Purpose/background: Based on a population-pharmacokinetic model, the European Medicines Agency has recently approved a simplified starting strategy of aripiprazole once a month (AOM), injectable and long-acting antipsychotic, with two 400 mg injections and a single oral 20 mg dose of aripiprazole, administered on the same day, instead of 1 injection and 14 daily administrations of concurrent oral aripiprazole. However, to our knowledge, no previous study has reported the safety and tolerability of this regimen in real-world patients. Methods/procedures: We retrospectively reviewed medical records of 133 patients who received the newly approved 2-injection start regimen as part of their standard care in 10 Italian clinical centers. Findings/results: Adverse effects were mild or moderate, with no clinically evident difference from the adverse effects observed in previous trials where AOM was started with a single injection followed by 14 days of orally administered aripiprazole. None of the patients who started AOM after the 2-injection start regimen experienced severe adverse effects or severe adverse effects. Implications/conclusions: The coadministration of 2 injections of 400 mg aripiprazole and 20 mg oral aripiprazole was not associated with safety concerns beyond those reported after a single injection followed by 14 days of orally administered aripiprazole. Our results should be interpreted with caution, due to the limited sample size and to the retrospective design of the study.
Optimized controls are particularly promising for flexible and efficient management of space heating and cooling systems in buildings. However, when controls are based on predictive models, their effectiveness is affected by the reliability of the models used. In this paper we propose a quantification analysis of some of the main uncertainty factors that can be observed in an optimal control really implemented in a building. A day-ahead optimal scheduling was applied to the heating system (composed of smart electric heaters with thermal storage) of a single room in an office building located in Osimo (Italy). The control algorithm is formulated to determine the charging periods of the heaters with the objective of minimizing the withdrawal of energy from the grid. The control takes into account the electricity produced by a photovoltaic plant and must maintain the internal air temperature close to an imposed setpoint. Firstly, the actual application of the control is shown during two selected days. Secondly, the analysis is extended to quantify the impact on the control performance of the prediction uncertainty of the input variables. The variable that has the greatest impact is the weather forecast and, specifically, the cloudiness index, which determines the solar gains. The different moment in time in which the weather forecast is predicted has proved to have a significant impact on the charging periods of the heaters (expected variation ranges from -50% to + 100%) and on the prediction of the indoor air temperature (variations observed up to 40%).
Purpose: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. Materials and methods: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method. Results: A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4-6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. Conclusions: This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians.
Fiscal deficits and public debt have risen sharply in response to the global financial crisis, the pandemic shock, and the Russia–Ukraine war, bringing up the issue of fiscal consolidation. There is, however, considerable uncertainty about the policy mix and timing of such budgetary adjustment, and this can have a harmful impact on economic activity. Reducing this source of uncertainty calls for a reliable indicator—theoretically grounded and internally consistent—measuring the fiscal adjustment needed to warrant the long-run sustainability of the government budget. In this chapter, we show, in the context of an endogenous growth model, that forward-looking agents’ optimizing behavior typically gives rise to a wealth-based and not to an output-based sustainability index of government policy. Calibrating the new index from 2001 to 2018 for 15 European countries along with the U.S. and Japan as reference countries gives results that are very different from common wisdom and makes explicit that tests of debt sustainability based on the debt-to-GDP ratio are strongly biased and misleading and may conduct to wrong and perverse policy strategies. This may contribute to explain the recent pickup in policy-induced uncertainty and the observed adverse effects on economic activity and growth perspective.
Glyoxalase 2 (Glo2) is the second enzyme in the glyoxalase system, and while its cytoplasmic function is well-established, its subcellular localization in the nucleus and potential role there remain unexplored. This study investigates nuclear localization and function of Glo2 in human breast cancer (MCF7) and normal fibroblast-derived (HDF) cells. Glo2 was present in both cytoplasm and nucleus of MCF7 and HDF cells. Interestingly, Glo2 expression levels were significantly higher in MCF7 compared to HDF, especially when considering the nuclear Glo2. Western-blot analysis revealed the monomeric 29 KDa Glo2 form and a 47 KDa Glo2 form suggesting complex formation with other proteins in the cytoplasm of MCF7 and HDF cells. Interestingly, at the nuclear level only the tumor cells showed the 47 KDa Glo2 form. Sequential salt extraction indicated a potential association of Glo2 with non-histone proteins. Intriguingly, nuclear Glo2 positively correlated with cell cycle proliferative phase (G2/M), more markedly in MCF7. Furthermore, higher levels of S-glutathionylation of nuclear proteins were observed in MCF7 compared to HDFs, and “in vitro” addition of Glo2 to nuclear extracts increased S-glutathionylation levels, significantly in MCF7. Finally, inhibiting Glo2 increased doxorubicin cytotoxicity in MCF7. Overall, these results indicate that nuclear Glo2 may play a role in in promoting cancer cell survival and targeting Glo2 could be a promising strategy to improve the efficacy of some anticancer therapies in breast cancer.
Background miRNA‐based strategies have recently emerged as a promising therapeutic approach in several neurodegenerative diseases. Unregulated cation influx is implicated in several cellular mechanisms underlying neural cell death during ischemia. The brain constitutively active isoform of transient receptor potential melastatin 7 (TRPM7) represents a glutamate excitotoxicity‐independent pathway that significantly contributes to the pathological Ca ²⁺ overload during ischemia. Aims In the light of these premises, inhibition of TRPM7 may be a reasonable strategy to reduce ischemic injury. Since TRPM7 is a putative target of miRNA135a, the aim of the present paper was to evaluate the role played by miRNA135a in cerebral ischemia. Therefore, the specific objectives of the present paper were: (1) to evaluate miR135a expression in temporoparietal cortex of ischemic rats; (2) to investigate the effect of the intracerebroventricular (icv) infusion of miR135a on ischemic damage and neurological functions; and (3) to verify whether miR135a effects may be mediated by an alteration of TRPM7 expression. Methods miR135a expression was evaluated by RT‐ PCR and FISH assay in temporoparietal cortex of ischemic rats. Ischemic volume and neurological functions were determined in rats subjected to transient middle cerebral artery occlusion (tMCAo) after miR135a intracerebroventricular perfusion. Target analysis was performed by Western blot. Results Our results demonstrated that, in brain cortex, 72 h after ischemia, miR135a expression increased, while TRPM7 expression was parallelly downregulated. Interestingly, miR135a icv perfusion strongly ameliorated the ischemic damage and improved neurological functions, and downregulated TRPM7 protein levels. Conclusions The early prevention of TRPM7 activation is protective during brain ischemia.
In times when technological advancements rapidly follow one another, two points have to be always remembered: the starting point of the modern history of rectal cancer surgery can be well placed in time and we are witnessing the incoming of a new era in surgery, where machines are increasingly providing stronger support for the human hand. In the twenty-first century, the limits of rectal cancer treatment continue to be pushed, with surgery still representing the primary form of therapy for optimal oncological and functional results. The advent of transanal approaches has been a natural development responding to the increasing demand for minimally invasive approaches that has characterized the last few decades.
Regional variability in the spatial distribution of resident population and across-country density divides have consolidated heterogeneous demographic patterns at the base of modern urban systems in Europe. Although economic, historical, institutional, and cultural factors have demonstrated to affect the spatial distribution of resident population, density-dependence and path-dependence are mechanisms persistently shaping demographic dynamics at both local and regional scale. Analysis of density-dependent patterns of population growth (and decline) over sufficiently long time intervals allows a refined comprehension of socioeconomic processes underlying demographic divides. Despite a long settlement history, empirical investigation of the role of density-dependence in the long-term evolution of human populations along urban–rural gradients is relatively scarce especially in Mediterranean countries. The present study performs a comparative analysis of population distribution in 1033 Greek municipalities identifying (and testing the significance of) density-dependent and path-dependent mechanisms of population growth between 1961 and 2011, using spatially implicit and explicit econometric approaches. Results highlight a positive impact of density on population growth where settlements are concentrated. Assuming goodness of fit of the tested models as a proxy of density-dependence, the empirical findings clarify how density-dependent mechanisms were not significant all over the study period, being instead associated with specific phases of the city life cycle—basically urbanization with population concentrating in central locations. Density-dependence was less intense with suburbanization and counter-urbanization—when population sprawled over larger areas at medium–low density. An improved understanding of density-dependent and path-dependent mechanisms of population growth contributes to rethink spatial planning, regional development strategies, and socio-demographic policies adapting to heterogeneous (and rapidly changing) local contexts.
We present herein an in-depth study on the activity of amidinoquinoxaline N-oxides 1 against Gram-positive and Gram-negative anaerobic bacteria. Based on 5-phenyl-2,3-dihydropyrimidoquinoxaline N-oxide 1a, the selected structural variations included in our study comprise the substituents α− to the N-oxide function, the benzofused ring, substitution and quaternization of the amidine moiety, and the amidine ring size. Compounds 1 showed good to excellent antianaerobic activity, evaluated as the corresponding CIM50 and CIM90 values, and an antimicrobial spectrum similar to metronidazole. Six out of 13 compounds 1 had CIM90 values significantly lower than the reference drug. Among them, imidazoline derivatives 1i–l were the most active structures. Such compounds were synthesized by base-promoted ring closure of the corresponding amidines. The N-oxides under study showed no significant cytotoxicity against RAW 264.7 cells, with high selectivity indexes. Their calculated ADME properties indicate that the compounds are potentially good oral drug candidates. The antianaerobic activity correlated satisfactorily with the electron affinity of the compounds, suggesting that they may undergo bioreductive activation before exerting their antibacterial activity.
Heliconius butterflies, a speciose genus of Müllerian mimics, represent a classic example of an adaptive radiation that includes a range of derived dietary, life history, physiological and neural traits. However, key lineages within the genus, and across the broader Heliconiini tribe, lack genomic resources, limiting our understanding of how adaptive and neutral processes shaped genome evolution during their radiation. Here, we generate highly contiguous genome assemblies for nine Heliconiini, 29 additional reference-assembled genomes, and improve 10 existing assemblies. Altogether, we provide a dataset of annotated genomes for a total of 63 species, including 58 species within the Heliconiini tribe. We use this extensive dataset to generate a robust and dated heliconiine phylogeny, describe major patterns of introgression, explore the evolution of genome architecture, and the genomic basis of key innovations in this enigmatic group, including an assessment of the evolution of putative regulatory regions at the Heliconius stem. Our work illustrates how the increased resolution provided by such dense genomic sampling improves our power to generate and test gene-phenotype hypotheses, and precisely characterize how genomes evolve.
In this paper, we study two related features of the regularity of the weak solutions to the following strongly degenerate parabolic equation u t − div (|Du| − 1) p−1 + Du |Du| = f in T = × (0, T), where is a bounded domain in R n for n ≥ 2, p ≥ and T > 0. We prove the higher differentiability of a nonlinear function of the spatial gradient of the weak solutions, assuming only that f ∈ L 2 loc (T). This allows us to establish the higher integrability of the spatial gradient under the same minimal requirement on the datum f. Mathematics Subject Classification 35B45 · 35B65 · 35D30 · 35K10 · 35K65
Background: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by drug-resistant, lifelong seizures. The management of seizures in DS has changed in recent years with the approval of new antiseizure medications (ASMs). Objective: The aim of this study was to estimate the comparative efficacy and tolerability of the ASMs for the treatment of seizures associated with DS using a network meta-analysis (NMA). Methods: Studies were identified by conducting a systematic search (week 4, January 2023) of the MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and US National Institutes of Health Clinical Trials Registry ( http://www. Clinicaltrials: gov ) databases. Any randomized, controlled, double- or single-blinded, parallel-group study comparing at least one ASM therapy against placebo, another ASM, or a different dose of the same ASM in participants with a diagnosis of DS was identified. The efficacy outcomes were the proportions of participants with ≥ 50% (seizure response) and 100% reduction (seizure freedom) in baseline convulsive seizure frequency during the maintenance period. The tolerability outcomes included the proportions of patients who withdrew from treatment for any reason and who experienced at least one adverse event (AE). Effect sizes were estimated by network meta-analyses within a frequentist framework. Results: Eight placebo-controlled trials were included, and the active add-on treatments were stiripentol (n = 2), pharmaceutical-grade cannabidiol (n = 3), fenfluramine hydrochloride (n = 2), and soticlestat (n = 1). The studies recruited 680 participants, of whom 409 were randomized to active treatments (stiripentol = 33, pharmaceutical-grade cannabidiol = 228, fenfluramine hydrochloride = 122, and soticlestat = 26) and 271 to placebo. Pharmaceutical-grade cannabidiol was associated with a lower rate of seizure response than fenfluramine hydrochloride (odds ratio [OR] 0.20, 95% confidence interval [CI] 0.07-0.54), and stiripentol was associated with a higher seizure response rate than pharmaceutical-grade cannabidiol (OR 14.07, 95% CI 2.57-76.87). No statistically significant differences emerged across the different ASMs for the seizure freedom outcome. Stiripentol was associated with a lower probability of drug discontinuation for any reason than pharmaceutical-grade cannabidiol (OR 0.45, 95% CI 0.04-5.69), and pharmaceutical-grade cannabidiol was associated with a lower proportion of participants experiencing any AE than fenfluramine hydrochloride (OR 0.22, 95% CI 0.06-0.78). Stiripentol had a higher risk of AE occurrence than pharmaceutical-grade cannabidiol (OR 75.72, 95% CI 3.59-1598.58). The study found high-quality evidence of efficacy and tolerability of the four ASMs in the treatment of convulsive seizures in DS. Conclusions: There exists first-class evidence that documents the efficacy and tolerability of stiripentol, pharmaceutical-grade cannabidiol, fenfluramine hydrochloride, and soticlestat for the treatment of seizures associated with DS, and allows discussion about the expected outcomes regarding seizure frequency reduction and tolerability profiles.
Diabetes is a metabolic disease due to impaired or defective insulin secretion and is considered one of the most serious chronic diseases worldwide. Gamma-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid commonly present in a wide range of foods. A number of studies documented that GABA has good anti-diabetic potential. This review summarized the available dietary sources of GABA as well as animal and human studies on the anti-diabetic properties of GABA, while also discussing the underlying mechanisms. GABA may modulate diabetes through various pathways such as inhibiting the activities of α-amylase and α-glucosidase, promoting β-cell proliferation, stimulating insulin secretion from β-cells, inhibiting glucagon secretion from α-cells, improving insulin resistance and glucose tolerance, and increasing antioxidant and anti-inflammatory activities. However, further mechanistic studies on animals and human are needed to confirm the therapeutic effects of GABA against diabetes.
Background Food products with < 20 mg/kg gluten can be labeled ‘gluten-free’ according to international regulations. Several antibodies based ELISAs have been develop to track gluten traces in food products. Among them, R5 and G12 antibody-based ELISAs are the frequently used methods. However, these antibodies have certain limitations. Aims We evaluated the accuracy of G12/A1 antibody-based 'Glutentox ELISA Rapid G12' and compared the results with the current reference method i.e., R5 antibody-based ‘Ridascreen R5 ELISA’. Methods In the first step, performance of Glutentox ELISA Rapid G12 kit was inspected by determination of the threshold value i.e.,> or < 20 mg/kg gluten in different food products. In the second step, quantification accuracy was assessed by quantification of gluten in gluten-free food products spiked with gliadin reference material. Results In total 47 food products (naturally and labeled gluten-free, and food with traces of gluten) were included. Of them, 29 products were quantified with < 20 mg/kg, and 18 with a low level of gluten by both the kits. Six out of 29 gluten-free products were used for the recovery test at different spike levels. Gluten concentration and mean recovery rates of individual kits showed consintency. Conclusions GlutenTox Rapid G12 ELISA could be an appropriate choice for detecting gluten in food products but needs more investigation e.g. more in-house validation and a collaborative test.
Background Health literacy has a strong influence on individual health outcomes and the sustainability of healthcare systems. Healthcare professionals often overestimate patients’ health literacy levels and lack adequate competencies to address limited health literacy effectively. Therefore, promoting understanding through effective health communication between professionals and citizens is becoming increasingly important. Although health literacy has recently gained more attention, health literacy educational programmes targeting future healthcare professionals are still scarce, especially in Europe. This study describes the piloting process of a pan-European health literacy educational programme and shows how the educational material is being used during time of crisis such as the COVID-19 pandemic. Methods The educational programme was developed through the definition of an educational philosophy and iterative co-creation processes consisting of stakeholders’ consultations, material development and pilots with students. The evaluation was carried out in Italy through four pilot tests involving 107 students of health-related degrees. An evaluation questionnaire and a pre-post test were developed and used to collect students’ and educators’ feedback (quantitative and qualitative) and assess changes in health literacy awareness, respectively. Three additional pilots were organized in Italy and Germany mostly during the COVID-19 pandemic to evaluate the feasibility of the educational programme through online and hybrid learning, respectively. Results The pilots received positive feedback from both students and educators. Students were highly satisfied with the courses, reported their relevance for their future profession and appreciated the interactive teaching methods. The pre-post test showed a significant improvement in health literacy awareness after the training. Educators reported the adequacy and flexibility of the training material, the ease of transferability of the content of the lessons into practice, and the validity of the tested options to integrate the educational programme into the curricula. Conclusions Our comprehensive, evidence-based educational programme contributes to addressing the existing challenges in Europe, and its flexibility allows for easy integration in the curricula, through different options, hence supporting a widespread uptake in the European Union and maybe beyond. Health literacy education is a useful tool to improve citizens’ access to healthcare information and services, achieve better health outcomes and support healthcare systems’ sustainability.
Background There has been a consistent increase in the last decades in prevalence of renal stones in elderly. Aims To evaluate outcomes of retrograde intrarenal surgery (RIRS) for renal stones in elderly and factors associated with postoperative complications and residual fragments (RFs). Methods Data from 12 centers were retrospectively reviewed. Inclusion criteria: ≥ 75 years, renal stones only, normal renal anatomy. Patients were divided into three groups; Group 1: patients aged 75–79 years; Group 2: age 80–84 years; Group 3: age ≥ 85 years. Multivariable logistic regression analyses were performed to assess factors associated with perioperative complications, sepsis, and RFs. Results 366 patients were included. There were 189 patients in Group 1, 113 in Group 2, and 64 in Group 3. There was no difference between groups regarding stone features and total surgical time. Median length of stay was significantly longer in Group 3 (6.0 days, vs 2.0 days in Group 2 vs 2.5 days in Group 1, p = 0.043). There was no significant difference in postoperative complications and RFs between the groups. At multivariable logistic regression analysis, female gender (OR 2.82) and maximum stone diameter (OR 1.14) were associated with higher odds of sepsis, while surgical time (OR 1.12) and the use of a reusable ureteroscope (OR 6.51) with overall complications. Stone size (OR 1.23) was associated with higher odds of RFs. Conclusion RIRS showed safety and efficacy for kidney stones in elderly patients. Surgical time should be kept as short as possible to avoid higher odds of postoperative complications, particularly in females.
Introduction We wanted to analyze the trend of publications in a period of 30 years from 1994 to 2023, on the application of ‘artificial intelligence (AI), machine learning (ML), virtual reality (VR), and radiomics in percutaneous nephrolithotomy (PCNL)’. We conducted this study by looking at published papers associated with AI and PCNL procedures, including simulation training, with preoperative and intraoperative applications. Materials and Methods Although MeSH terms research on the PubMed database, we performed a comprehensive review of the literature from 1994 to 2023 for all published papers on ‘AI, ML, VR, and radiomics’ in ‘PCNL’, with papers in all languages included. Papers were divided into three 10-year periods: Period 1 (1994–2003), Period 2 (2004–2013), and Period 3 (2014–2023). Results Over a 30-year timeframe, 143 papers have been published on the subject with 116 (81%) published in the last decade, with a relative increase from Period 2 to Period 3 of +427% ( p = 0.0027). There was a gradual increase in areas such as automated diagnosis of larger stones, automated intraoperative needle targeting, and VR simulators in surgical planning and training. This increase was most marked in Period 3 with automated targeting with 52 papers (45%), followed by the application of AI, ML, and radiomics in predicting operative outcomes (22%, n = 26) and VR for simulation (18%, n = 21). Papers on technological innovations in PCNL ( n = 9), intelligent construction of personalized protocols ( n = 6), and automated diagnosis ( n = 2) accounted for 15% of publications. A rise in automated targeting for PCNL and PCNL training between Period 2 and Period 3 was +247% ( p = 0.0055) and +200% ( p = 0.0161), respectively. Conclusion An interest in the application of AI in PCNL procedures has increased in the last 30 years, and a steep rise has been witnessed in the last 10 years. As new technologies are developed, their application in devices for training and automated systems for precise renal puncture and outcome prediction seems to play a leading role in modern-day AI-based publication trends on PCNL.
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