BACKGROUND Diabetes mellitus is an independent risk factor for stroke and atrial fibrillation. Therefore, the risk/benefit profile of the oral factor Xa inhibitor edoxaban stratified by diabetes is of clinical interest. METHODS 21,105 patients enrolled in ENGAGE AF-TIMI 48 were stratified into 2 pre-specified groups: without (N = 13,481) and with diabetes (N = 7,624). RESULTS On average, patients with diabetes were younger, and had a higher body mass index, CHA2DS2-VASc score and baseline endogenous Factor Xa activity. After multivariate adjustments, patients with diabetes had a similar rate of stroke and systemic embolism compared to those without diabetes (adjusted hazard ratio (HRadj) 1.08; 95% confidence interval (CI) 0.94-1.24; p = 0.28). However, the risk of major bleeding was significantly higher in patients with diabetes (HRadj 1.28; 95% CI 1.14-1.44; p < 0.001). The treatment effect of edoxaban (vs warfarin) was not modified by diabetes (all p-interactions > 0.05), a finding supported by the preserved edoxaban concentrations and inhibition of Factor Xa regardless of diabetes. The HRs of stroke and systemic embolism in patients receiving the higher-dose edoxaban regimen vs warfarin were 0.93 and 0.84 (p-interaction = 0.54) in those with and without diabetes respectively. The higher-dose edoxaban regimen reduced major bleeding (by 19-21%) and cardiovascular death (by 7-17%) regardless of diabetes (p-interactions = 0.81 and 0.33 respectively). CONCLUSION Patients with diabetes in ENGAGE AF-TIMI 48 had higher bleeding risk, but after adjustment similar stroke risk, compared to those without diabetes. The higher-dose edoxaban regimen had similar efficacy compared to warfarin, while reducing bleeding and cardiovascular mortality, irrespective of diabetes.

Sore throat is a common reason for seeking medical help [1]. It can have infectious and non-infectious etiology [2]. The term “sore throat” is usually associated with an infectious agent (bacteria, viruses, and less commonly fungi) [1,3,4]. The terms “throat discomfort“, “throat irritation“, or “functional dysphonia due to the occupational diseases“ (which represents voice disorder) are often used in the same sense as non-infectious sore throat [2,3]. It is identified by the exclusion of infectious etiology symptoms accompanied with persistent sore throat symptoms (tingling and scratching sensation in the throat, hoarseness or muffled voice, foreign body sensation in the throat, coughing, and difficulty in swallowing accompanied by pain) [2,5]. Various factors can lead to non-infectious sore throat. The most important are: environmental (exposure to smog and irritants), individual risk factors (smoking, alcohol and excessive caffeine consumption, incorrect technique of using voice, and snoring), existence of other diseases (allergies, hormonal disorders, gastroesophageal refluxes, and anxiety disorders), and the use of some medications [2,6]. Epidemiological studies for non-infectious sore throat are rare. In a study performed on 1326 adults in the USA, it was found that 6.6% of respondents had current voice disorders while lifetime prevalence was 29.9% [6]. Professions more susceptible to non-infectious sore throat have high demands on vocal performance (for example, teachers, singers, sports coaches, receptionists, television and radio presenters, lawyers, touristic tour guides, and politicians) [2,3,7]. In modern societies, about one-third of the working population belongs to occupations in which the voice is the primary tool [8]. Teaching is a high-risk occupation for developing voice disorders. In a study performed on 2531 adults in the USA, teachers had higher prevalence of lifetime voice disorders (57.7%) as compared to other professions (28.8%) [5]. Voice problems may lead to a lower quality of teaching and a serious personal and emotional burden. This can have detrimental effects on the career of teachers, with negative consequences on pupils and employers [9]. Despite the adverse impact of non-infectious sore throat on professional performance and reduced quality of life, only a small number of teachers is seeking professional medical help [10]. This can be due to a low level of awareness on this topic. Although exact mechanisms of non-infectious sore throat development vary with etiology, inflammation can be found in the majority of cases [2], with elevated pro-inflammatory cytokines such as interleukin (IL)-6, IL-β, and tumor necrosis factor-α (TNF-α) [2,11,12]. There has been little systematic assessment of treatments for non-infectious sore throat. The field lacks objective outcomes, with most studies relying on subjective (self-reported) endpoints [2]. Although there is no unique doctrine in the treatment, anti-inflammatory medicines and antiseptics are usually used. Inflammation is the pathophysiological mechanism of both infectious and non-infectious sore throat, so similar anti-inflammatory therapies have beneficial effects in both etiologies [2]. Few studies showed positive effects of non-steroidal anti-inflammatory medicines, paracetamol, and steroids [13]. Various herbal formulations and antiseptic lozenges, sprays, and mouthwashes (with or without the addition of an anesthetic or analgesic) are most commonly used [2,12]. Lysozyme is natural enzybiotic with properties that could be beneficial in the treatment of non-infectious sore throat. Different types of lysozymes can be found in nature. They have similar structures and share the ability to hydrolyze bacterial cell wall peptidoglycan [14]. Lysozyme is a significant part of the immune system. In humans, it can be found in body secretions, mucosal surfaces, liver, blood, and immune cells [14]. Human milk is rich in lysozyme, which plays an important role in our immunity from the first days of life [15]. The pharmaceutical industry is mainly using hen egg white lysozyme in products for treatment of certain infectious and inflammatory diseases [16]. Besides its direct antibacterial activity, lysozyme has immunomodulatory and anti-inflammatory effects. Immunomodulatory effects have been demonstrated in cancer patients after chemotherapy, where it improved the recovery of CD4+/CD8+ lymphocyte ratio [17]. One of the proposed mechanisms is through the release of immunomodulatory Lysozyme in the treatment of non-infectious sore throat

Stable isotopically labelled organisms have found wide application in life science research including plant physiology, plant stress and defense as well as metabolism related sciences. Therefore, the reproducible production of plant material enriched with stable isotopes such as 13C and 15N is of considerable interest. A high degree of enrichment (> 96 atom %) with a uniformly distributed isotope (global labelling) is accomplished by a continuous substrate supply during plant growth/cultivation. In the case of plants, 13C-labelling can be achieved by growth in 13CO2(g) atmosphere while global 15N-labelling needs 15N- containing salts in the watering/nutrient solution. Here, we present a method for the preparation of 13C and 15N-labelled plants by the use of closed growth chambers and hydroponic nutrient supply. The method is exemplified with durum wheat. In total, 330 g of globally 13C- and 295 g of 15N-labelled Triticum durum wheat was produced during 87 cultivation days. For this, a total of 3.88 mol of 13CO2(g) and 58 mmol of 15N were consumed. The degree of enrichment was determined by LC-HRMS and ranged between 96 and 98 atom % for 13C and 95–99 atom % for 15N, respectively. Additionally, the isotopically labelled plant extracts were successfully used for metabolome-wide internal standardisation of native T.durum plants. Application of an isotope-assisted LC-HRMS workflow enabled the detection of 652 truly wheat-derived metabolites out of which 143 contain N. A reproducible cultivation which makes use of climate chambers and hydroponics was successfully adapted to produce highly enriched, uniformly 13C- and 15N-labelled wheat. The obtained plant material is suitable to be used in all kinds of isotope-assisted research. The described technical equipment and protocol can easily be applied to other plants to produce 13C-enriched biological samples when the necessary specific adaptations e.g. temperature and light regime, as well as nutrient supply are considered. Additionally, the 15N-labelling method can also be carried out under regular glasshouse conditions without the need for customised atmosphere.

A preterm female infant with a birthweight 1770 g was born via spontaneous vaginal delivery at 34 weeks’ gestation to a 21-yearold mother who received an adequate prenatal care. Routine prenatal ultrasound at 30 weeks revealed a proximal dilatation of the gut and polyhydramnios. At delivery, initial physical exam revealed a soft ‘scaphoid’ abdomen. Apgar score was 7 and 8 at 1st and 5th minute, respectively. A nasogastric tube (NGT) was placed for gastric decompression and bilious drain was observed. Post-natal erect X-ray of the abdomen showed dilated loops in the upper abdomen with the paucity of gas in the pelvis and confirmed proximal bowel obstruction (Fig. 1). After 24 h of stabilisation and care in the neonatal intensive care unit, the patient was taken to the operating room for surgical repair of her presumed jejunal atresia. Surgical exploration revealed a markedly distended atretic jejunum with a ‘type 3B’ intestinal atresia (apple-peel jejunal atresia) and a significant loss of intestinal length. The proximal end of the jejunal atresia was located 15 cm below the ligament of Treitz. On the distal end of ileal atresia, there were two multiple ileal atresias, each 7 cm of length. Approximately, 55 cm of the small bowel distal from the ileal atresias was found to be patent (Fig. 2a). In our case, the total length of small intestine was 70 cm (15 cm distal to the ligament of Treitz and 55 cm proximal to the ileocecal valve). All atretic segments were resected. The remaining segments were preserved (without tapering proximal jejunoplasty) and connected with the end-to-end jejunoileal anastomosis using 5/0 polyglactin sutures in the single extramucosal layer employing the Cheatle technique for size mismatch (Fig. 2b). Appendectomy was also performed. Post-operatively, the patient was placed on mechanical ventilation and extubated on the 6th post-operative day (POD). Total parenteral nutrition (TPN) via a central line along with enteral nutrition via NGT were administered and lasted until the 39th POD. After 2 weeks, enteral feeding gradually improved, so the baby started receiving peroral nutrition via bottle. The patient achieved her full enteral intake on POD 38. The baby was discharged from the hospital on POD 46 with highly improved body weight – 2485 g. At the follow-up of 9 months (Fig. 3), the baby was doing well with a body weight of 7500 g.

The overall control system for an open-frame Remotely Operated Vehicle (ROV) is typically built from three subsystems: guidance, navigation and control (GNC). The control allocation plays a vital role in the control subsystem. Typically, open-frame underwater vehicles have p actuators (thrusters) for the motion in the horizontal plane, and the control allocation problem, in this case, is very complex and hard to visualise, because the normalised constrained control subset is a p-dimensional unit cube. The aim of this paper is to give a clear picture and a geometric interpretation of the problem and to introduce a hybrid method, based on the integration of a weighted pseudoinverse and the fixed-point method. The main idea of the hybrid method is visualised, and the deep geometric insight is provided using a “virtual” ROV in low-dimensional control spaces, including visualisation of the attainable command set, solution lines, control energy spheres and the role of pseudoinverse and fixed-point iterations. The same concepts are then extended to higher-dimensional cases, for open-frame ROV with four X-shaped (vectored) horizontal thrusters, which is one of the most common thruster configurations for commercial ROVs. The proposed hybrid method has been developed, integrated into a generic fault-tolerant ROV control system and evaluated in virtual and real-world environments off the west coast of Ireland using observation-class ROV Latis and work-class ROV Étaín.

E-learning is considered a leading application of digital technologies in educational systems. The aim of the paper is to explore the utilization and impact of digital technologies on an e-learning platform. For this purpose, research was conducted at the Moodle learning management system. Data from the e-learning platform were empirically evaluated in order to find key indicators of student performance in different courses. Student success with the e-learning system was evaluated using a mixed-method: Social Network Analysis, K-Means Clustering, and Multiple Linear Regression. The research was conducted at the University of Novi Sad, Faculty of Technical Sciences, Serbia. The results indicate a significant relationship between the performance of students and the use of digital educational resources from the e-learning platform.

Abstract:Charitable endowments known as vakıf bolstered the urbanization, Islamization, and Ottomanization of the western Balkans. Some of the wealthiest and the most famous of these endowments were established by Ottoman state officials native to the region. This article focuses on two such officials, Hüseyin Pasha Boljanić (d. 1595) and Kara Sinan Bey Boljanić (d. 1582). These two brothers entered into Ottoman service through the devşirme, a levy of young men from rural and mostly Christian subjects living in parts of Anatolia and the Balkans. Hüseyin Pasha and Kara Sinan Bey are somewhat exceptional because they were Poturnak oğlanları, Muslim recruits for the devşirme. This article examines the motives behind their endowments. It places these motives in the larger context of the brothers’ shared identity as Poturnak oğlanları, their commercial and military interests, their relationship with the republic of Ragusa (Dubrovnik), and their family’s connection to the famed Sokollus. In doing so, this article elucidates how endowments in the western Balkans reflected the backgrounds, regional identities, and personal interests of their benefactors, as well as how they were shaped by their benefactors’ intisap (political clientage) and kinship ties.

ABSTRACT The use of disease-specific signatures of microRNAs (miRNAs) in exosomes has become promising for clinical applications, either as biomarkers or direct therapeutic targets. However, a new approach for exosome enrichment and quantification of miRNAs is urgently needed for its clinical application, since the commercial techniques have shortcomings in quantity and quality. To overcome these deficiencies, we developed a new method for purification of exosomes with subsequent miRNA extraction, followed by quantitative reverse transcription polymerase chain reaction (RT-qPCR), and compared our assays with commercial techniques. For the establishment of these methods, numerous reagents, parameters, and combinations thereof were examined. Our new technique for exosome extraction is based on a mannuronate-guluronate polymer (MGP) which avoids co-precipitating plasma proteins. Quality, concentration and biological activity of the isolated exosomes were examined by Western blot, Nanoparticle Tracking Analysis (NTA), and confocal microscopy. A combination of chaotropic and non-chaotropic salts was used to extract miRNAs from plasma, serum, and exosomes, allowing the exclusion of hazardous components, such as phenol/chloroform. The performance of the miRNAs extraction was verified by RT-qPCR. The chemistry and TaqMan probe were also optimized for RT-qPCR. Sensitivity, efficiency, and linearity of RT-qPCR were tested on serial dilutions of synthetic miR-16 and miR-142. Our established procedure covers all steps of miRNA analyses, and measures the levels of either cell-free and exosomal miRNAs in plasma, serum and other body fluids with high performance.

Following publication of the original article [1], the authors opted to correct the name of co-author Amra Zalihić from Zahilić to Zalihić. The original article has been corrected.