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Background: Fear of Falling (FOF) significantly affects Parkinson's Disease (PD) patients by limiting daily activities and reducing quality of life (QoL). Though common in PD, the relation between FOF, mobility, and QoL remains unclear. This study examines the connections between FOF, gait, daily motor activity, and QoL in PD patients., Methods: Fifty PD patients on stable levodopa therapy were enrolled, excluding those with dementia or walking impairments. Assessments included UPDRS-III, Hoehn and Yahr, MoCA, Berg Balance scale, Geriatric Depression Scale and Fall Efficacy Scale International (FES-I). QoL was evaluated using PDQ39. The Timed-Up-and-Go (TUG) test was performed at regular and fast paces, with data collected via smartphone apps for TUG gait parameters and for 24-h quantity of movement monitoring (Activity Index, AIX). A subgroup of 10 patients also underwent 24-h gait monitoring., Results: FOF was found in 38% of patients, correlating with worse motor scores and QoL (UPDRS-III, 26 vs 17, p < 0.0001; PDQ39 36 vs 14, p < 0.0001). FOF patients showed slower walking (0.73 m/s vs 1.13 m/s, p < 0.001), reduced step length (0.151 vs 0.220 m, p < 0.001), and poorer adaptation to fast walking and environment (being unable to vary their speed and frequency). FOF and sex were both associated with a reduced mobility QoL, with a significant contribution of AIX only in women (r -0.648, p = 0.012)., Conclusions: This study supports the existence of a significant correlation between FOF, motor activity and QoL in PD, especially in women, emphasize the need for targeted interventions, early rehabilitation and prospective studies focusing on gender., Competing Interests: Declarations. Competing interests: Ziv Yekutieli is CEO of Mon4t; Keren Karlinsky is employed by Mon4t. Massimo Marano, Gabriele Sergi, Alessandro Magliozzi, Federica Bressi, Marco Bravi, Alice Laudisio, Claudio Pedone, Vincenzo Di Lazzaro declare no competing interest for the present study. Informed consent: The present work has been approved by the local ethic committee and has been performed in accordance with the Helsinki declaration, all patients provided informed consent., (© 2025. Fondazione Società Italiana di Neurologia.)

Introduction: Parkinson's disease patients may experience altered body image perception. Advanced Parkinson's disease (aPD) with motor complications often requires surgical and device-aided treatments (DAT), such as levodopa-carbidopa intestinal gel (LCIG) and deep brain stimulation (DBS). Understanding body image perception is crucial when managing these devices. This study aims to explore body image perception in aPD patients, hypothesizing a link between DAT and body image perception., Methods: We performed a cross-sectional study including non-demented aPD patients with and without DAT and age- and sex-matched controls. Participants were assessed using the Appearance Schemas Inventory-Revised (ASI-R), including Motivational Salience (MS) and Self-Evaluative Salience (SES) scores. Additional data included age, education, BMI, comorbidities, pharmacotherapy, and psychopathologies. PD patients were also evaluated with UPDRS, Hoehn and Yahr scales and LEDD calculation., Results: 70 aPD and 36 controls were enrolled. No differences in ASI-R scores were found between PD patients and controls, but women with PD had significantly lower MS scores than controls (16.1 ± 5.6 vs 19.7 ± 5.8; p = 0.023). Among aPD patients, those on DAT had longer disease duration, higher Hoehn and Yahr, and lower UPDRS IV scores. The lowest MS was observed in women on LCIG (12.7 ± 3.3; p = 0.001)., Discussion: This study shows low MS ratings driven by female gender and LCIG treatment. Women on LCIG show reduced attention and management of their appearance. This may be influenced by cultural, environmental, and biological factors. Prospective research is needed to understand the impact of DAT on body image., Competing Interests: Declarations. Ethical approval and Informed consent: The present work has been approved by the local ethic committee, all patients provided written informed consent. Disclosures: Authors have nothing to disclose. Competing interests: Authors have no competing interests., (© 2024. Fondazione Società Italiana di Neurologia.)

Objective: The mechanisms of actions of transcutaneous auricular vagus nerve stimulation (taVNS) are still unclear, however the activity of the cholinergic system seems to be critical for the induction of VNS-mediated plasticity. Transcranial Magnetic Stimulation (TMS) is a well-suited, non-invasive tool to investigate cortical microcircuits involving different neurotransmitters. Herein, we evaluated the effect of taVNS on short-latency afferent inhibition (SAI), a TMS paradigm specifically measuring cholinergic neurotransmission., Methods: Fifteen healthy subjects participated in this randomized placebo-controlled double-blind study. Each subject underwent two different sessions of 1-hour exposure to taVNS (real and sham) separated by a minimum of 48 h. Real taVNS was administered at left external acoustic meatus, while sham stimulation was performed at left ear lobe. We evaluated SAI bilaterally over the motor cortex before and after exposure to taVNS., Results: No side effects were reported by any of the participants. Statistical analysis did not show any significant effect of taVNS on SAI., Conclusions: Our study demonstrated that cholinergic circuits explored by SAI are different from circuits engaged by taVNS., Significance: Since the influence of VNS on cholinergic neurotransmission has been exhaustively demonstrated in animal models, further studies are mandatory to understand the actual impact of VNS on cholinergic circuits in humans., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The genome sequencing revolution has revealed that all species possess a large number of unique genes critical for trait variation, adaptation, and evolutionary innovation. One widely used approach to identify such genes consists of detecting protein-coding sequences with no homology in other genomes, termed orphan genes. These genes have been extensively studied, under the assumption that they represent valid proxies for species-specific genes. Here, we critically evaluate taxonomic, phylogenetic, and sequence evolution evidence showing that orphan genes belong to a range of evolutionary ages and thus cannot be assigned to a single lineage. Furthermore, we show that the processes generating orphan genes are substantially more diverse than generally thought and include horizontal gene transfer, transposable element domestication, and overprinting. Thus, orphan genes represent a heterogeneous collection of genes rather than a single biological entity, making them unsuitable as a subject for meaningful investigation of gene evolution and phenotypic innovation., (© 2024 The Author(s). BioEssays published by Wiley Periodicals LLC.)

The coordinate regulation of metabolism and epigenetics to establish cell state-specific gene expression patterns during lineage progression is a central aspect of cell differentiation, but the factors that regulate this elaborate interplay are not well-defined. The imprinted Dlk1-Dio3 noncoding RNA (ncRNA) cluster has been associated with metabolism in various progenitor cells, suggesting it functions as a regulator of metabolism and cell state. Here, we directly demonstrate that the Dlk1-Dio3 ncRNA cluster coordinates mitochondrial respiration and chromatin structure to maintain proper cell state. Stable mouse muscle cell lines were generated harboring two distinct deletions in the proximal promoter region, resulting in either greatly upregulated or downregulated expression of the entire Dlk1-Dio3 ncRNA cluster. Both mutant lines displayed impaired muscle differentiation along with dysregulated structural gene expression and abnormalities in mitochondrial respiration. Genome-wide chromatin accessibility and histone methylation patterns were also severely affected in these mutants. Our results strongly suggest that muscle cells are sensitive to Dlk1-Dio3 ncRNA dosage, and that the cluster coordinately regulates metabolic activity and the epigenome to maintain proper cell state in the myogenic lineage., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Peripheral immune cells critically contribute to the clinical-pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard., Objective: Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort., Methods: Seventy-one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil-to-lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2-related factor (NRF2)/heme oxygenase 1 (HO-1) pathway and the total tau (t-tau) and phosphorylated tau (p-tau) proteins. Case-control comparison and correlation analyses were performed., Results: PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO-1 pathway activated in patients. P-tau, but not t-tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS., Conclusions: PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO-1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p-tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society., (© 2024 International Parkinson and Movement Disorder Society.)

Leg Ulcer (LU) pathophysiology is still not well understood in sickle cell anaemia (SCA). We hypothesised that SCA patients with LU would be characterised by lower microvascular reactivity. The aim of the present study was to compare the microcirculatory function (transcutaneous oxygen pressure (TcPO 2 ) on the foot and laser Doppler flowmetry on the arm) and several blood biological parameters between nine SCA patients with active LU (LU+) and 56 SCA patients with no positive history of LU (LU-). We also tested the effects of plasma from LU+ and LU- patients on endothelial cell activation. We observed a reduction of the TcPO 2 in LU+ compared to LU- patients. In addition, LU+ patients exhibited lower cutaneous microvascular vasodilatory capacity in response to acetylcholine, current and local heating compared to LU- patients. Inflammation and endothelial cell activation in response to plasma did not differ between the two groups. Among the nine patients from the LU+ group, eight were followed and six achieved healing in 4.4 ± 2.5 months. Among thus achieving healing, microvascular vasodilatory capacity in response to acetylcholine, current and local heating and TcPO 2 improved after healing. In conclusion, microcirculatory function is impaired in patients with LU, and improves with healing., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Objective: Linkage to HIV medical care is important in the continuum of HIV care and health outcomes for people with HIV. The objective of this analysis was to identify how the community-based organization (CBO) program contributes to linkage to HIV medical care among people with newly diagnosed HIV in the Centers for Disease Control and Prevention's (CDC's) HIV testing program., Methods: We analyzed HIV linkage-to-care data submitted to CDC from 2019 through 2021. Linkage was defined as confirmation that an individual attended their first HIV medical care appointment within 30 days of their HIV test date. We included in the analysis data submitted from the health department (HD) program that included 61 state and local HDs in the United States, Puerto Rico, and the US Virgin Islands and the CBO program that included 150 CBOs., Results: The CBO program linked a higher proportion of people to HIV medical care within 30 days of diagnosis (86.7%) than the HD program (73.7%). By population group, the proportion linked in the CBO program was higher than the proportion linked in the HD program among men who have sex with men (prevalence ratio [PR] = 1.13; P  < .001), men who have sex with men/people who inject drugs (PR = 1.29; P  < .001), transgender people (PR = 1.28; P  < .001), and those reporting no sexual contact or injection drug use (PR = 1.34; P  < .001). In the Cox proportional hazards model, time to linkage in the CBO program was significantly shorter than in the HD program (hazard ratio = 0.63; P  < .001)., Conclusion: This analysis shows that the CBO program fills a vital need in linking newly diagnosed HIV-positive people to HIV medical care, which is important in the HIV care continuum and for viral suppression., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background/objectives: Driving abilities require the synchronized activity of cerebral networks associated with sensorimotor integration, motricity, and executive functions. Drivers with Parkinson's disease (DwP) have impaired driving ability, but little is known about the impact of "wearing-off" and therapies in addition to L-DOPA on driving capacities. This study aimed to (i) compare driving performance between DwP during different motor states and healthy controls and (ii) assess the impact of add-on therapies on driving abilities., Methods: DwP ( n = 26) were enrolled as individuals experiencing wearing-off symptoms and treated (within 6 months before the enrollment) with add-on therapies to L-DOPA, including MAO inhibitors for DwP-A ( n = 12) or opicapone for DwP-B ( n = 14). Age- and sex-matched controls (CON, n = 12) were also enrolled. DwP received two driving assessments in a driving simulator during their "best-on" time and during their wearing-off time on different days. An anamnestic driving questionnaire was collected with the assistance of partners. A Virtual Driving Rating Scale (VDRS) was calculated, as well as learning curves (LCs) for driving items calculated in minutes., Results: DwP reported worse driving performance than CON at the driving questionnaire. In line with this, DwP showed worse VDRS ( p < 0.01) and LC ( p = 0.021) than CON. Lower VDRS was associated with wearing-off ( p < 0.01), but DwP-B had better driving performance while in their "best-on" time ( p = 0.037) and more items improving with LCs (7 vs. 3) than DwP-A., Conclusions: DwP demonstrated impaired driving compared to controls. Wearing-off symptoms can also affect driving ability, but therapies (opicapone more so than MAO inhibitors) may play a role in preserving specific driving skills, possibly through maintaining learning abilities.

Heterozygous mutations or genetic variants in the GBA1 gene, which encodes for the β-glucocerebrosidase (GCase), a lysosomal hydrolase enzyme, may increase the risk of Parkinson's disease (PD) onset. The heterozygous E326K form is one of the most common genetic risk factors for PD worldwide, but, to date, the underlying molecular mechanisms remain unclear. Here, we investigate the effect of the E326K on the structure, stability, dimerization process, and interaction mode with some proteins of the interactome of GCase using multiple molecular dynamics (MD) simulations at pH 5.5 and pH 7.0 to mimic the lysosomal and endoplasmic reticulum environments, respectively. The analysis of the MD trajectories highlights that the E326K mutation did not significantly alter the structural conformation of the catalytic dyad but significantly makes the structure of the dimeric complexes unstable, especially at lysosomal pH, potentially impacting the organization of the quaternary structure. Furthermore, the E326K mutation significantly impacts protein interactions by altering the binding mode with the activator Saposin C (SapC), reducing the binding affinity with the inhibitor α-Synuclein (α-Syn), and increasing the affinity for the Lysosomal integral membrane protein-2 (LIMP-2) transporter.

Background: Haemophilic arthropathy (HArt) is a serious complication in patients with hemophilia. Early diagnosis and treatment are essential to minimise the development of HArt. The use of biomarkers may improve early diagnosis of HArt. Circulating microRNAs (miRNAs) are small, non-coding RNAsthat regulate gene expression, and are being investigated as promising biomarkers due to their role in joint and bone metabolism., Aims: To investigate differential expression of miRNAs and their relationship to arthropathy in patients with hemophilia A., Methods: miRNA expression was examined in a pilot study followed by a validation study (100 hemophilia A patients with [n = 83] and without HArt [n = 17], 14 controls). Differential miRNA expression was investigated using real-time quantitative PCR., Results: The pilot study identified 2 miRNAs differentially expressed in patients with Hart (Pettersson score ≥ 1), after adjusting for the false discovery rate (FDR). The validation study evaluated these 2 miRNAs. The results demonstrated that two miRNAs (miR- 208a-3p and 524-3p) were significantly underexpressed in plasma of patients with HArt compared to patients without arthropathy, with FDR <0.05 (Fig. 1). In addition, 3 miRNAs (130a-3p, miR- and 506-3p) were significantly underexpressed in patients with moderate HArt (Pettersson score 4 to 7)., Conclusions: In this proof of concept study we identified a signature of 5 circulating miRNAs associated with Hart with potential as diagnosis tools for HArt. These miRNAs are potential negative regulators of gene expression, suggesting their activity in HArt by interfering with osteoblastic (miR- 208a-3p) and osteoclastic (miR-506-3p) differentiation to impair bone mineralization and remodeling processes, or regulating chondrogenesis (miR-335-5p). miRNAs associated with earlier stages of HArt will be further investigated in a sub-study of the prospective clinical trial PROVE, which will investigate the effects of long-term prophylaxis with simoctocog alfa versus emicizumab in adults with hemophilia A., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms, including alteration in emotional processing and recognition of emotions. We explored the effects of PD on the emotional behavioral ratings using a battery of affective visual stimuli selected from the International Affective Picture System (IAPS)., Methods: Twenty-two patients diagnosed with idiopathic PD and 22 healthy controls (HC), matched by age, gender, and education, were enrolled in the study. Following a clinical assessment, each participant was asked to evaluate the arousal and valence of affective visual stimuli, and response time was recorded. Disease-specific measures including the MDS Unified Parkinson's Disease Rating Scale (MDS UPDRS) and the Non-Motor Symptom Scale (NMSS) were also collected., Results: PD patients exhibited higher arousal responses compared to HC for negative/unpleasant pictures (scoring 7.32 ± 0.88 vs 5.43 ± 2.06, p < 0.001). The arousal response to negative/unpleasant pictures was correlated with measures of non-motor burden in PD (MDS UPDRS I and NMSS, rho = 0.480 and p = 0.023, rho = 0.533 and p = 0.010, respectively)., Conclusion: Impaired emotional processing characterizes PD patients with mild disease and is related to the non-motor symptom burden. Given the importance of emotional processing for the development and maintenance of close interpersonal relationship and for coping with specific medical situations, it is crucial to direct PD patients towards therapeutic interventions focused on the recognition and processing of emotions., (© 2024. Fondazione Società Italiana di Neurologia.)

Hypomyelinating leukodystrophies (HLD) are a group of heterogeneous genetic disorders characterized by a deficit in myelin deposition during brain development. Specifically, 4H-Leukodystrophy is a recessive disease due to biallelic mutations in the POLR3A gene, which encodes one of the subunits forming the catalytic core of RNA polymerase III (PolIII). The disease also presents non-neurological signs such as hypodontia and hypogonadotropic hypogonadism. Here, we report the generation of a human induced pluripotent stem cell (hiPSC) line from fibroblasts of the first identified carrier of the biallelic POLR3A variants c.1802 T > A and c.4072G > A., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jessica Rosati reports financial support, article publishing charges, and equipment, drugs, or supplies were provided by Ministry of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: The wearing-off phenomenon is characterized by the recurrence of motor and non-motor symptoms of Parkinsonism during a period free from levodopa. It is a pivotal aspect marking the end of the pharmacological "honeymoon" period in Parkinson's disease (PD). A growing body of literature is connecting sex with the likelihood of developing fluctuations. We investigated such an association in a post-hoc analysis of the large WORK-PD study., Methods: WORK-PD analyzed the usability of the wearing-off questionnaire 19 (WOQ19) in clinical practice and included cross-sectional data on age, disease duration, time on levodopa, Hoehn and Yahr stage, and WOQ19 scores of 532 PD patients. In the present study, we selected patients with an exposure time to levodopa of at least 1 year., Results: A total of 380 patients were included. Women reported a higher number of wearing-off symptoms than men (6.09 ± 3.39 vs 4.96 ± 3.11, p = 0.0006). Sex groups also differed in non-motor symptoms (2 ± 1.9 vs 1.5 ± 1.5, p = 0.021), particularly behavioral wearing-off scores being higher in women (p < 0.001). The latter were primarily featured by anxiety-related phenomena. Finally, there was a significant interaction between behavioral symptoms, sex, and age at onset (df = 2, F = 9.79, p < 0.0001), whereas no such interaction was observed with levodopa exposure and motor impairment, unlike motor symptoms., Discussion: Women showed a greater propensity than men to experience wearing-off, particularly non-motor fluctuations on the anxiety spectrum. The latter may demonstrate a lesser reliance on dopamine compared to motor symptoms. This observation could be underpinned by biological variances between genders at the neurotransmitter level., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Introduction: Gaucher's disease (GD) is caused by biallelic mutations in the GBA1 gene, leading to reduced glucocerebrosidase (GCase) activity and substrate (glucosylceramide and glucosylsphingosine, GlcSph) accumulation. GBA1 variant carriers are at risk of Parkinson's disease (PD), but only those with biallelic mutations cross the threshold of GCase reduction, leading to substrate accumulation and GD. The link between GBA1 mutations, GD and PD is not fully understood. Here we aimed at reporting the results of a large PD population screening with dried blood spot tests for GD., Methods: We measured GCase activity and GlcSph levels in 1344 PD patients with dried blood spot tests, and performed GBA1 genetic sequencing., Results: While the GCase activity was reduced in GBA1-PD carriers compared to wild type PD, GlcSph was increased in GBA1-PD compared to GBA1-controls, regardless of the underlying type of GBA1 variant. 13.6 % and 0.4 % of PD patients had mono- or biallelic GBA1 mutations respectively. GCase deficiency, lipid accumulation and clinical manifestations of GD was detected in five PD patients with biallelic GBA1 mutations, of whom four had a risk combined with a GD causing variant., Conclusions: GlcSph appearing higher in PD may represent a reliable biomarker of the disease and deserves to be further investigated. This study highlights the importance of screening PD patients for possible underlying GD, which is a treatable condition that should not be missed. We diagnosed GD cases carrying a "risk" variant in one allele, which is an unprecedented finding deserving further investigation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Malnutrition remains a pressing health concern in developing nations, contributing to growth delay (stunting) and psychomotor impairments among the youth. Tanzania has the highest prevalence of stunting, yet the psychomotor status of its population has not been previously studied. To address this gap, we gathered anthropometric, nutritional, and psychomotor data from 211 children with the aim of assessing the reliability of digital tools as indicators of psychomotor performance in relation to the nutritional status. Collected anthropometric measures included middle-upper arm circumference (MUAC), triceps skinfold thickness (TST), and handgrip strength, while psychomotor variables were assessed using digital finger tapping test (DFTT), eye-tracking test (ETT), and nine-hole peg test (9HPT). Statistical analysis revealed significant associations between age and both MUAC and handgrip strength (R = 0.5, p < 0.001). Moreover, DFTT and 9HPT demonstrated a correlation with each other (p = 0.026) and with MUAC, handgrip strength, and age (p < 0.001). Notably, lower stature was independently linked to slower horizontal eye movements (p < 0.001). Findings underscores the crucial link between nutrition and psychomotor skills in Tanzanian children. Digital tests like DFTT, ETT, and the 9HPT show promise for assessing psychomotor performance. Addressing malnutrition requires comprehensive interventions. Future research should explore long-term effects of interventions in resource-limited settings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Poststroke spasticity (PSS) affects up to 40% of patients who had a stroke. Botulinum neurotoxin type A (BoNT-A) has been shown to improve spasticity, but the optimal timing of its application remains unclear. While several predictors of upper limb PSS are known, their utility in clinical practice in relation to BoNT-A treatment has yet to be fully elucidated. The COLOSSEO-BoNT study aims to investigate predictors of PSS and the effects of BoNT-A timing on spasticity-related metrics in a real-world setting., Methods and Analysis: The recruitment will involve approximately 960 patients who have recently experienced an ischaemic stroke (within 10 days, V0) and will follow them up for 24 months. Parameters will be gathered at specific intervals: (V1) 4, (V2) 8, (V3) 12, (V4) 18 months and (V5) 24 months following enrolment. Patients will be monitored throughout their rehabilitation and outpatient clinic journeys and will be compared based on their BoNT-A treatment status-distinguishing between patients receiving treatment at different timings and those who undergo rehabilitation without treatment. Potential predictors will encompass the Fugl-Meyer assessment, the National Institute of Health Stroke Scale (NIHSS), stroke radiological characteristics, performance status, therapies and access to patient care pathways. Outcomes will evaluate muscle stiffness using the modified Ashworth scale and passive range of motion, along with measures of quality of life, pain, and functionality., Ethics and Dissemination: This study underwent review and approval by the Ethics Committee of the Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy. Regardless of the outcome, the findings will be disseminated through publication in peer-reviewed journals and presentations at national and international conferences., Trial Registration Number: NCT05379413., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Parkinson's disease (PD) patients are frequently exposed to antidepressant medications (ADMs). Norepinephrine (NE) and serotonin (5HT) systems have a role in levodopa-induced dyskinesias (LID) pathophysiology., Methods: We performed a longitudinal analysis on the PPMI cohort including drug-naïve PD patients, who are progressively exposed to dopamine replacement therapies (DRTs) to test the effect of ADM exposure on LID development by the 4th year of follow-up., Results: LID prevalence (according to MDS UPDRS score 4.1 ≥ 1) was 16% (42/251); these patients were more likely women (p = 0.01), had higher motor (p < 0.001) and depression scores (p = 0.01) and lower putaminal DAT binding ratio (p = 0.01). LID were associated with the exposure time to L-DOPA (2.2 ± 1.07 vs 2.6 ± 0.9, p = 0.02) and to the exposure to ADMs, in particular to SNRI (4.8% vs 21.4%, p < 0.001). The latter persisted after correcting for significant covariates (e.g., disease duration, cognitive status, motor impairment, depression, dopaminergic denervation). A similar difference in LID prevalence in PD patients exposed vs non-exposed to SNRI was observed on matched data by the real-world TriNetX repository (22% vs 13%, p < 0.001)., Discussion: This study supports the presence of an effect of SNRI on LID priming in patients with early PD. Independent prospective cohort studies are warranted to further verify such association., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Objective : Interatrial block (IAB) is defined as a conduction delay between the right and left atria. No data are available about the prevalence of both partial IAB and advanced IAB among the different stages of chronic kidney disease. The aim of this study was to describe the prevalence and type of advanced IAB across the spectrum of renal function, including patients on dialysis and the clinical characteristics associated with advanced IAB. Materials and Methods : Retrospective, single-center study of 151 patients consecutively admitted to the Nephrology and Ophthalmology Unit for 3 months. The study population was divided into three groups according to stages of chronic kidney disease. We evaluated the prevalence and pattern of IAB among the groups and the clinical characteristics associated with advanced IAB. Results : The prevalence of partial IAB was significantly lower in end-stage kidney disease (ESKD) group compared to control group (36.7% vs. 59.6%; p = 0.02); in contrast the prevalence of advanced IAB was significantly higher in both chronic kidney disease (CKD) (17.8% vs. 5.3%, p = 0.04) and ESKD group (24.5% vs. 5.3%, p = 0.005) compared to control group. The atypical pattern of advanced IAB was more frequent in both the ESKD and CKD group than in the control group (100% and 75% vs. 33.3%; p = 0.02). Overall, among patients that showed advanced IAB, 17 (73.9%) showed an atypical pattern by morphology and 2 (8.7%) showed an atypical pattern by duration of advanced IAB. The ESKD group was younger than the control group (65.7 ± 12.3 years vs. 71.3 ± 9.9 years; p = 0.01) and showed a higher prevalence of beta blockers (42.9% vs. 19.3%; p = 0.009), as in the CKD group (37.8% vs. 19.3%; p = 0.04). Conclusions: The progressive worsening of renal function was associated with an increasing prevalence of advanced IAB. Advanced IAB may be a sign of uremic cardiomyopathy and may suggest further evaluation with long-term follow-up to investigate its prognostic significance in chronic kidney disease.

Emotional dysfunctions in Parkinson's disease (PD) remain a controversial issue. While previous investigations showed compromised recognition of expressive faces in PD, no studies evaluated potential deficits in recognizing the emotional valence of affective scenes. This study aimed to investigate both facial emotion recognition performance and the ability to judge affective scenes in PD patients. Forty PD patients (mean age ± SD: 64.50 ± 8.19 years; 27 men) and forty healthy subjects (64.95 ± 8.25 years; 27 men) were included. Exclusion criteria were previous psychiatric disorders, previous Deep Brain Stimulation, and cognitive impairment. Participants were evaluated through the Ekman 60-Faces test and the International Affective Picture System. The accuracy in recognizing the emotional valence of facial expressions and affective scenes was compared between groups using linear mixed models. Pearson's correlation was performed to test the association between accuracy measures. The groups did not differ in sex, age, education, and Mini-Mental State Examination scores. Patients showed a lower recognition accuracy of facial expressions (68.54 % ± 15.83 %) than healthy participants (78.67 % ± 12.04 %; p < 0.001). Specifically, the PD group was characterized by lower recognition of faces expressing fear, sadness, and anger than the control group (all p < 0.020). No difference was detected for faces expressing disgust, surprise, and happiness (all p ≥ 0.25). Furthermore, patients showed lower accuracy in recognizing the emotional valence of affective scenes (66.75 % ± 14.59 %) than healthy subjects (74.83 % ± 12.65 %; p = 0.010). Pearson's correlations indicated that higher accuracy in recognizing the emotional facial expressions was associated with higher accuracy in classifying the valence of affective scenes in patients (r = 0.57, p < 0.001) and control participants (r = 0.57, p < 0.001). Our study suggested maladaptive affective processing in PD, leading patients to misinterpret both facial expressions and the emotional valence of complex evocative scenes., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Co-author is a member of the Advisory Board of the Journal - F.S. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Restless leg syndrome (RLS) is an invalidating neurological disorder with a complex, largely unknown pathophysiology. While RLS is observed in Parkinson's disease and in renal failure, idiopathic cases are common. Limited reports associate RLS with parathyroid hormone (PTH). This study analyzes a cohort of patients with primary hyperparathyroidism (PHPT) and chronic post-surgical hypoparathyroidism (hypo PTH), to investigate RLS prevalence, and associated risk factors., Methods: Ninety-five patients (54 PHPT, 41 hypo PTH) were consecutively enrolled at the bone metabolism outpatient clinic. The revised IRLSSG diagnostic criteria were used to diagnose RLS, with assessments conducted through face-to-face interviews and neurological examination. When RLS was confirmed, the RLS severity scale was applied. Retrospective records included calcium-phosphate metabolism-related parameters, surgery details, renal lithiasis, fragility fractures, and densitometric features (T-score)., Results: RLS was diagnosed in 22.2% PHPT patients, compared to 4.9% of patients with hypo PTH (p = 0.02). Of RLS diagnosed patients, 91.7% had a history of parathyroidectomy, compared to 47.6% of patients without RLS (p = 0.01). Most of the operated patients reported that surgery determined an improvement of symptoms; however, mean score severity of RLS at our evaluation was 15/40, defined as moderate. PTH and calcium levels were not statistically associated to the presence of RLS., Conclusion: Our study suggests that PHPT may be one of the etiologies of RLS. Parathyroidectomy alleviates symptoms in the vast majority of the cases but does not remove them., (© 2024. Fondazione Società Italiana di Neurologia.)

The purpose of this analysis is to describe HIV tests and associated outcomes for Asian people reached by the Centers for Disease Control and Prevention (CDC) HIV testing program. We analyzed CDC-funded HIV tests among Asian individuals in the United States, Puerto Rico, and the U.S. Virgin Islands (2014-2020). Of the 415,560 tests, the positivity of new diagnoses was higher among males (0.49%, aPR = 7.64) than females (0.06%), and in the West (0.42%, aPR = 1.15) than in the South (0.25%). In non-health care settings, positivity was highest among men who have sex with men (MSM; 0.87%) and transgender people (0.46%). Linkage to HIV medical care among Asian people was 87.5%, and 70.7% were interviewed for partner services. Our findings suggest that improvements are crucial, particularly for Asian MSM, in linkage to care and interview for partner services.

Background: Factor (F)IX can bind to type IV collagen in the endothelial basement membrane and diffuse into extravascular spaces. Previous studies in rodents have reported a large biodistribution of FIX., Objectives: The aim of the study was to evaluate the potential hemostatic activity of extravascular FIX and its role in protecting against joint bleeds., Methods: The capacity of 4 different FIX molecules (plasma-derived and recombinant) to bind type I and type IV collagen was studied here. FIX molecules were also administered intravenously at doses of 50 to 3000 IU/kg in FIX knockout mice., Results: A specific FIX signal was detected in immunohistochemistry in the liver as well as in muscles and knee joints with recombinant FIX molecules injected at 1000 and 3000 IU/kg but not at the usual clinical doses of 50 to 100 IU/kg, while plasma-derived FIX generated a FIX signal at all doses, including 50 IU/kg. Such a signal was also detected after five 100 IU/kg daily infusions of recombinant FIX, suggesting that FIX can accumulate in the extravascular space during prophylaxis. The extravascular procoagulant activity of FIX, assessed in saphenous vein bleeding assays, was significantly higher in hemophilia B mice after these 5 days of prophylaxis compared to a single infusion of 100 IU/kg of FIX and assessment of FIX activity 7 days later., Conclusion: Taken together, these results show that in individuals with severe hemophilia B receiving regular prophylaxis with FIX, extravascular accumulation of FIX over time may have a significant impact on the coagulation capacity and protection toward bleeding., Competing Interests: Declaration of competing interests Y.D. has received grants/research support from Bayer, Baxter, Baxalta, Novo Nordisk, CSL Behring, LFB, Pfizer, LEO Pharma, Octapharma, and Stago; an educational grant from Takeda; and honoraria from Bayer, Baxter, Novo Nordisk, CSL Behring, Sobi, and Octapharma. Other authors have no conflict of interest to declare., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Transcutaneous vagus nerve stimulation (VNS) showed early evidence of efficacy for the gait treatment of Parkinson's disease (PD)., Objectives: Providing data on neurophysiological and clinical effects of transauricular VNS (taVNS)., Methods: Ten patients with recording deep brain stimulation (DBS) have been enrolled in a within participant design pilot study, double-blind crossover sham-controlled trial of taVNS. Subthalamic local field potentials (β band power), Unified Parkinson's Disease Rating Scales (UPDRS), and a digital timed-up-and-go test (TUG) were measured and compared with real versus sham taVNS during medication-off/DBS-OFF condition., Results: The left taVNS induced a reduction of the total β power in the contralateral (ie, right) subthalamic nucleus and an improvement of TUG time, speed, and variability. The taVNS-induced β reduction correlated with the improvement of gait speed. No major clinical changes were observed at UPDRS., Conclusions: taVNS is a promising strategy for the management of PD gait, deserving prospective trials of chronic neuromodulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Hemophilia is a rare constitutional bleeding disorder due to a deficiency in Factor VIII or Factor IX. Recurrent hemarthroses, one of the major complications of the disease, lead to hemophilic arthropathy, a disabling condition that requires early diagnosis. Traditionally, clinical examination and plain film radiography have been used to diagnose hemophilic arthropathy. Magnetic resonance imaging (MRI) and ultrasound can be more useful for diagnosing soft-tissue changes. However, but each of these methods has limitations and diagnosis of arthropathy can be delayed., Aim: The aim of this project was to assess plasmatic biomolecules indicative of osteo-cartilaginous damage in patients with hemophilia with or without known arthropathy, in order to improve the diagnosis of this major complication of the disease., Methods: In this monocentric retrospective study, 40 patients with hemophilia A or B, for whom a plasma sample was available, provided informed consent for further analyses (multiplex immunoassays and ELISA) and collection of relevant clinical information in their medical files. Correlations were sought for between biomarkers of interest and the severity of joint lesions assessed according to Pettersson's radiologic score., Results: Two biomarkers were identified, respectively SDF-1α and COMP. Their plasmatic levels were significantly increased in patients with arthropathy compared to controls and patients without arthropathy. These values correlated significantly with the Pettersson score in patients under regular prophylaxis., Conclusion: Two plasma biomarkers have been identified that could help assess the presence and severity of hemophilic arthropathy., (© 2024 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Perfluorocarbons (PFCs) are organic liquids derived from hydrocarbons in which some of the hydrogen atoms have been replaced by fluorine atoms. They are chemically and biologically inert substances with a good safety profile. They are stable at room temperature, easy to store, and immiscible in water. Perfluorocarbons have been studied in biomedical research since 1960 for their unique properties as oxygen carriers. In particular, PFCs have been used for liquid ventilation in unusual environments such as deep-sea diving and simulations of zero gravity, and more recently for drug delivery and diagnostic imaging. Additionally, when delivered as emulsions, PFCs have been used as red blood cell substitutes. This narrative review will discuss the multifaceted utilization of PFCs in therapeutics, diagnostics, and research. We will specifically emphasize the potential role of PFCs as red blood cell substitutes, as airway mechanotransducers during artificial placenta procedures, as a means to improve donor organ perfusion during the ex vivo assessment, and as an adjunct in cancer therapies because of their ability to reduce local tissue hypoxia., Competing Interests: Disclosure: M.D.N. is an advisory board member for Eurosets, Medolla Modena, Italy. The other authors have no conflicts of interest to report., (Copyright © ASAIO 2023.)

Abnormal retention of mitochondria in mature red blood cells (RBC) has been recently reported in sickle cell anemia (SCA) but their functionality and their role in the pathophysiology of SCA remain unknown. The presence of mitochondria within RBC was determined by flow cytometry in 61 SCA patients and ten healthy donors. Patients were classified according to the percentage of mature RBC with mitochondria contained in the whole RBC population: low (0-4%), moderate (>4% and <8%), or high level (>8%). RBC rheological, hematological, senescence and oxidative stress markers were compared between the three groups. RBC senescence and oxidative stress markers were also compared between mature RBC containing mitochondria and those without. The functionality of residual mitochondria in sickle RBC was measured by high-resolution respirometry assay and showed detectable mitochondrial oxygen consumption in sickle mature RBC but not in healthy RBC. Increased levels of mitochondrial reactive oxygen species were observed in mature sickle RBC when incubated with Antimycin A versus without. In addition, mature RBC retaining mitochondria exhibited greater levels of reactive oxygen species compared to RBC without mitochondria, as well as greater Ca2+, lower CD47 and greater phosphatidylserine exposure. Hematocrit and RBC deformability were lower, and the propensity of RBC to sickle under deoxygenation was higher, in the SCA group with a high percentage of mitochondria retention in mature RBC. This study showed the presence of functional mitochondria in mature sickle RBC, which could favor RBC sickling and accelerate RBC senescence, leading to increased cellular fragility and hemolysis.

Objective: An estimated 1 in 5 American Indian and Alaska Native (AI/AN) adults living with HIV are unaware of their status. We investigated HIV testing among AI/AN people receiving a Centers for Disease Control and Prevention (CDC)-funded test from 2014 through 2020., Methods: We analyzed data on CDC-funded HIV tests reported by health departments and community-based organizations in the United States. We described the number of CDC-funded HIV tests, the percentage of people with newly and previously diagnosed HIV, and linkage to HIV medical care within 90 days of diagnosis., Results: CDC-funded health departments and community-based organizations provided 99 227 HIV tests to AI/AN people during 2014-2020. Seven hundred thirty-five (0.7%) AI/AN people were diagnosed with HIV; 361 (0.4%) were newly diagnosed, 319 (0.3%) had a previous HIV diagnosis, and 55 (0.1%) had a previously unknown HIV status. Positivity for new diagnoses was highest among the following population groups tested in non-health care settings: men who had sex with men (MSM; n = 72, 1.2%), MSM who inject drugs (n = 12, 1.8%), and transgender people (n = 12, 1.5%). The percentage of linkage to HIV medical care was 80.6% for newly diagnosed people and 78.2% for previously diagnosed people., Conclusions: MSM AI/AN, including those who inject drugs, and transgender AI/AN may benefit from prioritized HIV testing. All AI/AN people with HIV, whether newly or previously diagnosed, should rapidly link to HIV medical care and receive support throughout the continuum of care. Our findings can inform which AI/AN population subgroups may benefit from enhanced HIV testing efforts and interventions.

Objective: Deprescribing, i.e. the suspension of drugs whose existing or potential harms outweigh the benefits in the context of care for the individual patient, is an increasingly frequently encountered topic in various congresses today. This issue becomes predominant especially in patients with chronic pathologies with a life expectancy of less than a year, in whom the goal of the treatments passes from healing to caring. Currently there are few validated deprescribing tools, one of these is certainly the STOPPFrail, currently available in its second version. Therefore, we decided to provide for the translation into Italian, to make the description for the elderly patient with limited life expectation more applicable., Methods: For the translation, we used the method expressed by the European organisation for research and treatment of cancer (Eortc), using forward-backward translation and a Pilot Testing to verify the clarity and comprehensibility of the translation itself., Results: We interviewed 15 experts, of whom 13 responded and completed the evaluation, without bringing to light any unclear sections or sources of misunderstanding., Conclusions: STOPPFrail2 can be a valid deprescribing tool in the elderly with limited life expectancy; the Italian version can help the physicians in the therapeutic appropriateness in this time of life where it is necessary to focus on the quality of life and on the ethical aspect of the choices, as well as being of help in a "cost-opportunity" logic.

Background: Extracorporeal therapies (ET) are increasingly used in pediatric settings as adjuvant therapeutic strategies for overwhelming inflammatory conditions. Although these treatments seem to be effective for removing inflammatory mediators, their influence on antimicrobials pharmacokinetic should not be neglected. Methods: A prospective observational study of children admitted to the pediatric intensive care unit (PICU) with a diagnosis of sepsis/septic shock. All critically ill children received hemoadsorption treatment with CytoSorb (CS) in combination with CKRT. Therapeutic drug monitoring has been performed on 10 critically ill children, testing four antimicrobial molecules: meropenem, ceftazidime, amikacin and levofloxacin. In order to evaluate the total and isolated CKRT and CS contributions to antibiotic removal, blood samples at each circuit point (post-hemofilter, post-CS and in the effluent line) were performed. Therefore, the clearance and mass Removal (MR) of the hemofilter and CS were calculated. Results: Our preliminary report describes a different impact of CS on these target drugs removal: CS clearance was low for amikacine (6-12%), moderate for ceftazidime (43%) and moderate to high for levofloxacine (52-72%). Higher MR and clearance were observed with CKRT compared to CS. To the best of our knowledge, this is the first report regarding pharmacokinetic dynamics in critically ill children treated with CKRT and CS for septic shock.

Background and Objective: Children with medical complexity (CMC) have chronic and severe conditions leading to medical fragility. CMC represent less than 1% of children but account for one-third of paediatric healthcare expenditures. Enrollment to a complex care program (CCP) decreases health care resource utilization while improving parental satisfaction. An in-depth understanding of how these changes operate in real-world setting is needed to further support CMC and their families. This study aimed at assessing the possible reasons for a decrease in emergency department (ED) visits and hospitalization length of stay related to enrollment to a CCP, based on parental perspectives., Study Design: Using a qualitative approach, data were collected using in-depth, semi-structured interviews with parents of CMC enrolled in a CCP from a university hospital centre in Montreal, Canada. The interview guide was co-constructed by an interdisciplinary team, including a parent partner and a clinical nurse coordinator. Themes have been identified inductively, using thematic analysis., Results: Parents identified personalized care , family empowerment and guidance as enablers arising from the CCP that contributed to the decrease in hospital-delivered care utilization. Improvement in medical baseline condition was also identified as a contributing factor, while not necessarily related to program's support., Conclusions: In this study, we identified personalized care, parental empowerment, and guidance as three strategies for a CCP to potentially decrease ED visits and hospital length of stay, from the parents' perspective. Parents identified the clinical nurse coordinator as playing a central role in supporting the implementation of these strategies., Competing Interests: All authors reported that there are no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives: Older adults represent nearly half of people living with HIV in the United States. The objective of this analysis was to describe HIV testing, demographic characteristics, and risks of adults aged ≥50 years (older adults) reached in 2019 by HIV testing programs funded by the Centers for Disease Control and Prevention (CDC)., Methods: We collected data from 101 CDC-funded community-based organizations and 61 health departments. All funding recipients submitted deidentified program service data for 2019 through a secure online CDC-supported system. We used multivariable robust Poisson regression to assess the association between demographic and risk characteristics and the proportion of tests that resulted in a new diagnosis. We also assessed the proportion of people who received a positive test result, were linked to HIV medical care, and were interviewed for partner services., Results: During 2019, among 2 452 507 CDC-funded HIV tests provided in the United States, 412 164 (16.8%) were provided to older adults. Among the 1059 (0.26% positivity) older adults with newly diagnosed HIV infection for whom we had data, 582 (68.4%) were linked to HIV medical care within 30 days of diagnosis and 494 (72.1%) were interviewed for partner services. Among the 2858 older adults with previously diagnosed HIV infection, 1321 (46.2%) reported not being in HIV medical care at the time of the test; of those with linkage data, 425 (49.9%) were linked to HIV medical care within 30 days of testing HIV positive., Conclusions: More rapid disease progression and higher morbidity and mortality rates among older adults suggest that services are needed to ensure early diagnosis, rapid linkage, and interview for partner services.

Introduction: The current study aims at describing a sample of adolescents admitted to a tertiary referral pediatric hospital for drug self-poisoning and to identify variables that could explain and predict a higher severity of intoxication., Methods: We retrospectively reviewed the cases of drug self-poisoning in adolescents admitted to the Bambino Gesù Children's Hospital between January 2014 and June 2022 requiring consultation by the local Pediatric Poison Control Center (PPCC). We reported the type and class of drug ingested and correlated the clinical characteristics of the patients with their Poison Severity Score., Results: The data of 267 patients were reported. Most patients were female (85.8 %), with a median age of 15.8 years at presentation. Half of the patients were symptomatic at admission (44.2 %), and most had at least one psychiatric comorbidity (71.1 %). Most patients were hospitalized (79.6 %), 16.6 % of cases required antidote administration and a minority required intensive care. Most patients received a PSS score of 0 (59.6 %). The most frequently ingested drug was acetaminophen (28.1 %) followed by ibuprofen (10.1 %) and aripiprazole (10.1 %). Antipsychotics as a class were the most abused drugs (33.1 %). The correlation of clinical variables with the PSS showed that older and male patients were more prone to be severely intoxicated., Conclusions: This single-center study identifies the most commonly ingested drugs in a large sample of adolescents with voluntary drug self-poisoning, also showing that older and male patients are more susceptible to severe intoxication., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Botulinum neurotoxin type A is a remarkable therapeutic approach for muscle hyperactivity syndromes, pain, and related disorders. Despite its wide application in neurology, there is a poor knowledge on delivery protocols and dispatch from the healthcare providers. In this study, we reported the result of a 2020 survey about the administration provisions of botulinum neurotoxin type A in Italy. Seven questions including information on characteristics of botulinum neurotoxin facilities, prescription, reimbursement, and execution modalities were adopted. Sixty participants answered the survey. Despite the wide availability of dedicated centers all over the national territory, there was a surprising lack of standardized and shared administration provisions. Most of the Italian medical structures delivered botulinum neurotoxin through outpatient clinics located in public hospital facilities, through the "F file" reimbursement modality. However, there was no agreement on the reimbursement request modality, creating differences in public costs relative to the botulinum toxin consumption across Italy., (© 2023. Fondazione Società Italiana di Neurologia.)