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Introduction: Supracondylar humerus fractures (SCHFs) represent a significant segment of paediatric bone injuries, posing unique challenges due to their potential for severe complications. This study aims to provide a detailed analysis of the surgically treated SCHF cases recorded in our registry., Materials and Methods: Prospectively collected data from seven institutes were retrospectively analysed using the Hungarian SCHF Registry, with data about surgically treated paediatric patients with SCHFs. We created three groups based on fracture type (Gartland IIA, IIB and III), and compared their preoperative, operative, and postoperative data. We analysed differences between the groups using the Chi-Squared test or Fisher's Exact test for categorical variables. The Kruskal-Wallis rank sum test was performed for continuous variables. If there was a significant difference between the groups, we conducted Dunn's post-hoc analysis., Results: The fracture type was available for 214 patients (Gartland IIA group contained 31, IIB 121, and III 62 children). Our investigation highlighted notable patterns: lower oxygen saturation levels at initial assessment correlated with higher fracture severity (p = 0.0125); Body Mass Index (BMI) did not significantly influence the type of fracture (p = 0.2254); neither the mechanism of injury (flexion vs. extension) (p = 0.5606), nor the initial radial pulse (p = 0.0647) showed significant difference; the complexity of fractures was directly proportional to operative time (p < 0.01); less severe fractures required longer time to heal before pin removal (p = 0.0125); while severe fractures showed a tendency towards neurological complications, the overall complication rates did not vary significantly across different fracture types (p = 0.0988)., Conclusions: Our study emphasizes the significance of initial oxygen saturation levels as potential indicators of fracture severity. It also stresses the need for detailed attention to neurological complications and the prolonged use of pins, thereby highlighting the importance of customized treatment strategies in paediatric SCHFs., Level of Evidence: II., Competing Interests: Declarations. Ethics approval and consent to participate: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Scientific and Research Ethics Committee of the Medical Research Council (35335-2/2018/EKU). Consent to participate: Written informed consent was obtained from the parents. Competing interests: The authors have no competing interests to declare that are relevant to the content of this article., (© 2024. The Author(s).)

A major challenge in the development of wearable artificial kidneys (WAKs) lies in the efficient removal of urea, which is found at an extremely high concentration in the blood of patients with chronic kidney disease (CKD). Urease is an enzyme that hydrolyzes urea. While it can efficiently remove urea, toxic ammonium is produced as a byproduct. In this study, nanofibers capable of removing both urea and ammonium from the blood were fabricated. Specifically, urease was immobilized on electrospun poly(ethylene- co -vinyl alcohol) (EVOH)/chitosan nanofiber membranes via covalent cross-linking. Chitosan not only helped covalent immobilization via its free amino groups but also improved hemocompatibility by suppressing protein adhesion. The resulting urease-immobilized EVOH/chitosan nanofibers exhibited an outstanding urea removal performance of 690 mg/g per hour. For ammonium removal, EVOH nanofiber membranes containing sodium cobalt(II) hexacyanoferrate(II) (NaCoHCF), an ammonium adsorbent, were prepared. The fabricated EVOH/NaCoHCF membranes exhibited an ammonium adsorption capacity of 135.5 mg/g. The two types of nanofiber membranes were combined to form a double-layered nanofiber membrane that was placed in a filter holder for continuous-flow cycling experiments. Under such conditions, all urea at a concentration similar to that in the blood of CKD patients was degraded within 1 h, and ammonium production was reduced by approximately 90% of the normal level. This double-layered nanofiber membrane can achieve both urea degradation and ammonium adsorption and is expected to advance the development of WAKs, a game changer in the treatment of CKD.

The Linearbandkeramik (LBK) Neolithic communities were the first to spread farming across large parts of Europe. We report genome-wide data for 250 individuals: 178 individuals from whole-cemetery surveys of the Alföld Linearbankeramik Culture eastern LBK site of Polgár-Ferenci-hát, the western LBK site of Nitra Horné Krškany and the western LBK settlement and massacre site of Asparn-Schletz, as well as 48 LBK individuals from 16 other sites and 24 earlier Körös and Starčevo individuals from 17 more sites. Here we show a systematically higher percentage of western hunter-gatherer ancestry in eastern than in western LBK sites, showing that these two distinct LBK groups had different genetic trajectories. We find evidence for patrilocality, with more structure across sites in the male than in the female lines and a higher rate of within-site relatives for males. At Asparn-Schletz we find almost no relatives, showing that the massacred individuals were from a large population, not a small community., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Progressive atelectasis regularly occurs during general anaesthesia; hence, positive end-expiratory pressure (PEEP) is often applied. Individualised PEEP titration may reduce the incidence of postoperative pulmonary complications (PPCs) and improve oxygenation as compared to fixed PEEP settings; however, evidence is lacking. Methods: This systematic review and meta-analysis was registered on PROSPERO (CRD42021282228). A systematic search in four databases (MEDLINE Via PubMed, EMBASE, CENTRAL, and Web of Science) was performed on 14 October 2021 and updated on 26 April 2024. We searched for randomised controlled trials comparing the effects of individually titrated versus fixed PEEP strategies during abdominal surgeries. The primary endpoint was the incidence of PPCs. The secondary endpoints included the PaO 2 /FiO 2 at the end of surgery, individually set PEEP value, vasopressor requirements, and respiratory mechanics. Results: We identified 30 trials (2602 patients). The incidence of PPCs was significantly lower among patients in the individualised group (RR = 0.70, CI: 0.58-0.84). A significantly higher PaO 2 /FiO 2 ratio was found in the individualised group as compared to controls at the end of the surgery (MD = 55.99 mmHg, 95% CI: 31.78-80.21). Individual PEEP was significantly higher as compared to conventional settings (MD = 6.27 cm H 2 O, CI: 4.30-8.23). Fewer patients in the control group needed vasopressor support; however, this result was non-significant. Lung-function-related outcomes showed better respiratory mechanics in the individualised group (Cstat: MD = 11.92 cm H 2 O 95% CI: 6.40-17.45). Conclusions: Our results show that individually titrated PEEP results in fewer PPCs and better oxygenation in patients undergoing abdominal surgery.

Background and Objectives : The anti-Müllerian hormone (AMH) is a crucial biomarker in regulating ovarian follicle development and female fertility. AMH levels predict ovarian responses in in vitro fertilization (IVF) cycles, helping clinicians tailor treatment strategies. This study aims to determine whether thyroid autoimmunity, age, body mass index (BMI), sexual hormone levels, and 25-hydroxyvitamin D levels influence serum AMH in non-polycystic-ovary-syndrome (PCOS) euthyroid women. Materials and Methods : This retrospective cross-sectional study examined 52 female patients at Zygota Fertility Clinic between 2018 and 2022. Women aged 20-45 years with regular menstrual cycles were included, while conditions such as abnormal thyroid-stimulating hormone (TSH) levels, PCOS, and systemic autoimmune diseases were excluded. A number of parameters were measured in the study, including the subjects' age, BMI, 25-hydroxyvitamin D, serum free thyroxine (fT4), TSH, various antibodies, and a range of reproductive hormones. An analysis of the relationships between AMH and other variables was conducted using Spearman's correlation coefficient, and an assessment of the impact of confounding factors on AMH levels was conducted using a multivariable linear regression model. Results : The results revealed significant negative correlations between AMH levels and age (rho: -0.484, p < 0.001) and follicle-stimulating hormone (FSH) (rho: -0.550, p < 0.001), while positive correlations existed between AMH and estradiol (rho: 0.352, p = 0.011) and total testosterone (rho: 0.542, p < 0.001). No significant correlations were found between AMH levels and BMI, LH, or 25-hydroxyvitamin D. Conclusions : In this study, ovarian reserve was influenced by age, estradiol, and total testosterone in non-PCOS euthyroid women undergoing IVF. Conversely, BMI and vitamin D status did not significantly impact AMH levels. In order to better understand and possibly manage ovarian reserve, a holistic approach is absolutely essential, taking into account age, weight, hormonal balance, nutrition, and thyroid health.

Background: Primary hyperparathyroidism (PHPT), a condition that manifests in various clinical forms, is a significant health concern. Normocalcemic primary hyperparathyroidism (NPHPT) is characterized by normal calcemia despite elevated parathyroid hormone (PTH) levels. Vitamin D deficiency can contribute to the clinical spectrum and complexity of NPHPT. Low vitamin D levels can elevate PTH, making it difficult to distinguish between NPHPT and secondary hyperparathyroidism. Additionally, it might mask hypercalcemia, leading to an underestimation of the disease severity. Our study aims to shed light on these complexities by investigating normocalcemic and hypercalcemic PHPT patient's clinical, hormonal, and biochemical patterns, including their vitamin D status.    Materials: In this retrospective study, we enrolled 60 PHPT patients with autonomous parathyroid function confirmed using a combination of ultrasonography, radionuclide scan, and parathyroid function index calculation. We evaluated the albumin-corrected calcemia, calciuria, PTH, 25(OH)D level, serum phosphate, bone mineral density, and major clinical symptoms (fracture, nephrolithiasis). A comparative analysis and a correlation study were performed between normo- and hypercalcemic and vitamin D-deficient and vitamin D-non-deficient groups., Results:  The median age was 62 years, 51.66% (31/60) being normocalcemic and 46.66% (29/60) presenting a deficient 25(OH)D level. In the group with 25(OH)D below 20 ng/mL, we observed a reduced level of albumin-corrected calcemia, without a significant increase of PTH compared to the adequate 25(OH)D level group. The frequency of the NPHPT and the risk of fracture were significantly higher in the deficient 25(OH)D group (20/60, 33.33% and 8/60, 13.33%) than in the adequate one (11/60, 18.33% and 1/60, 1.66%) with OR=4.7 (p<0.004) and OR=9.7 (p<0.027), respectively. We also found a positive correlation between PTH and adenoma size, the parathyroid function index and adenoma size, as well as PTH and phosphate levels. However, the correlation between 25(OH)D and phosphate levels was negative and moderate (rho=-0.504, p<0.001), adding a new layer of complexity to our understanding of these relationships., Conclusion: Our study provided significant insight into the link between vitamin D status and normocalcemic PHPT. We found that vitamin D-deficient patients with normocalcemic PHPT have an increased fracture risk, which requires meticulous monitoring and possible supplementation with vitamin D. This should be done carefully to avoid exacerbating hypercalcemia or hypercalciuria. Further research is needed to refine these management strategies and deepen our understanding of the complex relationships between the analyzed parameters., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Ethics Committee of the George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mures issued approval 747/18.02.2020. This study complies with the Declaration of Helsinki and was performed according to ethics committee approval. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kolcsar et al.)

BACKGROUND Computer-aided design (CAD) has been used in the Nuss procedure to determine the bar length and shape. Despite computer aid, the shape and design remain quite intuitive. We tested a new algorithm to determine the optimal bar shape. MATERIAL AND METHODS The normal sterno-vertebral distance was defined on computed tomography (CT) scans of patients without pectus excavatum (PEx) at the same level where the deepest depression was found on CT scans of 97 patients with PEx. Four points were marked on the CT scan of 60 patients with PEx at the deepest deformity: P1: edge of the vertebra; P2: edge of the deformity; P3: the expected contact point of the bar and the rib; and P4: the expected end of the bar. The algorithm generated 3 circles upon these points, and the fusion of the arcs drew the line of the ideal bar. Corrected and normal sterno-vertebral distance values were compared with the Mann-Whitney U test. Ten bars were bent manually guided by a 1: 1 printout of the designed bar and were implanted in 10 adolescents. RESULTS The shortest sterno-vertebral distance was 3 cm below the intermammillary line in PEx patients. The normal mean sterno-vertebral distance at this level was 10.16±1.35 cm in non-PEx patients. The mean virtually corrected sterno-vertebral distance was 10.28±1.27 cm. No significant difference was found (P=0.44). The bars were seamless and were successfully implanted. No bar needed adjustment, the operation time was shorter, and the patient satisfaction score was 9.4/10. CONCLUSIONS With our new algorithm, an optimal Nuss bar can be designed.

The Piezo1 mechanosensitive ion channel is abundant on several elements of the central nervous system including astrocytes. It has been already demonstrated that activation of these channels is able to elicit calcium waves on astrocytes, which contributes to the release of gliotransmitters. Astrocyte- and N-methyl-D-aspartate (NMDA) receptor-dependent slow inward currents (SICs) are hallmarks of astrocyte-neuron communication. These currents are triggered by glutamate released as gliotransmitter, which in turn activates neuronal NMDA receptors responsible for this inward current having slower kinetics than any synaptic events. In this project, we aimed to investigate whether Piezo1 activation and inhibition is able to alter spontaneous SIC activity of murine neocortical pyramidal neurons. When the Piezo1 opener Yoda1 was applied, the SIC frequency and the charge transfer by these events in a minute time was significantly increased. These changes were prevented by treating the preparations with the NMDA receptor inhibitor D-AP5. Furthermore, Yoda1 did not alter the spontaneous EPSC frequency and amplitude when SICs were absent. The Piezo1 inhibitor Dooku1 effectively reverted the actions of Yoda1 and decreased the rise time of SICs when applied alone. In conclusion, activation of Piezo1 channels is able to alter astrocyte-neuron communication. Via enhancement of SIC activity, astrocytic Piezo1 channels have the capacity to determine neuronal excitability.

Background : Glucocorticoids may grant a protective effect against postoperative complications. The evidence on their efficacy, however, has been inconclusive thus far. We investigated the effects of preoperatively administered glucocorticoids on the overall postoperative complication rate, and on liver function recovery in patients undergoing major liver surgery. Methods: We performed a systematic literature search on PubMed, Embase, and CENTRAL in October 2021, and repeated the search in April 2023. Pre-study protocol was registered on PROSPERO (ID: CRD42021284559). Studies investigating patients undergoing liver resections or transplantation who were administered glucocorticoids preoperatively and reported postoperative complications were eligible. Meta-analyses were performed using META and DMETAR packages in R with a random effects model. Risk of bias was assessed using RoB2. Results: The selection yielded 11 eligible randomized controlled trials (RCTs) with 964 patients. Data from nine RCTs ( n = 837) revealed a tendency toward a lower overall complication rate with glucocorticoid administration (odds ratio: 0.71; 95% confidence interval: 0.38-1.31, p = 0.23), but it was not statistically significant. Data pooled from seven RCTs showed a significant reduction in wound infections with glucocorticoid administration [odds ratio: 0.64; 95% confidence interval: 0.45-0.92 p = 0.02]. Due to limited data availability, meta-analysis of liver function recovery parameters was not possible. Conclusions : The preoperative administration of glucocorticoids did not significantly reduce the overall postoperative complication rate. Future clinical trials should investigate homogenous patient populations with a specific focus on postoperative liver recovery.

Purpose: A total of 894 hips were evaluated to describe the survivorship of Exeter cemented femoral stems and report the outcomes and complications of our 'Exeter- era', and there is no study from Central or Eastern Europe demonstrating similar results., Methods: Between January 2000 and December 2009, a total of 894 hips were included who underwent Exeter universal and V40 femoral stems with a mean follow up of 13 years. Cemented Exeter low profile polyethylene cups were used in 889 patients (99.4%) cups. Harris hip score (HHS) was used and statistical outcome measures were calculated with revision as an endpoint for aseptic loosening of the stem, aseptic loosening of any component, all-cause revision of the stem, and all-cause revision of the hip., Results: A total of 103 patients died and 129 (14.4%) operated hips were lost to follow-up before ten years. Out of the 662, ten stems (1.5%) were revised for aseptic loosening. Aseptic loosening of any component was the reason for revision in 43 cases (6.5%), consisting of 40 cup revisions and ten stem exchanges. Periprosthetic fracture occurred in 17 cases (1.9%) Periprosthetic joint infection occurred in 18 cases (2.01%). Three cups were exchanged for recurrent dislocation, and two stems had broken., Conclusion: Exeter hip system has provided reproducible results across different centres worldwide, as it did in our series. Thorough surgical and cementing technique is of utmost importance for achieving these results. The cup is the weak point of the system and use of a hybrid system is worth considering., (© 2023. The Author(s) under exclusive licence to SICOT aisbl.)

Background: Postpartum hemorrhage (PPH) is the leading cause of maternal death worldwide. The World Maternal Antifibrinolytic trial showed that antifibrinolytic tranexamic acid (TXA) reduces PPH deaths. Maternal anemia increases the risk of PPH. The World Maternal Antifibrinolytic-2 trial is now assessing whether TXA can prevent PPH in women with anemia. Low red blood cell (RBC) counts promote fibrinolysis by altering fibrin structure and plasminogen activation., Objectives: We explored interactions between RBCs and TXA in inhibiting fibrinolysis., Methods: We used global fibrinolytic assays (ball sedimentation and viscoelasticity) to monitor the lysis of fibrin containing plasminogen and tissue-type plasminogen activator. We applied a fluorogenic kinetic assay to measure plasmin generation in fibrin clots and scanning electron microscopy to study fibrin structure., Results: According to parallel-line bioassay analysis of the fibrin lysis-time data, the antifibrinolytic potency of 4-128 μM TXA was increased in the presence of 10% to 40% (v/v) RBCs. Global fibrinolysis assays showed that the joint effect of RBCs and TXA was about 15% larger than the sum of their individual effects in the inhibition of fibrinolysis. In plasminogen activation, TXA added the same increment of inhibition to the effect of RBCs at any cell count in the fibrin clot. Regarding fibrin structure, TXA thickened fibrin fibers, which impaired plasminogen activation, whereas RBCs promoted fine fibers that were more resistant to plasmin., Conclusions: The antifibrinolytic potency of TXA is enhanced in fibrin formed in the presence of RBCs through inhibition of plasminogen activation and fibrin lysis, which correlates with modifications of fibrin structures., Competing Interests: Declaration of competing interests There are no competing interests to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Highly efficient adsorbents are needed to remove uremic toxins and reduce the economic and societal burden of the current dialysis treatments in resource-limited environments. In this study, nanostructured porous carbon nanofibers with nitrogen-doped zeolites (NZ-PCNF) were prepared, by electrospinning zeolites with chitosan-poly(ethylene oxide) blends, followed by a one-step carbonization process, without further activation steps or aggressive chemical additives for N-doping. The results showed that N-zeolites were successfully integrated into an ultrafine carbon nanofiber network, with a uniform nanofiber diameter of approximately 25 nm, hierarchical porous structure (micro- and mesopores), and high specific surface area (639.29 m 2 /g), facilitating uremic toxin diffusion and adsorption. The self-N-doped structure in the NZ-PCNF removed more creatinine (∼1.8 times) than the porous carbon nanofibers when using the same weight of precursor materials. Cytotoxicity and hemolysis tests were performed to verify the safety of NZ-PCNF. This study provides a novel strategy for transforming chitosan-based materials into state-of-the-art porous carbon nanofiber/zeolite self-N-doped composites, affording an efficient bioderived adsorbent for the removal of uremic toxins in patients with chronic kidney disease., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The pronounced growth in livestock populations since the 1950s has altered the epidemiological and evolutionary trajectory of their associated pathogens. For example, Marek's disease virus (MDV), which causes lymphoid tumors in chickens, has experienced a marked increase in virulence over the past century. Today, MDV infections kill >90% of unvaccinated birds, and controlling it costs more than US$1 billion annually. By sequencing MDV genomes derived from archeological chickens, we demonstrate that it has been circulating for at least 1000 years. We functionally tested the Meq oncogene, one of 49 viral genes positively selected in modern strains, demonstrating that ancient MDV was likely incapable of driving tumor formation. Our results demonstrate the power of ancient DNA approaches to trace the molecular basis of virulence in economically relevant pathogens.

The golden jackal (Canis aureus) is a reoccurring species in the centre of the Carpathian basin, in Hungary. In total, 31 golden jackal tissue samples were collected, from 8 white-coated, 2 black-coated and one mottled animal across Hungary. Sequences and fragment length polymorphisms were studied for white colour (MC1R), and for black coat colouration (CBD103). In each white animal, the most widespread mutation causing white fur colour in dogs in homozygous form was detected. Three animals were found to carry the mutation in heterozygous form. The two black golden jackals were heterozygous for the 3 bp deletion in CBD103 that mutation for black coat colouration in dogs, and one of them also carried the mutation causing white fur. None of the white animals showed signs of hybridization, but both the black and the mottled coloured individuals were found to be hybrids based on genetic testing. Kinship was found three times, twice between white animals, and once between a white animal and an agouti animal carrying the mutation of white coat. Our results confirm the findings that golden jackal-dog hybrids may occur without human intervention, and the detected mutation causing white fur colour in golden jackals could possibly be due to an early hybridization event., (© 2023. The Author(s).)

Tuberculosis (TB) has long been a major scourge of humankind. Paleopathological and paleomicrobiological studies have revealed the past presence of the disease on a large spatial and temporal scale. The antiquity of the disease has extensively been studied in the Carpathian Basin, given its dynamic population and cultural changes since prehistory. These studies, however, have mainly focused on the populations living during the Common Era. The aim of this paper is to present the published and the recently discovered cases of prehistoric TB, from the Neolithic (6000-4500/4400 BCE) to the Bronze Age (2600/2500-800 BCE) Central Carpathian Basin (Hungary). We summarize 18 published cases and present new cases dating to the Neolithic period and introduce 3 newly discovered Bronze Age cases of TB. Despite extensive research, TB has not yet been identified from the Copper and Iron Ages in the Carpathian Basin. Considering the state of TB research, and supplemented by our prehistoric dataset, the spatio-temporal pattern of the disease can be further elucidated, thus advancing future molecular and paleopathological studies. Our dataset offers comprehensive spatial and temporal information on the spread of the disease in the Carpathian Basin, along with a detailed biological profile of the demonstrated cases and extensive paleopathological descriptions of the observed lesions, complemented by photographic evidence. This invaluable resource paves the way for enhanced understanding and progress in the field., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Ltd.)

Stimulation of thermogenesis by inducing uncoupling protein 1 (UCP1) expression in adipocytes is thought to promote weight loss by increasing energy expenditure, and it is postulated that the human newborn has thermogenic subcutaneous fat depots. However, it remains unclear whether a relevant number of UCP1-expressing (UCP1 + ) adipocytes exist in the early postnatal life. Here we studied the distribution of UCP1 and the expression of thermogenic genes in the subcutaneous adipose tissues of the human fetus, infant and child. We show that the deep layer of human fetal and neonatal subcutaneous fat, particularly the abdominal wall, is rich in UCP1 + adipocytes. These adipocytes develop in the late third trimester and persist throughout childhood, expressing a panel of genes linked to mitochondrial biogenesis and thermogenesis. During the early childhood adiposity rebound-a critical phase that determines obesity risk later in life-the absence of adipose tissue UCP1 expression in children with normal body mass index (BMI) correlates with an obesity-associated gene expression signature. Finally, UCP1 expression is negatively correlated with BMI z -score and adipocyte size in infants and children. Overall, our results show that the absence of UCP1 expression in adipose tissue is an early indicator of adipose tissue expansion in children.

Small lowland watercourses, strongly exposed to anthropogenic activities and climate change, have received negligible odonatological attention. This study provides a revised checklist of three typical lowland small watercourses (Kállai-főfolyás, Konyári-Kálló and Ölyvös) within the Pannonian Lowland and presents the changes in their diversity over the past decades. Results revealed a significant biodiversity loss, with a 31.6% decline in Odonata fauna over the last 53 years. The upper and middle sections degraded the most, where the habitats have dried out or become intermittent. However, a diverse Odonata assemblage (1,277 individuals of 27 species) was observed at the 14 sampling sites of the three watercourses, containing protected and sensitive species ( Somatochloraflavomaculata , Orthetrumbrunneum , Aeshnaisoceles , Libellulafulva ). However, the low abundance of larval and exuvial forms (59 individuals of 13 species) suggests that the majority of the observed adults were developed in other watercourses. While recolonisation from nearby habitats is still possible, a parallel degradation of adjecent waterbodies could lead to an irreversible biodiversity loss., Competing Interests: No conflict of interest to declare Disclaimer: This article is (co-)authored by any of the Editors-in-Chief, Managing Editors or their deputies in this journal., (Kálmán Szanyi, István Grigorszky, László J Szabó, György Dévai.)

Background: Staged laparoscopic traction orchiopexy (SLTO) is a novel technique for the intra-abdominal testis (IAT) based on elongation of the testicular vessels without separating them. This multicenter study evaluated the medium-term results of this technique., Methods: Data of SLTO performed in three pediatric surgical centers between 2013 and 2020 were analyzed retrospectively. In 2021, physical and Doppler ultrasound examinations were performed to determine the position and viability of testes. Success was defined as an intra-scrotal testicle without atrophy., Results: SLTO was performed on 48 cases (55 testes, 7 bilateral). Mean age at first stage was 2.9 (0.8-12.6) years. High intra-abdominal testes were found in 16.4% and in 60% morphological abnormalities were observed. To fix the testes to the abdominal wall monofilament suture was used in 67.3%, braided in 29.1%. Mean time between the two stages was 16.4 weeks; three testes required redo traction. Perioperative complications occurred in 21 patients (38.2%) including insufficient fixation (11), testicular atrophy (4), wound complications (4), adhesion of the spermatic cords (1) and hydrocele (1). In case of insufficient fixation monofilament sutures were used in 90.9%. In 2021 38 patients (43 testes) had physical and 36 patients (41 testes) had ultrasound examinations. Mean follow-up was 2.7 (0.34-7.9) years. Altogether five atrophies were identified, and three testicular ascents (7.0%) occurred. The overall success rate was 82.2%., Conclusions: SLTO may be a feasible alternative to conventional treatments of IATs. Additionally, braided suture seems to be a better option to fix the testicle to the abdominal wall., Level of Evidence: LEVEL IV., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Innate immune signaling in adipocytes affects systemic metabolism. Cytosolic nucleic acid sensing has been recently shown to stimulate thermogenic adipocyte differentiation and protect from obesity; however, DNA efflux from adipocyte mitochondria is a potential proinflammatory signal that causes adipose tissue dysfunction and insulin resistance. Cytosolic DNA activates the stimulator of interferon response genes (STING), a key signal transducer which triggers type I interferon (IFN-I) expression; hence, STING activation is expected to induce IFN-I response and adipocyte dysfunction. However, we show herein that mouse adipocytes had a diminished IFN-I response to STING stimulation by 2'3'-cyclic-GMP-AMP (cGAMP). We also show that cGAMP triggered autophagy in murine and human adipocytes. In turn, STING inhibition reduced autophagosome number, compromised the mitochondrial network and caused inflammation and fat accumulation in adipocytes. STING hence stimulates a process that removes damaged mitochondria, thereby protecting adipocytes from an excessive IFN-I response to mitochondrial DNA efflux. In summary, STING appears to limit inflammation in adipocytes by promoting mitophagy under non-obesogenic conditions.

Septins are considered the fourth component of the cytoskeleton with the septin7 isoform playing a critical role in the formation of diffusion barriers in phospholipid bilayers and intra- and extracellular scaffolds. While its importance has already been confirmed in different intracellular processes, very little is known about its role in skeletal muscle. Muscle regeneration was studied in a Sept7 conditional knock-down mouse model to prove the possible role of septin7 in this process. Sterile inflammation in skeletal muscle was induced which was followed by regeneration resulting in the upregulation of septin7 expression. Partial knock-down of Sept7 resulted in an increased number of inflammatory cells and myofibers containing central nuclei. Taken together, our data suggest that partial knock-down of Sept7 hinders the kinetics of muscle regeneration, indicating its crucial role in skeletal muscle functions.

Background: Staphylocoagulase (SCG) is a virulence factor of Staphylococcus aureus , one of the most lethal pathogens of our times. The complex of SCG with prothrombin (SCG/ProT) can clot fibrinogen, and SCG/ProT-induced fibrin and plasma clots have been described to show decreased mechanical and lytic resistance, which may contribute to septic emboli from infected cardiac vegetations. At infection sites, neutrophils can release DNA and histones, as parts of neutrophil extracellular traps (NETs), which in turn favor thrombosis, inhibit fibrinolysis and strengthen clot structure., Objectives: To characterize the combined effects of major NET-components (DNA, histone H1 and H3) on SCG/ProT-induced clot structure, mechanical and lytic stability., Methods: Recombinant SCG was used to clot purified fibrinogen and plasma. The kinetics of formation and lysis of fibrin and plasma clots containing H1 or core histones+/-DNA were followed by turbidimetry. Fibrin structure and mechanical stability were characterized with scanning electron microscopy, pressure-driven permeation, and oscillation rheometry., Results: Histones and DNA favored the formation of thicker fibrin fibers and a more heterogeneous clot structure including high porosity with H1 histone, whereas low porosity with core histones and DNA. As opposed to previous observations with thrombin-induced clots, SCG/ProT-induced fibrin was not mechanically stabilized by histones. Similarly to thrombin-induced clots, the DNA-histone complexes prolonged fibrinolysis with tissue-type plasminogen activator (up to 2-fold). The anti-fibrinolytic effect of the DNA and DNA-H3 complex was observed in plasma clots too. Heparin (low molecular weight) accelerated the lysis of SCG/ProT-clots from plasma, even if DNA and histones were also present., Conclusions: In the interplay of NETs and fibrin formed by SCG, DNA and histones promote structural heterogeneity in the clots, and fail to stabilize them against mechanical stress. The DNA-histone complexes render the SCG-fibrin more resistant to lysis and thereby less prone to embolization., 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 Komorowicz, Farkas, Szabó, Cherrington, Thelwell and Kolev.)

Septin7 as a unique member of the GTP binding protein family, is widely expressed in the eukaryotic cells and considered to be essential in the formation of hetero-oligomeric septin complexes. As a cytoskeletal component, Septin7 is involved in many important cellular processes. However, its contribution in striated muscle physiology is poorly described. In skeletal muscle, a highly orchestrated process of migration is crucial in the development of functional fibers and in regeneration. Here, we describe the pronounced appearance of Septin7 filaments and a continuous change of Septin7 protein architecture during the migration of myogenic cells. In Septin7 knockdown C2C12 cultures, the basic parameters of migration are significantly different, and the intracellular calcium concentration change in migrating cells are lower compared to that of scrambled cultures. Using a plant cytokinin, forchlorfenuron, to dampen septin dynamics, the altered behavior of the migrating cells is described, where Septin7-depleted cells are more resistant to the treatment. These results indicate the functional relevance of Septin7 in the migration of myoblasts, implying its contribution to muscle myogenesis and regeneration.

Recently, the field of epigenetics has been intensively studied in relation to nutrition. In our study, the gene expression patterns of histone deacetylases ( HDAC s), which regulate the stability of histone proteins, and DNA methyltransferases ( DNMT s), which regulate DNA methylation, were determined in mice. The animals were fed a human-equivalent dose of the aqueous extract of fruit seeds and peels, which is rich in flavonoids and polyphenols, for 28 days and then exposed to the carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). The concentrations of trans-resveratrol and trans-piceid were determined in the consumed extract by HPLC and were 1.74 mg/L (SD 0.13 mg/L) and 2.37 mg/L (SD 0.32 mg/L), respectively, which corresponds to the consumption of 0.2-1 L of red wine, the main dietary source of resveratrol, in humans daily. Subsequently, 24 h after DMBA exposure, the expression patterns of the HDAC and DNMT genes in the liver and kidneys were determined by qRT-PCR. The DMBA-induced expression of the tested genes HDAC1 , HDAC2 , DNMT1 , DNMT3A and DNMT3B was reduced in most cases by the extract. It has already been shown that inhibition of the DNMT and HDAC genes may delay cancer development and tumour progression. We hypothesise that the extract studied may exert chemopreventive effects.

Since the recent discovery of the mechanosensitive Piezo1 channels, many studies have addressed the role of the channel in various physiological or even pathological processes of different organs. Although the number of studies on their effects on the musculoskeletal system is constantly increasing, we are still far from a precise understanding. In this review, the knowledge available so far regarding the musculoskeletal system is summarized, reviewing the results achieved in the field of skeletal muscles, bones, joints and cartilage, tendons and ligaments, as well as intervertebral discs.

The early, appropriate management of acute onset dyspnea is important but often challenging. The aim of this study was to investigate the effects of the use of Point-of-Care Ultrasound (PoCUS) versus conventional management on clinical outcomes in patients with acute onset dyspnea. The Cochrane Library, MEDLINE, EMBASE and reference lists were searched to identify eligible trials (inception to October 14, 2021). There were no language restrictions. Randomized controlled trials (RCTs), and prospective and retrospective cohort studies that compared PoCUS with conventional diagnostic modalities (controls) in patients with acute onset dyspnea were included. Two independent reviewers extracted data and assessed the risk of bias. Disagreements were resolved by consensus. The primary study outcomes were time to diagnosis, time to treatment, and length of stay (LOS). Secondary outcomes included rate of appropriate treatment, 30-day re-admission rate, and mortality. We included eight RCTs and six observational studies with a total of 5393 participants. Heterogeneity across studies was variable (from low to considerable), with overall low or moderate study quality and low or moderate risk of bias (except one article with serious risk of bias). Time to diagnosis (mean difference [MD], - 63 min; 95% CI, - 115 to - 11 min] and time to treatment (MD, - 27 min; 95% CI - 43 to - 11 min) were significantly shorter in the PoCUS group. In-hospital LOS showed no differences between the two groups, but LOS in the Intensive Care Unit (MD, - 1.27 days; - 1.94 to - 0.61 days) was significantly shorter in the PoCUS group. Patients in the PoCUS group showed significantly higher odds of receiving appropriate therapy compared to controls (odds ratio [OR], 2.31; 95% CI, 1.61-3.32), but there was no significant effect on 30-day re-admission rate and in-hospital or 30-day mortality. Our results indicate that PoCUS use contributes to early diagnosis and better outcomes compared to conventional methods in patients admitted with acute onset dyspnea., (© 2022. The Author(s).)

Aims: To establish normal reference values of urine flow acceleration (Q acc ) in healthy children, as there is a lack of nomograms for normative reference values of Q acc by voided volumes in the pediatric population so far. Q acc might be an early indicator of autonomic neuropathy in children and adolescents., Methods: Data were retrospectively collected from healthy children who underwent uroflowmetry between 1990 and 1992. Exclusion criteria were voided volume less than 20 ml, and postvoid residual more than 15%. Baseline characteristics and uroflowmetry parameters were collected from girls and boys aged between 6 and 18 years. Voided volume, voiding time, time to maximum flow rate, and maximum and average flow rates of urine were measured, and Q acc was calculated. Postvoid bladder diameter was measured by ultrasonography and converted to volume., Results: Uroflowmetry parameters of 208 children (≤18 years old, 45.2% girls, mean age 9.68 ± 3.09 years) who performed 404 micturition were analyzed. Median voided volume, voiding time, time to Q max , Q ave , Q max , Q acc , and postvoid residual volume were 130 [20-460] ml, 10 [3-56] s, 3 [1-14] s, 11.7 [2.5-36.6] ml/s, 20.5 [5-50] ml/s, 6 [0.81-25] ml/s 2 , and 1.83 [0-38.62] ml, respectively. Q acc nomograms were given in centile forms for girls and boys separately, which show an inversely proportional correlation between voided volumes., Conclusions: These are the first nomograms for normative reference values of Q acc in the pediatric population (girls and boys separately) by voided volumes in centile forms. These may be useful to interpret abnormal Q acc values and diagnose lower urinary tract diseases over a wide range of voided volumes., (© 2022 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

The endocannabinoid system (ECS) refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Cannabinoid receptors (CBRs) are highly expressed in the central nervous system and many peripheral tissues. Evidence suggests that CB1Rs are expressed in human and murine skeletal muscle mainly in the cell membrane, but a subpopulation is present also in the mitochondria. However, very little is known about the latter population. To date, the connection between the function of CB1Rs and the regulation of intracellular Ca 2+ signaling has not been investigated yet. Tamoxifen-inducible skeletal muscle-specific conditional CB1 knock-down (skmCB1-KD, hereafter referred to as Cre +/- ) mice were used in this study for functional and morphological analysis. After confirming CB1R down-regulation on the mRNA and protein level, we performed in vitro muscle force measurements and found that peak twitch, tetanus, and fatigue were decreased significantly in Cre +/- mice. Resting intracellular calcium concentration, voltage dependence of the calcium transients as well as the activity dependent mitochondrial calcium uptake were essentially unaltered by Cnr1 gene manipulation. Nevertheless, we found striking differences in the ultrastructural architecture of the mitochondrial network of muscle tissue from the Cre +/- mice. Our results suggest a role of CB1Rs in maintaining physiological muscle function and morphology. Targeting ECS could be a potential tool in certain diseases, including muscular dystrophies where increased endocannabinoid levels have already been described.

Childhood obesity is a serious public health crisis and a critical factor that determines future obesity prevalence. Signals affecting adipocyte development in early postnatal life have a strong potential to trigger childhood obesity; however, these signals are still poorly understood. We show here that mitochondrial (mt)RNA efflux stimulates transcription of nuclear-encoded genes for mitobiogenesis and thermogenesis in adipocytes of young mice and human infants. While cytosolic mtRNA is a potential trigger of the interferon (IFN) response, young adipocytes lack such a response to cytosolic mtRNA due to the suppression of IFN regulatory factor (IRF)7 expression by vitamin D receptor signalling. Adult and obese adipocytes, however, strongly express IRF7 and mount an IFN response to cytosolic mtRNA. In turn, suppressing IRF7 expression in adult adipocytes restores mtRNA-induced mitobiogenesis and thermogenesis and eventually mitigates obesity. Retrograde mitochondrion-to-nucleus signalling by mtRNA is thus a mechanism to evoke thermogenic potential during early adipocyte development and to protect against obesity., (© 2022. The Author(s).)

Background: Fibrin, the main scaffold of thrombi, is susceptible to citrullination by PAD (peptidyl arginine deiminase) 4, secreted from neutrophils during the formation of neutrophil extracellular traps. Citrullinated fibrinogen (citFg) has been detected in human plasma as well as in murine venous thrombi, and it decreases the lysability and mechanical resistance of fibrin clots., Objective: To investigate the effect of fibrinogen citrullination on the structure of fibrin clots., Methods: Fibrinogen was citrullinated with PAD4 and clotted with thrombin. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) were used to measure fiber thickness, fiber height/width ratio, and fiber persistence length in clots containing citFg. Fiber density was measured with laser scanning microscopy (LSM) and permeability measurements were carried out to estimate the porosity of the clots. The intra-fiber structure of fibrin was analyzed with small-angle X-ray scattering (SAXS)., Results: SEM images revealed a decrease in the median fiber diameter that correlated with the fraction of citFg in the clot, while the fiber width/length ratio remained unchanged according to AFM. With SAXS we observed that citrullination resulted in the formation of denser clots in line with increased fiber density shown by LSM. The permeability constant of citrullinated fibrin decreased more than 3-fold indicating significantly decreased porosity. SAXS also showed largely preserved periodicity in the longitudinal assembly of fibrin monomers., Conclusion: The current observations of thin fibers combined with dense packing and low porosity in the presence of citFg can provide a structural framework for the mechanical fragility and lytic resistance of citrullinated fibrin., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Introduction: Bladder emptying abnormalities and cardiovascular autonomic dysfunction are manifestations of autonomic dysfunction in people with diabetes mellitus (DM), which are major causes of morbidity and mortality. Since they can reduce the quality of life, they are urgent to be addressed before resulting in complications. As uroflowmetry might determine autonomic neuropathy earlier than cardiovascular autonomic dysfunction symptoms occur, our aim is to detect early abnormalities in bladder muscle function in children with DM. We investigate the diagnostic accuracy of uroflowmetry. As a secondary aim, we compare the prevalence of uroflowmetry abnormalities to the appearance of measures of cardiovascular autonomic neuropathy. Finally, as an ancillary study, we examine the association of uroflowmetry with the appearance of peripheral neuropathy. These three aims, we feel, will put our results regarding uroflowmetry into an overall context of nerve disease early in the course of type 1 DM. To our knowledge, such an approach has heretofore not been performed., Methods and Analysis: This will be a prospective, observational, single-centre clinical study. Patients with DM fulfilling the inclusion criteria and healthy controls will have uroflowmetry examination, cardiovascular autonomic dysfunction tests (heart rate response to deep breathing, to Valsalva manoeuvre, blood pressure and heart rate response to standing up, and to sustained handgrip) and nerve conduction test. The autonomic nervous system function will be examined by the reproducible and standardised cardiovascular reflex tests described by Ewing et al . During the examination, electrocardiogram (ECG) and blood pressure values will be recorded continuously. Heart rate response to deep inspiration will be executed to investigate the parasympathetic nervous system. Peripheral neuropathy will be evaluated by nerve conduction test. After a pilot period, when the first 50 diabetic and 50 healthy children will be assessed, sample size calculation will be carried out. The primary objective of this trial is to evaluate the diagnostic accuracy (sensitivity, specificity, positive and negative predictive value) of uroflowmetry. To do so, we compare uroflowmetry to the gold standard neuropathy tests, which are cardiovascular autonomic dysfunction tests (heart rate response to deep breathing, to Valsalva manoeuvre, blood pressure and heart rate response to standing up and to sustained handgrip)., Ethics and Dissemination: Ethics approval was obtained from the Scientific and Research Ethics Committee of the Heim Pál National Paediatric Institute in Budapest, Hungary (registration number KUT-37/2021). Results will be submitted for publication in a peer-reviewed journal., Trial Registration Number: NCT05247840., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Vascular calcification (VC) is associated with a number of cardiovascular diseases, as well as chronic kidney disease. The role of smooth muscle cells (SMC) has already been widely explored in VC, as has the role of intracellular Ca 2+ in regulating SMC function. Increased intracellular calcium concentration ([Ca 2+ ] i ) in vascular SMC has been proposed to stimulate VC. However, the contribution of the non-selective Piezo1 mechanosensitive cation channels to the elevation of [Ca 2+ ] i , and consequently to the process of VC has never been examined. In this work the essential contribution of Piezo1 channels to arterial medial calcification is demonstrated. The presence of Piezo1 was proved on human aortic smooth muscle samples using immunohistochemistry. Quantitative PCR and Western blot analysis confirmed the expression of the channel on the human aortic smooth muscle cell line (HAoSMC). Functional measurements were done on HAoSMC under control and calcifying condition. Calcification was induced by supplementing the growth medium with inorganic phosphate (1.5 mmol/L, pH 7.4) and calcium (CaCl 2 , 0.6 mmol/L) for 7 days. Measurement of [Ca 2+ ] i using fluorescent Fura-2 dye upon stimulation of Piezo1 channels (either by hypoosmolarity, or Yoda1) demonstrated significantly higher calcium transients in calcified as compared to control HAoSMCs. The expression of mechanosensitive Piezo1 channel is augmented in calcified arterial SMCs leading to a higher calcium influx upon stimulation. Activation of the channel by Yoda1 (10 μmol/L) enhanced calcification of HAoSMCs, while Dooku1, which antagonizes the effect of Yoda1, reduced this amplification. Application of Dooku1 alone inhibited the calcification. Knockdown of Piezo1 by siRNA suppressed the calcification evoked by Yoda1 under calcifying conditions. Our results demonstrate the pivotal role of Piezo1 channels in arterial medial calcification., (Copyright © 2022 Szabó, Balogh, Tóth, Angyal, Gönczi, Csiki, Tóth, Balatoni, Jeney, Csernoch and Dienes.)

The mechanical and rheological characterizations of flexible investment casting patterns capable of 3D printing are reported. The wax pattern was composed of microcrystalline hydrocarbon wax (DMW7478), Piccotex 75 (a copolymer of α-methyl-styrene and vinyl toluene with a 75/25 molar ratio, respectively) and Escorene (a copolymer of ethylene and vinyl acetate with a 72/28 mass ratio, respectively). It was found that in order to obtain a wax pattern with appreciable mechanical properties, the content of the microcrystalline hydrocarbon wax in these blends should not exceed 30% (m/m). Thus, a series of patterns with 28% (m/m) wax and varying Piccotex and Escorene contents spanning from 0 to 72% (m/m) was prepared. The dependence of the dynamic viscosities of the wax patterns on the composition was described using a stretched exponential model, whereas their variations with the temperature were interpreted in terms of the Arrhenius-Guzman equation. Furthermore, the slopes of the lines fitted to the viscosity versus temperature curves at the pour point decreased linearly with the Piccotex content. Non-Newtonian changes in the shear stress with the shear rate and shear stress crystallization were observed at temperatures near the pour points. The mechanical properties were evaluated using the uniaxial tensile mode and by three-point bending experiments. It was found that the stress (σ) versus the relative elongation (ε) curves can effectively be rendered by means of the standard linear solid (SLS) viscoelastic model. In addition, it was also established that the Young's modulus varied according to a sigmoid-type curve with the piccotex content, while the yield stress decreased linearly with the concentration of Piccotex. In addition, based on the spooling suitability and printability, the patterns were rated and it was found that the most appropriate wax pattern compositions for 3D printing were those which contained 30% (m/m) and 35% (m/m) Piccotex.

Introduction: Hypercoagulation is one the main features of COVID-19. It is induced by the hyperinflammatory response that shifts the balance of haemostasis towards pro-coagulation. Interleukin-6 (IL-6) antagonist therapy has been recommended in certain subgroups of critically ill patients with COVID-19 to modulate inflammatory response. The interaction between immune response and haemostasis is well recognised. Therefore, our objective is to evaluate whether the modulation of the inflammatory response by IL-6 antagonist inflicts any changes in whole blood coagulation as assessed by viscoelastic methods in critically ill patients with COVID-19., Methods and Analysis: In this prospective observational study, we are going to collect data on inflammatory parameters and blood coagulation using the ClotPro ® device. The primary outcome is the change of the fibrinolytic system measured by the Lysis Time and Lysis onset time before and after immunomodulation therapy. Data will be collected before the IL-6 antagonist administration at baseline (T 0 ) then after 24, 48 hours, then on day 5 and 7 (T 1-4 , respectively). Secondary outcomes include changes in other parameters related to inflammation, blood coagulation and biomarkers of endothelial injury., Ethics and Dissemination: Ethical approval was given by the Medical Research Council of Hungary (1405-3/2022/EÜG). All participants provided written consent. The results of the study will be disseminated through peer-reviewed journals., Trial Registration Number: NCT05218369; Clinicaltrials.gov., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The use of fibrinolytic therapy has been proposed in severe acute respiratory distress syndrome (ARDS). During the COVID-19 pandemic, anticoagulation has received special attention due to the frequent findings of microthrombi and fibrin deposits in the lungs and other organs. Therefore, the use of fibrinolysis has been regarded as a potential rescue therapy in these patients. In this prospective meta-analysis, we plan to synthesise evidence from ongoing clinical trials and thus assess whether fibrinolytic therapy can improve the ventilation/perfusion ratio in patients with severe COVID-19-caused ARDS as compared with standard of care., Methods and Analysis: This protocol was registered in PROSPERO. All randomised controlled trials and prospective observational trials that compare fibrinolytic therapy with standard of care in adult patients with COVID-19 and define their primary or secondary outcome as improvement in oxygenation and/or gas exchange, or mortality will be considered eligible. Safety outcomes will include bleeding event rate and requirement for transfusion. Our search on 25 January 2022 identified five eligible ongoing clinical trials. A formal search of MEDLINE (via PubMed), Embase, CENTRAL will be performed every month to identify published results and to search for further trials that meet our eligibility criteria., Dissemination: This could be the first qualitative and quantitative synthesis summarising evidence of the efficacy and safety of fibrinolytic therapy in critically ill patients with COVID-19. We plan to publish our results in peer-reviewed journals., Prospero Registration Number: CRD42021285281., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Nutritional interventions may highly contribute to the maintenance or restoration of human health. Grapes ( Vitis vinifera ) are one of the oldest known beneficial nutritional components of the human diet. Their high polyphenol content has been proven to enhance human health beyond doubt in statistics-based public health studies, especially in the prevention of cardiovascular disease and cancer. The current review concentrates on presenting and classifying polyphenol bioactive molecules (resveratrol, quercetin, catechin/epicatechin, etc.) available in high quantities in Vitis vinifera grapes or their byproducts. The molecular pathways and cellular signaling cascades involved in the effects of these polyphenol molecules are also presented in this review, which summarizes currently available in vitro and in vivo experimental literature data on their biological activities mostly in easily accessible tabular form. New molecules for different therapeutic purposes can also be synthesized based on existing polyphenol compound classes available in high quantities in grape, wine, and grape marc. Therefore an overview of these molecular structures is provided. Novel possibilities as dendrimer nanobioconjugates are reviewed, too. Currently available in vitro and in vivo experimental literature data on polyphenol biological activities are presented in easily accessible tabular form. The scope of the review details the antidiabetic, anticarcinogenic, antiviral, vasoprotective, and neuroprotective roles of grape-origin flavonoids. The novelty of the study lies in the description of the processing of agricultural by-products (grape seeds and skins) of industrial relevance, and the detailed description of the molecular mechanisms of action. In addition, the review of the clinical therapeutic applications of polyphenols is unique as no summary study has yet been done.

Implementation of higher dose (HD) thromboprophylaxis has been considered in patients infected with coronavirus disease 2019 (COVID-19). Our aim was to compare HD to standard dose (SD) thromboprophylaxis in COVID-19 patients. The protocol is registered on PROSPERO (CRD42021284808). We searched for randomised controlled studies (CENTRAL, Embase, Medline and medRxviv) that compared HD to SD anticoagulation in COVID-19 and analysed outcomes such as mortality, thrombotic events, bleedings, and disease progression. The statistical analyses were made using the random effects model. Fourteen articles were included (6253 patients). HD compared with SD showed no difference in mortality (OR 0.83 [95% CI 0.54−1.28]). The use of HD was associated with a decreased risk of thrombosis (OR 0.58 [95% CI 0.44−0.76]), although with an increased risk of major bleeding (OR 1.64 [95% CI 1.25−2.16]). The cohort with D-dimer < 1 mg/mL showed no effect (OR 1.19 [95% CI 0.67−2.11]), but in the case of D-dimer > 1 mg/mL, a tendency of lower risk in the HD group was observed (OR 0.56 [95% CI 0.31−1.00]). The need for intubation in moderately ill patients showed a nonsignificant lower likelihood in the HD group (OR 0.82 [95% CI 0.63−1.08]). We cannot advocate for HD in all COVID-19 patients, although it shows some nonsignificant benefits on disease progression in those with elevated D-dimer who do not need ICU admission., Competing Interests: The authors declare no conflict of interest.

Ocular surface squamous neoplasia (OSSN) has different treatment modalities. Although surgical excision has been the gold standard therapeutic option, topical pharmacotherapy agents such as 5-fluorouracil (5-FU), interferon alfa-2b (IFN) and mitomycin-C (MMC) are also commonly used. The protocol was registered (CRD42021224961). Comprehensive literature research was carried out to compare topical pharmacotherapy (5-FU or IFN or MMC) to surgical excision regarding clinical success (tumor resolution), recurrence and complications in patients undergoing treatment for OSSN. From 7859 records, 7 articles were included in the qualitative and 4 in the quantitative synthesis. The outcomes of surgical excision and topical pharmacotherapy were comparable in the included articles. There were no significant differences between surgical excision and topical pharmacotherapy regarding the clinical success [odds ratio (OR): 0.785; confidence interval (CI): 0.130-4.736, P = 0.792)] and tumor recurrence (OR: 0.746; CI: 0.213-2.609; P = 0.646). The most common side effect of the different therapeutic options was dry eye. The highest rate of dry eye symptoms was reported after surgical excision (in 59%). Topical pharmacotherapy with all the 3 agents is as effective and well-tolerable as surgical excision in terms of tumor resolution, recurrence rate and side effects in all OSSN patients suggesting similar long-term clinical benefits., (© 2022. The Author(s).)

Today septins are considered as the fourth component of the cytoskeleton, with the Septin7 isoform playing a critical role in the formation of higher-order structures. While its importance has already been confirmed in several intracellular processes of different organs, very little is known about its role in skeletal muscle. Here, using Septin7 conditional knockdown (KD) mouse model, the C2C12 cell line, and enzymatically isolated adult muscle fibers, the organization and localization of septin filaments are revealed, and an ontogenesis-dependent expression of Septin7 is demonstrated. KD mice displayed a characteristic hunchback phenotype with skeletal deformities, reduction in in vivo and in vitro force generation, and disorganized mitochondrial networks. Furthermore, knockout of Septin7 in C2C12 cells resulted in complete loss of cell division while KD cells provided evidence that Septin7 is essential for proper myotube differentiation. These and the transient increase in Septin7 expression following muscle injury suggest that it may be involved in muscle regeneration and development., Competing Interests: MG, ZR, LS, JF, AT, ND, NB, PS, GK, MA, GT, BD, LC No competing interests declared, (© 2022, Gönczi et al.)

BACKGROUND Urodynamics can detect subtle voiding changes before cystopathy symptoms manifest. The aim of the present study was to assess urodynamic changes in diabetic women. MATERIAL AND METHODS A systematic search was performed on 04 November 2021 to identify studies reporting urodynamic parameters in diabetic women. Data were analyzed in a single-arm meta-analysis due to lack of sufficient studies with direct comparisons to healthy women. For data synthesis, a random-effects model with restricted maximum-likelihood estimation was applied. The calculated effect sizes were visualized in forest plots. Statistical heterogeneity was assessed using the I² measure and the χ² test. The risk of bias was assessed using the QUIPS tool. PROSPERO ID: CRD42021256275. RESULTS Out of 1750 records, 10 studies were used in the analysis (n=2342 diabetic women). Pooled event rates showed that mean voided volume was 288.21 mL [95% confidence interval (CI): 217.35-359.06, I²=98%], mean postvoid residual volume was 93.67 mL [95% CI: 31.35-155.99, I²=100%], mean Qmax was 18.80 mL/sec [95% CI: 15.27-22.33, I²=99%], mean PdetQmax is 30.13 cmH2O [95% CI: 25.53-34.73, I²=90%], mean first sensation of bladder filling was 178.66 mL [95% CI: 150.59-206.72, I²=97%], and mean cystometric capacity was 480.41 mL [95% CI: 409.32-551.50, I²=98%] in diabetic women. CONCLUSIONS Pooled results indicate that diabetic women tend to have a smaller voided volume, slower Qmax and PdetQmax, larger postvoid residual, and higher first sensation of bladder filling and cystometric capacity compared to the general female population.

Objective: To assess the connection of postpartum sexual dysfunction with mode of delivery, amenorrhea, depressive symptoms, and relationship satisfaction., Methods: For a prospective longitudinal study, we invited 729 Hungarian obstetrics patients to complete questionnaires at 3 months (T1), 6 months (T2), and 12 months (T3) postpartum. We sent them the Female Sexual Function Index (FSFI), the Edinburgh Postnatal Depression Scale (EDPS), the Relationship Assessment Scale (RAS), and a self-constructed questionnaire for body mass index (BMI; calculated as weight in kilograms divided by the square of height in meters) and other data. Of the 389 who responded at T1, we selected 293 who met our criteria for age, obstetrical history, relationship history, completeness of response, and sexual activity. At T2 and T3, we selected 214 and 95. We analyzed their data by multivariate logit regression., Results: The rates of sexual dysfunction were 44.70% (T1), 40.18% (T2), and 23.15% (T3). Mode of delivery was not a risk factor. Amenorrhea was a risk factor at T1 (P = 0.012) and T2 (P = 0.001). Obesity was a protective factor at T1 (P = 0.021). The higher the EPDS score (T1: P < 0.001; T2: P = 0.035; T3: P = 0.043), and the lower the RAS score (T1: P = 0.016; T2: P = 0.010; T3: P = 0.032), the greater was the risk of dysfunction., Conclusion: Level of relationship satisfaction, severity of depressive symptoms, amenorrhea, and BMI are connected with sexual dysfunction within a year postpartum., (© 2021 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Obstructive sleep apnea (OSA) is associated with treatment-resistant hypertension and high cardiovascular risk. Continuous positive airway pressure (CPAP) fails to reduce cardiovascular risks consistently. Obesity and OSA show reciprocal association and they synergistically increase hypertension via different pathways. Our meta-analysis aimed to assess the cardiovascular benefits of combining weight loss (WL) with CPAP (vs. WL or CPAP alone) in OSA. Outcomes included systolic and diastolic blood pressure (BP) and blood lipid parameters. We explored Medline, Embase, Cochrane, and Scopus. Eight randomized controlled studies (2627 patients) were included. The combined therapy decreased systolic BP more than CPAP alone. Weighted mean difference (WMD) for CPAP + WL versus CPAP was -8.89 mmHg, 95% confidence interval (95% CI; -13.67 to -4.10, p < 0.001) for systolic BP. For diastolic BP, this decrease was not significant. In case of blood lipids, the combined treatment decreased triglyceride levels more than CPAP alone (WMD = -0.31, 95% CI -0.58 to -0.04, p = 0.027). On the other hand, addition of CPAP to WL failed to suppress BP further. The certainty of evidence according to GRADE was very low to moderate. In conclusion, our results showed that the addition of WL to CPAP significantly improved BP and blood lipid values in OSA. On the other hand, the addition of CPAP to WL could not significantly improve BP or blood lipid values. Review protocol: PROSPERO CRD42019138998., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Beyond the three-dimensional fibrin network, the mechanical and lytic stability of thrombi is supported by the matrix of neutrophil extracellular traps (NETs) composed of polyanionic DNA meshwork with attached proteins including polycationic histones. Polyphosphates represent another type of polyanions, which in their linear form are known to enhance the fibrin stabilizing effects of DNA and histones. However, in vivo polyphosphates are also present in the form of nanoparticles (PolyP-NP), the interference of which with the fibrin/NET matrix is poorly characterized., Aims: To compare the effects of linear and nanoparticulate polyphosphates, and their combinations with relevant NET components (DNA, histone H3) on fibrin formation, structure, and lysis in in vitro assays focusing on histone-polyphosphate interactions., Methods: Transmission electron microscopy and dynamic light scattering for stability of the PolyP-NP preparations. Turbidimetry for kinetics of fibrinogen clotting by thrombin and fibrin dissolution by tissue-type plasminogen activator/plasminogen. Scanning electron microscopy for fibrin structure. Surface plasmon resonance for strength of histone-PolyP interactions., Results: Both linear PolyP and PolyP-NP accelerated the fibrin formation and slowed down its dissolution and these effects were strongly dependent on the number of individual PolyP particles and not on their size. Addition of DNA did not modify significantly the PolyP-NP effects on fibrin formation and lysis. Both linear and nanoparticulate PolyP counteracted the effect of histone in the acceleration of fibrinogen clotting by thrombin. PolyP-NP, but not linear PolyP enhanced the prolongation of lysis time in fibrin containing histone and caused more pronounced thickening of the fibrin fibers than the linear form. Finally, PolyP-NP bound weaker to histone than the linear form., Conclusions: The interaction of PolyP with histone was a stronger modulator of fibrin formation and lysis than its interaction with DNA. In addition, the PolyP nanoparticles enhanced the thrombus stabilizing effects of histone more effectively than linear PolyP., Competing Interests: The authors have declared that no competing interests exist.

Background: Laboratory skills training is an essential step before conducting minimally invasive surgery in clinical practice. Our main aim was to develop an animal model for training in clinically highly challenging laparoscopic duodenal atresia repair that could be useful in establishing a minimum number of repetitions to indicate safe performance of similar interventions on humans., Materials and Methods: A rabbit model of laparoscopic duodenum atresia surgery involving a diamond-shaped duodeno-duodenostomy was designed. This approach was tested in two groups of surgeons: in a beginner group without any previous clinical laparoscopic experience (but having undergone previous standardized dry-lab training, n = 8) and in an advanced group comprising pediatric surgery fellows with previous clinical experience of laparoscopy (n = 7). Each participant performed eight interventions. Surgical time, expert assessment using the Global Operative Assessment of Laparoscopic Skills (GOALS) score, anastomosis quality (leakage) and results from participant feedback questionnaires were analyzed., Results: Participants in both groups successfully completed all eight surgeries. The surgical time gradually improved in both groups, but it was typically shorter in the advanced group than in the beginner group. The leakage rate was significantly lower in the advanced group in the first two interventions, and it reached its optimal level after five operations in both groups. The GOALS and participant feedback scores showed gradual increases, evident even after the fifth surgery., Conclusions: Our data confirm the feasibility of this advanced pediatric laparoscopic model. Surgical time, anastomosis quality, GOALS score and self-assessment parameters adequately quantify technical improvement among the participants. Anastomosis quality reaches its optimal value after the fifth operation even in novice, but uniformly trained surgeons. A minimum number of wet-lab operations can be determined before surgery can be safely conducted in a clinical setting, where the development of further non-technical skills is also required., (© 2021. The Author(s).)

BACKGROUND Prolonged fever in pediatric patients is often a diagnostic challenge. Clinicians tend to associate prolonged fever with COVID-19-related diseases in patients with a history of SARS-CoV-2 infection. Here we present a patient who was admitted with a clinical suspicion of multi-inflammatory syndrome in children (MIS-C) and was finally diagnosed with a renal abscess. CASE REPORT A 16-year-old girl with prolonged fever, bilateral non-purulent conjunctivitis, weight loss, muscle pain, general malaise, cough, and yellow sputum was admitted to Heim Pál National Pediatric Institute, Budapest, Hungary. She had proven SARS-CoV-2 infection 3 weeks prior to admission. Although inflammatory markers were elevated, repeated urine analyses, aerobic and anaerobic urine cultures, hemoculture, chest X-ray, and otorhinolaryngology examinations were negative. Based on clinical and laboratory criteria, the diagnosis of MIS-C was eventually ruled out. Abdominal ultrasound revealed a 17×20×15 mm simplex cyst at the edge of the parenchyma in the upper third of the left kidney. Magnetic resonance imaging was performed, showing a multi-compartment, septated, thick-walled parenchymal lesion of 50×40×52 mm in the upper pole of the right kidney, which showed signal characteristics of an abscess, and 20×16 mm and 8 mm lesions in the upper pole of the left kidney, which appeared to be cysts. After being unresponsive to intravenous wide-spectrum antibiotic therapy (meropenem 2 g tid for 5 days), surgical intervention was needed to remove the abscess. CONCLUSIONS This case demonstrates that during the COVID-19 pandemic, besides the obvious post-COVID etiology, other life-threatening conditions should be investigated in the first line.

Carbon nanoarchitectures derived from biobased building blocks are potential sustainable alternatives to electrode materials generated with petroleum-derived resources. We aim at developing a fundamental understanding on the connection between the structure and electrochemical performance of porous carbon nanofiber (PCNF) architectures from the polysaccharide chitosan as a biobased building block. We fabricated a range of PCNF architectures from the chitosan carbon precursor and tailored their structure by varying the amount and molecular weight of the sacrificial pore-forming polymer poly(ethylene oxide). The morphology (high-resolution scanning electron microscopy), carbon structure (X-ray diffraction, transmission electron microscopy), pore network (N 2 gas adsorption, small-angle X-ray scattering), and surface/bulk composition (X-ray photoelectron spectroscopy, energy-dispersive X-ray spectroscopy) were studied in detail together with a comprehensive electrochemical analysis on the fabricated electrodes. In supercapacitor devices, the best-performing freestanding electrode had (1) a high accessible surface area ( a s,BET ≈ 700 m 2 g -1 ) and hierarchical pore network (micro- and mesopores) providing a fast ion diffusion process, high specific capacitance, and rate capability, (2) surface chemistry allowing a high Coulombic efficiency by avoiding parasitic Faradaic side reactions, and (3) a unique turbostratic carbon nanostructure leading to low charge transfer resistance while keeping good electrical conductivity. This electrode exhibited good stability over 2000 cycles (at 2 A g -1 ) with high capacitance retention (>80%) and charge efficiency (>90%). In the capacitive deionization (CDI) device, our electrode demonstrated an ultrahigh salt adsorption capacity of 23.6 mg g -1 , which is among the state-of-the-art values reported for a biobased carbon. A high charge efficiency (85%) was achieved during the CDI process using low-cost materials, in contrast to similarly performing devices fabricated with expensive ion exchange membranes or petroleum-based carbon precursors. Our results demonstrate that inexpensive chitosan-based materials can be readily transformed in one carbonization step without any aggressive activating chemicals into tailor-made hierarchically ordered state-of-the-art carbon materials for charge storage devices.

Pain, fatigue, and physical activity are major determinants of life quality in rheumatoid arthritis (RA). Janus kinase (JAK) inhibitors have emerged as effective medications in RA and have been reported to exert direct analgesic effect in addition to reducing joint inflammation. This analysis aims to give an extensive summary of JAK inhibitors especially focusing on pain and patient reported outcomes (PRO). MEDLINE, CENTRAL, Embase, Scopus, and Web of Science databases were searched on the 26 October 2020, and 50 randomized controlled trials including 24,135 adult patients with active RA met the inclusion criteria. JAK inhibitors yielded significantly better results in all 36 outcomes compared to placebo. JAK monotherapy proved to be more effective than methotrexate in 9 out of 11 efficacy outcomes. In comparison to biological disease-modifying antirheumatic drugs, JAK inhibitors show statistical superiority in 13 of the 19 efficacy outcomes. Analgesic effect determined using the visual analogue scale and American College of Rheumatology (ACR) 20/50/70 response rates was significantly greater in the JAK group in all comparisons, and no significant difference regarding safety could be explored. This meta-analysis gives a comprehensive overview of JAK inhibitors and provides evidence for their superiority in improving PROs and disease activity indices in RA.

Astaxanthin is a lipid-soluble carotenoid influencing lipid metabolism, body weight, and insulin sensitivity. We provide a systematic analysis of acute and chronic effects of astaxanthin on different organs. Changes by chronic astaxanthin feeding were analyzed on general metabolism, expression of regulatory proteins in the skeletal muscle, as well as changes of excitation and synaptic activity in the hypothalamic arcuate nucleus of mice. Acute responses were also tested on canine cardiac muscle and different neuronal populations of the hypothalamic arcuate nucleus in mice. Dietary astaxanthin significantly increased food intake. It also increased protein levels affecting glucose metabolism and fatty acid biosynthesis in skeletal muscle. Inhibitory inputs innervating neurons of the arcuate nucleus regulating metabolism and food intake were strengthened by both acute and chronic astaxanthin treatment. Astaxanthin moderately shortened cardiac action potentials, depressed their plateau potential, and reduced the maximal rate of depolarization. Based on its complex actions on metabolism and food intake, our data support the previous findings that astaxanthin is suitable for supplementing the diet of patients with disturbances in energy homeostasis.

Introduction: The composition of thrombi determines their structure, mechanical stability, susceptibility to lysis, and consequently, the clinical outcome in coronary artery disease (CAD), acute ischemic stroke (AIS), and peripheral artery disease (PAD). Fibrin forms the primary matrix of thrombi intertwined with DNA, derived from neutrophil extracellular traps (NETs), and von Willebrand factor (VWF) bridging DNA and platelets. Here we examined the relative content of fibrin, DNA and VWF in thrombi and analyzed their interrelations and quantitative associations with systemic biomarkers of inflammation and clinical characteristics of the patients., Patients, Methods: Thrombi extracted from AIS (n = 17), CAD (n = 18) or PAD (n = 19) patients were processed for scanning electron microscopy, (immune)stained for fibrin, VWF and extracellular DNA. Fibrin fiber diameter, cellular components, fibrin/DNA and fibrin/VWF ratios were measured., Results: Patients' age presented as a strong explanatory factor for a linear decline trend of the VWF content relative to fibrin in thrombi from CAD (adjusted-R 2  = 0.43) and male AIS (adjusted-R 2  = 0.66) patients. In a subgroup of CAD and PAD patients with dyslipidemia and high (above 80%) prevalence of atherothrombosis a significant correlation was observed between the VWF and DNA content in thrombi (adjusted-R 2  = 0.40), whereas a 3.7-fold lower linear regression coefficient was seen in AIS patients, in whom the fraction of thrombi of atherosclerotic origin was 57%. Independently of anatomical location, in patients with atherosclerosis the VWF in thrombi correlated with the plasma C-reactive protein levels., Conclusions: The observed interrelations between thrombus constituents and systemic inflammatory biomarkers suggest an intricate interplay along the VWF/NET/fibrin axis in arterial thrombosis., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The chemical changes caused by electron beam and γ irradiations and the biochemical characteristics of degradation products of a frequently used antibiotic oxacillin were investigated and compared with those of cloxacillin by applying pulse radiolysis, chemical and biochemical oxygen demand, total organic carbon content, oxygen uptake rate, toxicity and antibacterial activity measurements. Oxacillin was found to be non-toxic, but poorly biodegradable by the mixed microbial population of the activated sludge of a wastewater treatment plant. Therefore, it can significantly contribute to the spread of β-lactam antibiotic resistant bacteria. However, the products formed by γ-irradiation were more easily biodegradable as they were utilized as nutrient source by the microbes of the activated sludge and the products did not show antibacterial activity. During irradiation treatment of aerated aqueous solutions mainly hydroxyl radicals induce the elimination of antimicrobial activity by making alterations at the bicyclic β-lactam part of these antibiotics. Since the β-lactam part is the same in oxacillin and cloxacillin, the biochemical characteristics of products of the two antibiotics are similar. The attack of hydrated electron takes place on the carbonyl groups. When the irradiation is made under anoxic conditions these reactions may also contribute considerably to alterations at the β-lactam part and thereby to the loss of antibacterial activity., (Copyright © 2021. Published by Elsevier Ltd.)