue in a significant portion of the patients who were discharged.

The renin-angiotensin-aldosterone system was shown to be activated in severe COVID-19 infection. We aimed to investigate the relationship between angiotensin converting enzyme (ACE) levels, ACE gene polymorphism, type 2 diabetes (T2DM), and hypertension (HT) and the prognosis of COVID-19 infection. This cross-sectional study analyzed the clinical features of adult patients with SARS-CoV-2 infection. ACE gene analysis and ACE level measurements were performed. The patients were grouped according to ACE gene polymorphism (DD, ID or II), disease severity (mild, moderate, or severe), and the use of dipeptidyl peptidase-4 enzyme inhibitor (DPP4i), ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARB). Intensive care unit (ICU) admissions and mortality were also recorded. A total of 266 patients were enrolled. Gene analysis detected DD polymorphism in the ACE 1 gene in 32.7% (n = 87), ID in 51.5% (n = 137), and II in 15.8% (n = 42) of the patients. ACE gene polymorphisms were not associated with disease severity, ICU admission, or mortality. ACE levels were higher in patients who died (p = 0.004) or were admitted to the ICU (p<0.001) and in those with severe disease compared to cases with mild (p = 0.023) or moderate (p<0.001) disease. HT, T2DM, and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission. ACE levels were similar in patients with or without HT (p = 0.374) and with HT using or not using ACEi/ARB (p = 0.999). They were also similar in patients with and without T2DM (p = 0.062) and in those with and without DPP4i treatment (p = 0.427). ACE level was a weak predictor of mortality but an important predictor of ICU admission. It predicted ICU admission in total (cutoff value >37.092 ng/mL, AUC: 0.775, p<0.001). Our findings suggest that higher ACE levels, but not ACE gene polymorphism, ACEi/ARB or DPP4i use, were associated with the prognosis of COVID-19 infection. The presence of HT and T2DM and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission.

Introduction: Bronchoscopy in the Intensive Care Unit (ICU) is essential for managing respiratory failure, secretions, airway obstructions, and pulmonary infections. This study aimed to evaluate the indications, frequency, and clinical outcomes of bronchoscopy in the ICU. Materials and Methods: This retrospective study analyzed patients who underwent bronchoscopy in the ICU of Kosuyolu High Specialization Training and Research Hospital from January 1, 2022, to December 31, 2024. Data were obtained from the hospital's automation system. Patients from the cardiology, cardiovascular surgery, chest surgery, and gastroenterology departments who underwent bronchoscopy were included. Pediatric ICU patients, non-ICU ward patients, and lung transplant recipients were excluded. A total of 258 procedures were analyzed. Data were analyzed using IBM SPSS 26, with Chi-square and Kruskal-Wallis tests. A p-value of < 0.05 was considered significant. Results: A total of 258 bronchoscopy procedures were performed on 162 patients (62.3% male, median age 60.4 years). The most common diagnoses were coronary artery bypass graft (CABG) (30.2%), non-surgical cardiovascular diseases (21.6%), and heart valve surgery (16.7%). The main indications for bronchoscopy were increased secretions (41.1%), atelectasis (25.9%), and hemoptysis (9.7%). Increased secretions (53.5%) were the most common finding, with 9.3% of procedures reported as normal. Of the patients, 62.8% required mechanical ventilation, and 7.4% received ECMO. Lavage for culture was performed in 63.4%, with microbial growth detected in 43%. Klebsiella pneumoniae was the most common microorganism. Conclusion: Our study confirms the safe use of bronchoscopy in patients with major cardiac surgery or advanced heart failure. Bronchoscopy is frequently used in the ICU for managing secretion accumulation and atelectasis. Bronchoalveolar lavage is crucial for identifying infectious agents like Klebsiella pneumoniae and Pseudomonas aeruginosa in specific patient groups. Keywords: Bronchoscopy, intensive care, respiratory management, lavage culture

The renin-angiotensin-aldosterone system was shown to be activated in severe COVID-19 infection. We aimed to investigate the relationship between angiotensin converting enzyme (ACE) levels, ACE gene polymorphism, type 2 diabetes (T2DM), and hypertension (HT) and the prognosis of COVID-19 infection. This cross-sectional study analyzed the clinical features of adult patients with SARS-CoV-2 infection. ACE gene analysis and ACE level measurements were performed. The patients were grouped according to ACE gene polymorphism (DD, ID or II), disease severity (mild, moderate, or severe), and the use of dipeptidyl peptidase-4 enzyme inhibitor (DPP4i), ACE-inhibitor (ACEi) or angiotensin receptor blocker (ARB). Intensive care unit (ICU) admissions and mortality were also recorded. A total of 266 patients were enrolled. Gene analysis detected DD polymorphism in the ACE 1 gene in 32.7% (n = 87), ID in 51.5% (n = 137), and II in 15.8% (n = 42) of the patients. ACE gene polymorphisms were not associated with disease severity, ICU admission, or mortality. ACE levels were higher in patients who died (p = 0.004) or were admitted to the ICU (p<0.001) and in those with severe disease compared to cases with mild (p = 0.023) or moderate (p37.092 ng/mL, AUC: 0.775, p<0.001). Our findings suggest that higher ACE levels, but not ACE gene polymorphism, ACEi/ARB or DPP4i use, were associated with the prognosis of COVID-19 infection. The presence of HT and T2DM and ACEi/ARB or DPP4i use were not associated with mortality or ICU admission.

Montelukast, a leukotriene receptor antagonist (LTRA) approved for the treatment of asthma and allergic rhinitis, is widely used, though real-world data on its application in asthma management remain limited. This registry-based study evaluated the use of montelukast in adult asthma patients, examining demographic and disease characteristics, asthma control status, asthma phenotypes, presence of atopy, and treatment regimens. Among 2053 patients analyzed, 61.76% (n = 1268; mean age: 46.2 ± 14.3 years), predominantly females (~76%), received montelukast. Montelukast users showed higher rates of allergic rhinitis (P < 0.001), hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) (P = 0.008), and chronic rhinosinusitis (P = 0.008). Montelukast group also had higher atopy and total IgE levels and tended to be more eosinophilic. Montelukast was commonly preferred in allergic, eosinophilic, NSAID-exacerbated respiratory disease, and severe asthma phenotypes (P < 0.001). Patients receiving Steps 4 and 5 treatments are more likely to be prescribed montelukast (P < 0.001). Montelukast usage was higher among patients with uncontrolled asthma [ACT< 20 (OR:1.29, 95%CI:1.052–1.582, P = 0.014)]. In addition, logistic regression analyses identified the main factors associated with increased montelukast use as; female gender (OR:1.33, 95%CI:1.041–1.713, P = 0.02), presence of atopy (OR:1.46, 95%CI:1.157–1.864, P = 0.002), comorbid allergic rhinitis (OR:2.12, 95%CI:1.679–2.293, P < 0.001), and severe asthma (OR:2.18, 95%CI:1.712–2.784, P < 0.001). These findings reveal that montelukast use is prevalent among asthma patients, particularly in females, middle-aged adults, and those with comorbid allergic rhinitis, uncontrolled asthma, or specific asthma phenotypes, underscoring the factors that influence its prescription in asthma management.

Objective This study aimed to investigate the effects of neuromuscular blocking drugs on the viability of human umbilical vein endothelial cells (HUVECs) and to investigate whether they cause vascular complications due to cell proliferation. Methods HUVECs were cultivated with 5% CO2 at 37°C in a predefined supplemented medium over 7 days until confluence of cell monolayers. Assays were conducted during the exponential growth phase. Suxamethonium chloride, vecuronium bromide, atracurium besylate, and rocuronium bromide were used at concentrations of 10–5, 10–6, and 10–7 M in proliferation assays in which cells were incubated with these drugs for 24, 48, and 72 hours. All experiments were performed in four replicates. Results The neuromuscular blocking drugs used had comparable effects on the survivability of HUVECs. Overall, no significant difference was observed in the survivability of HUVECs in a dose-dependent manner after exposure to the study drugs. However, some significant differences in the viability of HUVECs were found among the different measurement times. Conclusions The findings of the current study support the safety of the studied neuromuscular blocking drugs in clinically relevant concentrations regarding their effects on endothelial cell proliferation.

Introduction: Aortic pseudoaneurysms (APA) are rare aortic conditions that are generally asymptomatic but have the potential to be fatal. They most commonly occur following cardiac surgery but can also result from trauma or infection. Large APAs may compress adjacent structures, leading to serious complications such as rupture, thrombosis, embolization, and fistula formation. Therefore, routine follow-up with computed tomography (CT) is necessary. The traditional treatment method is surgical repair, which carries a high risk of morbidity and mortality, especially in patients with a history of cardiac surgery. Alternative treatment options include thoracic endovascular aortic repair (TEVAR), coil embolization, thrombin injection, vascular plugs, and occluder devices. Case Report: A 70-year-old female patient, who had undergone coronary artery bypass grafting (CABG) and ascending aortic replacement (AAR) four years prior, was presented. Following her initial surgery, the patient developed mediastinitis, which required prolonged antibiotic therapy and an additional open surgical intervention. During routine follow-up, CT imaging revealed a collection in the substernal area, irregularity in the left anterolateral wall of the ascending aorta, and focal contrast fillings at two levels suggestive of pseudoaneurysms (Fig. 1). Transesophageal echocardiography (TEE) identified a rupture (pseudoaneurysm) measuring 14x5 mm (Fig. 2) confined by a hematoma, located 12 mm superior to the left main coronary artery (LMCA), along with a collection beneath the sternum. Blood cultures and other laboratory tests showed no signs of mediastinitis. However, to rule out infection, a sample was obtained from the collection via needle aspiration through the left second intercostal space (Fig. 3), confirming the absence of infection. Given the high surgical risk associated with aortic rupture in a case with a hematoma located just beneath the sternum, percutaneous closure was preferred. To minimize the risk of further rupture, no guidewire or catheter was advanced directly through the defect. Instead, an 8.5F Agilis Small catheter was introduced via the right femoral artery and positioned at the aortic root. After achieving the appropriate angulation, the device was placed at the defect opening. A 14x12 mm Konar VSD Occluder device was deployed distally through the catheter (Fig. 4), and successful closure of the rupture was confirmed via 3D TEE and angiography (Figs. 4-6). No complications were observed. Follow-up transthoracic echocardiography (TTE) and contrast-enhanced CT performed a few days after the procedure confirmed the correct positioning of the device. The patient was discharged one week later. Conclusion: APA development following AAR surgery is a known potential complication. Although conventional treatment involves open surgical repair, percutaneous closure is emerging as a viable alternative, particularly in high-risk patient groups due to the associated morbidity and mortality risks. In this case, we aimed to highlight the efficacy of percutaneous closure using a Konar VSD Occluder device as a potential alternative treatment for APA.