EP-1349: Long term results of a phase I-II study of moderate hypofractionated IGRT in prostate cancer

Pregnant women diagnosed with gestational diabetes mellitus subjected to diet (GDMd) that do not reach normal glycaemia are passed to insulin therapy (GDMi). GDMd associates with increased human cationic amino acid transporter 1 (hCAT-1)-mediated transport of L-arginine and nitric oxide synthase (NOS) activity in foetoplacental vasculature, a phenomenon reversed by exogenous insulin. Whether insulin therapy results in reversal of the GDMd effect on the foetoplacental vasculature is unknown. We assayed whether insulin therapy normalizes GDMd-associated foetoplacental endothelial dysfunction. Primary cultures of human umbilical vein endothelial cells (HUVECs) from GDMi pregnancies were used to assay L-arginine transport kinetics, NOS activity, p44/42mapk and protein kinase B/Akt activation, and umbilical vein rings reactivity. HUVECs from GDMi or GDMd show increased hCAT-1 expression and maximal transport capacity, NOS activity, and eNOS, and p44/42mapk, but not Akt activator phosphorylation. Dilation in response to insulin or calcitonin-gene related peptide was impaired in umbilical vein rings from GDMi and GDMd pregnancies. Incubation of HUVECs in vitro with insulin (1 nmol/L) restored hCAT-1 and eNOS expression and activity, and eNOS and p44/42mapk activator phosphorylation. Thus, maternal insulin therapy does not seem to reverse GDMd-associated alterations in human foetoplacental vasculature.Fondo Nacional de Desarrollo Científico y Tecnológico Chileno 1150377 , 1150344 , 11150083Servicio de Salud de Medicina Oriente de Chile 1938–2016Marie Curie International Research 295185 - EULAMDIM

Some Considerations about the Anodic Limit of Ionic Liquids Obtained by Means of DFT Calculations

Ionic liquids are good candidates as the main component of safe electrolytes for high-energy lithium-ion batteries. The identification of a reliable algorithm to estimate the electrochemical stability of ionic liquids can greatly speed up the discovery of suitable anions able to sustain high potentials. In this work, we critically assess the linear dependence of the anodic limit from the HOMO level of 27 anions, whose performances have been experimentally investigated in the previous literature. A limited r Pearson’s value of ≈0.7 is found even with the most computationally demanding DFT functionals. A different model considering vertical transitions in a vacuum between the charged state and the neutral molecule is also exploited. In this case, the best-performing functional (M08-HX) provides a Mean Squared Error (MSE) of 1.61 V2 on the 27 anions here considered. The ions which give the largest deviations are those with a large value of the solvation energy, and therefore, an empirical model that linearly combines the anodic limit calculated by vertical transitions in a vacuum and in a medium with a weight dependent on the solvation energy is proposed for the first time. This empirical method can decrease the MSE to 1.29 V2 but still provides an r Pearson’s value of ≈0.72

Violent video games and morality: a meta-ethical approach

This paper considers what it is about violent video games that leads one reasonably minded person to declare "That is immoral" while another denies it. Three interpretations of video game content a re discussed: reductionist, narrow, and broad. It is argued that a broad interpretation is required for a moral objection to be justified. It is further argued that understanding the meaning of moral utterances – like "x is immoral" – is important to an understanding of why there is a lack of moral consensus when it comes to the content of violent video games. Constructive ecumenical expressivism is presented as a means of explaining what it is that we are doing when we make moral pronouncements and why, when it comes to video game content, differing moral attitudes abound. Constructive ecumenical expressivism is also presented as a means of illuminating what would be required for moral consensus to be achieved

Inflammatory polyradiculoneuropathies: Clinical and immunological aspects, current therapies, and future perspectives

Inflammatory polyradiculoneuropathies are heterogeneous disorders characterized by immune-mediated leukocyte infiltration of peripheral nerves and nerve roots leading to demyelination or axonal degeneration or both. Inflammatory polyradiculoneuropathies can be divided into acute and chronic: Guillain–Barré syndrome and chronic inflammatory demyelinating polyneuropathy and their variants. Despite major advances in immunology and molecular biology have been made in the last years, the pathogenesis of these disorders is not completely understood. This review summarizes the current literature of the clinical features and pathogenic mechanisms of inflammatory polyradiculoneuropathies and focuses on current therapies and new potential treatment for the future

Wnt5a induces ROR1 to complex with HS1 to enhance migration of chronic lymphocytic leukemia cells.

ROR1 (receptor tyrosine kinase-like orphan receptor 1) is a conserved, oncoembryonic surface antigen expressed in chronic lymphocytic leukemia (CLL). We found that ROR1 associates with hematopoietic-lineage-cell-specific protein 1 (HS1) in freshly isolated CLL cells or in CLL cells cultured with exogenous Wnt5a. Wnt5a also induced HS1 tyrosine phosphorylation, recruitment of ARHGEF1, activation of RhoA and enhanced chemokine-directed migration; such effects could be inhibited by cirmtuzumab, a humanized anti-ROR1 mAb. We generated truncated forms of ROR1 and found its extracellular cysteine-rich domain or kringle domain was necessary for Wnt5a-induced HS1 phosphorylation. Moreover, the cytoplamic, and more specifically the proline-rich domain (PRD), of ROR1 was required for it to associate with HS1 and allow for F-actin polymerization in response to Wnt5a. Accordingly, we introduced single amino acid substitutions of proline (P) to alanine (A) in the ROR1 PRD at positions 784, 808, 826, 841 or 850 in potential SH3-binding motifs. In contrast to wild-type ROR1, or other ROR1P→︀A mutants, ROR1P(841)A had impaired capacity to recruit HS1 and ARHGEF1 to ROR1 in response to Wnt5a. Moreover, Wnt5a could not induce cells expressing ROR1P(841)A to phosphorylate HS1 or activate ARHGEF1, and was unable to enhance CLL-cell motility. Collectively, these studies indicate HS1 plays an important role in ROR1-dependent Wnt5a-enhanced chemokine-directed leukemia-cell migration

The effects of suppressing inflammation by tofacitinib may simultaneously improve glycaemic parameters and inflammatory markers in rheumatoid arthritis patients with comorbid type 2 diabetes: a proof-of-concept, open, prospective, clinical study

Background: A consistent connection has been increasingly reported between rheumatoid arthritis (RA), insulin resistance (IR), and type 2 diabetes (T2D). The β-cell apoptosis induced by pro-inflammatory cytokines, which could be exaggerated in the context of RA, is associated with increased expression pro-apoptotic proteins, which is dependent on JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) activation. On these bases, we aimed to evaluate if the administration of tofacitinib, a potent and selective JAK inhibitor, could simultaneously improve glycaemic parameters and inflammatory markers in patients with RA and comorbid T2D. Methods: The primary endpoint was the change in the 1998-updated homeostatic model assessment of IR (HOMA2-IR) after 6 months of treatment with tofacitinib in RA patients with T2D. Consecutive RA patients with T2D diagnosis were included in this proof-of-concept, open, prospective, clinical study, which was planned before the recent emergence of safety signals about tofacitinib. Additional endpoints were also assessed regarding RA disease activity and metabolic parameters. Results: Forty consecutive RA patients with T2D were included (female sex 68.9%, mean age of 63.4 ± 9.9 years). During 6-month follow-up, a progressive reduction of HOMA2-IR was observed in RA patients with T2D treated with tofacitinib. Specifically, a significant effect of tofacitinib was shown on the overall reduction of HOMA2-IR (β = − 1.1, p = 0.019, 95%CI − 1.5 to − 0.76). Also, HOMA2-β enhanced in these patients highlighting an improvement of insulin sensitivity. Furthermore, although a longer follow-up is required, a trend in glycated haemoglobin reduction was also recorded. The administration of tofacitinib induced an improvement in RA disease activity, and a significant reduction of DAS28-CRP and SDAI was observed; 76.8% of patients achieved a good clinical response. In this study, no major adverse events (AEs) were retrieved without the identification of new safety signals. Specifically, no life-threatening AEs and cardiovascular and/or thromboembolic events were recorded. Conclusions: The administration of tofacitinib in RA with T2D led to a simultaneous improvement of IR and inflammatory disease activity, inducing a “bidirectional” benefit in these patients. However, further specific designed and powered studies are warranted to entirely evaluate the metabolic effects of tofacitinib in RA patients with T2D

Median-to-ulnar nerve communication in carpal tunnel syndrome: An electrophysiological study

The median-to-ulnar communicating branch (MUC) is an asymptomatic variant of the upper limb innervation that can lead to interpretation errors in routine nerve conduction studies. The diagnosis of carpal tunnel syndrome (CTS) or ulnar nerve lesions can be complicated by the presence of MUC. In this study, we describe electrophysiological features of MUC in CTS patients presenting to our clinic. We enrolled MUB cases from consecutive CTS patients referred to our laboratory between the years 2014 and 2019. MUC was present in 53 limbs (36 patients) from the studied population. MUC was bilateral in 53% of patients. MUC type II was the most common subtype (74%), followed by types III and I; more coexisting MUC types were found in the majority of tested limbs. A positive correlation was demonstrated between the severity of CTS and the presence of positive onset, faster CV, or a double component of the compound muscle action potentials. We emphasize the importance of suspecting the presence of MUC in CTS in the presence of a positive onset or a double component in routine motor conduction studies

Social determinants of health and Google trends. A worldwide infodemiological report

OBJECTIVE: Several sociodemographic variables are essential to the complete comprehension of people’s health conditions. Also, social determinants of health are decisive in influencing people’s health and healthcare strategy outcomes. Nevertheless, the level of awareness of the general population about the social determinants of health still seems poorly investigated. In this scenario, using an infodemiological approach, Google Trends represents a handy tool for monitoring internet-related search activities concerning this specific topic. This study aimed to assess the general population’s consciousness about social determinants of health, testing widespread knowledge of these items and evaluating the association of the results obtained through Google-specific search volumes. MATERIALS AND METHODS: Data were collected using the Google Trends tool using several search terms related to food, social problems, and economic issues, which are useful for defining some social determinants of health variables. Descriptive data analysis was performed to show the worldwide Relative Search Volume variations from 1 September 2013 to 31 August 2023. Pearson’s correlation analysis tested Relative Search Volumes and later logarithmic transformation. The K-Nearest Neighbors analysis was used to define and assess Relative Search Volumes (RSV) associations. RESULTS: The results have shown that the general population was mainly interested in topics such as “social support” and “economic burden”, showing frequent peaks during the 10 years of the study. According to Pearson’s coefficients test, other specific interests and relative correlations emerged regarding social variables (i.e., social support and social problems), food, and financial distress. Moreover, the K-Nearest Neighbors analysis showed that searching activities for “social support”, “lack of food”, and “social problems” were highly related; for “economic burden”, “financial burden”, and “out of pocket” suggested the existence of financial distress. CONCLUSIONS: The results of this study underline that social determinants of health are significant barriers to health and well-being and that non-medical factors should be considered more. Healthcare professionals involved in public health should study and understand more about the social determinants of health in relation to health outcomes to provide patient-centered care. Finally, this research suggests that we should encourage and maintain a more comprehensive approach to addressing the health needs of patients and communities, also by an infodemiological assessment

Cancer patients and telenursing interventions in Italy. a systematic review

Objective: The use of digital technologies could improve patients’ quality of care, satisfaction, and health-related outcomes in cancer patients. This paper aims to explore the use of digital technologies in nursing management of cancer patients in Italy. Patients and Methods: A systematic literature review was performed. PubMed, Excerpta Medica dataBASE (Embase), Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Cochrane Library databases were consulted from September 1, 2021, to January 31, 2022. Key terms for Telenurs-ing/Telemedicine and cancer in Italy were used. The quality of each study was assessed through the Grading of Recommendations, Assessment, Development, and Evaluations method. Results: 131 articles were found and 5 were included: two randomized-clinical-trial protocols aimed to explore the impact of medication management apps on patients’ quality of life; one validation trial suggested good reliability in the therapeutic adherence of patients on chemotherapy but limited sensitivity in detecting related adverse events; two observational studies described the validation of telephone triage prehospitalization programs performed by nurses during the pandemic. Conclusions: The use of digital technologies in nursing management of cancer patients is in-frequent in Italy, however, increased during the pandemic. Further studies are needed to evaluate the impact and effectiveness of the use of digital technologies in nursing management in cancer patients

Effectiveness and Safety of Mycophenolate Mophetil in Myasthenia Gravis: A Real-Life Multicenter Experience

Background: Myasthenia gravis (MG) is an autoimmune disease characterized by fluctuating muscle weakness due to autoantibodies targeting neuromuscular junction proteins. Mycophenolate mofetil (MMF), an immunosuppressive therapy, has shown potential for managing MG with fewer side effects compared to other treatments. This study aims to evaluate the effectiveness and safety of MMF in MG patients in a real-life multicenter setting. Methods: A retrospective cohort study was conducted on generalized MG patients, refractory to azathioprine (AZA) and treated with MMF alone or with steroids, at three Italian centers from January 2011 to February 2024. Patients were assessed using the Myasthenia Gravis Foundation of America (MGFA) classification, MG composite score (MGCS), and MG activity of daily living (MGADL) scores at baseline, 6, 12, 18, and 24 months. Statistical analyses included the Spearman correlation, the Friedman test, and ANOVA. Results: Thirty-two patients were enrolled (13 males, mean age 66.5 ± 11.5 years). Significant improvements in MGADL and MGCS scores were observed at 6 and 12 months (p < 0.001), with continued improvement over 24 months. Side effects were reported in 12% of patients. MMF showed a faster onset of symptom control compared to azathioprine, with a significant improvement noted within 6 months. Conclusions: A recent study found that MMF and AZA were equally effective in improving patients’ quality of life, but because AZA had more serious adverse events than MMF, lower doses of AZA were therefore recommended to reduce the adverse events while maintaining efficacy. Conversely, results showed that MMF is effective and well-tolerated in the long-term management of MG, providing faster symptom control and a favorable safety profile. Future prospective studies with larger cohorts are needed to confirm these findings and explore sex differences in response to MMF treatment