Introduction Systemic corticosteroids are the mainstay of treatment for immune checkpoint inhibitor induced (CPI) colitis but are associated with complications including life-threatening infection. The topically acting oral corticosteroid beclomethasone dipropionate (BD) is an effective treatment for mild to moderate flares of ulcerative colitis, and has fewer side effects than systemic corticosteroids. We hypothesized that BD would be an effective treatment for CPI-induced colitis. Methods We performed a retrospective analysis of all patients who started BD for CPI-induced colitis at three UK cancer centers between November 2017 and October 2020. All patients underwent endoscopic assessment and biopsy. The initial regimen of BD was 5 mg once daily for 28 days. Data were collected from electronic patient records. Clinical outcomes were assessed at 28 days after initiation of treatment. Results Twenty-two patients (14 male) with a median age of 64 (range 45–84) with CPI-induced colitis were treated with BD. At baseline, the median number of loose stools in a 24-hour period was six (common terminology criteria for adverse events, CTCAE grade diarrhea=2). Thirteen patients (59%) were dependent on systemic corticosteroids prior to starting BD. Baseline sigmoidoscopy showed moderate inflammation (Mayo Endoscopic Score (MES) = 2) in two patients (9%), mild inflammation (MES=1) in nine patients (41%) and normal findings (MES=0) in eleven patients (50%). Twenty patients (91%) had histopathological features of inflammation. All 22 patients (100%) had a clinical response to BD and 21 (95%) achieved clinical remission with a return to baseline stool frequency (CTCAE diarrhea=0). Ten patients (45%) had symptomatic relapse on cessation of BD, half within 7 days of stopping. All patients recaptured response on restarting BD. No adverse events were reported in patients treated with BD. Conclusions Topical BD represents an appealing alternative option to systemic immunosuppressive treatments to treat colonic inflammation. In this study, BD was effective and safe at inducing remission in CPI-induced colitis, which was refractory to systemic corticosteroids. Further randomized studies are needed to confirm these findings and determine the optimum dosing regimen.

Abstract This scientific paper examines the relationship between macroeconomic variables whose performance is measured under the implementation of Quantitative Easing in the US, by estimating vector autoregression (VAR) and Impulse Response Function with monthly data from US Federal Reserve, observed during the period January 1994-January 2022. Variables include: Consumer Price Index (CPIAUCSL); Industrial Production (INDPRO); Unemployment Rate (UNRATE); Interest Rates, Government Securities, Government Bonds (INTGSBUSM193N); Volatility Index (VIXCLS), Real Broad Effective Exchange Rate (RBUSBIS), Federal Surplus or Deficit (MTSDS133FMS), Money Supply M1 (WM1NS), M2 (WMNS), M3 (MABMM301USM189S). An evidence on macroeconomic variables of Consumer Price Index and Industrial Production when evaluating the effectiveness of QE is provided.

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.

Reliable power system operation with 100% inverter-based resources (IBRs) is an unsolved and challenging problem. One of the most challenging factors is ensuring power system stability after N-1 contingencies. This paper presents a promising solution using an operator support system (OSS) to enable stable operation of power system with up to 100% IBR generation. The OSS consists of two components. First is dynamic security assessment to evaluate the system resiliency, and identify critical N-1 contingencies that could endanger the system. The second component, as the key technology behind the OSS, is dynamic security optimization (DSO). The DSO optimizes the control parameters of generators and inverters to improve the stability of the system towards the identified N-1 contingencies. The key to system with 100% IBRs, as emphasized in many recent studies, is to establish the grid frequency reference using grid-forming (GFM) inverters. We show through high-fidelity Electro-Magnetic-Transient (EMT) simulations of the future generation models of Hawai‘i Island system with 100% IBR capacity that a system with 100% IBRs can be operated stably with the help of GFM inverters, and appropriate controller parameters can be found by DSO for the inverters. The DSO is verified via 28 critical N-1 contingencies of Hawai‘i Island system identified by Hawaiian Electric. The simulation results verify the effectiveness of DSO, and show significant stability improvement from DSO.

The integration of renewable generation in electrical power systems is exponentially increasing for multiple reasons. First, a fast decarbonization of the electrical energy system is a critical milestone to slow climate change and facilitate the decarbonization of other energy sectors, such as transportation and heat. Second, renewable generation from wind and solar have become much cheaper compared to conventional sources like gas, coal, and nuclear. Third, renewable generation is in many cases decentralized, which increases the resilience of the energy system, for example, in the face of natural disasters.

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.

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.

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.