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This paper highlights the potentiality of the time series decomposition applied to transient regime groundwater flow models, as water balance management tool. In particular, this work presents results obtained by applying statistical analysis to some observed time series and to time series derived from the groundwater flow model of the coastal plain of Cecina (Tuscany region, Italy), developed in transient regime within the period 2005-2017. The time series of rainfall, river stage and hydraulic heads were firstly analysed, and then time series decomposition was applied to the “accumulated net storage”, to finally discern and quantify two meaningful components of the groundwater budget, the regulatory reserve (Wr = 22 Mm3) and the seasonal resource (Wd = 2.5 Mm3). These values compared with withdrawal volumes (average of 6.4 Mm3/y within the period 2005-2017) allowed to highlight potentially critical balance conditions, especially in periods with repeated negative climatic trends. Operational monitoring and modeling as following corrective and planning actions for the groundwater resource are suggested.

This work provides a groundwater flow and transport model of trichlorethylene and tetrachlorethylene contamination in the Cecina's coastal aquifer. The contamination analysis, with source located in the Poggio Gagliardo area (Montescudaio, Pisa), was necessary to optimize the groundwater monitoring and remediation design. The work was carried out in two phases: • design of a conceptual model of the aquifer using GIS analysis of many stratigraphic, chemical and hydrogeological data, collected from 2004 to 2012 in six aqueduct wells; • implementation of a groundwater flow and transport numerical model using the MODFLOW 88/96 and MT3D code and the graphical user interface GroundWaterVistas 5. The conceptual model hypothesizes a multilayer aquifer in the coastal plain extended to the sandy-clay hills, recharged by rainfall and by the Cecina River. The aquifer shows important hydrodynamic features affecting both the contamination spreading, due to the presence of a perched and heavily polluted layer separate from the underlying productive aquifer, and the hydrological balance, due to a thick separation layer that limits exchanges between the river and the second groundwater aquifer. The numerical model, built using increasingly complex versions of the initial conceptual model, has been calibrated using monitoring surveys conducted by the Environmental Protection Agency of Regione Toscana (ARPAT), in order to obtain possible forecast scenarios based on the minimum and maximum flow periods, and it is currently used as a tool for decision support regarding the reclamation and/or protection of the aquifer. Future developments will regard the implementation of the multilayer transport model, based on a new survey, and the final coupling with the regional hydrological model named MOBIDIC.

Background Lung cancer remains the leading cause of cancer-related mortality worldwide, with early detection playing a crucial role in reducing both deaths and healthcare costs. In Switzerland, the Swiss Cancer Screening Committee has conditionally recommended lung cancer screening using low-dose computed tomography (LDCT). Building on prior national experiences, we conducted a pilot study in Ticino to assess recruitment strategies, infrastructure suitability, and facility availability for a potential screening program. Methods A single round of LDCT was offered to at-risk individuals based on established inclusion criteria (age and smoking exposure, and/or 6-year lung cancer risk). General practitioners (GPs) played a central role in identifying and referring participants, ensuring a more targeted recruitment strategy. Participants were referred to community hospitals trough a dedicated and homogenous pathway involving lung cancer specialists. Visits results and structured CT reports were shared with GPs, and multidisciplinary recommendations were issued in case of suspicious findings. Clinical and psycho-social characteristics of participants were recorded and analyzed. Results Over a four-month period, 100 participants were enrolled, with a median lung cancer risk of 3.3% (IQR 2.1–5.6) and a mean smoking history of 42.2 pack-years (IQR 35.9–53.7). Mean age was 63 years, 69% were male and 86% were active smokers. Scattered distribution compared to general population was observed in educational level. The LDCT detected pulmonary nodules in 44% of participants (30% category 1–2, 10% category 3, 4% category 4A), with 32% requiring follow-up imaging (12 LDCT at 12 months, 10 LDCT at 6 months, 2 LDCT at 3 months and 2 PET scans). One case of early-stage lung cancer was identified at baseline scan and 2 at follow-up (lung cancer detection rate 3%); all successfully treated. Conclusions Compared to previous Swiss studies, our GP-driven approach enabled rapid recruitment and may improve accessibility, particularly for non-urban populations. However, disparities in educational backgrounds among participants suggest that further refinements in outreach strategies are needed. Additionally, the study highlighted the feasibility of integrating LDCT screening within Ticino’s existing healthcare infrastructure, benefiting from its decentralized hub-and-spoke model. These findings provide valuable insights for future lung cancer screening programs in Switzerland, emphasizing the importance of primary care engagement, geographic accessibility, and tailored recruitment strategies to enhance effectiveness and equity.

MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors.

Background Resting-state functional magnetic resonance imaging (RS-fMRI) has demonstrated disrupted default mode network (DMN) connectivity in a number of pain conditions, including migraine. However, the significance of altered resting-state brain functional connectivity in migraine is still unknown. The present study is aimed to explore DMN functional connectivity in patients with migraine without aura (MwoA) and investigate its clinical significance. Methods To calculate and compare the resting-state functional connectivity of the DMN in 20 patients with MwoA, during the interictal period, and 20 gender- and age-matched HC, Brain Voyager QX was used. Voxel-based morphometry was used to assess whether between-group differences in DMN functional connectivity were related to structural differences. Secondary analyses explored associations between DMN functional connectivity, clinical and neuropsychological features of migraineurs. Results In comparison to HC, patients with MwoA showed decreased connectivity in prefrontal and temporal regions of the DMN. Functional abnormalities were unrelated to detectable structural abnormalities or clinical and neuropsychological features of migraineurs. Conclusions Our study provides further evidence of disrupted DMN connectivity in patients with MwoA. We hypothesize that a DMN dysfunction may be related to behavioural processes such as a maladaptive response to stress which seems to characterize patients with migraine.

Objective Biallelic mutations in PRDX3 have been linked to autosomal recessive spinocerebellar ataxia type 32. In this study, which aims to contribute to the growing body of knowledge on this rare disease, we identified two unrelated patients with mutations in PRDX3. We explored the impact of PRDX3 mutation in patient skin fibroblasts and the role of the gene in neurodevelopment. Methods We performed trio exome sequencing that identified mutations in PRDX3 in two unrelated patients. We also performed functional studies in patient skin fibroblasts and generated a “crispant” zebrafish (Danio rerio) model to investigate the role of the gene during nervous system development. Results Our study reports two additional patients. Patient 1 is a 19‐year‐old male who showed a novel homozygous c.525_535delGTTAGAAGGTT (p. Leu176TrpfsTer11) mutation as the genetic cause of cerebellar ataxia. Patient 2 is a 20‐year‐old male who was found to present the known c.425C>G/p. Ala142Gly variant in compound heterozygosity with the p. Leu176TrpfsTer11 one. While the fibroblast model failed to recapitulate the pathological features associated with PRDX3 loss of function, our functional characterization of the prdx3 zebrafish model revealed motor defects, increased susceptibility to reactive oxygen species‐triggered apoptosis, and an impaired oxygen consumption rate. Conclusions We identified a new variant, thereby expanding the genetic spectrum of PRDX3‐related disease. We developed a novel zebrafish model to investigate the consequences of prdx3 depletion on neurodevelopment and thus offered a potential new tool for identifying new treatment opportunities.

Objectives To investigate the reliability of a new in-house automatic algorithm for calculating the Magnetic Resonance Parkinsonism Index (MRPI), in a large multicentre study population of patients affected by progressive supranuclear palsy (PSP) or Parkinson’s disease (PD), and healthy controls (HC), and to compare the diagnostic accuracy of the automatic and manual MRPI values. Methods The study included 88 PSP patients, 234 PD patients and 117 controls. MRI was performed using both 3T and 1.5T scanners. Automatic and manual MRPI values were evaluated, and accuracy of both methods in distinguishing PSP from PD and controls was calculated. Results No statistical differences were found between automated and manual MRPI values in all groups. The automatic MRPI values differentiated PSP from PD with an accuracy of 95 % (manual MRPI accuracy 96 %) and 97 % (manual MRPI accuracy 100 %) for 1.5T and 3T scanners, respectively. Conclusion Our study showed that the new in-house automated method for MRPI calculation was highly accurate in distinguishing PSP from PD. Our automatic approach allows a widespread use of MRPI in clinical practice and in longitudinal research studies. Key Points • A new automatic method for calculating the MRPI is presented. • Automatic MRPI values are in good agreement with manual values. • Automatic MRPI can distinguish patients with PSP from patients with PD. • The automatic method overcomes MRPI application limitations in routine practice. • The automatic method may allow a more widespread use of MRPI.

Pregnancy and lactation-associated osteoporosis is a rare form of osteoporosis occurring during late pregnancy and early lactation, featuring fragility fractures, primarily involving the vertebral bodies and leading to back pain. Its management involves osteoporosis treatment, complicated by potential drug-related dangerous effects on the fetus. Nevertheless, many controversies remain regarding diagnosis, prognosis, and treatment options. Herein, we propose a multicentric case series to provide a comprehensive neurosurgical, gynecological, and endocrinological perspective on the management of pregnancy and lactation-associated osteoporotic vertebral fractures. A multicenter retrospective study was conducted at the Neurosurgical Department of Università degli Studi di Napoli Federico II, the Neurosurgical Unit of Hopitaux Universitaires de Genève, and the Spine and Spinal Cord Surgery Unit of the University Hospital of Udine, collecting data from January 2014 to December 2022. The study has been approved by the ethical committee of each hospital.  N  = 11 patients with an overall number of 31 fractures were eligible, with a mean age of 36. N  = 5 (16%) fractures in 4 patients (36%) developed during pregnancy, and N  = 26 (84%) fractures in 7 (64%) patients occurred during lactation. The mean number of fractures per patient was 2,81. In 10 (90%) patients, fractures occurred at the first pregnancy, and 5 (45%) patients had uneventful subsequent pregnancies. The mean clinical signs and symptoms were back pain (92%), followed by loss of height (75%) and kyphosis (4 patients, 35%). One (9,09%) patient underwent in vitro fertilization (IVF), and one patient (9,09%) was receiving hormonal therapy (ethinylestradiol/drosiprenone). 10 out of 11 (90%) patients were treated conservatively, and 6 of them (60%) were managed with an orthosis. One (9,1%) patient underwent surgery for 5-level kyphoplasty. The mean average reduction of pain after one year of follow-up was 6,7 on the visual analogue scale (p-value 0,04). Pregnancy-related osteoporotic vertebral fractures are an emerging issue in developing countries, for which a conservative strategy ensures the best outcomes. The main goal is to improve bone mineral density through calcium and vitamin D supplementation and bone-active drugs as bisphosphonates or teriparatide. Surgery is warranted only in cases of a risk of severe deterioration of neurological functions.

Background Autosomal-dominant spinocerebellar ataxia (ADCA) due to intronic GAA repeat expansion in FGF14 (SCA27B) is a recent, relatively common form of late-onset ataxia. Objective Here, we aimed to: (1) investigate the relative frequency of SCA27B in different clinically defined disease subgroups with late-onset ataxia collected among 16 tertiary Italian centers; (2) characterize phenotype and diagnostic findings of patients with SCA27B; (3) compare the Italian cohort with other cohorts reported in recent studies. Methods We screened 396 clinically diagnosed late-onset cerebellar ataxias of unknown cause, subdivided in sporadic cerebellar ataxia, ADCA, and multisystem atrophy cerebellar type. We identified 72 new genetically defined subjects with SCA27B. Then, we analyzed the clinical, neurophysiological, and imaging features of 64 symptomatic cases. Results In our cohort, the prevalence of SCA27B was 13.4% (53/396) with as high as 38.5% (22/57) in ADCA. The median age of onset of SCA27B patients was 62 years. All symptomatic individuals showed evidence of impaired balance and gait; cerebellar ocular motor signs were also frequent. Episodic manifestations at onset occurred in 31% of patients. Extrapyramidal features (17%) and cognitive impairment (25%) were also reported. Brain magnetic resonance imaging showed cerebellar atrophy in most cases (78%). Pseudo-longitudinal assessments indicated slow progression of ataxia and minimal functional impairment. Conclusion Patients with SCA27B in Italy present as an adult-onset, slowly progressive cerebellar ataxia with predominant axial involvement and frequent cerebellar ocular motor signs. The high consistency of clinical features in SCA27B cohorts in multiple populations paves the way toward large-scale, multicenter studies.

Background Real-world studies on fremanezumab, an anti-calcitonin gene-related peptide monoclonal antibody for migraine prevention, are few and with limited follow-up. Objective We aimed to evaluate the long-term (up to 52 weeks) effectiveness and tolerability of fremanezumab in high-frequency episodic migraine and chronic migraine. Methods This s an independent, prospective, multicenter cohort study enrolling outpatients in 17 Italian Headache Centers with high-frequency episodic migraine or chronic migraine and multiple preventive treatment failures. Patients were treated with fremanezumab 225 mg monthly. The primary outcomes included changes from baseline (1 month before treatment) in monthly headache days, response rates (reduction in monthly headache days from baseline), and persistence in medication overuse at months 3, 6, and 12 (all outcome timeframes refer to the stated month). Secondary outcomes included changes from baseline in acute medication intake and disability questionnaires scores at the same timepoints. A last observation carried forward analysis was also performed. Results A total of 90 patients who received at least one dose of fremanezumab and with a potential 12-month follow-up were included. Among them, 15 (18.0%) patients discontinued treatment for the entire population, a reduction in monthly headache days compared with baseline was reported at month 3, with a significant median [interquartile range] reduction in monthly headache days (− 9.0 [11.5], p < 0.001). A statistically different reduction was also reported at month 6 compared with baseline (− 10.0 [12.0]; p < 0.001) and at 12 months of treatment (− 10.0 [14.0]; p < 0.001). The percentage of patients with medication overuse was significantly reduced compared with baseline from 68.7% (57/83) to 29.6% (24/81), 25.3% (19/75), and 14.7% (10/68) at 3, 6, and 12 months of treatment, respectively ( p < 0.001). Acute medication use (days and total number) and disability scores were also significantly reduced ( p < 0.001). A ≥ 50% response rate was achieved for 51.9, 67.9, and 76.5% of all patients at 3, 6, and 12 months, respectively. Last observation carried forward analyses confirmed these findings. Fremanezumab was well tolerated, with just one patient discontinuing treatment because of adverse events. Conclusions This study provides evidence for the real-world effectiveness of fremanezumab in treating both high-frequency episodic migraine and chronic migraine, with meaningful and sustained improvements in multiple migraine-related variables. No new safety issue was identified.