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According to the World Health Organization (WHO), the incidence of HCV remains high (around 1.5 million new patients every year), and 80% of patients with acute infection will progress to chronic hepatitis and develop cirrhosis and even liver cancer. Furthermore, some extrahepatic pathologies may be correlated with HCV (such as mixed cryoglobulinemia, porphyria cutanea tarda, lichen planus, glomerulonephritis, Sjogren’s syndrome, Hodgkin and non-Hodgkin cell lymphoma, and others). In view of these secondary complications, together with the substantial risk of liver damage, the objective of this review was to research and suggest, based on the scientific evidence, the appropriate clinical use of drugs with direct antiviral action (AAD) according to the criteria of international medical organizations. This is to maximize the clinical benefits for patients and to facilitate access to DAA therapy for all patients with chronic hepatitis C. According to the WHO, no vaccine is currently available, and therapies using new antivirals and their combinations are now an effective and safer solution for patients than they have been in the past with the use of interferons. This study aims to analyse the history and knowledge of the pathogenic biomolecular mechanisms and current therapies for HCV.

Abstract The aim of this study was to investigate the relationship between source-specific ambient particulate air pollution concentrations and the incidence of dementia. The study encompassed 70,057 participants from the Västerbotten intervention program cohort in Northern Sweden with a median age of 40 years at baseline. High-resolution dispersion models were employed to estimate source-specific particulate matter (PM) concentrations, such as PM10 and PM2.5 from traffic, exhaust, and biomass (mainly wood) burning, at the residential addresses of each participant. Cox regression models, adjusted for potential confounding factors, were used for the assessment. Over 884,847 person-years of follow-up, 409 incident dementia cases, identified through national registers, were observed. The study population’s average exposure to annual mean total PM10 and PM2.5 lag 1–5 years was 9.50 µg/m3 and 5.61 µg/m3, respectively. Increased risks were identified for PM10-Traffic (35% [95% CI 0–82%]) and PM2.5-Exhaust (33% [95% CI − 2 to 79%]) in the second exposure tertile for lag 1–5 years, although no such risks were observed in the third tertile. Interestingly, a negative association was observed between PM2.5-Wood burning and the risk of dementia. In summary, this register-based study did not conclusively establish a strong association between air pollution exposure and the incidence of dementia. While some evidence indicated elevated risks for PM10-Traffic and PM2.5-Exhaust, and conversely, a negative association for PM2.5-Wood burning, no clear exposure–response relationships were evident.

A severe condition of sepsis can be a complication of necrotizing enterocolitis (NEC), which can occur in premature infants and becomes a medical challenge in the neonatal intensive care unit (NICU). It is a multifactorial intestinal disease (can affect both the small and large intestine) that can lead to ischemia of the intestinal tissues that evolves into acute organ necrosis. One of these factors is that different types of nutrition can influence the onset or the progression of the disease. Cow-milk-based infant formulas have been shown to cause it in premature infants more frequently than human milk. Recently, nutrition has been shown to be beneficial after surgery. Several issues still under study, such as the pathogenesis and the insufficient and often difficult therapeutic approach, as well as the lack of a common and effective prevention strategy, make this disease an enigma in daily clinical practice. Recent studies outlined the emerging role of the host immune system and resident gut microbiota, showing their close connection in NEC pathophysiology. In its initial stages, broad-spectrum antibiotics, bowel rest, and breastfeeding are currently used, as well as probiotics to help the development of the intestinal microbiota and its eubiosis. This paper aims to present the current knowledge and potential fields of research in NEC pathophysiology and therapeutic assessment.

The gastric milieu, because of its very low acidic pH, is very harsh for bacterial growth. The discovery of Helicobacter pylori (H.p.) has opened a new avenue for studies on the gastric microbiota, thus indicating that the stomach is not a sterile environment. Nowadays, new technologies of bacterial identification have demonstrated the existence of other microorganisms in the gastric habitat, which play an important role in health and disease. This bacterium possesses an arsenal of compounds which enable its survival but, at the same time, damage the gastric mucosa. Toxins, such as cytotoxin-associated gene A, vacuolar cytotoxin A, lipopolysaccharides, and adhesins, determine an inflammatory status of the gastric mucosa which may become chronic, ultimately leading to a gastric carcinoma. In the initial stage, H.p. persistence alters the gastric microbiota with a condition of dysbiosis, predisposing to inflammation. Probiotics and prebiotics exhibit beneficial effects on H.p. infection, and, among them, anti-inflammatory, antioxidant, and antibacterial activities are the major ones. Moreover, the association of probiotics with prebiotics (synbiotics) to conventional anti-H.p. therapy contributes to a more efficacious eradication of the bacterium. Also, polyphenols, largely present in the vegetal kingdom, have been demonstrated to alleviate H.p.-dependent pathologies, even including the inhibition of tumorigenesis. The gastric microbiota composition in health and disease is described. Then, cellular and molecular mechanisms of H.p.-mediated damage are clarified. Finally, the use of probiotics, prebiotics, and polyphenols in experimental models and in patients infected with H.p. is discussed.

Introduction: Pain management is paramount in paediatric dental care, influencing patient cooperation and future perceptions of dental treatment. The widely used Inferior Alveolar Nerve Block (IANB) anaesthesia faces challenges in children due to anatomical variations. The position of the mandibular foramen, which evolves with age, growth patterns, and facial types, necessitates customised approaches for effective paediatric pain management. Aim: To identify the position of the mandibular foramen amongst children aged 7-14 years with respect to age, gender, and facial types. Materials and Methods: In a cross-sectional study conducted in West Bengal, India, 126 children aged 7-14 were investigated from March 2021 to August 2022. The Orthopantomograms (OPG) and lateral cephalograms were assessed for the location of the mandibular foramen with respect to age, sex, and facial type in clear radiographs with normal growth. Statistical analysis encompassed descriptive statistics, Analysis of Variance (ANOVA), and multiple linear regression analysis. Results: A total of 126 x-rays were analysed across age, gender, and facial types, showing a mean age of 10.78 years. There were 52 (41.3%) males and 74 (58.7%) females. The distribution of subjects according to facial types was as follows: short (n=33, 26.2%), normal (n=19, 15.1%), and long (n=74, 58.7%). The vertical position of the mandibular foramen increased with age. No significant gender difference was observed regarding the vertical position of the mandibular foramen. However, a significant variation across facial types was observed, with individuals with normal faces exhibiting a greater vertical position. Conclusion: This study revealed that the vertical position of the mandibular foramen increases with age. There was no significant difference found between males and females in the location of the mandibular foramen; however, individuals with normal faces exhibited a greater vertical position of the same.

In recent years, Albania has seen a significant increase in wine production, which can be attributed to the growing interest in the diversity of native grape varieties. Among the most popular grape varieties are Kallmet, Shesh i zi (ShiZ), Shesh i bardhë (ShiB), and Cerruje, which are known for their distinctive wines as well as the planted area. A study was conducted to investigate the influence of the territory and vintage on phenolic compounds of single-variety wines from these grape varieties. Liquid chromatography identified and quantified thirty-one phenolic compounds, sub-grouped into flavonoids and non-flavonoids, with diode-array detection coupled to electrospray ionization tandem mass spectrometry (LC–DAD–ESI/MSn). Within the red wines group, the ShiZ variety wine presented the highest phenolic content (1037 mg/L), followed by Kallmet cv. (539 mg/L); conversely, in the white wine group, the ShiB wines (699 mg/L) were distinguished from the Cerruje variety. Gallic acid was the main phenolic compound, followed by procyanidin B3. ShiB and ShiZ had the highest levels, at 215 and 136 mg/L, respectively. Among flavanols, (+)-catechin was found in the highest levels, with the maximum in Kallmet cv. red wine (58.9 mg/L), followed by (-)-epicatechin (29.1 mg/L). The ShiB wine had the highest content of flavonols, with quercetin-3-O-glucuronide and quercetin-3-O-glucoside as the main contributors. The highest quantity of stilbenoids belonged to Kallmet red wine (1.59 mg/L). Applying Principal Component Analysis (PCA) in red and white wine groups made a good separation possible according to variety and region. However, a separation according to vintage year was not successful.

Background: Today, mycotoxins are considered critical contaminants in foodstuffs produced by fungi, highlighting the importance of food safety to human health. The toxigenic fungi invasion and mycotoxin production are highly variable and depend on climate, plant, and agronomic practices. Among these, Aflatoxins (AFs) are considered the most potent toxins. This study investigated the fungi presence and AFB1 contamination in corn and wheat grown in Albania during the 2022 harvesting year. Methods: Wheat samples were collected during the summer, while corn during the autumn, and further analyzed. Mycological contamination assessment applied the Verband Deutscher Landëirtschaftlicher Untersuchungs ̶ und Forschungsanstalten (VDLUFA) procedures. The AFB1 levels were measured using the Enzyme-Linked Immunosorbent Assay (ELISA) method. The MATLAB R2016b software was applied to perform statistical analysis. The Estimated Daily Intake on AFB1 was calculated to evaluate human exposure. Results: The genera Alternaria, Aspergillus, Cladosporium, Fusarium, and Penicillium were isolated, with higher rates of contamination in corn and the highest frequency Penicillium genus (77.89%). The Korça region presented a higher fungal load, 104 Colony Forming Unit (CFU)/g in corn. The AFB1 incidence (88.23%) in corn, was significantly higher than in wheat (4.91%). Additionally, the maximum level in corn was found 69.120 μg/kg, while in wheat, only 0.402 μg/kg. None of the wheat samples, in contrast to the 41.18% of corn samples, exceeded the threshold when referring to the respective Maximum Residue Levels. Conclusions: Our observation indicates a higher rate of AFB1 contamination in corn than in wheat. The high concentration levels and contamination incidence in corn require targeted interventions to reduce the AFB1 amounts. Strengthened regulation based on scientific evidence can reduce contamination outbreaks, economic implications, and potential benefits, such as increased consumer trust. Our study indicates that the exposure to AFB1 originates from corn consumption among the adult population. DOI: 10.18502/jfqhc.11.1.14996

Abstract In normal colon tissue, oestrogen receptor alpha (ERα) is expressed at low levels, while oestrogen receptor beta (ERβ) is considered the dominant subtype. However, in colon carcinomas, the ERα/β ratio is often increased, an observation that prompted us to further investigate ERα’s role in colorectal cancer (CRC). Here, we assessed ERα nuclear expression in 351 CRC patients. Among them, 119 exhibited positive ERα nuclear expression, which was significantly higher in cancer tissues than in matched normal tissues. Importantly, patients with positive nuclear ERα expression had a poor prognosis. Furthermore, positive ERα expression correlated with increased levels of the G-protein coupled cysteinyl leukotriene receptor 1 (CysLT1R) and nuclear β-catenin, both known tumour promoters. In mouse models, ERα expression was decreased in Cysltr1 −/− CAC (colitis-associated colon cancer) mice but increased in Apc Min/+ mice with wild-type Cysltr1. In cell experiments, an ERα-specific agonist (PPT) increased cell survival via WNT/β-catenin signalling. ERα activation also promoted metastasis in a zebrafish xenograft model by affecting the tight junction proteins ZO-1 and Occludin. Pharmacological blockade or siRNA silencing of ERα limited cell survival and metastasis while restoring tight junction protein expression. In conclusion, these findings highlight the potential of ERα as a prognostic marker for CRC and its role in metastasis.

Hepsin, a type II transmembrane serine protease, is commonly overexpressed in prostate and breast cancer. The hepsin protein is stabilized by the Ras‐MAPK pathway, and, downstream, this protease regulates the degradation of extracellular matrix components and activates growth factor pathways, such as the hepatocyte growth factor (HGF) and transforming growth factor beta (TGFβ) pathway. However, how exactly active hepsin promotes cell proliferation machinery to sustain tumor growth is not fully understood. Here, we show that genetic deletion of the gene encoding hepsin (Hpn) in a WAP‐Myc model of aggressive MYC‐driven breast cancer inhibits tumor growth in the primary syngrafted sites and the growth of disseminated tumors in the lungs. The suppression of tumor growth upon loss of hepsin was accompanied by downregulation of TGFβ and EGFR signaling together with a reduction in epidermal growth factor receptor (EGFR) protein levels. We further demonstrate in 3D cultures of patient‐derived breast cancer explants that both basal TGFβ signaling and EGFR protein expression are inhibited by neutralizing antibodies or small‐molecule inhibitors of hepsin. The study demonstrates a role for hepsin as a regulator of cell proliferation and tumor growth through TGFβ and EGFR pathways, warranting consideration of hepsin as a potential indirect upstream target for therapeutic inhibition of TGFβ and EGFR pathways in cancer.

The use of vertical-cavity-surface-emitting lasers with ability to operate at cryogenic temperatures (Cryo-VCSELs) is a promising path to implement optical data links between superconducting processors maintained in cryogenic environments (4 K range) and room temperature (RT) computing hardware. In order to achieve energy-efficient operation of a cryo-VCSEL, whether by passing current through the mirrors or utilizing intra-cavity contacts, a critical bottleneck for improving the operation is related to the p-doped distribute Bragg Reflectors (DBRs). This is because holes exhibit lower mobility and lower thermal conductivity compared to their n-side counterparts. To determine the actual temperature of an operating p-doped DBR and its impact on the behavior of the DBRs and the cryo-VCSEL, a thermal simulation using the finite-element method was conducted and validated with experimental results. Furthermore, we explored different mirror geometries to optimize both current flow and the growth complexity of the DBR. DBR layers with various interface shapes, such as uni-parabolic grading and three to five steps with different Al mole fractions, have been investigated. As a result of the study, we achieved more efficient operation at cryogenic temperatures, with a 60% reduction of the series resistance and a 39% reduction of the voltage penalty related to the p-doped DBR.

Superantigens, i.e., staphylococcal enterotoxins and toxic shock syndrome toxin-1, interact with T cells in a different manner in comparison to conventional antigens. In fact, they activate a larger contingent of T lymphocytes, binding outside the peptide-binding groove of the major histocompatibility complex class II. Involvement of many T cells by superantigens leads to a massive release of pro-inflammatory cytokines, such as interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor-alpha and interferon-gamma. Such a storm of mediators has been shown to account for tissue damage, multiorgan failure and shock. Besides conventional drugs and biotherapeutics, experiments with natural and biological products have been undertaken to attenuate the toxic effects exerted by superantigens. In this review, emphasis will be placed on polyphenols, probiotics, beta-glucans and antimicrobial peptides. In fact, these substances share a common functional denominator, since they skew the immune response toward an anti-inflammatory profile, thus mitigating the cytokine wave evoked by superantigens. However, clinical applications of these products are still scarce, and more trials are needed to validate their usefulness in humans.

Over 20 years after introducing and popularizing agile software development methods, those methods have proven effective in delivering projects that meet agile assumptions. Those assumptions require that projects be small and simple in scope and utilize small, colocated teams. Given this success, many agile advocates argue that agile should replace plan-driven methods in most or all project contexts, including those projects that deviate significantly from agile assumptions. However, today's reality is that a diversity of agile, plan-driven, and hybrid approaches continue to be widely used, with many individual organizations using multiple approaches across different projects. Furthermore, while agile advocates argue that the primary barrier to agile adoption is the inertia of traditional organizational cultures, there are, in fact, many rational motivations for utilizing plan-driven and hybrid methods based on individual project characteristics. For information systems students, this creates confusion in two ways: 1) understanding that there is no single best way to develop software in all circumstances but, rather, teams should choose an optimal project approach based on project characteristics, and 2) unpacking and analyzing the wide range of project characteristics -- including multiple dimensions in functional requirements, non-functional requirements (NFRs), and team characteristics -- that impact that choice. This paper addresses both sources of confusion by utilizing case studies from 22 interviews of enterprise software development leaders. The paper analyzes each case utilizing a "home grounds" model that graphically portrays key project characteristics and their impact on the optimal choice of software development project approach.

Background and purpose: Investigation of treatment options in the pediatric population necessitates the use of valid patient-reported outcome measures (PROMs). We aimed to assess the construct validity and internal consistency of the Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) in the pediatric population with upper extremity fractures treated both operatively and conservatively. Patients and methods: QuickDASH, along with several reference PROMs and objective outcome measures, was obtained from 148 5- to 18-year-old patients with a humeral medial epicondyle fracture or a fracture of the distal forearm in a cross-sectional setting with a single follow-up visit. Spearman’s rank correlation and linear regression models were used to assess convergent validity, exploratory factor analysis (EFA) to assess structural validity, and Cronbach’s alpha to investigate internal consistency. Results: The direction and magnitude of correlation showed by QuickDASH with reference outcome measures was consistent and demonstrated good convergent validity. EFA indicated a 3-factor model with poor fit indices and structural validity remained questionable. Construct validity was considered acceptable overall. QuickDASH demonstrated good internal consistency with an acceptable Cronbach’s alpha (α = 0.75). Conclusion: QuickDASH demonstrated acceptable construct validity and good internal consistency and is thus a valid instrument, with some limitations, to assess disability and quality of life in pediatric patients with upper extremity fractures.

Abstract Research‐based knowledge is essential for effective conservation and restoration of threatened aquatic species and habitats. Here, our aim was to gather this knowledge on the lake‐dwelling grayling (Thymallus thymallus), typically a riverine fish. Such atypical populations are particularly vulnerable to anthropogenic impacts, including fishing pressure, climate change, eutrophication and waterway construction, some of which affect especially the early life stages. However, there is little information available to guide management and conservation of grayling in lakes. Accordingly, we assessed characteristics of the nursery areas in the threatened grayling population of Lake Puruvesi (eastern Finland). In particular, we used beach seines in two consecutive years to sample lakeshore sites (including islands) that were a priori presumed suitable for grayling. We assessed the occurrence of grayling fry (larvae and post‐larvae

Purpose Various complications are associated with percutaneous endoscopic gastrostomy (PEG) procedures in children. The push technique is being increasingly used, but its complications are insufficiently characterized. We aimed to assess all complications related to PEG procedures and compare the safety of the pull and push techniques.Methods Retrospective review of consecutive pediatric patients who underwent PEG between 2002 and 2020.Results In total, 216 children underwent 217 PEG procedures. The push technique was used in 138 (64%) cases, and the pull technique in 79 (36%) cases. The median follow-up time was 6.1 (0.1–18.3) years. The complication rate was high (57%) and patients experienced complications years after the procedure. Overall, 51% and 67% of patients experienced complications in the push and pull groups, respectively. The rates of minor and major complications were higher in the pull group than in the push group (63% vs 48%, p=0.028; and 11% vs 6%, p=0.140, respectively). Reoperation was also more common in the pull group (17% vs 7%, p=0.020).Conclusions The overall complication rate of PEG procedures is high. Fortunately, most complications are mild and do not require reoperations. The increasing push technique appears to be safer than the traditional pull technique. Significant long-term morbidity is related to gastrostomies in children.

Abstract The immunoglobulin (Ig) superfamily members are involved in cell adhesion and migration, complex multistep processes that play critical roles in embryogenesis, wound healing, tissue formation, and many other processes, but their specific functions during embryonic development remain unclear. Here, we have studied the function of the immunoglobulin superfamily member 3 (IGSF3) by generating an Igsf3 knockout (KO) mouse model with CRISPR/Cas9-mediated genome engineering. By combining RNA and protein detection methodology, we show that during development, IGSF3 localizes to the neural crest and a subset of its derivatives, suggesting a role in normal embryonic and early postnatal development. Indeed, inactivation of Igsf3 impairs the ability of the vagal neural crest cells to migrate and normally innervate the intestine. The small intestine of Igsf3 KO mice shows reduced thickness of the muscularis externa and diminished number of enteric neurons. Also, misalignment of neurons and smooth muscle cells in the developing intestinal villi is detected. Taken together, our results suggest that IGSF3 functions contribute to the formation of the enteric nervous system. Given the essential role of the enteric nervous system in maintaining normal gastrointestinal function, our study adds to the pool of information required for further understanding the mechanisms of gut innervation and etiology behind bowel motility disorders.