The need for alternative treatment of multi-drug-resistant bacteria led to the increased design of antimicrobial peptides (AMPs). AMPs exhibit a broad antimicrobial spectrum without a distinct preference for a specific species. Thus, their mechanism, disruption of fundamental barrier function by permeabilization of the bacterial cytoplasmic membrane is considered to be rather general and less likely related to antimicrobial resistance. Of all physico-chemical properties of AMPs, their positive charge seems to be crucial for their interaction with negatively charged bacterial membranes. Therefore, we elucidate the role of electrostatic interaction on bacterial surface neutralization and on membrane disruption potential of two potent antimicrobial peptides, namely, OP-145 and SAAP-148. Experiments were performed on Escherichia coli, a Gram-negative bacterium, and Enterococcus hirae, a Gram-positive bacterium, as well as on their model membranes. Zeta potential measurements demonstrated that both peptides neutralized the surface charge of E. coli immediately after their exposure, but not of E. hirae. Second, peptides neutralized all model membranes, but failed to efficiently disrupt model membranes mimicking Gram-negative bacteria. This was further confirmed by flow cytometry showing reduced membrane permeability for SAAP-148 and the lack of OP-145 to permeabilize the E. coli membrane. As neutralization of E. coli surface charges was achieved before the cells were killed, we conclude that electrostatic forces are more important for actions on the surface of Gram-negative bacteria than on their cytoplasmic membranes.

Abstract The present study proposes the conceptual model, which traces the role of consumers’ high-quality consciousness, perceived brand equity, and luxury value perceptions on the intention to purchase masstige brands and tests it for the moderating role of generational cohort membership (X-ers, Y-ers, and Z-ers). To explore the relationship between variables of interest, we used a quantitative survey-based research design and emphasised a single product category – consumer electronics and a single masstige brand – Apple. The online survey questionnaire was developed on the Google platform and distributed among residents of Bosnia and Herzegovina using a snowball sampling technique. In the end, we received 354 usable responses. We used structural equation modelling and multigroup analysis to test the proposed conceptual model. Our findings suggest that quality consciousness is the most significant predictor of consumers’ intentions to buy a masstige brand, followed by perceived brand equity. Also, our results indicate that the relationships between independent variables (consumer-based brand equity, quality consciousness, overall luxury value) and dependent variables (intention to purchase a masstige brand) are contingent on generational differences. The present study deepens our scholarly understanding of masstige consumption and contributes to the theoretical notion of generation cohort theory in the context of masstige consumption.

Objective. The objective of this non-interventional post-marketing clinical trial was to analyze the antihypertensive effect and safety of a fixed combination of perindopril and indapamide in the treatment of unregulated essential hypertension. Patients and Methods. The prospective clinical trial included patients aged 20 to 75 years with essential hypertension and blood pressure values ≥140/90 mmHg at baseline. On the basis of the investigator’s decision, patients received 2 mg perindopril + 0.625 mg indapamide (group 2+0.625) or 4 mg perindopril + 1.25 mg indapamide (group 4+1.25). Results. The study included 1173 patients (426 patients in group 2+0.625 and 747 patients in group 4+1.25) at 27 investigational centers in Bosnia and Herzegovina. Mean blood pressure values at baseline and visits after nine months were significantly higher in the 4+1.25 group compared to the 2+0.625 group. There was a significant drop in systolic and diastolic blood pressure in both groups. The target values of systolic and diastolic blood pressure, according to the European Society of Cardiology (2018), were reached after nine months of therapy by more than 80% of patients in the 2+0.625 group, and this number was significantly higher compared to the 4+1.25 group where more than 60% of patients reached target values. Newly diagnosed patients had a better response to therapy. The percentage of patients receiving additional antihypertensive therapy decreased by the end of the study. Age, gender and the existence of diabetes mellitus were identified as negative predictors of target blood pressure achievement. The therapy showed a good safety profile. Conclusion. A fixed combination of perindopril and indapamide was effective and safe in the treatment of unregulated essential hypertension.

Objectives Oral health in children is additionally burdened with the presence of dental fear and anxiety (DFA). These clinical psychologic entities in their progressive stages inevitably lead to avoidance of dental appointments, which makes prevention and therapy of oral diseases more difficult. Upon the onset of DFA in general, as one of the emotional outcomes of stress in a dental office, most children patients could define the specific stressors that were most intense for them, which could predict the presence of DFA. Aim To examine the predictors of DFA presence in 9-12-year-old children, and investigate how they could explain the DFA occurrence in study participants. Material and Methods The sample consisted of 200 children aged from 9 to 12 years. The DFA presence was determined by the modified version of the CFSS-DS scale. The child's behavior in the dental office during the treatment was evaluated by the trained observer using Venham anxiety and behavior rating scales. Socioeconomic status, characteristics of dental office visits, and previous caries experience were also analyzed. Results The main DFA predictors were related to invasive dental treatments, where the behavior during dental treatment was the most accurate expression of the DFA appearance. Conclusions Invasive dental procedures are the main stressful factor for DFA occurrence. Predisposing factors could strengthen the DFA occurrence.

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Background: In the academic world, the debate continues on the subject of how far a lack of vitamin D can affect the healing of various wounds. Objective: To determine if basal serum levels of vitamin D significantly influence clinical parameters linked to post-extraction wound healing after surgical removal of impacted/semi-impacted third molars. Methods: A total of 23 patients were included in this study. Clinical outcome parameters were: edema, trismus, pain, soft tissue healing, and dry socket signs. The research was divided into four stages. Results: Due to the high prevalence of hypovitaminosis D (91%), patients were classified into an insufficient (≥ 20 ng/ml) or a deficient group (<20 ng/ml). The results showed no statistically significant differences in pain, edema, trismus, or soft tissue healing between those two groups. A slight statistical interaction was observed in the clinical parameters related to edema and trismus assessment, but not statistically significant. We did not notice signs of “dry socket” on any of the patients. Conclusion: Within its limitations (low number of patients, high prevalence of vitamin D deficiency), this pilot study failed to find a significant influence of serum vitamin D concentrations in wound healing or post-surgery symptom (pain, edema, trismus) development after third molar extraction. Further clinical investigations are necessary to elaborate on this function of vitamin D more precisely.

Atrial fibrillation is the most commonly experienced type of cardiac arrhythmia and is the most associated with substantial clinical occurrences and expenses. This arrhythmia often occurs in its "silent" asymptomatic form, revealed only after complications such as a stroke or congestive heart failure have transpired. New smart devices confer effective advantages in the detection of this heart arrhythmia, of which photoplethysmography-based smart devices have shown great potential, according to previous research. However, the solution becomes a problem as widespread use and high availability of various applications and smart devices may lead to substantial amounts of false and misleading recordings and information, causing unnecessary anxiety regarding arrhythmic occurrences diagnosed by the devices but not professionally confirmed. Thus, with most of the devices being photoplethysmography based for detection of atrial fibrillation, it is important to research devices studied up to this point to find the best smart device to detect the aforementioned arrhythmias.

In the present review, we briefly discuss the breakthrough advances in precision medicine using a tumor-agnostic approach and focus on BRAF treatment modalities, the mechanisms of resistance and the diagnostic approach in cancers with BRAF mutations. Tumor-type agnostic drug therapies work across cancer types and present a significant novel shift in precision cancer medicine. They are the consequence of carefully designed clinical trials that showed the value of tumor biomarkers, not just in diagnosis but in therapy guidance. Six tumor-agnostic drugs (with seven indications) have been approved through October 2022 by FDA. The first tumor-agnostic treatment modality was pembrolizumab for MSI-H/dMMR solid tumors, approved in 2017. This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions. Conclusion. Precision cancer medicine has substantially improved cancer diagnostics and treatment. Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration.

Background: Zearalenone is a widely spread mycotoxin, contaminant of most cereal grains. It has uterotropic, estrogenic and anabolic activity in farm animals. The results are hormonal disbalances as hyperestrogenism, Zearalenone inhibits follicle-stimulating hormone production, thus supressing ovarian follicle development and ovulation. Also, it induces oxidative stress. Melatonin acts as a potent natural antioxidant and regulates the reproductive function by modification of steroidogenesis. Objective: The present study was conducted to provide detailed qualitative histological analysis of uterus of female rats treated with zearalenone and melatonin and contribute to better understanding of the topic. Methods: Forty adult, female Wistar rats were equally divided into five groups: Z group – zearalenone, 0,3 mg/kg, i.g.; M group – melatonin, 10 mg/kg, i.p.; ZM group –concomitant application of zearalenone and melatonin in the same dosing regimen, VZ group–zearalenone vehiculum/sunflower oil, i.g. and MZ group–melatonin vehiculum/5% ethanol in Ringer, i.p. Animals were treated daily for 28 consecutive days. After that period, all animals were sacrificed to obtain samples for qualitative histological analysis using the light microscope. Results: Zearalenone led to the alterations of the uterine structures, predominantly in the endometrium that were characterized by metaplasia and hypertrophy of the epithelial cells and hypercellularity of the stroma. In the myometrium, zearalenone induced hypertrophy and hyperplasia of the myocytes. Conclusion: Melatonin, when applied together with zearalenone, blocked the adverse effects of the zearalenone.

The rapid pace of change in technology, business models, and work practices is causing ever-increasing strain on the global workforce. Companies in every industry need to train professionals with updated skill-sets in a rapid and continuous manner. However, traditional educational models — university classes and in-person degrees— are increasingly incompatible with the needs of professionals, the market, and society as a whole. New models of education require more flexible, granular and affordable alternatives. MIT is currently developing a new educational framework called Agile Continuous Education (ACE). ACE describes workforce level education offered in a flexible, cost-effective and time-efficient manner by combining individual, group, and real-life mentored learning through multiple traditional and emerging learning modalities. This paper introduces the ACE framework along with its different learning approaches and modalities (e.g. asynchronous and synchronous online courses, virtual synchronous bootcamps, and real-life mentored apprenticeships and internships) and presents the MIT Refugee Action Hub (ReACT) as an illustrative example. MIT ReACT is an institute-wide effort to develop global education programs for underserved communities, including refugees, displaced persons, migrants and economically disadvantaged populations, with the goal of promoting the learner’s social integration and formal inclusion into the job market. MIT ReACT’s core programs are the Certificate in Computer and Data Science (CDS) and the MicroMasters in Data, Economics and Development Policy, which consist of a combination of online courses, bootcamps, and global apprenticeships. Currently, MIT ReACT has regional presence in the Middle East and North Africa, East Africa, South America, Asia, Europe and North America.

In order to reduce CO2 emissions, hydrogen combustion has become increasingly relevant for technical applications. In this context, lean H2-air flames show promising features but, among other characteristics, they tend to exhibit thermo-diffusive instabilities. The formation of cellular structures associated with these instabilities leads to an increased flame surface area which further promotes the flame propagation speed, an important reference quantity for design, control, and safe operation of technical combustors. While many studies have addressed the physical phenomena of intrinsic flame instabilities in the past, there is also a demand to predict such flame characteristics with reduced-order models to allow computationally efficient simulations. In this work, a H2-air spherical expanding flame, which exhibits thermo-diffusive instabilities, is studied with flamelet-based modeling approaches both in a-priori and a-posteriori manner. A recently proposed Flamelet/Progress Variable (FPV) model, with a manifold based on unstretched planar flames, and a novel FPV approach, which takes into account a large curvature variation in the tabulated manifold, are compared to detailed chemistry (DC) calculations. First, both FPV approaches are assessed in terms of an a-priori test with the DC reference dataset. Thereafter, the a-posteriori assessment contains two parts: a linear stability analysis of perturbed planar flames and the simulation of the spherical expanding flame. Both FPV models are systematically analyzed considering global and local flame properties in comparison to the DC reference data. It is shown that the new FPV model, incorporating large curvature variations in the manifold, leads to improved predictions for the microstructure of the corrugated flame front and the formation of cellular structures, while global flame properties are reasonably well reproduced by both models.