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Aim: The aim of this study was to investigate the effect of the use of projector kaleidoscope and matching card on children's fear and physiological parameters in children aged 3-6 years receiving inhaled medication., Methods: This randomised controlled study was conducted with the guidelines of Consolidated Standards of Reporting Trials (CONSORT). The sample of children was allocated to the projector kaleidoscope group (n = 38), matching card group (n = 38) and control group (n = 38). Fear and vital signs were measured., Results: In the study, the mean age of the children in the projector kaleidoscope group was 4.39 ± 1.10, the mean age of the children in the matching card group was 4.34 ± 0.96 and the mean age of the children in the control group was 4.28 ± 1.18. There was a statistically significant difference between the post-test scores of the Children's Fear Scale in the evaluation of parents and nurses according to the groups of children. There was a statistically significant difference between the respiratory post-test scores according to the groups of children. It was observed that the mean heart rate of the control group participants was higher than that of the children in the matching card group. There were no statistically significant differences in the post-test saturation values among the groups of children., Conclusion: It was observed that the projector kaleidoscope and matching card reduced fear and prevented increased respiratory rate in children receiving inhaler medication. In addition, it was determined that matching card had more effect on heart and respiratory rate than projector kaleidoscope., (© 2024 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Severe congenital neutropenia (SCN) is frequently associated with dominant point mutations in ELANE, the gene encoding neutrophil elastase (NE). Chronic administration of granulocyte colony-stimulating factor (G-CSF) is a first-line treatment of ELANE-mutant (ELANEmut) SCN. However, some ELANEmut patients including patients with ELANE start codon mutations do not respond to G-CSF. Here, through directed granulopoiesis of gene-edited isogenic normal and patient-derived iPSCs, we demonstrate that ELANE start codon mutations suffice to induce G-CSF resistant granulocytic precursor cell death and refractory SCN. ELANE start codon mutated neutrophil precursors express predominantly nuclear N-terminal truncated alternate NE. Unlike G-CSF sensitive ELANE mutations that induce endoplasmic reticulum and unfolded protein response stress, we found that the mutation of the ELANE translation initiation codon resulted in NE aggregates and activated pro-apoptotic aggrephagy as determined by downregulated BAG1 expression, decreased BAG1/BAG3 ratio, NE co-localization with BAG3, and localized expression of autophagic LC3B. We found that SERF1, an RNA-chaperone protein, known to localize in misfolded protein aggregates in neurodegenerative diseases, was highly upregulated and interacted with cytoplasmic NE of mutant neutrophil precursors. Silencing of SERF1 enhanced survival and differentiation of iPSC-derived neutrophil precursors, restoring their responsiveness to G-CSF. These observations provide a mechanistic insight of G-CSF-resistant ELANEmut SCN, revealing targets for therapeutic intervention.

An uncontrolled activity of neutrophil serine proteases (NSPs) contributes to inflammatory diseases. Cathepsin C (CatC) is known to activate NSPs during neutrophilic differentiation and represents a promising pharmacological target in NSP-mediated diseases. In humans, Papillon-Lefèvre syndrome (PLS) patients have mutations in theirCTSC gene, resulting in the complete absence of CatC activity. Despite this, low residual NSP activities are detected in PLS neutrophils (<10% vs healthy individuals), suggesting the involvement of CatC-independent proteolytic pathway(s) in the activation of proNSPs. This prompted us to characterize CatC-independent NSP activation pathways by blocking proCatC maturation. In this study, we show that inhibition of intracellular CatS almost completely blocked CatC maturation in human promyeloid HL-60 cells. Despite this, NSP activation was not significantly reduced, confirming the presence of a CatC-independent activation pathway involving a CatC-like protease that we termed NSPs-AAP-1. Similarly, when human CD34 + progenitor cells were treated with CatS inhibitors during neutrophilic differentiation in vitro, CatC activity was nearly abrogated but ∼30% NSP activities remained, further supporting the existence of NSPs-AAP-1. Our data indicate that NSPs-AAP-1 is a cysteine protease that is inhibited by reversible nitrile compounds designed for CatC inhibition. We further established a proof of concept for the indirect, although incomplete, inhibition of NSPs by pharmacological targeting of CatC maturation using CatS inhibitors. This emphasizes the potential of CatS as a therapeutic target for inflammatory diseases. Thus, preventing proNSP maturation using a CatS inhibitor, alone or in combination with a CatC/NSPs-AAP-1 inhibitor, represents a promising approach to efficiently control the extent of tissue injury in neutrophil-mediated inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brice Korkmaz has been paid for the time spent as a committee member for advisory boards (Brensocatib Advisory Board (BRAB), INSMED, USA), other forms of consulting (Boehringer Ingelheim (Germany), Neuprozyme Therapeutics Aps (Denmark), Santhera Pharmaceuticals (Switzerland), Chiesi (Italy), Gerson Lehrman Group (GLG) (USA), Slingshot Insights expert network (USA)), symposium organisation (INSMED, Boehringer Ingelheim, Chiesi) and travel support, lectures or presentations, outside the submitted work. Other authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Upper extremity dysfunction is frequently seen in Parkinson's disease (PD). Existing research has shown that bradykinesia, which is main symptom of PD, is primarily responsible but the combined effects of spinal posture and axial rigidity on upper extremity functions were not investigated yet. The aim of this study was to investigate upper extremity functions in patients with PD and to evaluate relationship of these with spinal posture and axial rigidity., Methods: This prospective controlled study included 40 patients with PD and 40 healthy controls. Upper extremity function was measured with the 9-Hole Peg Test. Spinal posture and axial rigidity were measured with a Spinal Mouse., Results: Compared with the control group, a decrease in upper extremity functions (p < 0.001), decreased lumbar lordosis (p = 0.003), and posterior sacral tilt (p = 0.021) were determined in patients' group. Thoracic and lumbar mobility in the sagittal (all p < 0.001) and frontal planes (p = 0.004, p < 0.001) was found to be reduced in the patient group. A correlation was determined between upper extremity functions and lumbar mobility in the sagittal (p = 0.022, r= -0.362) and frontal planes (p = 0.045, r= -0.319) and lumbar lordosis (p = 0.048, r = 0.302)., Conclusions: The results of this study demonstrated that altered spinal posture and increased axial rigidity were related with decreased upper extremity functions in patients with PD. There is a need for further studies to investigate effect of trunk-based therapies on upper extremity function in patients with PD., (© 2024. The Author(s) under exclusive licence to Belgian Neurological Society.)

Background: With widespread smartphone use, there is growing concern about their potential impact on human health., Objective: The effects of smartphone use on self-reported hearing ability, tinnitus, balance, falls, and anxiety level were investigated in this study., Methods: This study included 682 participants who were divided into 2 groups: a high smartphone use (HSU) group and a low smartphone use (LSU) group. Both groups were evaluated for hearing ability using the Amsterdam inventory for auditory disability and handicap; balance status using the vertigo, dizziness, imbalance symptom scale; anxiety status using the Beck anxiety index; and fall and tinnitus status using the visual analog scale., Results: The HSU group showed significantly worse hearing ability, tinnitus, balance, falling, and anxiety status results than the LSU group (p < 0.001). There was a positive correlation between smartphone addiction severity and auditory impairment, tinnitus, risk of falling, and anxiety, as well as a negative correlation with balance score (p < 0.001)., Conclusion: The findings suggest that individuals with excessive smartphone use are more likely to experience hearing, tinnitus, balance, falling, and anxiety problems than those who use smartphones less frequently. Excessive smartphone use may be considered a potential risk factor for these problems., (© 2024. The Author(s).)

The CHA₂DS₂-VASc (congestive heart failure, hypertension, age, diabetes mellitus, stroke, vascular disease, sex) scoring system, which includes conventional risk factors of coronary artery disease, was originally created to quantify the risk of thromboembolism in patients with atrial fibrillation. This study evaluated the usefulness of this score to predict adverse outcomes in STEMI (ST-elevation myocardial infarction) patients without atrial fibrillation. Primary end points were identified as MACE (major adverse cardiovascular events) which included in-hospital death or cerebrovascular accident. MACE rate was 10% (193 patients). The CHA₂DS₂-VASc score was an independent predictor of MACE (95% CI, 2.31 [1.37-3.9]; P = .0016). Other independent predictors of MACE included heart rate (95% CI, 1.56 [0.97-2.50]; P = .0242), admission Killip class (95% CI, 24.19 [10.74-54.46]; P < .0001), admission creatinine level (95% CI, 1.54 [1.10-2.16]; P = .0024), peak CK-MB level (95% CI, 1.63 [0.98-2.70]; P = .0001), and no-reflow (95% CI, 2.45 [1.25-4.80]; P = .0085). A nomogram was developed to estimate the risk of in-hospital adverse outcomes for STEMI patients. The CHA₂DS₂-VASc score was an independent predictor of MACE in STEMI patients. Linear analysis of CHA₂DS₂-VASc score without dichotomization was the main difference of this study from others., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Phenothiazines (PTZ) are antipsychotics known to modulate a variety of neurotransmitter activities that include dopaminergic and cholinergic signaling and have been identified as potential anticancer agents in vitro. However, it is important to also test whether a highly cytotoxic, repurposed, or novel PTZ has low toxicity and neuromodulatory activity in vivo using vertebrate model organisms, such as zebrafish. In this study, we synthesized novel phenothiazines and screened them in vitro in liver cancer and in vivo in zebrafish embryos/larvae. The syntheses of several intermediate PTZ 10-yl acyl chlorides were followed by elemental analysis and determination of 1 H NMR and 13 C NMR mass (ESI + ) spectra of a large number of novel PTZ 10-carboxamides. Cytotoxicities of 28 PTZ derivatives (1-28) screened against Hep3B and SkHep1 liver cancer cell lines revealed five intermediate and five novel leads along with trifluoperazine (TFP), prochlorperazine (PCP), and perphenazine, which are relatively more cytotoxic than the basic PTZ core. Overall, the derivatives were more cytotoxic to Hep3B than SkHep1 cells. Moreover, in silico target screening identified cholinesterases as some of the commonest targets of the screened phenothiazines. Interestingly, molecular docking studies with acetylcholinesterase (AChE) and butyrylcholinesterase proteins showed that the most cytotoxic compounds 1 , 3 , PCP, and TFP behaved similar to Huprin W in their amino acid interactions with the AChE protein. The highly cytotoxic intermediate PTZ derivative 1 exhibited a relatively lower toxicity profile than those of 2 and 3 during the zebrafish development. It also modulated in vivo the cholinesterase activity in a dose-dependent manner while significantly increasing the total cholinesterase activity and/or ACHE mRNA levels, independent of the liver cancer cell type. Our screen also identified novel phenothiazines, i.e., 8 and 10 , with significant cytotoxic and cholinesterase modulatory effects in liver cancer cells; yet both compounds had low levels of toxicity in zebrafish. Moreover, they modulated the cholinesterase activity or expression of ACHE in a cancer cell line-specific manner, and compound 10 significantly inhibited the cholinesterase activity in zebrafish. Accordingly, using a successful combination of in silico, in vitro, and in vivo approaches, we identified several lead anticancer and cholinesterase modulatory PTZ derivatives for future research., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The leading cause of composite restoration failure is secondary caries, and although caries is a multifactorial problem, weak, damage-prone adhesives play a pivotal role in the high susceptibility of composite restorations to secondary caries. Our group has developed synthetic resins that capitalize on free-radical polymerization and sol-gel reactions to provide dental adhesives with enhanced properties. The resins contain γ-methacryloxypropyltrimethoxysilane (MPS) as the Si-based compound. This study investigated the properties of methacrylate-based resins containing methacryloxymethyltrimethoxysilane (MMeS) as a short-chain alternative. The degree of conversion (DC), polymerization kinetics, water sorption, mechanical properties, and leachates of MMeS- and MPS-resins with 55 and 30 wt% BisGMA-crosslinker were determined. The formulations were used as model adhesives, and the adhesive/dentin (a/d) interfaces were analyzed using chemometrics-assisted micro-Raman spectroscopy. The properties of the 55 wt% formulations were comparable. In the 30 wt% BisGMA formulations, the MMeS-resin exhibited faster polymerization, lower DC, reduced leachates, and increased storage and loss moduli, glass transition (T g ), crosslink density, and heterogeneity. The spectroscopic results indicated a comparable spatial distribution of resin, mineralized, and demineralized dentin across the a/d interfaces. The hydrolytically stable experimental short-chain-silane-monomer dental adhesive provides enhanced mechanical properties through autonomous strengthening and offers a promising strategy for the development of restorative dental materials with extended service life.

Sortase A (SrtA) is an attractive target for developing new anti-infective drugs that aim to interfere with essential virulence mechanisms, such as adhesion to host cells and biofilm formation. Herein, twenty hydroxy, nitro, bromo, fluoro, and methoxy substituted chalcone compounds were synthesized, antimicrobial activities and molecular modeling strategies against the SrtA enzyme were investigated. The most active compounds were found to be T2, T4, and T19 against Streptococcus mutans (S. mutans) with MIC values of 1.93, 3.8, 3.94 μg/mL, and docking scores of -6.46, -6.63, -6.73 kcal/mol, respectively. Also, these three active compounds showed better activity than the chlorohexidine (CHX) (MIC value: 4.88 μg/mL, docking score: -6.29 kcal/mol) in both in vitro and in silico. Structural stability and binding free energy analysis of S.mutans SrtA with active compounds were measured by molecular dynamic (MD) simulations throughout 100 nanoseconds (ns) time. It was observed that the stability of the critical interactions between these compounds and the target enzyme was preserved. To prove further, in vivo biological evaluation studies could be conducted for the most promising precursor compounds T2, T4, and T19, and it might open new avenues to the discovery of more potent SrtA inhibitors., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Objective: This study aims to classify tongue lesion types using tongue images utilizing Deep Convolutional Neural Networks (DCNNs)., Methods: A dataset consisting of five classes, four tongue lesion classes (coated, geographical, fissured tongue, and median rhomboid glossitis), and one healthy/normal tongue class, was constructed using tongue images of 623 patients who were admitted to our clinic. Classification performance was evaluated on VGG19, ResNet50, ResNet101, and GoogLeNet networks using fusion based majority voting (FBMV) approach for the first time in the literature., Results: In the binary classification problem (normal vs. tongue lesion), the highest classification accuracy performance of 93,53% was achieved utilizing ResNet101, and this rate was increased to 95,15% with the application of the FBMV approach. In the five-class classification problem of tongue lesion types, the VGG19 network yielded the best accuracy rate of 83.93%, and the fusion approach improved this rate to 88.76%., Conclusion: The obtained test results showed that tongue lesions could be identified with a high accuracy by applying DCNNs. Further improvement of these results has the potential for the use of the proposed method in clinic applications., (© 2024. The Author(s).)

We assessed the ability of predicting mortality and total in-hospital bleeding and adverse outcomes by the Academic Research Consortium High Bleeding Risk (ARC-HBR) criteria in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). A total of 1441 STEMI patients were recruited: HBR group 354 (25%) patients and non-HBR group of 1087 (75%) patients. A total of 131 patients (9%) had a bleeding complication during hospitalization. The bleeding complications were also categorized according to other conventional bleeding scores. According to these conventional scores, all bleeding categories were associated with HBR. In univariate logistic regression analysis, female gender, diabetes mellitus, hypertension (HT) and HBR were associated with in-hospital bleeding. However, in multivariable analysis only HT (Odds Ratio [OR] 1.528, 95% CI 1.020-2.290; P = .040) and HBR (OR 1.612, 95% CI 1.075-2.428; P = .022) independently predicted total in-hospital bleeding complications. Hospital duration was longer and mortality rate was significantly higher in patients with HBR (OR 8.755, 95% CI 5.864-13.074; P < .01). The ARC-HBR criteria may predict in-hospital bleeding events and adverse outcomes in STEMI patients undergoing pPCI., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Like pneumonia, coronavirus disease 2019 (COVID-19) is characterized by a massive infiltration of innate immune cells (such as polymorphonuclear leukocytes) into the airways and alveolar spaces. These cells release proteases that may degrade therapeutic antibodies and thus limit their effectiveness. Here, we investigated the in vitro and ex vivo impact on anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) IgG1s and other IgG subclasses (IgG2 and IgG4) of the neutrophil elastase, proteinase 3 and cathepsin G (the three main neutrophil serine proteases) found in endotracheal aspirates from patients with severe COVID-19. Although the IgGs were sensitive to neutrophil serine proteases, IgG2 was most resistant to proteolytic degradation. The two anti-SARS CoV2 antibodies (casirivimab and imdevimab) were sensitive to the lung's proteolytic environment, although neutrophil serine protease inhibitors only partly limited the degradation. Overall, our results show that the pneumonia-associated imbalance between proteases and their inhibitors in the airways contributes to degradation of antiviral antibodies., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. Blin, C. Parent, G. Pichon, and R. Domain have nothing to disclose. B. Korkmaz has been paid for service as an advisory board member (INSMED), other forms of consulting (Neuprozyme Therapeutics Aps (Denmark), Santhera Pharmaceuticals (Switzerland)), symposium organisation (INSMED) and travel support, lectures or presentations outside the scope of the present work. N. Aubrey, Y. Jouan, A. Guillon, T. Sécher and H. Allouchi have nothing to disclose. N. Heuzé-Vourc’h N.H.V. is a cofounder and scientific expert for Cynbiose Respiratory. In the last few years, she has been paid as a scientific advisor (Novartis, European Commission, Immune Biosolution, ANR, Alvea/Telis Bioscience) and her group has financial relationships with private-sector entities (Aerogen, Nemera, Aptar Pharma, and Ablynx) outside the scope of the present work., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Cathepsin C (CatC, syn. Dipeptidyl peptidase I) is a lysosomal cysteine proteinase expressed in several tissues including inflammatory cells. This enzyme is important for maintaining multiple cellular functions and for processing immune cell-derived proteases. While mutations in the CatC gene were reported in Papillon-Lefèvre syndrome, a rare autosomal recessive disorder featuring hyperkeratosis and periodontitis, evidence from clinical and preclinical studies points toward pro-inflammatory effects of CatC in various disease processes that are mainly mediated by the activation of neutrophil serine proteinases. Moreover, tumor-promoting effects were ascribed to CatC. The aim of this review is to highlight current knowledge of the CatC as a potential therapeutic target in inflammatory disorders., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

The leading cause of composite restoration failure is recurrent marginal decay. The margin between the composite and tooth is initially sealed by a low-viscosity adhesive, but chemical, physical, and mechanical stresses work synergistically and simultaneously to degrade the adhesive, destroying the interfacial seal and providing an ideal environment for bacteria to proliferate. Our group has been developing self-strengthening adhesives with improved chemical and mechanical characteristics. This paper reports a self-strengthening adhesive formulation that resists hydrolysis-mediated degradation by providing intrinsic reinforcement of the polymer network through synergistic stimulation of free-radical polymerization, sol-gel reaction, and hydrophobicity. Hydrophobic resin formulation (NE1) was developed using HEMA/BisGMA 28/55w/w and 15 wt% MPS. Control (NC1) contained HEMA/BisGMA 28/55 w/w and 15 wt% MES. The polymerization kinetics, water sorption, leachates, and dynamic mechanical properties of the resin samples were investigated. The NC1 and NE1 samples showed comparable polymerization kinetics, degree of conversion and water sorption. In contrast, NC1 showed significantly higher levels of HEMA and BisGMA leachate, indicating faster degradation in ethanol. At day 3, cumulative HEMA leachate for NC1 was tenfold greater than NE1 ( p < 0.05 ). Dynamic mechanical properties were measured at 37 and 70°C in both dry and wet conditions. Under dry conditions, the storage moduli of NC1 and NE1 were comparable and the glass transition temperature ( T g ) of NC1 was statistically significant lower ( p < 0.001) than NE1. Under wet conditions, the storage modulus of NC1 was lower than NE1 and at 70°C there is a threefold difference in storage modulus. At this temperature and under wet conditions, the storage modulus of NC1 is statistically significantly lower ( p < 0.001) than NE1. The results indicated that in the wet environment, NE1 provided lower chain mobility, higher crosslink density, and more hydrogen bonds. The newly formulated methacrylate-based adhesive capitalizes on free-radical polymerization, sol-gel reactions, and hydrophobicity to provide enhanced mechanical properties at elevated temperatures in wet environments and hydrolytic stability under aggressive aging conditions., Competing Interests: Conflict of interest QY is employed by Canon Virginia, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background/aim: Trunk control, which plays a key role in balance and mobility, decreases in patients with multiple sclerosis (PwMS) and many parameters such as sensory, motor, and musculoskeletal systems affect trunk control. The aim of this study was to compare trunk control, spinal mobility, and spinal posture in PwMS with healthy controls and investigate the relationship between trunk control with spinal posture and spinal mobility in PwMS., Materials and Methods: The study was completed with 38 PwMS and 38 healthy controls with matched age and sex. Trunk control was evaluated with the Trunk Impairment Scale (TIS). Spinal posture and mobility were evaluated in sagittal and frontal planes using an IDIAG M360 Spinal Mouse. Spinal posture was evaluated in upright, maximum flexion, extension, left and right lateral flexion positions, and spinal mobility was evaluated from upright to flexion, extension, right and left flexion positions in sagittal and frontal planes., Results: TIS scores, thoracic mobility angles (from upright to flexion and left lateral flexion), lumbar mobility angles (from upright to extension and right lateral flexion) and lumbar posture angle (maximum right lateral flexion) were lower, and thoracic posture angles (upright and maximum extension) were higher in PwMS than healthy controls (p < 0.05). No significant difference was found between other spinal postures and mobility values. In addition, there was only a negative relationship between thoracic spinal mobility from upright to extension and trunk control in PwMS (r = -0.349; p = 0.032)., Conclusion: These findings indicate the importance of early detection of trunk disturbances in PwMS. Thus, even in the early stages of multiple sclerosis, detailed trunk assessment will guide the implementation of comprehensive exercise programs., Competing Interests: Conflict of interest: The authors declared no conflicts of interest., (© TÜBİTAK.)

Neutrophils have a critical role in the innate immune response to infection and the control of inflammation. A key component of this process is the release of neutrophil serine proteases (NSPs), primarily neutrophil elastase, proteinase 3, cathepsin G, and NSP4, which have essential functions in immune modulation and tissue repair following injury. Normally, NSP activity is controlled and modulated by endogenous antiproteases. However, disruption of this homeostatic relationship can cause diseases in which neutrophilic inflammation is central to the pathology, such as chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, bronchiectasis, and cystic fibrosis, as well as many non-pulmonary pathologies. Although the pathobiology of these diseases varies, evidence indicates that excessive NSP activity is common and a principal mediator of tissue damage and clinical decline. NSPs are synthesized as inactive zymogens and activated primarily by the ubiquitous enzyme dipeptidyl peptidase 1, also known as cathepsin C. Preclinical data confirm that inactivation of this protease reduces activation of NSPs. Thus, pharmacological inhibition of dipeptidyl peptidase 1 potentially reduces the contribution of aberrant NSP activity to the severity and/or progression of multiple inflammatory diseases. Initial clinical data support this view. Ongoing research continues to explore the role of NSP activation by dipeptidyl peptidase 1 in different disease states and the potential clinical benefits of dipeptidyl peptidase 1 inhibition., Competing Interests: JDC has received grants and personal fees from AstraZeneca, Boehringer-Ingelheim, GSK, Zambon, and Insmed Incorporated, a grant from Gilead, and personal fees from Novartis and Chiesi. RK has received a grant from Boehringer-Ingelheim and personal fees from Insmed Incorporated. BK has been paid for the time spent as a committee member for advisory boards (Brensocatib Advisory Board [BRAB] Insmed Incorporated, USA), other forms of consulting (Boehringer Ingelheim [Germany], Neuprozyme Therapeutics Aps [Denmark], Santhera Pharmaceuticals [Switzerland], Chiesi [Italy], Gerson Lehrman Group [GLG] [USA]), symposium organisation (Insmed Incorporated) and travel support, and lectures or presentations, outside of the submitted work., (Copyright © 2023 Chalmers, Kettritz and Korkmaz.)

Background: Heart transplantation (HTX) is the standard treatment for end-stage heart failure. However, reperfusion following an ischemic period can contribute to myocardial injury. Neutrophil infiltration, along with the subsequent release of tissue-degrading neutrophil elastase (NE)-related serine proteases and oxygen-derived radicals, is associated with adverse graft outcomes. The inhibition of cathepsin C (CatC) has been shown to block NE-related protease activation. We hypothesized that the CatC inhibitor BI-9740 improves graft function after HTX., Methods: In a rat model of HTX, the recipient Lewis rats were orally administered with either a placebo (n = 12) or BI-9740 (n = 11, 20 mg/kg) once daily for 12 days. Donor hearts from untreated Lewis rats were explanted, preserved in a cardioplegic solution, and subsequently heterotopically implanted. In vivo left-ventricular (LV) graft function was assessed after 1 h of reperfusion. The proteolytic activity of neutrophil serine proteases was determined in bone marrow lysates from BI-9740-treated and control rats. Additionally, myocardial morphological changes were examined, and heart samples underwent immunohistochemistry and western blot analysis., Results: The NE-related proteolytic activity in bone marrow cell lysates was markedly decreased in the BI-9740-treated rats compared to those of the placebo group. Histopathological lesions, elevated CatC and myeloperoxidase-positive cell infiltration, and nitrotyrosine immunoreactivity with an increased number of poly(ADP-ribose) polymerase (PARP)-1-positive cells were lowered in the hearts of animals treated with BI-9740 compared to placebo groups. Regarding the functional parameters of the implanted graft, improvements were observed in both systolic function (LV systolic pressure 110 ± 6 vs 74 ± 6 mmHg; dP/dt max 2782 ± 149 vs 2076 ± 167 mmHg/s, LV developed pressure, at an intraventricular volume of 200 µl, p < 0.05) and diastolic function in the hearts of BI-9740 treated animals compared with those receiving the only placebo. Furthermore, the administration of BI-9740 resulted in a shorter graft re-beating time compared to the placebo group. However, this study did not provide evidence of DNA fragmentation, the generation of both superoxide anions and hydrogen peroxide, correlating with the absence of protein alterations related to apoptosis, as evidenced by western blot in grafts after HTX., Conclusions: We provided experimental evidence that pharmacological inhibition of CatC improves graft function following HTX in rats., (© 2023. The Author(s).)

Background and Purpose: There are controversies regarding the role of presynaptic inhibition (PSI) in the mechanisms underlying the efficacy of deep-brain stimulation (DBS) in Parkinson's disease (PD). We sought to determine the involvement of PSI in DBS-related mechanisms and clinical correlates., Methods: We enrolled PD subjects who had received subthalamic nucleus DBS (STN-DBS) therapy and had been admitted to our clinic between January 2022 and March 2022. The tibial H-reflex was studied bilaterally during the medication-off state, and all tests were repeated 10 and 20 minutes after the simulation was turned off. Simultaneous evaluations based on the Movement-Disorder-Society-sponsored revision of the Unified Parkinson's Disease Rating Scale part III (MDS-UPDRS-III) were performed in all of the patients., Results: Ultimately we enrolled 18 patients aged 58.7±9.3 years (mean±standard deviation, 10 females). Fifty percent of the patients showed a decrease in the MDS-UPDRS-III score of more than 60% during the stimulation-on period. Comparative analyses of the repeated measurements made according to the stimulation status revealed significant differences only in the left H-reflex/M-response amplitude ratio (H/M ratio). However, no difference in the left H/M ratio was found in the subgroup of patients with a prominent clinical response to stimulation ( n =9). Analyses of the less-affected side revealed differences in the H-reflex amplitude and H/M ratio., Conclusions: We found evidence of PSI recovery on the less-affected side of our PD subjects associated with STN-DBS. We hypothesize that the involvement of this spinal pathway and its contribution to the mechanisms of DBS differ between individuals based on the severity of the disease and which brainstem regions and descending tracts are involved., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2023 Korean Neurological Association.)

Background: Patients with Multiple Sclerosis (PwMS) may experience a decline in balance, gait, and mobility as well as an increase in fear of falling (FoF) and fatigue due to weaker muscles and proprioceptive loss in their lower limbs. The study aimed to compare lower extremity muscle strength and proprioception, balance, functional mobility, gait, FoF, and fatigue between PwMS and healthy controls and to investigate the relationship between lower extremity muscle strength and proprioception and balance, functional mobility, gait, FoF, and fatigue in PwMS., Methods: The study was completed with 35 PwMS and 35 healthy controls with matching age and gender. The 5 Repetition Sit-to Stand Test (5-STS-test), knee and ankle reposition tests (using a digital inclinometer), the Berg Balance Scale (BBS), the Timed Up and Go (TUG) test, the Dynamic Gait Index (DGI), the Falls Efficacy-International (FES-I), and the Fatigue Severity Scale (FSS) were used for evaluations., Results: The 5-STS test, knee and ankle reposition tests, TUG, FES-I, and FSS Test scores were higher and BBS and DGI scores were lower in PwMS compared to healthy controls (p < 0.05). BBS, DGI, TUG, FES-I, and FSS were associated with 5-STS test and knee and ankle reposition tests except for some nondominant reposition tests in PwMS (r between 0.342 and -0.714; p < 0.05 for all)., Conclusion: Lower extremity muscle strength and proprioception were associated with balance, functional mobility, gait, FoF, and fatigue in PwMS. These results suggested that detailed assessment of neuromuscular parameters in lower extremity function is important in determining the appropriate rehabilitation programs., Competing Interests: Declaration of Competing Interest The authors declared no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

In the present study, the volatile composition of Ulva rigida (U. rigida) was elucidated by two different methods. As a result of the identification process of volatile components using the GC/MS-FID instrument, 31 compounds were identified by hydrodistillation (HD) method, and 15 compounds were identified by solid-phase microextraction (SPME) method, elucidating the structure of 99.86 % and 92.65 %, respectively. The most abundant compounds in the essential oil of U. rigida were n-hexadecanoic acid and pentadecanal, while the most abundant compound according to the SPME analysis was heptadecyne, a hydrocarbon compound. In the next step, hexane, dichloromethane, chloroform and methanol solvent extracts of U. rigida were prepared and the antimicrobial activities of the extracts and the essential oil obtained by hydro-distillation as well as the scolicidal activities of the solvent extracts were determined. The results of the antimicrobial activity test of the essential oil showed a high level of activity against Bacillus cereus ATCC 10876 and MRSA. The highest activity was found on the microorganism of Pseudomonas aeruginosa ATCC 9027 in chloroform and methanol extracts of U. rigida. Furthermore, viability detection was performed and the scolicidal effects of the extracts on protoscoleces were assessed. The values of lethal concentration doses (LD 50 , LD 75 and LD 90 ) were calculated using probit analysis., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Beekeeping is an important agricultural and commercial activity globally practiced. Honey bee is attacked by certain infectious pathogens. Most important brood diseases are bacterial including American Foulbrood (AFB), caused by Paenibacillus larvae (P. larvae), and European Foulbrood (EFB) by Melissococcus plutonius (M. plutonius) in addition of secondary invaders, e.g. Paenibacillus alvei (P. alvei) and Paenibacillus dendritiformis (P. dendritiformis). These bacteria cause the death of larvae in honey bee colonies. In this work, antibacterial activities of extracts, fractions, and isolated certain compounds (nominated 1-3) all originated from moss, Dicranum polysetum Sw. ( D. polysetum), were tested against some honey bee bacterial pathogens. Minimum inhibitory concentration, minimum bactericidal concentration, and sporicidal values ​​of methanol extract, ethyl acetate, and n-hexane fractions ranged between 10.4 and 18.98, 83.4-303.75 & 5.86-18.98 µg/mL against P. larvae, respectively. Antimicrobial activities of the ethyl acetate sub-fractions (fraction) and the isolated compounds (1-3) were tested against AFB- and EFB-causing bacteria. Bio-guided chromatographic separation of ethyl acetate fraction, a crude methanolic extract obtained from aerial parts of D. polysetum resulted in three natural compounds: a novel one, i.e. glycer-2-yl hexadeca-4-yne-7Z,10Z,13Z-trienoate (1, dicrapolysetoate; given as trivial name), in addition to two known triterpenoids poriferasterol (2), and γ-taraxasterol (3). Minimum inhibitory concentration ranges were 1.4-60.75, 8.12-65.0, 2.09-33.44 & 1.8-28.75 µg/mL for sub-fractions, compounds 1, 2, and 3, respectively., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: The shortage of available donor hearts and the risk of ischemia/reperfusion injury restrict heart transplantation (HTX). Alpha-1-antitrypsin (AAT), a well-characterized inhibitor of neutrophil serine protease, is used in augmentation therapy to treat emphysema due to severe AAT deficiency. Evidence demonstrates its additional anti-inflammatory and tissue-protective effects. We hypothesized that adding human AAT in a preservation solution reduces graft dysfunction in a rat model of HTX following extended cold ischemic storage., Methods: The hearts from isogenic Lewis donor rats were explanted, stored for either 1h or 5h in cold Custodiol supplemented with either vehicle (1h ischemia, n=7 or 5h ischemia, n=7 groups) or 1 mg/ml AAT (1h ischemia+AAT, n=7 or 5h ischemia+AAT, n=9 groups) before heterotopic HTX. Left-ventricular (LV) graft function was evaluated in vivo 1.5h after HTX. Immunohistochemical detection of myeloperoxydase (MPO) was performed in myocardial tissue and expression of 88 gene quantified with PCR was analyzed both statistical and with machine-learning methods., Results: After HTX, LV systolic function (dP/dt max 1h ischemia+AAT 4197 ± 256 vs 1h ischemia 3123 ± 110; 5h ischemia+AAT 2858 ± 154 vs 5h ischemia 1843 ± 104mmHg/s, p <0.05) and diastolic function (dP/dt min 5h ischemia+AAT 1516 ± 68 vs 5h ischemia 1095 ± 67mmHg/s, p <0.05) at an intraventricular volume of 90µl were improved in the AAT groups compared with the corresponding vehicle groups. In addition, the rate pressure product (1h ischemia+AAT 53 ± 4 vs 1h ischemia 26 ± 1; 5h ischemia+AAT 37 ± 3 vs 5h ischemia 21 ± 1mmHg*beats/min at an intraventricular volume of 90µl; p <0.05) was increased in the AAT groups compared with the corresponding vehicle groups. Moreover, the 5h ischemia+AAT hearts exhibited a significant reduction in MPO-positive cell infiltration in comparison to the 5h ischemia group. Our computational analysis shows that ischemia+AAT network displays higher homogeneity, more positive and fewer negative gene correlations than the ischemia+placebo network., Discussion: We provided experimental evidence that AAT protects cardiac grafts from prolonged cold ischemia during HTX in rats., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Korkmaz-Icöz, Abulizi, Li, Korkmaz, Georgevici, Sayour, Loganathan, Canoglu, Karck and Szabó.)

Background: Brensocatib is an oral, selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), responsible for activating neutrophil serine proteases (NSPs) including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG). In chronic inflammatory lung diseases such as non-cystic fibrosis bronchiectasis (NCFBE), neutrophils accumulate in the airways resulting in excess active NSPs that cause damaging inflammation and lung destruction., Methods: The 24-week WILLOW trial (NCT03218917) was a randomized, double-blind, placebo-controlled, parallel-group trial in patients with NCFBE conducted at 116 sites across 14 countries. In this trial, treatment with brensocatib was associated with improvements in clinical outcomes including time to first exacerbation, reduction in exacerbation frequency and a reduction in NE activity in sputum. An exploratory analysis of NE activity in white blood cell (WBC) extracts and NE, PR3 and CatG activity in sputum was conducted to further characterize brensocatib's effect and identify potential correlated effects., Results: NE, PR3 and CatG activities were reduced in sputum and NE activity was reduced in WBC extracts in a dose-dependent manner after four weeks of brensocatib treatment, with a return to baseline four weeks after the end of treatment. Brensocatib produced the greatest reduction in the sputum activity of CatG, followed by NE and then PR3. Positive correlations among the sputum NSPs were observed both at baseline and in response to treatment, with the strongest correlation among the sputum NSPs for NE and CatG., Conclusions: These results suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients., Trial Registration: The study was approved by the corresponding ethical review boards of all participating centers. The trial was approved by the Food and Drug Administration and registered at clinicaltrials.gov (NCT03218917) on July 17, 2017 and approved by the European Medicines Agency and registered at the European Union Clinical trials Register (EudraCT No. 2017-002533-32). An independent, external data and safety monitoring committee (comprising physicians with pulmonary expertise, a statistician experienced in the evaluation of clinical safety, and experts in periodontal disease and dermatology) reviewed all adverse events., (© 2023. The Author(s).)

Reminiscence refers to the process or act of thinking or telling about past experiences. Few studies address the relationship between reminiscence functions and trauma-related cognitions and emotions. This study aimed to expand the previous literature by investigating the frequency of different types of reminiscence during the COVID-19 pandemic and their relations to the likelihood of developing post-traumatic growth (PTG) and post-traumatic stress disorder (PTSD), using an adult sample. Altogether, 184 participants ( M age  = 30.38; SD  = 10.95) completed the Reminiscence Functions Scale to report the purposes for which they shared their experiences during the first two waves of COVID-19. They also responded to the COVID-Transitional Impact Scale, Post-Traumatic Stress Disorder Checklist for DSM-5, Post Traumatic Growth Inventory, Revised Form of The Multidimensional Scale of Perceived Social Support, and Connor-Davidson Resilience Scale, when considering the first two waves of COVID-19. The results demonstrated that pro-social reminiscence and self-positive reminiscence were significantly more common than self-negative reminiscence. Yet, these differences disappeared when the presence of COVID virus was controlled. Pro-social and self-positive reminiscence significantly predicted PTG beyond demographic characteristics, COVID-19 impact, social support, and resilience. In contrast, only self-negative reminiscence predicted PTSD beyond COVID-19 impact and demographic characteristics. Furthermore, serial mediation analysis indicated that pro-social reminiscence predicted PTG via its association with perceived social support and resilience. Our findings suggest the benefit of using reminiscence therapy-type interventions to facilitate PTG and reduce PTSD after large-scale disasters like pandemics., Competing Interests: Conflict of interestThere is no conflict of interest to declare. The study has been reviewed and approved by TED University Human Research Ethics Board., (© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Proteinase 3 (PR3) is the main target antigen of antineutrophil cytoplasmic antibodies (ANCAs) in PR3-ANCA-associated vasculitis. A small fraction of PR3 is constitutively exposed on the surface of quiescent blood neutrophils in a proteolytically inactive form. When activated, neutrophils expose an induced form of membrane-bound PR3 (PR3 mb ) on their surface as well, which is enzymatically less active than unbound PR3 in solution due to its altered conformation. In this work, our objective was to understand the respective role of constitutive and induced PR3 mb in the immune activation of neutrophils triggered by murine anti-PR3 mAbs and human PR3-ANCA. We quantified immune activation of neutrophils by the measurement of the production of superoxide anions and secreted protease activity in the cell supernatant before and after treatment of the cells by alpha-1 protease inhibitor that clears induced PR3 mb from the cell surface. Incubation of TNFα-primed neutrophils with anti-PR3 antibodies resulted in a significant increase in superoxide anion production, membrane activation marker exposition, and secreted protease activity. When primed neutrophils were first treated with alpha-1 protease inhibitor, we observed a partial reduction in antibody-induced neutrophil activation, suggesting that constitutive PR3 mb is sufficient to activate neutrophils. The pretreatment of primed neutrophils with purified antigen-binding fragments used as competitor significantly reduced cell activation by whole antibodies. This led us to the conclusion that PR3 mb promoted immune activation of neutrophils. We propose that blocking and/or elimination of PR3 mb offers a new therapeutic strategy to attenuate neutrophil activation in patients with PR3-ANCA-associated vasculitis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Two new dihydroisocoumarins (scorzolongin I ( 1 ), and scorzolongin II ( 2 )) and nine known compounds (3',5'-dimethoxy hydrangenol (scorzolongin III, 3 ), cladantholide ( 4 ), dammar-24-ene-3 β -ol ( 5 ), taraxasterol ( 6 ), β -sitosterol ( 7 ), mangifgerursanone ( 8 ), and a mixture of α-amyrenone ( 9a ), β-amyrenone ( 9b ), and dammar-24-ene-3-one ( 9c ) in about 1:1:2 ratio) were identified from the dichloromethane fraction of Scorzonera longiana . The structure of all compounds ( 1-9a-c) were elucidated by extensive 1D and 2D NMR ( 1 H, 13 C/APT, COSY, HMBC, HSQC, and NOESY) spectroscopy, UV, FT-IR, and LC-QTOF-MS data and by comparison of their NMR data with the literature. These compounds have been isolated from S. longiana for the first time. An antimicrobial assay against eight microorganisms was applied to isolated compounds 1 - 3 . Scorzolongin I, and scorzolongin II, and scorzolongin III showed notable activity against gram (-) ( Escherichia coli and Yersinia pseudotuberculosis ) and fungi (Candida albicans, Saccharomyces cerevisiae ) with 20 mm inhibition zone each. Scorzolongin II ( 2) exhibited strong activity against E. coli , Y. pseudotuberculosis, Mycobacterium smegmatis C. albicans, S. cerevisiae with MIC value of 33.8 μg/mL.

Five new phenyl dihydroisocoumarin glycosides (1-5) and two known compounds (6-7) were identified from the butanol fraction of Scorzonera longiana. The structures of 1-7 were elucidated based on spectroscopic methods. Antimicrobial, antitubercular, and antifungal evaluation of compounds 1-7 were carried out using the microdilution method against nine microorganisms. Compound 1 was active only against Mycobacterium smegmatis (Ms) with a MIC value of 14.84 μg/mL. All tested compounds (1-7) were active against Ms but only compounds 3-7 were active against fungi (C. albicans, S. cerevisiae) with MIC values of 25.0-125 μg/mL. In addition, molecular docking studies were conducted against Ms DprE1 (PDB ID: 4F4Q), Mycobacterium tuberculosis (Mbt) DprE1 (PDB ID: 6HEZ), and arabinosyltransferase C (EmbC, PDB ID: 7BVE) enzymes. Compounds 2, 5, and 7 are the most effective Ms 4F4Q inhibitors. Compound 4 was the most promising inhibitory activity on Mbt DprE with the lowest binding energy of -9,9 kcal/mol., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)