Background: Cystic fibrosis (CF) is reported to be a risk factor for drug hypersensitivity. However, there is conflicting data about true prevalence of drug allergy in children with CF. Methods: The suspicious drug hypersensitivity reactions (DHR) of children with CF were enquired by European Network for Drug Allergy (ENDA) questionnaire and skin tests and/or drug provocation tests were performed according to established guidelines. Results: Two hundred and nineteen children (48.9% boys; median [IQR] age, 8.4 years [4.8-12.4 years]) with cystic fibrosis were included in the study, from whom 22 patients with 24 suspected DHRs were evaluated. Most of the suspected DHRs were non-immediate (n=16, 66.6%) type and the offending drugs were amoxicillin clavulanic acid (n=7), macrolides (n=4), trimethoprim sulfamethoxazole (TMP/SMX) (n=2), piperacillin tazobactam (n=1), pancrelipase (n=1) and ursodeoxycholic acid (n=1). Eight (33.3%) of the DHRs were classified as immediate [ceftriaxone (n=2), ceftazidim (n=2), meropenem (n=1), ambisome (n=2), vancomycin (n=1)]. The main presenting clinical presentations were maculopapular eruption (41.6%) and urticaria (37.5%), accompanied by angioedema (8.3%), flushing (12.5%) and vomiting (8.3%). Nine skin tests (with beta-lactam protocol in 6 patients) and 24 DPTs were performed and none of the skin tests revealed a positive result, however 2 DPTs with TMP/SMX were positive. Conclusion: Actual drug allergy was demonstrated in 2 of 219 patients (0.9%) with nonbeta-lactam antibiotics. These results conflict with previous researches that showed higher drug allergy rates but were consistent with some recent studies. Numerous and long-term use of multiple drugs during management of cystic fibrosis may contribute to tolerance development.

An unusual localization of genital ulcer in Behçet’s disease: external urethral meatusRunning head: Unusual genital ulcer in Behçet’s diseaseÇağrı Turan1, İbrahim Karabulut 21Department of Dermatology and Venereology, the Republic of Turkey, Health Sciences University Erzurum Regional Training and Research Hospital, Turkey2Department of Urology, the Republic of Turkey, Health Sciences University Erzurum Regional Training and Research Hospital, TurkeyCorresponding Author : Çağrı TURAN; Department of Dermatology and Venereology, the Republic of Turkey, Health Sciences University Erzurum Regional Training and Research Hospital, Turkey; Üniversite Mahallesi, Çat Yolu Cd., Yakutiye/Erzurum, Post Code: 25070e-mail: [email protected], telephone number: +905445252504Word count: 471Table count: 0Supplementary table: 0Figure count: 1Funding sources : We declare no financial support or relationships that may pose a conflict of interest.Conflict of interest: There is no conflict of interest.The paper has not been published or submitted for publication elsewhere.All authors have contributed significantly, and all authors agree with the content of the manuscript.Informed consent form was obtained from the patient.Key words: Behçet’s disease, genital ulcer, Urethra, VasculitisDear editor,Behçet’s disease (BD) is a chronic, recurrent, multisystemic vasculitis which can affect all vascular system. The most common symptom is genital ulcer accompanying oral aphthae, and its diagnosis is currently made according to the International Criteria for Behçet’s Disease (ICBD). Providing two points for oral aphthae, genital ulcers, and ocular involvement and one point for the other skin lesions (erythema nodosum, papulopustular/acneiform lesions in post-adolescent), vascular involvement, and neurological findings are evaluated if the patient scores reach four or more; the patient is considered to be BD1, 2. In men, genital aphthous ulcers occur in 60 to 65% of cases and are most common in the scrotum, shaft and glans penis, and rarely in the groin and perineum, extremely rare in the urethral orifice2, 3We presented a patient with a complaint of painful micturition, ultimately diagnosed with BD. A 34-year-old male patient was consulted from the urology following the evaluation of his painful voiding complaint 10 days accompanying wound in the periurethral orifice. On genital examination, an oval, and sharp circumscribed aphthous ulcer with a serous floor, approximately 4 mm in diameter, was seen on the external urethral orifice (Figure 1a). The patient who had no known disease has refused to use any medication, similar complaints, suspicious sexual contact, except for oral aphthae recurring 8-10 times a year (Figure 1b). After noticing a few pustular lesions with peripheral partial erythema on his back, we focused on BD and inflammatory bowel diseases in the examination (Figure 1c). We learned that the patient had no family history and other related symptoms. Bowel habits were normal. Hepatitis, HIV, syphilis serologies were negative. CRP and sedimentation were 3.2 mg/dl (0-5 mg/dl) and 27 mm/hour (0-20 mm/hour); respectively. Other hematological and biochemical parameters were within normal limits. Complement levels, antinuclear antibody, anti-dsDNA, p-ANCA, c-ANCA and rheumatoid factor were normal. Pathergy test was positive. The patient was diagnosed with BD with a score of 6 according to the current ICBD, and no pathology was found in the eye and cardiology consultations. His complaints improved within 1 week without leaving any scar, after treatment with topical betamethasone valerate applied to the urethral orifice and oral colchicine 1.5 mg/day. No clinical progression has been observed for 2 years in the follow-up.A urethral ulcer is an unusual finding in BD. Aktaş recently reported a 27-year-old male patient with clinical features quite similar to our case, but with negative pathergy4. Interestingly, Cobilinschi et al. reported that a 34-year-old female patient with BD who was admitted with progressive dysuria, pain in the right lumbar region, and hydronephrosis was determined a necrotic ulcer in the ureter whose histopathology was compatible with vasculitis5.We present this case to draw attention to the aphthous ulcer in the urethra as an unusual genital involvement for BD, and the importance of physical examination.

The soybean cyst nematode (Heterodera glycines) is a sedentary plant parasite that exceeds a billion dollars in yield losses annually. It has spread across the soybean-producing world, emerging as the primary pathogen of soybeans. This problem is exacerbated by H. glycines populations overcoming the limited sources of natural resistance in soybean and by the lack of effective and safe alternative treatments. Although there are genetic determinants that render soybean plants resistant to certain nematode genotypes, resistant soybean cultivars are increasingly ineffective because their multi-year usage has selected for virulent H. glycines populations. Successful H. glycines infection relies on the comprehensive re-engineering of soybean root cells into a syncytium, as well as the long-term suppression of host defenses to ensure syncytial viability. At the forefront of these complex molecular interactions are effectors, the proteins secreted by H. glycines into host root tissues. The mechanisms that control genomic effector acquisition, diversification, and selection are important insights needed for the development of essential novel control strategies. As a foundation to obtain this understanding, we developed a nine scaffold, 158Mb pseudomolecule assembly of the H. glycines genome using PacBio, Chicago, and Hi-C sequencing. An annotation of 22,465 genes was predicted using a Mikado pipeline informed by published short- and long-read expression data. Here we present results from our assembly and annotation of the H. glycines genome.

The biotechnological production of glycosides is an economically competitive manufacturing alternative to classical chemical synthesis. Through continuous production improvement, glycosides can now be used in low-cost products by various industries. However, many production systems still suffer from low yields. Directed evolution, coupled with a suitable screening method, can tackle this challenge. We generated glycosyltransferase mutants through error-prone-PCR and screened the library using a small-scale whole-cell biotransformation system. The screening of only 176 colonies yielded three putative candidates. Detailed investigations revealed that the reason for the increase in product titer was mainly due to different expression effects of the mutagenized genes rather than improved enzyme kinetics. In total, a 60-fold increase in product formation was achieved. Therefore, in addition to the quality of the mutant library, an efficient and stable expression system is crucial to achieve high concentrations of active enzyme and product, as formation of inclusion bodies and other inactive forms of the biocatalyst reduces productivity.

In this paper, Tetraphenyldipyranylidene (DPPh), a large quinoidal planar π-conjugated heterocyclic, was considered as primary organic molecule in organic field effect transistors (OFETs). Electron-withdrawing atoms such as F, Cl, and Br were attached to the H-atoms of four peripheral phenyl groups of para-positions relative to the O-atoms of DPPh. Density functional theory (DFT) calculations at the M06-2X/6-311G++ (d,p) level were performed. The influences of the different electron-withdrawing atoms such as F, Cl, and Br on the electronic and optical properties, charge transport parameters, and charge carrier mobility were investigated. The absorption and emission spectra of the DPPh and its derivatives were theoretically simulated in OFETs. The simulated spectra show an intense peak in the visible region (400-650 nm), in which the highest adsorption/emission intensity is related to DPPh-Br. Moreover, the charge injection energy barrier of DPPh and its derivatives were calculated by considering Pt as the source electrode. Based on the results, a greater hole transport is predicted than the electron transport. Moreover, the obtained ratio of the hole/electron mobility and the theoretical correlations between the charge transport parameters of monomers and dimers show that the insertion of the electron-withdrawing atoms in the DPPh structure is a promising strategy to have an ambipolar or n-type semiconductor, too. The obtained results show that introducing electron-withdrawing atoms at the para-position of the DPPh improves the hole/electron injection and transport process in the OFET devices. Finally, DPPh-Br shows a great performance in comparison with the substituted F and Cl atoms in the OFETs devices.

An 82-year-old man, suffering abscess secondary to femoral prosthesis replacement, complained of intractable watery diarrhea and melena. Autopsy disclosed 12 mm-sized perforation at the gastric prepylorus and purulent peritonitis. Amyloid A was deposited in systemic organs and tissues, including the site of gastric perforation. IgM was co-deposited in the glomeruli.

Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) syndrome is an early-onset monogenic inborn error of immunity characterized by multi-organ autoimmune disorders, growth failure and lymphoproliferation. We describe that STAT3 GOF syndrome may be presented with hypogammaglobulinemia and recurrent severe upper and lower respiratory tract infections. The patient we present here did not have multi-organ autoimmunity and lacked early-onset autoimmune manifestations. Chest CT examinations showed mild bronchiectasis with areas of non-fibrosing alveolar-interstitial disease and maldevelopment of bilateral first ribs. By using Sanger sequencing, we revealed a novel c.508G>C, p.D170H STAT3 variant affecting the coiled coil domain (CCD) of STAT3. Functional studies confirmed that p.D170H was a GOF variant as showed by increased pSTAT3 and STAT3 transcriptional activity. Our observation suggests that STAT3 GOF syndrome can manifest in early childhood with hypogammaglobulinemia and recurrent severe respiratory tract infections and may lack autoimmune manifestations. We suggest that patients with hypogammaglobulinemia and severe, recurrent infections should be screened for STAT3 variants even if autoimmune manifestations are missing.

Recently, a bacterium strain of Ideonella sakaiensis was identified with the uncommon ability to degrade the poly(ethylene terephthalate) (PET). The PETase from I. sakaiensis strain 201-F6 catalyzes the hydrolysis of PET converting it to mono(2-hydroxyethyl) terephthalic acid (MHET), bis(2-hydroxyethyl)-TPA (BHET), and terephthalic acid (TPA). Despite the potential of this enzyme for mitigation or elimination of environmental contaminants, one of the limitations of the use of PETase for PET degradation is the fact that it acts only at moderate temperature due to its low thermal stability. Besides, molecular details of the main interaction of PET in the active site of PETase remains unclear. Herein, molecular docking and molecular dynamics (MD) simulations were applied to analyze structural changes of PETase induced by PET binding. Results from the essential dynamics revealed that β1-β2 connecting loop is very flexible. This Loop is located far from the active site of PETase and we suggest that it can be considered for mutagenesis in order to increase the thermal stability of PETase. The free energy landscape (FEL) demonstrates that the main change in the transition between the unbounded to the bounded state is associated with β7-α5 connecting loop, where the catalytic residue Asp206 is located. Overall, the present study provides insights into the molecular binding mechanism of PET into the PETase structure and a computational strategy for mapping flexible regions of this enzyme, which can be useful for the engineering of more efficient enzymes for recycling the plastic polymers using biological systems.

The meta-analysis by Di Tommaso et al demonstrated as elderly patients with mitral regurgitation (MR) undergoing mitral valve repair (MVr) had lower short-term mortality and higher long-term survival with respect to patients undergoing mitral valve replacement (MVR). The benefit of repair is such, that initial surgical strategy is advisable in the elderly even in case of mild symptoms if compared with conservative management. However, even if repair can be performed in presence of some specific etiologies, as degenerative MR or secondary MR, there are always cases where a replacement can be an acceptable solution compared to a repair with uncertain future, regardless of our believes and our technical ability. In this subset of patients, the literature does not show any improvement in outcome of transcatheter mitral repair. Mitral valve repair has to be always done, but look at the etiologies and to the consequences that what is done today can cause tomorrow.

Uterus transplantation (UTx) is fast evolving from an experimental to a clinical procedure, combining solid organ transplantation with assisted reproductive technology. The commencement of the first human uterus transplant trial in the UK leads us to examine and reflect upon the legal and regulatory aspects closely intertwined with UTx from the process of donation to potential implications on fertility treatment and the birth of the resultant child. As the world’s first ephemeral transplant, the possibility of organ restitution requires consideration and is discussed herein. Public funding of fertility treatments pertaining to UTx remains variable and warrants review.

Clear-cutting means forest removing (stem only) and is the most common type of forest harvesting but undoubtedly has a negative impact on the C budget in soils. This work aimed to describe responses of soil organic matter in the forest soils to forest removing under temperate climate conditions of lowland and mountain regions in south-western Poland. Using advanced instrumental analysis, like EPR, 1H NMR and FT-IR spectroscopy it has been found that clear-cutting, alters C cycling and accelerates decomposition in the forest floor leading to loss of humic fractions in the investigated soils. In the mountain forests the more labile, low-molecular fulvic fraction decreased as the effect of harvesting practice. The transformation of organic matter after clear-cutting resulted in the loss of less humified organic matter containing humic substances of less polymerised molecules. Analysis of the semiquinone radical structures and concentrations showed a decrease in radical concentration observed for HA from mountain clear-cut areas compare to the undisturbed forest. Results presented in this paper have proved less aliphatic character of humic acid molecules from the lowlands, compared to the mountain forest as the effect of clear-cutting. Harvesting practices in mountain regions should be approached with particular care due to the risk of erosion of exposed surfaces and soils containing less humified and less stable organic matter than in the lowlands. Humic fractions of higher solubility, less stability and tendency to migrate through the soil profile may favour the leaching of nutrients and consequently cause the eutrophication of waters.

Solving numerically a non-Born-Oppenheimer time-dependent Schrödinger equation to study the dissociative-ionization of H2 subjected to strong field six-cycle laser pulses (I = 4 × 1014 W/cm2, λ = 800 nm) leads to newly ultrafast images of electron dynamics in H2+. The electron distribution in H2+ oscillates symmetrically with laser cycle with θ + π periodicity and gets trapped between two protons for about 8 fs by a Coulomb potential well. Nonetheless, this electron symmetrical distribution breaks up for the H2+ internuclear separation larger than 9 a.u. in the field-free region at a time duration of 24 fs as a result of the distortion of Coulomb potential where the ejected electron preferentially localizes in one of the double-well potential separated by the inner Coulomb potential barrier. Moreover, controlling laser carrier-envelope phase θ enables one to generate the highest total asymmetry Aetot of 0.75 and -0.75 at 10○ and 190○, respectively, associated with the electron preferential directionality being ionized to the left or the right paths along the H2+ molecular axis. Thus the laser-controlled electron slightly reorganizes its position accordingly to track the shift in the position of the protons despite much heavier the proton’s mass.

57-year-old man presented with a 3-month history of fatigue, fever and increasing abdominal pain.He had completed treatment for follicular lymphoma and JAK2 positive myeloproliferative disorder 2 months previously. This case demonstrates therapeutic and diagnostic rationale for open splenectomy in, to our knowledge, one of the largest recorded spleens

We described a minimally invasive technique for transoral removal of deep hiloparenchymal submandibular stones by Flex Robotic System; a step-by-step description of the transoral robotic approach to submandibular gland through a discrete incision of the oral floor is narrated. This approach guaranteed the preservation of the gland, minimizing complications.

Pacemakers are implanted through the subclavian vein to the right side of the heart. In rare cases, pacemakers may be inserted into the left ventricle via the subclavian artery, carrying a risk of thromboembolism. This is a case of a pacemaker inserted via the subclavian artery into the left ventricle.

Trans-radial approach (TRA) is nowdays a more common approach during percutaneous coronary angiography and intervention. Catheter knot is rare but still a matter of concern for a catheterizing cardiologist. Hence, we describe our case of catheter unknotting using balloon internal fixation of angiography catheter.

Parkinson’s disease (PD) is a highly common neurological disease affecting a large population worldwide. Several studies revealed that the degradation of voice is one of its initial symptoms, which is also known as dysarthria. In this work, we attempt to explore and harness the correlation between various features in the voice samples observed in PD subjects. To do so, a novel two-level ensemble-based feature selection method has been proposed, whose results were combined with an MLP based classifier using K-fold cross-validation as the re-sampling strategy. Three separate benchmark datasets of voice samples were used for the experimentation work. Results strongly suggest that the proposed feature selection framework helps in identifying an optimal set of features which further helps in highly accurate identification of PD patients using a Multi-Layer Perceptron from their voice samples. The proposed model achieves an overall accuracy of 98.3%, 95.1% and 100% on the three selected datasets respectively. These results are significantly better than those achieved by a non-feature selection based option, and even the recently proposed chi-square based feature selection option.

The studies of climatic-niche shifts over evolutionary time accompanied by key morphological innovations have attracted the interest of many researchers recently. We analyzed the realized niche dynamics across clades within Scutiger boulengeri using ecological niche models (ENMs), ordination method (environment principal component analysis; PCA-env), and correspondingly key morphological innovations combined phylogenetic comparative methods (PCMs) and phylogenetic generalized least squares (PGLS) regression methods throughout their distributions in Qinghai-Tibet Plateau (QTP) margins of China in Asia. Our analyses reveal that there is obvious niche divergence caused by niche expansion across S. boulengeri clades, especially in E. A, E. B and partial of E. C clades. Moreover, niche expansion is more popular than niche unfilling into novel environmental conditions. Annual mean temperature and Annual precipitation are the most important contributors in E. A and E. B clades, while Precipitation of driest month is most likely to be the leading limited factor in these two regions according to jackknife test of variable importance. In addition, we identified several key ecological and morphological traits that tend to be associated with niche expansion in S. boulengeri clades correspondingly. Specifically, we found that Elevation, Isothermality, Mean diurnal range and Max temperature of warmest month are significantly negative predictors of snout–vent length (SVL) under phylogenetic models, while the S. boulengeri toads from warmer and more arid environments tend to be larger. There seems to a trade-off strategy by trait covary of locomotor performance combined with enlarged SVL, which provide us a potential pattern of how a colonizing toad might seed a novel habit to begin the process of speciation and finally adaptive radiation. It is worth noting that we should not overlook that the Tibet continuously growing and moving northward over millions of years has laid the foundation for early divergence of clades within S. boulengeri.