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Abstract Background Fludarabine, is one of the most active single agents in the treatment of chronic lymphocytic leukemia (CLL). Over time, however, virtually all CLL patients become fludarabine-refractory. To elucidate whether microRNAs are involved in the development of fludarabine resistance, we analyzed the expression of 723 human miRNAs before and 5-days after fludarabine mono-therapy in 17 CLL patients which were classified as responder or refractory to fludarabine treatment based on NCI criteria. Results By comparing the expression profiles of these two groups of patients, we identified a microRNA signature able to distinguish refractory from sensitive CLLs. The expression of some microRNAs was also able to predict fludarabine resistance of 12 independent CLL patients. Among the identified microRNAs, miR-148a, miR-222 and miR-21 exhibited a significantly higher expression in non-responder patients either before and after fludarabine treatment. After performing messenger RNA expression profile of the same patients, the activation of p53-responsive genes was detected in fludarabine responsive cases only, therefore suggesting a possible mechanism linked to microRNA deregulation in non-responder patients. Importantly, inhibition of miR-21 and miR-222 by anti-miRNA oligonucleotides induced a significant increase in caspase activity in fludarabine-treated p53-mutant MEG-01 cells, suggesting that miR-21 and miR-222 up-regulation may be involved in the establishment of fludarabine resistance. Conclusions This is the first report that reveals the existence of a microRNA profile that differentiate refractory and sensitive CLLs, either before and after fludarabine mono-therapy. A p53 dysfunctional pathway emerged in refractory CLLs and could contribute in explaining the observed miRNA profile. Moreover, this work indicates that specific microRNAs can be used to predict fludarabine resistance and may potentially be used as therapeutic targets, therefore establishing an important starting point for future studies.

In the present article, we aimed at construing a new quantitative measure of children's agency in Palestine. Within a socio-ecological and culturally and contextually informed perspective, the study introduces the development of a new instrument to investigate and evaluate children's agentic practices within their living contexts and their daily lives. First, we evaluated the model of measurement of WCAAS-Pal using a sequential exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). Following the principles of testing a quantitative measure in the context of the dual-frame sampling method, the process of validating the quantitative measure was conducted on a group of 1166 Palestinian children aged 9 to 14 years (m = 11.58, sd = 1.54). Second, a sample of 251 Palestinian children aged between 9 and 14 years (m = 11.82, sd = 1.53) was used to compute the reliability of the instrument along with both convergent and divergent validity using the Children Hope Scale and the Children Revised Impact of Event Scale-Arabic Version measures, respectively. The results of the EFA suggested a baseline seven-factor structure to be further assessed via CFA. a complex web of agency domains that might contribute to the child psychological functioning when forced to leave in conditions of ongoing threat and military violence emerged from the analysis., Author(s): Guido Veronese [sup.1] , Alessandro Pepe [sup.1] , Federica Cavazzoni [sup.1] , Hania Obaid [sup.1] , Shaher Yaghi [sup.2] Author Affiliations: (1) grid.7563.7, 0000 0001 2174 1754, Department of [...]

The current investigation was conducted to test the correlation between fear due to coronavirus (COVID-19) and mental health outcomes (stress, depression, and anxiety) and the mediating role of social support during the Covid-19 Pandemic in Palestine. Structural equation modeling (SEM) was performed to test the conceptual model, where fear of Covid-19 was considered as a predictor, social support as a mediating variable, and mental health (stress, depression, and anxiety) as outcomes. The participants involved were 370 Palestinians, 266 females, and the remaining were males. Participants were recruited through online methods; Facebook advertising, Network email, and Twitter during the COVID-19 in Palestine. Results of the study showed that fear related to COVID-19 was positively and significantly correlated with mental health outcomes (anxiety; r = .29, p < .01, depression; r = .25, p < .01, and stress; r = .36, p < .01), while negatively correlated to perceived emotional support (r = -.30, p < .01), support seeking (r = -.29, p < .01), and received support (r = -.31, p < .01). Results of SEM indicated a standardized total effect of social support on mental health outcomes ([beta].sub.X, M = -.57; p < .001), and an indirect but statistically significant effect (via social support, [beta].sub.X, M, Y = -. 286; p < .01). These results indicate that social support fully mediated the relationship between fear associated with COVID-19 and mental health distress (stress, depression, and anxiety). The current study supported previous findings demonstrating that fear related to COVID-19 positively correlated with mental health distress (depression, anxiety, and stress). In addition, social support mediated the relationship between fear of COVID19 and mental health outcomes. However, further investigations are needed to test the correlation between current study variables and other associated factors and develop intervention programs targeting affected populations during crises to enhance mental health outcomes., Author(s): Fayez Azez Mahamid [sup.1] , Guido Veronese [sup.2] , Dana Bdier [sup.3] Author Affiliations: (1) grid.11942.3f, 0000 0004 0631 5695, Psychology and Counseling Department, An- Najah National University, , [...]

Typhoid fever (Typhoid or enteric fever) is still the most common bacterial bloodstream infection worldwide, caused by Salmonella typhi. The transmission route is indirect through passive vehicles such as contaminated water or food. Main clinical findings are a fever lasting more than three days, abdominal symptoms, leukocytosis, and anemia. Typhoid can cause a wide range of multi-organ complications. We report a particularly severe form of this infection complicated by superior mesenteric vein and splenic vein thrombosis, an extremely uncommon manifestation.

Abstract Background One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. Methods/Design The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. Discussion The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia. Trial Registration Clincaltrials.gov Identifier: NCT00395915

Abstract Background Colorectal cancer develops through two main genetic instability pathways characterized by distinct pathologic features and clinical outcome. Results We investigated colon cancer samples (23 characterized by microsatellite stability, MSS, and 16 by high microsatellite instability, MSI-H) for genome-wide expression of microRNA (miRNA) and mRNA. Based on combined miRNA and mRNA gene expression, a molecular signature consisting of twenty seven differentially expressed genes, inclusive of 8 miRNAs, could correctly distinguish MSI-H versus MSS colon cancer samples. Among the differentially expressed miRNAs, various members of the oncogenic miR-17-92 family were significantly up-regulated in MSS cancers. The majority of protein coding genes were also up-regulated in MSS cancers. Their functional classification revealed that they were most frequently associated with cell cycle, DNA replication, recombination, repair, gastrointestinal disease and immune response. Conclusion This is the first report that indicates the existence of differences in miRNA expression between MSS versus MSI-H colorectal cancers. In addition, the work suggests that the combination of mRNA/miRNA expression signatures may represent a general approach for improving bio-molecular classification of human cancer.

Abstract Background Nidogens are highly conserved proteins of basement membranes. Two nidogen proteins, nidogen 1 and nidogen 2, are known in mammals. Results We show that CpG islands of both NID1 and NID2 genes are aberrantly methylated in human cancer samples and cancer cell lines. For both genes, methylation was correlated with loss of gene transcription in human cell lines. Furthermore, demethylation of the NID1 and NID2 promoters restored gene transcription, demonstrating that methylation was responsible for silencing nidogen genes. In primary tumors, we detected NID1 promoter methylation in 67% of colon cancer samples and in 90% of gastric cancers. NID2 promoter was methylated in 29% of colon and 95% of gastric cancers. Immuno-staining for nidogen-2 confirmed the correlation between aberrant methylation and loss of nidogen expression also in primary tumors, implying that aberrant methylation was a mechanism for inhibiting nidogens expression in human gastrointestinal tumors. Conclusion These results suggest that loss of nidogens expression has a potential pathogenetic role in colon and stomach tumorigenesis. Nidogens are believed to connect laminin and collagen IV networks, hence stabilizing the basement membrane structure. Nidogens are also important for cell adhesion, as they establish contacts with various cellular integrins. Loss of nidogen expression may favor invasion and metastasis of cancer cells by loosening cell interaction with basal membrane and by weakening the strength of the basement membrane itself, first barrier from the connective vascularized matrix.

People with diabetes are at higher risk of serious complications from many vaccine-preventable diseases (VPDs). Some studies have highlighted the potential impact of glycosylated hemoglobin levels (HbA1c), but no systematic review has synthesized these findings. Of the 823 identified studies, 3 were included, for a total of 705,349 participants. Regarding the incidence of herpes zoster (HZ), one study found that higher HbA1c levels at the baseline (>10.3%) were associated with a significantly higher risk of HZ of 44%, compared to those with a good HbA1c control (6.7%). On the contrary, the second one reported that when compared to the reference group (HbA1c of 5.0–6.4%), participants with a HbA1c less than 5.0% were at higher risk of HZ of 63%, whilst participants with a HBA1c more than 9.5% had a similar risk. Finally, the third study observed that diabetes, defined using a value of HbA1c more than 7.5%, was associated with an increased risk of mortality in men with COVID-19. In conclusion, both high and low HBA1c levels appear to be associated with a higher risk of HZ. Regarding COVID-19, a value of HbA1c more than 7.5% was associated with a higher risk of death in COVID-19, but only in men.

Renewable energy communities foster the users’ engagement in the energy transition, paving the way to the integration of distributed renewable energy sources. So far, the scientific literature has focused on residential users in energy communities, thus overlooking the opportunities for industrial and commercial members. This paper seeks to bridge this gap by extending the analysis to the role of non-residential users. The proposed methodology develops an effective clustering approach targeted to actual non-residential consumption profiles. It is based on the k-means algorithm and statistical characterization based on relevant probability density function curves. The employed clusterization procedure allows for effectively reducing a sample of 49 real industrial load profiles up to 11 typical consumption curves, whilst capturing all the relevant characteristics of the initial population. Furthermore, a peer-to-peer sharing strategy is developed accounting for distributed and shared storage. Three scenarios are considered to validate the model with different shares of non-residential users, and the results are then evaluated by means of shared energy, self-consumption, and self-sufficiency indices. Moreover, the results show that the integration of a large non-residential prosumer in a REC may increase the self-sufficiency of residential members by 8.2%, self-consumption by 4.4%, and the overall shared energy by 37.3%. Therefore, the residential community consistently benefits from the presence of non-residential users, with larger users inducing more pronounced effects.

This paper focuses on developing a predictive model for wind energy production in Italy, aligning with the ambitious goals of the European Green Deal. In particular, by utilising real data from the SUD (South) Italian electricity zone over seven years, the model employs stochastic differential equations driven by (fractional) Brownian motion-based dynamic and generative adversarial networks to forecast wind energy production up to one week ahead accurately. Numerical simulations demonstrate the model’s effectiveness in capturing the complexities of wind energy prediction.

Background: Nurses play a pivotal role in combating antimicrobial resistance (AMR). However, the success of local and national AMR containment efforts hinges on the knowledge, attitude, and practice (KAP) of nursing staff and undergraduate students. Objectives: This study aims to explore the determinants of nurses’ KAP regarding AMR, offering insights to control the emergence and spread of drug-resistant pathogens. Methods: This cross-sectional, multicenter survey involving Italian nurses, nursing students, and healthcare professionals was conducted administering an anonymous online questionnaire focusing on AMR. The median score of 12 was taken as the cutoff for “good KAP.” The association between study variables and good KAP was assessed using chi-square or t-tests, followed by multivariable logistic regression analysis for statistically significant (p < 0.05) variables. Findings: Among 848 participants, 61.9% (n = 525) were students, and 39.6% (n = 336) scored as having “low KAP.” High KAP was associated with being female and studying AMR independently. Conversely, living in southern Italy and receiving AMR training from pharmaceutical companies were associated with low KAP. Conclusions: Among Italian nurses, AMR awareness relies on those who have studied AMR as self-taught and is affected by gender and region. Italian universities lack in lectures on AMR management, and much needs to be done to improve awareness of antimicrobial stewardship among nonmedical health workers.

The skin microbiota, with its millions of bacteria, fungi, and viruses, plays a key role in balancing the health of the skin and scalp. Its continuous exposure to potentially harmful stressors can lead to abnormalities such as local dysbiosis, altered barrier function, pathobiont overabundance, and infections often sustained by multidrug-resistant bacteria. These factors contribute to skin impairment, deregulation of immune response, and chronic inflammation, with local and systemic consequences. In this scenario, according to the needs of the bio-circular-green economy model, novel harmless strategies, both for regulating the diverse epidermal infectious and inflammatory processes and for preserving or restoring the host skin eubiosis and barrier selectivity, are requested. Vitis vinifera L. leaves and their derived extracts are rich in plant secondary metabolites, such as polyphenols, with antioxidant, anti-inflammatory, antimicrobial, and immunomodulatory properties that can be further exploited through microbe-driven fermentation processes. On this premise, this literature review aims to provide an informative summary of the most updated evidence on their interactions with skin commensals and pathogens and on their ability to manage inflammatory conditions and restore microbial biodiversity. The emerging research showcases the potential novel beneficial ingredients for addressing various skincare concerns and advancing the cosmeceutics field as well.

Clinical or microbiological factors potentially associated with prolonged COVID-19 PCR positivity are still poorly underexplored, but they could be of importance for public-health and clinical reasons. The objective of our analysis is to explore demographic, clinical, and microbiological factors potentially associated with a prolonged positivity to SARS-CoV-2 among 222 hospitalized patients. Prolonged detection positivity for SARS-CoV-2 RNA in swap samples, defined as positivity more than 21 days, was the outcome of interest. The 56 cases with a prolonged positivity to SARS-CoV-2 were matched for age and sex with 156 controls. The cases reported a significantly higher presence of diabetes mellitus, autoimmune diseases, chronic kidney diseases, and acute coronary syndrome. Moreover, the viral load was significantly higher in a period of prolonged positivity compared to a normal period. In the multivariable analysis, the presence of autoimmune diseases and chronic kidney disease were significantly associated with an increased risk of prolonged positivity as well as medium viral load or high viral load, i.e., low Ct value ≤ 30 indicating high viral load. The results of this study confirmed that in a large population of hospitalized patients with COVID-19 manifestations, the prolonged positivity of SARS-CoV-2 detection with nasopharyngeal swab was mainly related to autoimmune diseases, chronic kidney disease, and to baseline viral load.

Background: Prolactinoma, the most common pituitary adenoma, is usually treated with dopamine agonist (DA) therapy like cabergoline. Surgery is second-line therapy, and radiotherapy is used if surgical treatment fails or in relapsing macroprolactinoma. Objective: This study aimed to provide economic evidence for the management of prolactinoma in Italy, using a cost-of-illness and cost-utility analysis that considered various treatment options, including cabergoline, bromocriptine, temozolomide, radiation therapy, and surgical strategies. Methods: The researchers conducted a systematic literature review for each research question on scientific databases and surveyed a panel of experts for each therapeutic procedure’s specific drivers that contributed to its total cost. Results: The average cost of the first year of treatment was €2,558.91 and €3,287.40 for subjects with microprolactinoma and macroprolactinoma, respectively. Follow-up costs from the second to the fifth year after initial treatment were €798.13 and €1,084.59 per year in both groups. Cabergoline had an adequate cost-utility profile, with an incremental cost-effectiveness ratio (ICER) of €3,201.15 compared to bromocriptine, based on a willingness-to-pay of €40,000 per quality-adjusted life year (QALY) in the reference economy. Endoscopic surgery was more cost-effective than cabergoline, with an ICER of €44,846.64. Considering a willingness-to-pay of €40,000/QALY, the baseline findings show cabergoline to have high cost utility and endoscopic surgery just a tad above that. Conclusions: Due to the favorable cost-utility profile and safety of surgical treatment, pituitary surgery should be considered more frequently as the initial therapeutic approach. This management choice could lead to better outcomes and an appropriate allocation of healthcare resources.

The current study aimed to test the association between environmental degradation, eco-anxiety and post-traumatic symptoms, and whether coping strategies mediate the association between these variables among a sample of Palestinian adults. The sample of our study consisted of 554 Palestinian adults, of whom 392 identified as female and 162 as male. Participants’ age ranged from 19 to 54 years old (M = 35.8, SD = 12.31). They were all recruited from online advertisements, e-mail campaigns and social media. The findings of our study revealed that post-traumatic stress symptoms positively correlated with environmental degradation, eco-anxiety and avoidant coping and negatively correlated with problem-focused coping and emotion-focused coping. Results of structural equation modeling revealed that coping strategies mediated the association between environmental degradation, echo-anxiety and post-traumatic stress symptoms. The findings of our study emphasize the need for tailored psychological support and coping strategies for individuals experiencing eco-anxiety and post-traumatic stress symptoms in the face of environmental challenges.