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Nursing retention is a major challenge globally. Ongoing workforce instability across countries underscores the need to understand the factors influencing turnover and nursing retention. Trust is a crucial element in managing workplace relationships between nurse managers and nurses. Existing studies have shown the direct impact of trust on employees’ intention to leave their job but have not explored the effects of potential mediators such as organizational commitment. The aim of this study was to examine the impact of trust in the leader on nurses’ intention to leave their job through the mediation of organizational commitment. A cross-sectional study was conducted in Italy. A convenience sample of 1853 nurses completed a self-report survey. The study tested a hypothesis-based mediation model using structural equation modeling, which showed good fit indices. The results indicated that trust in the leader had a significant impact on nurses’ intention to leave, and this relationship was partially mediated by organizational commitment. Nurses who trust their leader are more likely to demonstrate higher levels of organizational commitment, resulting in a lower intention to leave their job. Furthermore, organizational commitment and trust emerge as critical factors in reducing nurses’ intention to leave their current positions. Therefore, managers can reduce nurses’ intention to leave by building trustful relationships that enhance organizational commitment.This study was not registered.

Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease with no approved therapies. The ursodeoxycholic acid (UDCA) has been widely used, although there is no evidence that the use of UDCA delays the time to liver transplant or increases survival. Several candidate drugs are currently being developed. The largest group of these new agents is represented by FXR agonists, including obeticholic acid, cilofexor, and tropifexor. Other agents that target bile acid metabolism are ASTB/IBAP inhibitors and fibroblasts growth factor (FGF)19 analogues. Cholangiocytes, the epithelial bile duct cells, play a role in PSC development. Recent studies have revealed that these cells undergo a downregulation of GPBAR1 (TGR5), a bile acid receptor involved in bicarbonate secretion and immune regulation. Additional agents under evaluation are PPARs (elafibranor and seladelpar), anti-itching agents such as MAS-related G-protein–coupled receptors antagonists, and anti-fibrotic and immunosuppressive agents. Drugs targeting gut bacteria and bile acid pathways are also under investigation, given the strong link between PSC and gut microbiota.

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.

The gastrointestinal tract (GIT) wet pool size (GITwps) refers to the total amount of wet contents in GIT, which in small ruminants can reach up to 19% of their body weight (BW). This study aimed to develop models to comprehensively predict GITwps in small ruminants using a meta-regression approach. A dataset was created based on 21 studies, comprising 750 individual records of sheep and goats. Various predictor variables, including BW, sex, breed, species, intake level, physiological states, stages and types of pregnancy, dry matter intake, and neutral detergent fiber intake (NDFI), were initially analyzed through simple linear regression. Subsequently, the variables were fitted using natural logarithm transformations, considering the random effect of the study and residual error, employing a supervised forward selection procedure. Overall, no significant relationship between GITwps and BW (p = 0.326) was observed for animals fed a milk-based diet. However, a strong negative linear relationship (p < 0.001) was found for animals on a solid diet, with the level of restriction influencing GITwps only at the intercept. Furthermore, the prediction of GITwps was independent of sex and influenced by species in cases where individuals were fed ad libitum. Pregnant females showed a noticeable reduction in GITwps, which was more pronounced in cases of multiple pregnancies, regardless of species (p < 0.01). The composition of the diet was found to be the primary factor affecting the modulation of GITwps, with NDFI able to override the species effect (p < 0.0001). Overall, this study sheds light on the factors influencing GITwps in small ruminants, providing valuable insights into their digestive processes and nutritional requirements.

Compounds featuring a 1,2,4-oxadiazole core have been recently identified as a new chemotype of farnesoid X receptor (FXR) antagonists. With the aim to expand this class of compounds and to understand the building blocks necessary to maintain the antagonistic activity, we describe herein the synthesis, the pharmacological evaluation, and the in vitro pharmacokinetic properties of a novel series of 1,2,4-oxadiazole derivatives decorated on the nitrogen of the piperidine ring with different N-alkyl and N-aryl side chains. In vitro pharmacological evaluation showed compounds 5 and 11 as the first examples of nonsteroidal dual FXR/Pregnane X receptor (PXR) modulators. In HepG2 cells, these compounds modulated PXR- and FXR-regulated genes, resulting in interesting leads in the treatment of inflammatory disorders. Moreover, molecular docking studies supported the experimental results, disclosing the ligand binding mode and allowing rationalization of the activities of compounds 5 and 11.

Pancreatic cancer is a leading cause of cancer mortality and is projected to become the second-most common cause of cancer mortality in the next decade. While gene-wide association studies and next generation sequencing analyses have identified molecular patterns and transcriptome profiles with prognostic relevance, therapeutic opportunities remain limited. Among the genes that are upregulated in pancreatic ductal adenocarcinomas (PDAC), the leukaemia inhibitory factor (LIF), a cytokine belonging to IL-6 family, has emerged as potential therapeutic candidate. LIF is aberrantly secreted by tumour cells and promotes tumour progression in pancreatic and other solid tumours through aberrant activation of the LIF receptor (LIFR) and downstream signalling that involves the JAK1/STAT3 pathway. Since there are no LIFR antagonists available for clinical use, we developed an in silico strategy to identify potential LIFR antagonists and drug repositioning with regard to LIFR antagonists. The results of these studies allowed the identification of mifepristone, a progesterone/glucocorticoid antagonist, clinically used in medical abortion, as a potent LIFR antagonist. Computational studies revealed that mifepristone binding partially overlapped the LIFR binding site. LIF and LIFR are expressed by human PDAC tissues and PDAC cell lines, including MIA-PaCa-2 and PANC-1 cells. Exposure of these cell lines to mifepristone reverses cell proliferation, migration and epithelial mesenchymal transition induced by LIF in a concentration-dependent manner. Mifepristone inhibits LIFR signalling and reverses STAT3 phosphorylation induced by LIF. Together, these data support the repositioning of mifepristone as a potential therapeutic agent in the treatment of PDAC.

Background: Physical fitness (PF) is positively related to skeletal and metabolic health, and it had an inverse relation with obesity. Adolescents with obesity have the worst performance in PF and speed-agility (SA) that contributes to an augmented risk to develop pathologies. To the best of our knowledge, many studies analyzed the trends of obesity and SA separately, but there is a lack of data about SA ability trends in adolescents with obesity. We aimed to investigate SA trends in children with obesity in the last few decades to define the association between body weight and physical performance. Methods: We recruited 3.923 Caucasian children across the period 1985–2010 in the same school in Northern Italy, near Milan. Once a year, at the ages of 11–12- and 13-years-old, we collected anthropometric measures and SA performance. We pooled the data into 5-year-period study waves and then stratified our analysis into test-sex-age BMI-z-score specific groups. Results: We reported an undetermined trend across years. The 4×5 m run test significantly decreased in adolescents with overweight/obesity, while we did not report a decline in 30 m and 60 m run tests. Conclusions: Fitness tests highlighted differences in normal weight compared to overweight/obese children, suggesting that it is crucial to carefully monitor PF capacities through the years.

Background & Aims: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. Methods: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn’s disease (CD) patients and three mouse models of colitis and Gpbar1−/− mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. Results: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. Conclusions: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α- and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2.

Medial compartment disease is a common occurrence in dogs affected by elbow dysplasia. Despite many treatments suggested in the literature, only few studies reported comparative outcomes in the short and long term. The aim of this study is to report and compare short- and long-term clinical and radiographic outcomes of dogs treated for medial compartment disease (MCD) by distal dynamic ulnar ostectomy (DUO), bi-oblique dynamic proximal ulnar osteotomy (BODPUO) and conservative management (CM). From 2016 to 2018, all medium to large dogs, aged between 5 and 12 months, affected by uni/bilateral MCD and treated by DUO, BODPUO or CM, were enrolled in this study and followed up for 24 months. Orthopedic and radiographic examinations were performed at T0, T2, T12 and T24 months after treatment. Lameness score, elbow arthralgia, elbow range of motion (ROM), osteoarthritis (OA) score and percentage of ulnar subtrochlear sclerosis (%STS) were evaluated at each time point. According to the treatment performed, dogs were divided into three groups: DUO, BODPUO and CM. Forty-five elbows from twenty-six dogs, treated with DUO (n = 17), BODPUO (n = 17) or CM (n = 11), were prospectively enrolled in the study. The patients enrolled in the CM group were older and showed more severe radiographic signs of OA, compared to those enrolled in the other two groups. Lameness and arthralgia scores (p < 10−4) were significantly decreased in patients that underwent surgical treatment and increased in patients managed conservatively (lameness p < 10−4, arthralgia p = 0.3068), at T12 and T24. OA score (p < 0.0040) and ROM (DUO, CM p < 10−4; BODPUO p = 0.0740) worsened in every study group, but %STS decreased in DUO (p = 0.0108), increased in the CM group (p = 0.0025) and remained unchanged in the BODPUO group (p = 0.2740). This study supports the clinical efficacy of DUO and BODPUO in reducing lameness, arthralgia and progression of %STS. Early diagnosis and surgical attention in patients affected by MCD can improve the short- and long-term outcome and reduce the progression of secondary changes.

The presence of intrathecal IgM synthesis (ITMS) has been associated with an aggressive multiple sclerosis (MS) clinical course. In the present systematic review, we aimed at assessing the prevalence of ITMS among different MS phenotypes. Moreover, we aimed at quantifying the risk of a second relapse in ITMS positive and oligoclonal IgG bands (OCGBs)-positive patients. We selected clinical studies reporting the ITMS prevalence assessed as oligoclonal IgM Bands (OCMBs), lipid-specific OCMBs (LS-OCMBs), and/or as an intrathecal IgM production > 0% (IgMLoc, Reiber formula). The overall prevalence of ITMS was higher in relapsing-remitting (RR) than clinically isolated syndrome (CIS) patients (40.1% versus 23.8%, p < 0.00001), while was in line with that detected in primary progressive MS (PPMS, 26.7%). Almost all patients (98%) with ITMS had also OCGBs. The risk of having a second relapse was higher in OCGBs positive patients (HR = 2.18, p = 0.007) but much higher in ITMS positive patients (HR = 3.62, p = 0.0005). This study revealed that the prevalence of ITMS is higher in RRMS patients. It suggests that the risk of having a second relapse, previously ascribed to OCGBs, may, to a certain extent, be related to the presence of intrathecal IgM.

Once known exclusively for their role in nutrients absorption, bile acids have emerged as signaling molecules, generated from cholesterol breakdown, acting on several immune cells by activating a variety of receptors including the G protein-coupled bile acid receptor 1 (GPABR1 or TGR5), the Farnesoid-X-receptor (FXR) and, as recently discovered, the retinoid-related orphan receptors (ROR)γt. GPBAR1, FXR, and RORγt are highly expressed in cells of the innate and adaptive immune system (i.e., dendritic cells (DCs), macrophages, innate lymphoid 3 cells (ILC3s), and T helper 17 (Th17) lymphocytes) and plays an important role in regulating intestinal and liver immunity, highlighting a role for various bile acid species in regulating immune responses to intestinal microbial antigens. While primary bile acids are generated from the cholesterol breakdown secondary bile acids, the GPBAR1 ligands, and oxo-bile acids derivatives, the RORγt ligands, are generated by the intestinal microbiota, highlighting the potential of these bile acids in mediating the chemical communication between the intestinal microbiota and the host. Changes in intestinal microbiota, dysbiosis, alter the composition of the bile acid pool, promoting the activation of the immune system and development of chronic inflammation. In this review, we focus on the molecular mechanisms by which an altered bile acid signaling promotes intestinal inflammation.

Pathogenic bacteria produce powerful virulent factors, such as pore-forming toxins, that promote their survival and cause serious damage to the host. Host cells reply to membrane stresses and ionic imbalance by modifying gene expression at the epigenetic, transcriptional and translational level, to recover from the toxin attack. The fact that the majority of the human transcriptome encodes for non-coding RNAs (ncRNAs) raises the question: do host cells deploy non-coding transcripts to rapidly control the most energy-consuming process in cells—i.e., host translation—to counteract the infection? Here, we discuss the intriguing possibility that membrane-damaging toxins induce, in the host, the expression of toxin-specific long non-coding RNAs (lncRNAs), which act as sponges for other molecules, encoding small peptides or binding target mRNAs to depress their translation efficiency. Unravelling the function of host-produced lncRNAs upon bacterial infection or membrane damage requires an improved understanding of host lncRNA expression patterns, their association with polysomes and their function during this stress. This field of investigation holds a unique opportunity to reveal unpredicted scenarios and novel approaches to counteract antibiotic-resistant infections.