University of L'Aquila

Individuals with Prader-Willi syndrome (PWS) exhibit hyperphagic behavior, the severity of which varies throughout life. The mechanisms underlying this behavior are still unknown. Asprosin is a new discovered adipokine involved in the regulation of food intake, glucose homeostasis and energy balance. In this study we assessed asprosin serum levels in a cohort of children, adolescents and adults with PWS with the aim to correlate them with hyperphagic behavior, body mass index (BMI) and metabolic parameters, and to evaluate age-related changes. This cross-sectional study included 87 children and adolescents and 31 adults with PWS. Auxological data, fasting levels of glucose, insulin, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), triglycerides (TG) and asprosin were collected, and the homeostasis model assessment for insulin resistance (HOMA-IR) was determined. The 11-item Italian version of the Hyperphagia Questionnaire (HQ) was administered to the parents/caregivers of the patients to assess hyperphagia. Patients were analysed according to age (children < 10 years, adolescents between 10 and 17.9 years, adults ≥ 18 years) or BMI categories [normal weight (NW), overweight (OW), and obesity (OB)]. No significant correlations were found between asprosin levels and cardiometabolic risk factors in the whole cohort. Higher values of asprosin were found in adults compared with adolescents, as well as in the OB group compared to the NW group (p = 0.014). Hyperphagia total score and hyperphagic subdimensions were significantly lower in children compared to adults (p < 0.05). Similarly, hyperphagia total score and hyperphagic subdimensions were significantly lower in the NW group compared to the OB group. Asprosin levels were significantly higher in patients with deletion versus patients with uniparental disomy (p = 0.037). By logistic regression analysis, HQ total score and hyperphagic subdimensions were significantly associated with BMI-SDS independently of age, sex, and asprosin levels. In conclusion, our data demonstrated higher asprosin levels in PWS individuals with OB compared to NW, while differences by age and sex were inconsistent. The lower levels of hyperphagia, BMI-SDS, and metabolic variables in children with PWS compared to adults underline that prevention of obesity should start very early in life and should be maintained over time.

Combination treatments for migraine prophylaxis present a promising approach to addressing the diverse and complex mechanisms underlying migraine. This review explores the potential of combining oral conventional prophylactics, onabotulinumtoxin A, monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway, and small molecule CGRP receptor antagonists (gepants). Among the most promising strategies, dual CGRP inhibition through mAbs and gepants may enhance efficacy by targeting both the CGRP peptide and its receptor, while the combination of onabotulinumtoxin A with CGRP treatments offers synergistic pain relief. Oral non-CGRP treatments, which are accessible and often prescribed for patients with comorbid conditions, provide an affordable and practical option in combination regimens. Despite the potential of these combinations, there is a lack of evidence to support their widespread inclusion in clinical guidelines. The high cost of certain combinations, such as onabotulinumtoxin A with a CGRP mAb or dual anti-CGRP mAbs, presents feasibility challenges. Further large-scale trials are needed to establish safe and effective combination protocols and solidify their role in clinical practice, particularly for treatment-resistant patients. Graphical Abstract

Background Resistant and refractory migraine are commonly encountered in specialized headache centers. Several comorbidities, mostly psychiatric conditions, have been linked to migraine worsening; however, there is little knowledge of the comorbidity profile of individuals with resistant and refractory migraine. Methods REFINE is a prospective observational multicenter international study involving individuals with migraine from 15 headache centers. Participants were categorized into three groups based on the European Headache Federation criteria: non-resistant and non-refractory (NRNRM), resistant (ResM), and refractory (RefM). We explored the prevalence of 20 comorbidities at baseline in the three groups. Results Of the 689 included patients (82.8% women), 262 (38.0%) had ResM, 73 (10.4%) had RefM and 354 (51.4%) NRNRM. A higher prevalence of psychiatric comorbidities, trigger points, temporomandibular joint disorders, thyroiditis, and cerebrovascular diseases was observed in the RefM group, followed by ResM and NRNRM. Multiple comorbidities were more common in the RefM group, followed by the ResM group and by the NRNRM group (41.6% vs. 24.5% vs. 14.1% respectively; p < 0.001). At the sensitivity analysis, exploring participants with chronic migraine, significant differences among the NRNRM, ResM, and RefM groups were found in the prevalence of anxiety (p < 0.001), asthma and rhinitis (p = 0.013), bipolar and other psychiatric disorders (p = 0.049), cerebrovascular diseases (p < 0.001), depression (p < 0.001), obesity (p = 0.002), thyroiditis (p < 0.001), and trigger points (p = 0.008). Conclusion REFINE data indicate that individuals with ResM and RefM have a higher burden of comorbidities than those with NRNRM. It can be postulated that those comorbidities may have an impact on the progression of migraine from a form that is easy to treat to a form that is resistant or refractory to treatments. Longitudinal studies are needed to understand the direction of the association between ResM or RefM and those comorbidities and if proper treatment of comorbidities might help overcome treatment resistance or refractoriness.

Type 2 diabetes mellitus (T2D) is defined by chronic hyperglycemia due to insufficient insulin secretion or activity and decreased insulin sensitivity, known as insulin resistance (IR). This condition leads to oxidative stress and inflammation, increasing the risk of systemic inflammatory diseases. Obesity and a sedentary lifestyle are major risk factors for IR and T2D. Various metabolites act as mediators of IR by disrupting communication between organs. Lipids, including free fatty acids and short-chain fatty acids, along with intracellular lipotoxins, impair insulin function and mitochondrial activity, contributing to IR through direct and indirect mechanisms such as oxidative stress and inflammation. Our research explores the role of TNFα and CXCR1/2 in IR conditions, emphasizing their interactions and potential as therapeutic targets. In this study we selected two models of IR, adipocytes and hepatocytes, since are key players in glucose and lipid metabolism. To develop IR model, TNFα was used as challenge and we focused on investigating the role of CXCR1/2 inhibition. We assessed glucose uptake, insulin signaling pathways, and gene expression related to IR. Cells treated with TNFα showed reduced p-Akt and increased p-JNK levels, indicative of IR. In contrast, CXCR1/2 inhibition restored p-Akt levels and reduced p-JNK levels, suggesting improvements in insulin signaling and glucose uptake. Furthermore, CXCR1/2 inhibition counteracted the TNFα-induced decrease in IGF expression and restored GLUT2 expression, indicating enhanced insulin sensitivity. These results underscore the pivotal role of CXCR1/2 in modulating the inflammatory response and insulin signaling in IR conditions in both IR models. CXCR1/2 inhibition can mitigate IR and improve glucose metabolism. Thus, targeting the TNFα-CXCR1/2 pathway presents a promising therapeutic approach for managing IR and T2D. Further investigation is necessary to understand the clinical implications of these findings and develop effective treatments for patients with IR and T2D.

We investigated potential germline‐specific radiosensitive biomarkers in the testes of large Japanese field mice (Apodemus speciosus) exposed to low‐dose‐rate (LDR) radiation after the Fukushima accident. Fukushima wild mice testes were analysed via RNA‐sequencing to identify genes differentially expressed in the breeding and non‐breeding seasons when compared to controls. Results revealed significant changes during the breeding season, with Lsp1 showing a considerable upregulation, while Ptprk and Tspear exhibited significant reductions. Conversely, in the non‐breeding season, Fmo2 and Fmo2 (highly similar) were significantly upregulated in radiation‐exposed Fukushima mice. qPCR analysis results were consistent with transcriptome sequencing, detecting Lsp1 and Ptprk regulation in the testes of Fukushima mice. While differences in gene expression were observed, these do not imply any causal association between the identified biomarkers and chronic LDR exposure, as other factors such as the environment and developmental age may contribute. This study provides valuable insights into the reproductive biology is affected by environmental radiation and highlights the value of assessing the effects of chronic LDR radiation exposure on testicular health in wild mice.

The use of antiplatelet therapy (APT) is prevalent among the general population, sometimes without clear indications. We provided updated figures on the incidence and prognosis of first-ever intracerebral hemorrhage occurring on APT (APT-ICH) over 10 years in a population-based stroke registry and investigated the rates of inappropriate APT prescription. We included all cases of first-ever ICH not on anticoagulants from January 2011 to December 2020 in the district of L’Aquila (Southern Italy). Indication to APT was adjudicated according to 2021 European Society of Cardiology (ESC) guidelines for cardiovascular prevention. We included 606 first-ever ICHs, of whom 251 (41.4%) were APT-related. One-hundred-forty-two APT-ICHs (56.6%) occurred in patients without clear indications to APT. While the incidence of non-APT-ICH decreased over time, the incidence of APT-ICH was stable. APT-ICH showed higher 30-day and 1-year case-fatality rates versus non-APT-ICH (44.7% versus 25.6%, 50.6% versus 34.4%; p < 0.001). APT intake was independently associated with higher 30-day case-fatality (HR 1.51, 95%CI 1.03–2.14; p = 0.023). Our findings suggest that APT-ICH exhibits sustained incidence over time and elevated mortality. Urgent initiatives are needed to enhance adherence to established guidelines for APT use. This effort has the potential to mitigate the risk of ICH and to reduce the associated mortality. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-81526-4.

Chronic hand eczema (CHE) is an inflammatory skin condition characterized by different pathomechanisms, clinical presentations, and prognoses. Treatment is often challenging because of limited approved drugs, and severe CHE is associated with reduced quality of life (QoL) and poor overall health measures in terms of psychological, functional, and occupational challenges. This study aims to describe the real-life management practices of Italian dermatologists who frequently treat patients with CHE, compare these practices with existing guidelines, and propose practical clinical recommendations for the management of these patients. An 11-question survey was administered to 14 participating dermatologists to gather their insights on the diagnosis, treatment, and management of CHE. Moreover, a comprehensive literature search was conducted over the previous 10 years as a starting point for discussion among experts. CHE was the reason for 6.9% of dermatological consultations by the 14 experts. Median time to CHE diagnosis was 12 (range: 2–24) months. Fissuring and itching (85.7% for both) were the most frequently reported signs and symptoms of CHE. The survey highlighted the need for long-term treatment that is effective and well tolerated, with experts emphasizing the importance of improving disease awareness among physicians and patients. Practical clinical approaches were proposed, emphasizing the significance of a thorough medical history and identification of symptoms in the management of CHE. Experts advocated for specifically developed CHE treatment approaches, concentrating on alleviating symptoms and signs, minimizing adverse events/safety issues, enhancing the QoL of patients, and long-term disease control. Findings from this survey were further discussed and compared to recommendations of the available guidelines for the management of CHE. Managing CHE requires a comprehensive approach that considers both objective clinical factors and subjective patient expectations. Experts emphasized the need for effective and well-tolerated long-term therapies, improved disease awareness, and communication among physicians and patients.

Objective To examine the association between semen parameters, assessed according to World Health Organization (WHO)‐2021 criteria, and paternal body mass index (BMI) and age, with embryological and clinical outcomes in ICSI cycles involving preimplantation genetic testing for aneuploidy (PGT‐A). Design Retrospective study at a private in vitro fertilization (IVF) clinic. Subjects 3101 couples undergoing 4013 intracytoplasmic sperm injection (ICSI) + PGT‐A cycles with own‐oocytes (years 2013–2021). Intervention We performed trophectoderm biopsy, and comprehensive chromosome testing to report uniform aneuploidies and vitrified‐warmed euploid single‐blastocyst‐transfers. Regression analyses adjusted for relevant confounders were conducted to outline putative associations of semen analysis and characteristics and paternal BMI and age with all embryological/clinical outcomes. Results Maternal age was the only significant confounding variable affecting euploidy blastocyst rate (EBR) (primary embryological outcome). When categorized, motility < 5 th ‐percentile (‐2.5%, 95%CI ‐4.9 to ‐0.2%, p = 0.03), concentration plus morphology < 5 th ‐percentile (‐2.7%,95%CI ‐4.8 to ‐0.6%, p = 0.01), concentration plus morphology plus motility < 5 th ‐percentile (‐4.0%,95%CI ‐5.5 to ‐2.6%, p < 0.01), obstructive‐azoospermia [OA] (‐5.5%,95%CI ‐9 to ‐2%, p = 0.02) and non‐obstructive azoospermia (NOA) (‐5.8%,95%CI ‐10.9 to ‐0.6%, p = 0.03) showed significantly lower results compared to all parameters > 5 th ‐percentile. Furthermore, after adjusting for maternal age and the number of metaphase‐II‐oocytes inseminated, the only significant confounding variable affecting the chance of obtaining ≥ 1 live birth among completed cycles (primary clinical outcome) was basal and post sperm processing motility. When categorized, concentration plus morphology plus motility < 5 th ‐percentile (multivariable‐OR: 0.73, 95%CI 0.58–0.93, p = 0.01) and OA (multivariable‐OR: 0.47, 95%CI 0.24–0.92, p = 0.03) showed significantly lower chances compared to all parameters > 5 th ‐percentile. Advanced paternal age (defined as > 44 years) was associated only with lower day 5‐blastocyst and Gardner's AA‐grade (i.e., top quality) blastocyst rates. Conclusions This comprehensive analysis provides IVF professionals with useful figures to counsel infertile couples about their chances of success, taking into account the impact of semen characteristics and paternal BMI and age. These estimates are valuable for personalized decision‐making about the most effective reproductive strategies to adopt, especially not underestimating male factor, by improving sperm concentration and motility whenever possible before assisted reproductive technologies.

This study investigates the ecological impact of a small hydroelectric power plant (SHPP) on the hyporheic zone of the venacquaro stream (VEN), a low‐order groundwater‐fed stream in Central Italy. The hyporheic zone, a critical ecological interface where groundwater and surface water interact, plays a pivotal role in nutrient cycling, pollutant retention, and supporting aquatic biodiversity. However, hydrological alterations from activities such as damming pose significant threats to this zone. The research employs a three‐pronged approach to assess the effect of a SHPP on hyporheic copepod communities. Copepods were selected as the focal group due to their dominance in this habitat. Initially, a generalized estimating equation (GEE) model was used to evaluate changes in copepod diversity, specifically alpha and beta diversity. The study then examines environmental shifts caused by the SHPP using permutational analysis of variance (PERMANOVA) and principal component analysis (PCA). Lastly, a multivariate species distribution model (mSDM) explores correlations between environmental variables and copepod abundances. Results reveal significant alterations in copepod assemblage structure and environmental variables downstream of the SHPP. The GEE model indicates a notable shift in beta diversity, primarily driven by disruptions in hyporheic connectivity rather than environmental changes alone. This disruption favours stygobitic species downstream, suggesting the influence of groundwater upwelling. Environmental analysis shows several differences between upstream and downstream sites, with changes in parameters such as pH, temperature, and dissolved organic carbon. The study highlights the need for effective management strategies to mitigate sediment accumulation and maintain habitat quality in SHPP‐affected streams. Techniques like sediment bypass tunnels (SBTs) are recommended to preserve both economic and ecological values. This research contributes to the still limited understanding of SHPP impacts on hyporheic ecosystems, emphasizing the importance of considering these effects in hydropower development and riverine ecosystem conservation.

Importance Prurigo nodularis (PN) is a chronic and debilitating skin condition, characterized by intense itch with multiple nodular lesions. Nemolizumab demonstrated significant improvements in itch and skin nodules in adults with moderate to severe PN in a previous 16-week phase 3 study (OLYMPIA 2). Objective To assess the efficacy and occurrence of adverse events in adults with moderate to severe PN treated with nemolizumab vs those receiving placebo. Design, Setting, and Participants OLYMPIA 1 was a multicenter, placebo-controlled, phase 3 randomized clinical trial, conducted from August 2020 to March 2023 at 77 centers across 10 countries in adults with moderate to severe PN (at least 20 nodules and an Investigator’s Global Assessment [IGA] score ≥3) and Peak Pruritus Numerical Rating Scale (PP-NRS) score of at least 7.0; consisted of screening (up to 4 weeks), 24-week treatment, and 8-week follow-up periods. Interventions Patients were randomized (2:1) to nemolizumab monotherapy, 30 mg or 60 mg (depending on baseline weight of less than 90 kg vs 90 kg or greater, respectively), or matching placebo administered every 4 weeks for 24 weeks. Main Outcomes and Measures The primary end points were the proportion of patients with itch response (≥4-point improvement from baseline in weekly average PP-NRS) and IGA success (score of 0/1 [clear/almost clear] and 2-grade or more improvement from baseline) at week 16. Results Of 286 patients (mean [SD] age, 57.5 [13.0] years; mean [SD] body weight, 85.0 [20.7] kg; 166 [58.0%] female), 190 were randomized to receive nemolizumab, and 96 were randomized to placebo. A significantly greater proportion of patients assigned to nemolizumab vs placebo achieved itch response (111/190 [58.4%] vs 16/96 [16.7%]; Δ, 40.1% [95% CI, 29.4%-50.8%]; P < .001) and IGA success (50/190 [26.3%] vs 7/96 [7.3%]; Δ, 14.6% [95% CI, 6.7%-22.6%]; P = .003) at week 16. At week 24, the proportion of patients with itch response was 58.3% vs 20.4% (Δ, 38.7% [95% CI, 27.5%-49.9%]) in the ad hoc analysis, and IGA success was 58/190 (30.5%) vs 9/96 (9.4%) (Δ, 19.2% [95% CI, 10.3%-28.1%]) in the nemolizumab-treated vs placebo group. During the treatment period, 134 patients (71.7%) receiving nemolizumab vs 62 patients (65.3%) receiving placebo had at least 1 adverse event; most events were of mild to moderate severity. Conclusions and Relevance In this randomized clinical trial, nemolizumab monotherapy led to clinically meaningful and statistically significant improvements in core signs and symptoms of PN. Trial Registration ClinicalTrials.gov Identifier: NCT04501666

The connection of two orthogonal families of parallel equispaced duoskelion beams results in a 2D microstructure characterizing so-called tetraskelion metamaterials. In this paper, based on the homogenization results already obtained for duoskelion beams, we retrieve the internally-constrained two-dimensional nonlinear Cosserat continuum describing the in-plane mechanical behaviour of tetraskelion metamaterials when rigid connection is considered among the two families of duoskelion beams. Contrarily to duoskelion beams, due to the dependence of the deformation energy upon partial derivatives of kinematic quantities along both space directions, the limit model of tetraskelion metamaterials cannot be reduced to an initial value problem describing the motion of an unconstrained particle subjected to a potential. This calls for the development of a finite element formulation taking into account the internal constraint. In this contribution, after introducing the continuum describing tetraskelion metamaterials in terms of its deformation energy, we exploit the Virtual Work Principle to get governing equations in weak form. These equations are then localised to get the equilibrium equations and the associated natural boundary conditions. The feasibility of a Galerkin approach to the approximation of tretraskelion metamaterials is tested on duoskelion beams by defining two different equivalent weak formulations that are discretised and then solved by a Newton–Rhapson scheme for clamped-clamped pulling/pushing tests. It is concluded that, given the high nonlinearity of the problem, the choice of the initial guess is crucial to get a solution and, particularly, a desired one among the several bifurcated ones.

Tuber spp. (Ascomycota) forms hypogeous fruiting bodies (truffles) that host many microbial species as well as invertebrates which feed on them. Despite the larvae and adults of Diptera and Coleoptera are commonly found to inhabit truffles, molecular investigations assessing their occurrence are still few and the number of species is probably underestimated. In this study, 52 larvae and adults of Diptera from 23 T. aestivum ascomata collected in two provinces of northern and central Italy were molecularly characterized. The sequences fell into four Diptera families, and four taxa were identified as Cheilosia soror, Phaonia cf. trimaculata, Drosophila subobscura, and Suillia gigantea. Morphology of adults belonging to these species confirmed their identity. Additional three taxa belonging to the Helomyzidae remained unclassified. The study highlighted the coexistence of different Diptera species in the same ascoma, suggesting potential lack of competitive exclusion. Geographical distribution analysis reveals non-site specificity for most species. This research contributes insights into the diversity of Dipteran species and their interactions with truffles and lays the groundwork for their monitoring, at a time where truffle resources are threatened by anthropic and environmental factors.

Purpose The aim of this study is to compare perioperative, functional, and oncological outcomes between robot-assisted partial nephrectomy (RAPN) and cryoablation (CRYO), based on a 3-year experience at our Institution. Additionally, a secondary aim is to conduct a comparative cost analysis between the two procedures. Methods A retrospective analysis was conducted, including patients who underwent RAPN or CRYO between January 2020 and December 2023. Group 1 consisted of 59 patients who underwent RAPN, while Group 2 included 38 patients who had CRYO. The evaluation parameters included baseline characteristics, perioperative, functional, and oncological outcomes, as well as total hospitalization costs. Results Operative time (OT), average length of hospital stay (LOS), and emetic blood loss (EBL) were significantly lower in the CRYO group. Furthermore, CRYO showed a significantly lower rate of postoperative complications of any grade (7.8% vs 16.9%); however, this was associated with a considerably higher recurrence rate (5.7% vs 1.7%). No substantial differences were found in long-term functional outcomes (ΔeGFR). In terms of costs, CRYO was more cost-effective than RAPN (€5473 vs €10,672), although the gap was partially offset by a higher reimbursement “DRG” rate for robotic partial nephrectomy (€7386 vs €4384). Conclusions Robot-assisted partial nephrectomy (RAPN) remains the preferred option for treating small renal masses (sRM), providing excellent oncological results and acceptable morbidity. However, percutaneous cryoablation is a valid alternative, particularly for patients unfit for surgery, as long as meticulous postoperative follow-up is carried out.

Background: Cerebral venous thrombosis (CVT) accounts for 0.5-1% of all strokes. The role of endovascular therapy (EVT) in the management of CVT remains controversial and variations in practice patterns are not well known. Aims: Here, we present a comprehensive, international characterization of practice patterns and perspectives on the use of EVT for CVT.Methods A comprehensive 42-question survey was distributed to stroke clinicians globally from May-October 2023, asking about practice patterns and perspectives on the use of EVT for CVT. Results: The overall response rate was 31% (863 respondents of 2744 invited) across 61 countries. The majority of respondents (74%) supported the use of EVT for CVT in certain clinical situations. Key considerations for decision-making in using EVT favored clinical over radiographic/procedural factors and included worsening level of consciousness (86%) and worsening neurological deficits (76%). In the past three years, 56% of respondents used EVT for the treatment of CVT, with most (49.5%) involved in 2-5 cases. Among interventionalists, significant variability existed in the techniques used for EVT (p<0.001), with aspiration thrombectomy (56%) and stent retriever (51%) being the most used overall. Regionally, interventionalists from China predominately used intra-sinus heparin (56%), while this technique was most commonly ranked as "never indicated" throughout the rest of the world (23%). Post-procedure, low molecular weight heparin was the most used anticoagulant (83%), although North American respondents favored unfractionated heparin (37%), while imaging was primarily split between magnetic resonance (71.8%) and computed tomography (65.9%) arteriography or venography. Conclusions: Our survey reveals significant heterogeneity in approaches to EVT for CVT, and provides a comprehensive characterization of indications, techniques and long-term management used by clinicians internationally. This resource will aid in optimizing patient selection and endovascular treatments for future trials.

Background Osteoporosis and metabolic syndrome (MetS) are conditions associated with ageing and chronic inflammation; among MetS’ components, visceral obesity has been correlated to low bone mineral density in postmenopausal women. However, data on an increased fracture risk in MetS are still contrasting. The trabecular bone score (TBS) is an indicator of bone quality and a potential predictive factor for fractures. We aim to explore the relationship between MetS components and TBS. Methods we analyzed data from 3962 women in the 2005-2006 and 2007-2008 NHANES cohorts, for whom a valid TBS value was available. All analyses were adjusted for the principal risk factors of altered bone metabolism. Results An inverse significant association was observed between TBS and most of the MetS variables investigated, with the strongest correlation found with waist circumference (WC) (P <0.001). WC represented the major predictor of degraded TBS (P <0.001), in adjusted models considering age, 25(OH)Vitamin D, smoke and insulin resistance. Increased WC was significantly associated with the presence of bone fractures at the logistic regression analysis (P = 0.001) in all study participants and in the subgroup of women ≤50 years old after adjustment for potential confounders (P = 0.006). Conclusion This study, using a large sample of women, found a negative association of MetS on bone health, mainly driven by visceral obesity.