Real-life effectiveness of dupilumab in chronic rhinosinusitis with nasal polyps. Results from eight Hungarian centres with 12-month follow-up.

BACKGROUND: Research on the immune mechanism behind chronic rhinosinusitis (CRS) has revealed various new endotypes, leading to targeted therapies, especially for severe uncontrolled CRS. Biologics are novel therapeutic strategies providing targeted treatment for the difficult-to-treat recalcitrant CRSwNP patients. Dupilumab is a fully human-derived monoclonal antibody that binds to IL4Rα, inhibiting the signalling of both IL-4 and IL-13. In Hungary, it is approved for the treatment of uncontrolled CRSwNP according to criteria based on the EPOS2020 and the Hungarian guidelines. METHODOLOGY: This study aimed to collect and evaluate real-world therapeutic data of CRSwNP patients treated with dupilumab. One hundred thirty-five patients from eight different referral centres have been enrolled in this study, who received dupilumab since 2020. All subjects were adult patients (over 18 years) with uncontrolled CRSwNP. Baseline data collection included demographics, medical history, previous surgeries, related comorbidities, total endoscopic nasal polyp score (NPS), SNOT22, nasal congestion parameters measured with visual analogue scale (VAS) and nasal obstruction evaluation scale (NOSE), loss of smell score (LSS) and eosinophil count. 300 mg dupilumab was administered subcutaneously every second week. Follow up visits were performed after 6 and 12 months. RESULTS: After 6 and 12 months of treatment significant improvement was detected in all clinical parameters. Safety was proved, no severe side effects occurred, and no rescue treatment was necessary. CONCLUSIONS: Our real-life findings show that continuous dupilumab treatment is effective and safe in daily clinical practice in CRSwNP and other type 2 comorbidities such as bronchial asthma and NERD.

Management of thoracic trauma.

Managing major thoracic trauma begins with identifying and anticipating injuries associated with the mechanism of injury. The key aims are to reduce early mortality and the impact of associated complications to expedite recovery and restore the patient to their pre-injury state. While imaging is imperative to identify the extent of thoracic trauma, some pathology may require immediate treatment. The majority can be managed with adequate pleural drainage, but respiratory failure and poor gas exchange may require either non-invasive or invasive ventilation. Ventilation strategies to protect from complications such as barotrauma, volutrauma and ventilator-induced lung injury are important to consider. The management of pain is vital in reducing respiratory complications. A multimodal strategy using local, regional and systemic analgesia may mitigate respiratory side effects of opioid use. With optimal pain management, physiotherapy can be fully utilised to reduce respiratory complications and enhance early recovery. Thoracic surgeons should be consulted early for consideration of surgical management of specific injuries. With a greater understanding of the mechanisms of injury and the appropriate use of available resources, favourable outcomes can be reached in this cohort of patients. Overall, a multidisciplinary and holistic approach results in the best patient outcomes.

Identification of putative genetic modifying factors that influence the development of Papillon-Lefévre or Haim-Munk syndrome phenotypes.

BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndrome (HMS; OMIM 245010), which are both characterized by palmoplantar hyperkeratosis and periodontitis, are phenotypic variants of the same disease caused by mutations of the cathepsin C (CTSC) gene. AIM: To identify putative genetic modifying factors responsible for the differential development of the PLS or HMS phenotypes, we investigated two Hungarian patients with different phenotypic variants (PLS and HMS) but carrying the same homozygous nonsense CTSC mutation (c.748C/T; p.Arg250X). METHODS: To gain insights into phenotype-modifying associations, whole exome sequencing (WES) was performed for both patients, and the results were compared to identify potentially relevant genetic modifying factors. RESULTS: WES revealed two putative phenotype-modifying variants: (i) a missense mutation (rs34608771) of the SH2 domain containing 4A (SH2D4A) gene encoding an adaptor protein involved in intracellular signalling of cystatin F, a known inhibitor of the cathepsin protein, and (ii) a missense variant (rs55695858) of the odorant binding protein 2A (OBP2A) gene, influencing the function of the cathepsin protein through the glycosyltransferase 6 domain containing 1 (GLT6D1) protein. CONCLUSION: Our study contributes to the accumulating evidence supporting the clinical importance of phenotype-modifying genetic factors, which have high potential to aid the elucidation of genotype-phenotype correlations and disease prognosis.

The unprecedented loss of Florida's reef-building corals and the emergence of a novel coral-reef assemblage.

Over the last half century, climate change, coral disease, and other anthropogenic disturbances have restructured coral-reef ecosystems on a global scale. The disproportionate loss of once-dominant, reef-building taxa has facilitated relative increases in the abundance of "weedy" or stress-tolerant coral species. Although the recent transformation of coral-reef assemblages is unprecedented on ecological timescales, determining whether modern coral reefs have truly reached a novel ecosystem state requires evaluating the dynamics of reef composition over much longer periods of time. Here, we provide a geologic perspective on the shifting composition of Florida's reefs by reconstructing the millennial-scale spatial and temporal variability in reef assemblages using 59 Holocene reef cores collected throughout the Florida Keys Reef Tract (FKRT). We then compare the relative abundances of reef-building species in the Holocene reef framework to data from contemporary reef surveys to determine how much Florida's modern reef assemblages have diverged from long-term baselines. We show that the composition of Florida's reefs was, until recently, remarkably stable over the last 8000 yr. The same corals that have dominated shallow-water reefs throughout the western Atlantic for hundreds of thousands of years, Acropora palmata, Orbicella spp., and other massive coral taxa, accounted for nearly 90% of Florida's Holocene reef framework. In contrast, the species that now have the highest relative abundances on the FKRT, primarily Porites astreoides and Siderastrea siderea, were rare in the reef framework, suggesting that recent shifts in species assemblages are unprecedented over millennial timescales. Although it may not be possible to return coral reefs to pre-Anthropocene states, our results suggest that coral-reef management focused on the conservation and restoration of the reef-building species of the past, will optimize efforts to preserve coral reefs, and the valuable ecosystem services they provide into the future.

Estimating the upper limit of prehistoric peak ground acceleration using an in situ, intact and vulnerable stalagmite from Plavecká priepast cave (Detrekoi-zsomboly), Little Carpathians, Slovakia-first results.

Earthquakes hit urban centres in Europe infrequently, but occasionally with disastrous effects. Obtaining an unbiased view of seismic hazard (and risk) is therefore very important. In principle, the best way to test probabilistic seismic hazard assessments (PSHAs) is to compare them with observations that are entirely independent of the procedure used to produce PSHA models. Arguably, the most valuable information in this context should be information on long-term hazard, namely maximum intensities (or magnitudes) occurring over time intervals that are at least as long as a seismic cycle. The new observations can provide information of maximum intensity (or magnitude) for long timescale as an input data for PSHA studies as well. Long-term information can be gained from intact stalagmites in natural caves. These formations survived all earthquakes that have occurred over thousands of years, depending on the age of the stalagmite. Their 'survival' requires that the horizontal ground acceleration (HGA) has never exceeded a certain critical value within that time period. Here, we present such a stalagmite-based case study from the Little Carpathians of Slovakia. A specially shaped, intact and vulnerable stalagmite in the Plavecká priepast cave was examined in 2013. This stalagmite is suitable for estimating the upper limit of horizontal peak ground acceleration generated by prehistoric earthquakes. The critical HGA values as a function of time going back into the past determined from the stalagmite that we investigated are presented. For example, at the time of Jóko event (1906), the critical HGA value cannot have been higher than 1 and 1.3 m/s2 at the time of the assumed Carnuntum event (∼340 AD), and 3000 years ago, it must have been lower than 1.7 m/s2. We claimed that the effect of Jóko earthquake (1906) on the location of the Plavecká priepast cave is consistent with the critical HGA value provided by the stalagmite we investigated. The approach used in this study yields significant new constraints on the seismic hazard, as tectonic structures close to Plavecká priepast cave did not generate strong earthquakes in the last few thousand years. The results of this study are highly relevant given that the two capitals, Vienna and Bratislava, are located within 40 and 70 km of the cave, respectively.

Nonreciprocal reconfigurable microwave optomechanical circuit.

Nonreciprocal microwave devices are ubiquitous in radar and radio communication and indispensable in the readout chains of superconducting quantum circuits. Since they commonly rely on ferrite materials requiring large magnetic fields that make them bulky and lossy, there has been significant interest in magnetic-field-free on-chip alternatives, such as those recently implemented using the Josephson nonlinearity. Here, we realize reconfigurable nonreciprocal transmission between two microwave modes using purely optomechanical interactions in a superconducting electromechanical circuit. The scheme relies on the interference in two mechanical modes that mediate coupling between the microwave cavities and requires no magnetic field. We analyse the isolation, transmission and the noise properties of this nonreciprocal circuit. Finally, we show how quantum-limited circulators can be realized with the same principle. All-optomechanically mediated nonreciprocity demonstrated here can also be extended to directional amplifiers, and it forms the basis towards realizing topological states of light and sound.Nonreciprocal optical devices traditionally rely on magnetic fields and magnetic-free approaches are rather recent. Here, Bernier et al. propose and demonstrate a purely optomechanical circulator with reconfigurable transmission without the need for direct coupling between input and output modes.

On-axis versus off-axis Transmission Kikuchi Diffraction technique: application to the characterisation of severe plastic deformation-induced ultrafine-grained microstructures.

A new configuration for Transmission Kikuchi Diffraction (TKD) in a scanning electron microscope is presented; called 'on-axis TKD'. Compared to the usual off-axis configuration, the scintillator is placed perpendicular to the incident beam under the electron-transparent sample, not in vertical position. In this way, the setup benefits from intense forward scattered electrons enabling short acquisition times. At equivalent diffraction pattern quality, the electron dose needed on the sample is estimated to be 20 times lower in comparison to the off-axis configuration. The technique is particularly suited to the characterisation of severe plastic deformation induced ultrafine grained microstructures. The evolution of the microstructure of an Al-Mg alloy deformed by high pressure tube twisting was analysed. It is shown that the grain refinement was in the steady state stage for a shear strain of 24 with a mean grain size of 120 nm.

STAT3 Activation in Circulating Monocytes Contributes to Neovascular Age-Related Macular Degeneration.

Infiltrating macrophages are critically involved in pathogenic angiogenesis such as neovascular agerelated macular degeneration (nAMD). Macrophages originate from circulating monocytes and three subtypes of monocyte exist in humans: classical (CD14(+)CD16(-)), non-classical (CD14(-)CD16(+)) and intermediate (CD14(+)CD16(+)) monocytes. The aim of this study was to investigate the role of circulating monocyte in neovascular age-related macular degeneration (nAMD). Flow cytometry analysis showed that the intermediate monocytes from nAMD patients expressed higher levels of CX3CR1 and HLA-DR compared to those from controls. Monocytes from nAMD patients expressed higher levels of phosphorylated Signal Transducer and Activator of Transcription 3 (pSTAT3), and produced higher amount of VEGF. In the mouse model of choroidal neovascularization (CNV), pSTAT3 expression was increased in the retina and RPE/choroid, and 49.24% of infiltrating macrophages express pSTAT3. Genetic deletion of the Suppressor of Cytokine Signalling 3 (SOCS3) in myeloid cells in the LysM-Cre(+/-):SOCS3(fl/fl) mice resulted in spontaneous STAT3 activation and accelerated CNV formation. Inhibition of STAT3 activation using a small peptide LLL12 suppressed laserinduced CNV. Our results suggest that monocytes, in particular the intermediate subset of monocytes are activated in nAMD patients. STAT3 activation in circulating monocytes may contribute to the development of choroidal neovascularisation in AMD.

One mutation, two phenotypes: a single nonsense mutation of the CTSC gene causes two clinically distinct phenotypes.

BACKGROUND: Papillon-Lefévre syndrome (PLS; OMIM 245000) and Haim-Munk syndromes (HMS; OMIM 245010) are phenotypic variants of the same rare disease caused by mutations of the cathepsin C (CTSC) gene, and they exhibit autosomal recessive inheritance. AIMS: To identify diseases caused by mutations of the CTSC gene in two Hungarian patients and to perform haplotype analysis to elucidate any familial relationship between them. METHODS: Mutation screening and polymorphism analysis were performed by direct sequencing of the CTSC gene. RESULTS: Mutation screening of the CTSC gene from the two patients revealed the presence of the same homozygous nonsense mutation (c.748C/T; p.Arg250X). However, one patient exhibited the PLS phenotype and the other the HMS phenotype. Although these patients were not aware that they were related, haplotype analysis, especially the genotypes of the rs217116 and the rs217115 polymorphisms, clearly indicated that the patients carry the same haplotype, whereas the unrelated healthy controls carried several different haplotypes. CONCLUSIONS: Our results demonstrate that PLS and HMS are phenotypic variants of the same disease and, additionally, exclude the presence of a putative genetic modifier factor within the CTSC gene that is responsible for the development of the two phenotypes. We suggest that this putative genetic modifier factor is located outside the CTSC gene, or alternatively, that the development of the different phenotypes is the consequence of different environmental or lifestyle factors.

HPLC-MS/MS analysis of steroid hormones in environmental water samples.

Today, freshwaters, such as lakes and rivers, are subject to controlled pollution. Steroid hormones are chemically very stable highly lipophilic molecules. Their biological properties have a strong impact on the endocrine regulation of species. Steroids have estrogenic, androgenic, thyroidogenic or progestogenic effects and based on them, they could disturb the physiological mechanisms of freshwater species. We focused on progestins as they are the main active ingredients of contraceptive pharmaceuticals. Progestins have been shown to impair reproduction in fish, amphibians, and mollusks at low ng/L concentrations. Certain progestins, such as levonorgestrel (LNG) have androgenic properties also. We selected the most used active substances drospirenone (DRO), LNG, and progesterone (PRG) and then developed and optimized a liquid chromatographic-mass spectrometric method with solid-phase extraction to measure them. Using our sensitive method (LOQ 0.03-0.11 ng/L) we could measure steroids even between 0.1 and 1 ng/L. Analyzing freshwater samples from the Lake Balaton catchment area, we found influents where the concentration of these hormones was 0.26-4.30 (DRO), 0.85-3.40 (LNG), and 0.23-13.67 (PRG) ng/L. Out of 53 collecting places, 21 contained measurable progestin levels, which clearly demonstrates the applicability of our method, legitimates toxicology experiments with effected species, and indicates monitoring efforts.

MLH1 and MSH2 mutation screening in HNPCC families of Hungary - Two new MMR gene mutations.

INTRODUCTION: Hereditary Non-Polyposis Colorectal Cancer is an inherited disease with deleterious germline mutations in the DNA mismatch repair genes causing the development of colon cancer and other malignancies. This is the first study in Hungary screening the population of our colorectal cancer patients in order to identify the prevalence of the disease. METHODS: In families who met the Modified Amsterdam and Bethesda Criteria the removed tumor tissue was first examined by immunohistochemistry and microsatellite instability analysis. Those cases which showed high microsatellite instability underwent DNA sequencing and multiple ligation dependent probe amplification. RESULTS: Of the 1576 patients with colorectal cancer underwent screening for the modified Amsterdam and Bethesda criteria, 69 (4.4%) and 166 (10.5%) fulfilled the criteria respectively. 15 patients (31%) of the Amsterdam positive group and 19 patients from the Bethesda positive (18.1%) were MSI-H. There were 8 pathogenic mutations identified in 9 families (60%) in the Amsterdam positive group. 5 mutations were found in 5 families (26%) in the Bethesda positive group. 12 pathogenic mutations were identified, two of these are newly identified, and being published first in this work. These two new mutations were located on MLH1 (g.31276_35231del) and MSH2 (c.969_970delTC) genes. CONCLUSION: The prevalence of the mutations in the MLH1 and MSH2 genes was almost equal in our Hungarian colorectal cancer patients. One mutation in the MLH1 gene (c.143A > C; p.Q48P) was identified in three different families. Whether this mutation is the most frequent in the Hungarian population is still unidentified and warrant further investigation.

The beneficial effect of plasmapheresis in mixed connective tissue disease with coexisting antiphospholipid syndrome.

The authors report a rare case of a female patient with mixed connective tissue disease (MCTD) with coexisting antiphospholipid syndrome (APS). Five years after the diagnosis of MCTD high concentrations of anticardiolipin (anti-CL) and anti-ß2-glycoprotein (anti-ß2GPI) autoantibodies were present in the patient's serum without thrombotic events. Epstein-Barr virus (EBV) reactivation provoked APS, with the clinical manifestations of livedo reticularis, digital gangrene and leg ulcers. Skin biopsy from the necrotic area showed multiple fibrin microthrombi in the superficial vessels. Corticosteroid pulse therapy, and plasma exchange in combination with synchronized cyclophosphamide was administered, which led to improvement of the digital gangrenes, while no new lesions developed. The number of CD27high plasma cells decreased, and the previous high levels of autoantibodies also normalized in the peripheral blood. In the case of MCTD with coexisting APS combination therapy, including plasmapheresis has beneficial effects.

Mechanism of the irreversible inhibition of human cyclooxygenase-1 by aspirin as predicted by QM/MM calculations.

Acetylsalicylic acid (aspirin) suppresses the generation of prostaglandin H2, which is the precursor of thromboxane A2. Aspirin acts as an acetylating agent in which its acetyl group is covalently attached to a serine residue (S530) in the active site of the cyclooxygenase-1 enzyme. The exact reaction mechanism has not been revealed by experimental methods. In this study the putative structure of human cyclooxygenase-1 was constructed from ovine cyclooxygenase-1 by homology modeling, and the acetylsalicylic acid was docked into the arachidonic acid binding cavity of the enzyme. To characterize the shape of the potential energy surface of the acetylating reaction and to determine the relative energies of the stationary points on the surface, a series of ONIOM-type quantum mechanical/molecular mechanical (QM/MM) calculations were carried out at different QM levels of theories applying electronic embedding approximations. The acetylsalicylic acid and the surrounding amino acids were included in these calculations. Frequency analyses were performed to prove the existence of first order saddle points (representing transition states) and local minima on the potential energy surface. It was found that all levels of theories predicted similar transition state geometries. The activation energy values, however, demonstrated significant dependence on the methods that were applied. All the applied "dependable" ab initio and DFT methods predicted that the breakage of the S530 Oγ--Hγ and formation of the Oγ--C(acetylsalicylic acid carbonyl) bonds occur in a single elementary step.

Overview of large animal myocardial infarction models (review).

There are several experimental models for the in vivo investigation of myocardial infarction (MI) in small (mouse, rat) and large animals (dog, pig, sheep and baboons). The application of large animal models raises ethical concerns, the design of experiments needs longer follow-up times, requiring proper breeding and housing conditions, therefore resulting in higher cost, than in vitro or small animal studies. On the other hand, the relevance of large animal models is very important, since they mostly resemble to human physiological and pathophysiological processes. The first main difference among MI models is the method of induction (open or closed chest, e.g. surgical or catheter based); the second main difference is the presence or absence of reperfusion. The former (i.e. reperfused MI) allows the investigation of reperfusion injury and new catheter based techniques during percutaneous coronary interventions, while the latter (i.e. nonreperfused MI) serves as a traditional coronary occlusion model, to test the effects of new pharmacological agents and biological therapies, as cell therapy. The reperfused and nonreperfused myocardial infarction has different outcomes, regarding left ventricular function, remodelling, subsequent heart failure, aneurysm formation and mortality. Our aim was to review the literature and report our findings regarding experimental MI models, regarding the differences among species, methods, reproducibility and interpretation.

Bilateral juvenile fibroadenosis of the breast: management with subcutaneous mastectomy and silicone implant placement.

Bilateral fibroadenosis is a rare, benign disorder, affecting adolescents or women of childbearing age. Choosing the most optimal therapy that manages both the physical and psychological aspects of the disease is a challenge. The goals of the treatment are complete resection of the lesions with optimal cosmesis. Options range from cryoablation, ultrasound-guided vacuum-assisted eradication and simple excision of the lesions to subcutaneous mastectomy with reconstruction. We present a case of a 25-year-old woman with 37 complex fibroadenomas affecting both breasts who was treated with nipple-sparing subcutaneous mastectomy and silicone implant reconstruction to both the surgeons' and patient's satisfaction.

Measurement-induced chaos with entangled states.

The dynamics of an ensemble of identically prepared two-qubit systems is investigated which is subjected to the iteratively applied measurements and conditional selection of a typical entanglement purification protocol. The resulting dynamics exhibits strong sensitivity to initial conditions. For one class of initial states two types of islands characterize the asymptotic limit. They correspond to a separable and a fully entangled two-qubit state, respectively, and their boundaries form fractal-like structures. In the presence of incoherent noise an additional stable asymptotic cycle appears.

Granular cell tumour of the breast: case series and review of the literature.

Granular cell tumours (GCTs) are uncommon rare neoplasms that may occur in any part of the body. Approximately 5-8% of granular cell tumours occur within the breast. Although nearly always benign in behaviour, granular cell tumours of the breast can often mimic breast malignancies both clinically and on the basis of imaging techniques. This article reports five cases of benign granular cell tumours appearing in the breast, mimicking a malignant breast lesion. In addition to reporting the cases, the relevant literature was reviewed.

Screening of common Plantago species in Hungary for bioactive molecules and antioxidant activity.

Five species of Plantago genus, namely P. lanceolata, P. major, P. media, P. altissima and P. maritima were screened for iridoid content (CE-MEKC), total caffeoyl phenylethanoid glycoside (CPG) content and antioxidant activity (CUPRAC assay). The five species could be distinguished by TLC pattern analysis in a single run in a system commonly used for quality management of P. lanceolata leaves, as shown by cluster analysis of major bands; with the exception, that P. altissima and P. lanceolata did not show enough pattern difference to be fully separated. P. maritima was shown to have the highest antioxidant capacity (0.42 µmol ascorbic acid equivalent (AAE)/g DW), and the highest level of CPGs (4.29%). P. altissima was shown to be chemically indistinguishable from P. lanceolata with repsect to iridoid content (aucubin 0.55 ± 0.04%, 0.68 ± 0.23%, catalpol 0.66 ± 0.13% and 0.89 ± 0.22%, respectively), CPG content (2.40 ± 0.38% and 2.54 ± 0.56%, respectively) and antioxidant capacity (0.2206 ± 0.0290 and 0.2428 ± 0.0191 µmol AAEAC/g DW). The presented data show the potency of medicinal use of Hungarian wild populations of the studied five species, especially in the case of P. maritima, and that P. altissima can be a potential replacement of P. lanceolata in herbal mixtures.

A new mutation in Muir-Torre syndrome associated with familiar transmission of different gastrointestinal adenocarcinomas.

Hereditary Nonpolyposis Colorectal Carcinoma (HNPCC) is the most frequent inherited disease which can lead to the development of tumors in the colon and other locations. Its genetic basis is related to the germline mutation of the Mismatch Repair (MMR) genes. Muir-Torre syndrome is considered one of the subtypes of this disease, in which the HNPCC tumor spectrum is frequently associated with sebaceous carcinoma of the skin or keratoacanthoma. A 57 years old male patient is presented with a mucinous carcinoma of the caecum and an adenocarcinoma of the pancreas head. A malignant sebaceous carcinoma was removed from his left neck area. His family history was significant for two cases of colon carcinoma, two cases of stomach cancer and a case of metacron endometrial and skin tumor as well. Both the colon carcinoma and the skin tumor proved to be microsatellite unstable. An Arg>Pro switch missense mutation was found in codon 265 of the hMLH1 gene. This error was found in 4 other members of his family. The detected genetic alteration was considered pathogenic and was not published yet in English literature. The significance of this particular case is the rare tumor association in a patient with Muir-Torre syndrome (MTS). In cases of sebaceous skin lesions, evaluation of family history is of utmost importance in the early detection of HNPCC and in the follow up care of family members with the particular mutation.