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Abstract Background . The present study aimed at deriving regression-based reliable change indices (RCIs) for the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented Parkinson’s disease (PD) patients. Methods N = 33 consecutive, non-demented PD patients were followed-up at a 5-to-8-month interval (M = 6.6; SD = 0.6) with the MoCA. Practice effects and test-retest reliability were assessed via dependent-sample t-tests and intra-class correlation (ICC) coefficients, respectively. RCIs were derived separately for raw and demographically adjusted MoCA scores according to a standardized regression-based approach by accounting for both baseline confounders (i.e., demographics, disease duration and Unified Parkinson’s Disease Rating Scale scores) and retest interval. Results No practice effects were found (t(32) = 0.29; p = .778), with acceptable test-retest reliability being detected (ICC = 0.67). MoCA scores at T0 proved to be the only significant predictor of T1 MoCA performances within both the model addressing raw scores and that addressing adjusted scores (ps

Abstract Background Parkinson’s disease (PD) is often accompanied by gait disorders and freezing of gait (FoG), disabling symptoms that are resistant to conventional dopamine treatments. Given the cerebellum’s connectivity with the motor cortex and basal ganglia, and its implication in PD, combining transcranial direct current stimulation targeting the cerebellum (ctDCS) with physical exercise might improve gait and balance. Objective This study aimed to evaluate the effectiveness of a novel rehabilitation approach that combines noninvasive cerebellar stimulation with motor-cognitive training via an augmented reality treadmill (C-Mill VR+) in individuals with PD and FoG. Methods Seventeen individuals with PD exhibiting FoG were enrolled in a randomized controlled trial. The participants were randomly assigned to a group receiving motor-cognitive training on the C-Mill VR+ with either ctDCS or sham ctDCS. Assessments were conducted pre-intervention (T0), post-intervention (T1) after 10 sessions, and at 4-week follow-up (T2), using various clinical scales. Additionally, C-Mill assessments of postural stability and gait were conducted at T0 and T1. Results Although no significant time*group interactions were observed for any of the clinical variables measured, some were found in the C-Mill measures. Specifically, right lower limb sway in static conditions, both with eyes open (OAD) and eyes closed (OCD), significantly improved at T1 in the ctDCS group compared with the sham group. Conclusions C-Mill outcomes indicate that the combined treatment may enhance motor control. Participants who received ctDCS along with augmented reality motor-cognitive training showed better postural stability.

Abstract Background Glioblastoma (GBM) stands as the most prevalent and aggressive form of adult gliomas. Despite the implementation of intensive therapeutic approaches involving surgery, radiation, and chemotherapy, Glioblastoma Stem Cells contribute to tumor recurrence and poor prognosis. The induction of Glioblastoma Stem Cells differentiation by manipulating the transcriptional machinery has emerged as a promising strategy for GBM treatment. Here, we explored an innovative approach by investigating the role of the depolarized resting membrane potential (RMP) observed in patient-derived GBM sphereforming cell (GSCs), which allows them to maintain a stemness profile when they reside in the G0 phase of the cell cycle. Methods We conducted molecular biology and electrophysiological experiments, both in vitro and in vivo, to examine the functional expression of the voltage-gated sodium channel (Nav) in GSCs, particularly focusing on its cell cycle-dependent functional expression. Nav activity was pharmacologically manipulated, and its effects on GSCs behavior were assessed by live imaging cell cycle analysis, self-renewal assays, and chemosensitivity assays. Mechanistic insights into the role of Nav in regulating GBM stemness were investigated through pathway analysis in vitro and through tumor proliferation assay in vivo. Results We demonstrated that Nav is functionally expressed by GSCs mainly during the G0 phase of the cell cycle, suggesting its pivotal role in modulating the RMP. The pharmacological blockade of Nav made GBM cells more susceptible to temozolomide (TMZ), a standard drug for this type of tumor, by inducing cell cycle re-entry from G0 phase to G1/S transition. Additionally, inhibition of Nav substantially influenced the self-renewal and multipotency features of GSCs, concomitantly enhancing their degree of differentiation. Finally, our data suggested that Nav positively regulates GBM stemness by depolarizing the RMP and suppressing the ERK signaling pathway. Of note, in vivo proliferation assessment confirmed the increased susceptibility to TMZ following pharmacological blockade of Nav. Conclusions This insight positions Nav as a promising prognostic biomarker and therapeutic target for GBM patients, particularly in conjunction with temozolomide treatment.

Profiling circulating lipids and metabolites in Parkinson's disease (PD) patients could be useful not only to highlight new pathways affected in PD condition but also to identify sensitive and effective biomarkers for early disease detection and potentially effective therapeutic interventions. In this study we adopted an untargeted omics approach in three groups of patients (No L-Dopa, L-Dopa and DBS) to disclose whether long-term levodopa treatment with or without deep brain stimulation (DBS) could reflect a characteristic lipidomic and metabolomic signature at circulating level. Our findings disclosed a wide up regulation of the majority of differentially regulated lipid species that increase with disease progression and severity. We found a relevant modulation of triacylglycerols and acyl-carnitines, together with an altered profile in adiponectin and leptin, that can differentiate the DBS treated group from the others PD patients. We found a highly significant increase of exosyl ceramides (Hex2Cer) and sphingoid bases (SPB) in PD patients mainly in DBS group (p

Objective. Patients Acceptable Symptom State (PASS) is a single dichotomized question assessing health satisfaction. We aimed to investigate PASS achievement within 4 weeks of treatment with Janus kinase (JAK) inhibitors (Jakinibs) and its association with treatment response after 4 and 12 weeks in rheumatoid arthritis (RA) patients. Methods. We recruited consecutive RA patients starting baricitinib or tofacitinib. At baseline, 4 and 12 weeks, we calculated disease activity [Disease Activity Score on 28 joints (DAS28), Clinical Disease Activity Index, Simplified Disease Activity Index], disease status [remission and low-disease activity (LDA)], percentage of patients achieving PASS, and the time to attain PASS. We assessed the impact of clinically relevant variables on PASS achievement by logistic regression analysis. Results. We enrolled 113 patients [98 (86.7%) females; median age 59.6 (interquartile range 16.9), median disease duration 144 (132) months]. 90 (79.6%) patients achieved PASS after 10 (8) days. A similar percentage of PASS achievers and non-achievers was in remission/LDA at weeks 4 and 12, but the reduction of disease activity was significantly greater in PASS achievers. All patients achieving Boolean remission at weeks 4 and 12 had achieved PASS within 4 weeks. The impact of Patients Global Assessment (PGA) on DAS28 was significantly greater in PASS non-achievers compared to PASS achievers; inversely, the impact of C-reactive protein was more relevant in PASS achievers. At multivariate analysis, pain and PGA were significantly associated with PASS. Conclusions. In our cohort, Jakinibs allowed an early achievement of PASS in a great percentage of RA patients. PASS is strictly dependent on PGA and pain and could suggest, early in the management of RA patients, therapeutic success.

Anorexia nervosa (AN) is an eating disorder (ED) that has seen an increase in its incidence in the last thirty years. Compared to other psychosomatic disorders, ED can be responsible for many major medical complications, moreover, in addition to the various systemic impairments, patients with AN undergo morphological and physiological changes affecting the cerebral cortex. Through immunohistochemical studies on portions of postmortem human brain of people affected by AN and healthy individuals, and western blot studies on leucocytes of young patients and healthy controls, this study investigated the role in the afore-mentioned processes of altered redox state. The results showed that the brain volume reduction in AN could be due to an increase in the rate of cell death, mainly by apoptosis, in which mitochondria, main cellular organelles affected by a decreased dietary intake, and a highly compromised intracellular redox balance, may play a pivotal role

Aim of the present study was to evaluate the relationship between sensory sensitivity and autistic eating behaviours or Eating Disorders (EDs) symptomatology, in a group of 75 adults with Autism Spectrum Disorders (ASDs) without intellectual disabilities, through a series of self-report questionnaires. We found that, controlling for demographic and clinical features: (i) hypersensitivity in the vision domain predicted higher levels of both EDs symptoms and autistic eating behaviours; (ii) hyposensitivity in the taste domain predicted higher levels of EDs symptoms. This gives preliminary evidence that not only in children diagnosed with ASDs, but even in adult individuals, the threshold of sensory sensitivity is associated with dysfunctional eating behaviours.

Abstract The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to suboptimal treatment. This is due to the lack of appropriate molecular markers that can guide patients toward the best therapeutic options. Here, we assess and confirm subtype-specific markers for IPMN across two independent cohorts of patients using two Spatial Transcriptomics (ST) technologies. Specifically, we identify HOXB3 and ZNF117 as markers for Low-Grade Dysplasia, SPDEF and gastric neck cell markers in borderline cases, and NKX6-2 and gastric isthmus cell markers in High-Grade-Dysplasia Gastric IPMN, highlighting the role of TNFα and MYC activation in IPMN progression and the role of NKX6-2 in the specific Gastric IPMN progression. In conclusion, our work provides a step forward in understanding the gene expression landscapes of IPMN and the critical transcriptional networks related to PDAC progression.

The deep brain stimulation (DBS) Think Tank X was held on August 17-19, 2022 in Orlando FL. The session organizers and moderators were all women with the theme women in neuromodulation. Dr. Helen Mayberg from Mt. Sinai, NY was the keynote speaker. She discussed milestones and her experiences in developing depression DBS. The DBS Think Tank was founded in 2012 and provides an open platform where clinicians, engineers and researchers (from industry and academia) can freely discuss current and emerging DBS technologies as well as the logistical and ethical issues facing the field. The consensus among the DBS Think Tank X speakers was that DBS has continued to expand in scope however several indications have reached the "trough of disillusionment." DBS for depression was considered as "re-emerging" and approaching a slope of enlightenment. DBS for depression will soon re-enter clinical trials. The group estimated that globally more than 244,000 DBS devices have been implanted for neurological and neuropsychiatric disorders. This year's meeting was focused on advances in the following areas: neuromodulation in Europe, Asia, and Australia; cutting-edge technologies, closed loop DBS, DBS tele-health, neuroethics, lesion therapy, interventional psychiatry, and adaptive DBS.

Esta entrevista objetiva refletir sobre o processo criativo da artista Laura Anderson Barbata, nascida na Cidade do México/México e que, atualmente, vive e trabalha entre Nova Iorque/EUA e Cidade do México. Artista transdisciplinar, autora de diversos livros, transita em distintas linguagens artísticas, e já realizou exposições em países como México, Estados Unidos e Brasil. O diálogo proposto nesta entrevista com Laura Anderson Barbata, aborda os trânsitos e deslocamentos fronteiriços, o sentido de pertença, as relações entre o global e o local, entoam suas criações artísticas que combinam diversas narrativas e protagonismos. Na expectativa de contribuir para a irradiação de seu trabalho, nos lançamos a essa interlocução, numa conversação sobre sua trajetória, experiências e práticas artísticas como possibilidades de novos laços entre artistas, saberes e linguagens.

Objective. Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis. Methods. This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA. The Kaplan-Meier method was applied to evaluate the ABA retention rate. Results. This analysis was conducted on 161 patients [male/female 21/140, median age 65 years, interquartile range (IQR) 18.7, median disease duration 169 months, IQR 144.0]. 111 patients (68.9%) received ABA subcutaneously. ABA was associated with methotrexate in 61.9% of patients and was the first biological disease-modifying antirheumatic drug in 41%. We observed a median ABA survival of 66 months [95% confidence interval (CI) 57.3-74.7], with a retention rate of 88% at 6 months and 50.9% at 5 years. Drug survival was significantly higher in patients treated with ABA subcutaneously and in male patients (p=0.039 and p=0.018, respectively). Adjusted for main confounders, female gender was the main predictor of withdrawal (hazard ratio 5.1, 95% CI 1.2-21.3). Conclusions. Our study shows that better survival is associated with subcutaneous administration and male gender, confirming ABA effectiveness.

Abstract Obsessive Compulsive Disorder (OCD) is listed as one of the top 10 most disabling neuropsychiatric conditions in the world. The neurobiology of OCD has not been completely understood and efforts are needed in order to develop new treatments. Beside the classical neurotransmitter systems and signalling pathways implicated in OCD, the possible involvement of the endocannabinoid system (ECS) has emerged in pathophysiology of OCD. We report here selective downregulation of the genes coding for enzymes allowing the synthesis of the endocannabinoids. We found reduced DAGLα and NAPE-PLD in blood samples of individuals with OCD (when compared to healthy controls) as well as in the amygdala complex and prefrontal cortex of dopamine transporter (DAT) heterozygous rats, manifesting compulsive behaviours. Also mRNA levels of the genes coding for cannabinoid receptors type 1 and type 2 resulted downregulated, respectively in the rat amygdala and in human blood. Moreover, NAPE-PLD changes in gene expression resulted to be associated with an increase in DNA methylation at gene promoter, and the modulation of this gene in OCD appears to be correlated to the progression of the disease. Finally, the alterations observed in ECS genes expression appears to be correlated with the modulation in oxytocin receptor gene expression, consistently with what recently reported. Overall, we confirm here a role for ECS in OCD at both preclinical and clinical level. Many potential biomarkers are suggested among its components, in particular NAPE-PLD, that might be of help for a prompt and clear diagnosis.

Conventional DBS (cDBS) for Parkinson’s disease uses constant, predefined stimulation parameters, while the currently available adaptive DBS (aDBS) provides the possibility of adjusting current amplitude with respect to subthalamic activity in the beta band (13–30 Hz). This preliminary study on one patient aims to describe how these two stimulation modes affect basal ganglia dynamics and, thus, behavior in the long term. We collected clinical data (UPDRS-III and -IV) and subthalamic recordings of one patient with Parkinson’s disease treated for one year with aDBS, alternated with short intervals of cDBS. Moreover, after nine months, the patient discontinued all dopaminergic drugs while keeping aDBS. Clinical benefits of aDBS were superior to those of cDBS, both with and without medications. This improvement was paralleled by larger daily fluctuations of subthalamic beta activity. Moreover, with aDBS, subthalamic beta activity decreased during asleep with respect to awake hours, while it remained stable in cDBS. These preliminary data suggest that aDBS might be more effective than cDBS in preserving the functional role of daily beta fluctuations, thus leading to superior clinical benefit. Our results open new perspectives for a restorative brain network effect of aDBS as a more physiological, bidirectional, brain–computer interface.

Background/Objectives: In the past two decades, significant advancements in neuromodulation techniques have occurred, such as transcranial magnetic stimulation (TMS) for treatment-resistant depression (TRD). According to the assumption that repeated stimulation within a condensed timeframe can yield sustained efficacy, an accelerated protocol may be more effective in reducing time to response. With those premises, this study aimed to evaluate a sample of TRD patients treated with standard repetitive TMS (rTMS) and accelerated rTMS (arTMS). Methods: Nine subjects were treated with standard rTMS and 19 with arTMS. Psychometric assessment was made at the baseline and one week, one month, and three months after the treatment. A linear mixed-effect regression was performed along with other appropriate statistical analyses. Results: A significant improvement over time was observed for both depressive and cognitive symptoms. Moreover, considering the reduction in the Montgomery–Asberg Depression Rating Scale scores, a better treatment response was observed in subjects treated with arTMS (p < 0.05). Conclusions: Our findings showed a significant difference between the two protocols in terms of clinical response. Although further studies are needed to confirm the superiority of arTMS, the better cost-effectiveness of this technique should be considered.

Introduction Motor Conversion Disorders (also called Functional Movement Disorders, FMD) are a group of neuropsychiatric conditions characterized by neurological symptoms of altered voluntary motor function that cannot be explained by typical neurological diseases or other medical conditions. In the last decade, several hypotheses have been formulated with respect to their pathophysiology, and a major line of research, trying to integrate psychological, cognitive, and neurobiological factors, focused on the subjective experience that patients feel of their own bodies. However, no study has, so far, directly investigated their Body Schema (the implicit sensorimotor representation of one’s own body) and its plasticity. Objectives To investigate the Body Schema in patients with FMD through a paradigm specifically designed to assess their perceived body metrics, through a spatial estimation of body parts length, and to compare their results with the ones obtain on a group of healthy control subjects (HC) Methods 10 patients with FMD and 11 HC underwent the Forearm Bisection Task, aimed at assessing perceived body metrics, which consists in asking the subject, blindfolded, to repeatedly point at the perceived middle point of their dominant forearm with the index finger of their contralateral hand, and a psychometric assessment for anxiety, depression, alexithymia, and tendency to dissociation. Results FMD patients bisected their forearm more proximally (with an increased shift towards their elbow equal to 7.5%) with respect to HC; average bisection point was positively associated with anxiety levels in the whole sample, and with the tendency to dissociation in the FMD group. Conclusions FMD patients seem to perceive their forearm as shorter than HC do, which might suggest an alteration of their Body Schema. The Body Schema can go through short- and long-term plastic changes in the life course, mainly related to the use of each body segment; we speculate that, despite FMD being a disorder of functional nature, characterized by variability and fluctuations in symptomatology, the lack of sense of agency over a body part might be interpreted by the nervous system as disuse and hence influence the Body Schema, as deficits of organic aetiology do. Disclosure of Interest None Declared

Objective: The search for market expansion challenges Brazilian craft breweries. Based on coopetition strategies, many join in seeking to overcome these challenges. The challenge for gypsy breweries is even more significant, as they must produce beer in a non-gypsy brewery. Some tensions emerge from this relationship, such as space availability and costs. Methods: From the actor-network theory, we analyze the relationship between gypsy and non-gypsy breweries, deepening the analysis of their tensions. Based on a case study with craft breweries in Rio de Janeiro State. Results: As the results highlighted, the tension between them starts at a level not mentioned in the literature on coopetition. Conclusions: This extension expands the existing literature on coopetition by highlighting the influence of nonhuman elements (e.g., factory, resources, equipment, and operations) in shaping inter-organizational relationships, with the factory being the main generator of this tension. The study offers insights into how actors (human and nonhuman) navigate, interact, and negotiate tensions to achieve mutual goals. By applying ANT to analyze coopetition dynamics, the study contributes to the theoretical framework by demonstrating how this approach can enhance understanding of complex mechanisms, processes, and relationships through which coopetition dynamics unfold in practice.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance. Methods We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy. Results Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration. Conclusions Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC.

Abstract Functional movement disorders (FMD) are characterized by the presence of neurological symptoms that cannot be explained by typical neurological diseases or other medical conditions. First evidence showed that, compared to healthy controls (CTR), FMD patients presented increased levels of glutamate+glutamine in the anterior cingulate cortex/medial prefrontal cortex, and decreased levels of glutamate in the cerebrospinal fluid, suggesting that a glutamatergic dysfunction might play a role in FMD pathophysiology. In this study, 12 FMD patients and 20 CTR were recruited and underwent venous blood sampling and urine collection: levels of glutamate, BDNF, dopamine, oxidative stress, creatinine, neopterin, and uric acid were analyzed. Participants also underwent a psychometric assessment investigating depression, anxiety, and alexithymia. We found that levels of glutamate, BDNF, and dopamine were significantly lower in the blood of FMD patients than CTR. Glutamate and dopamine levels were positively associated with levels of alexithymia. Our findings give further evidence that glutamatergic dysfunction might be involved in the pathophysiology of FMD, possibly representing a biomarker of disease; moreover, since glutamatergic and dopaminergic systems are closely interconnected, our results might have a relevance in terms of treatment options for FMD patients.

Long QT Syndrome type 8 (LQT8) is a cardiac arrhythmic disorder associated with Timothy Syndrome, stemming from mutations in the CACNA1C gene, particularly the G406R mutation. While prior studies hint at CACNA1C mutations' role in ventricular arrhythmia genesis, the mechanisms, especially in G406R presence, are not fully understood. This computational study explores how the G406R mutation, causing increased transmural dispersion of repolarization, induces and sustains reentrant ventricular arrhythmias. Using three-dimensional numerical simulations on an idealized left-ventricular model, integrating the Bidomain equations with the ten Tusscher-Panfilov ionic model, we observe that G406R mutation with 11% and 50% heterozygosis significantly increases transmural dispersion of repolarization. During S1-S4 stimulation protocols, these gradients facilitate conduction blocks, triggering reentrant ventricular tachycardia. Sustained reentry pathways occur only with G406R mutation at 50% heterozygosis, while neglecting transmural heterogeneities of action potential duration prevents stable reentry, regardless of G406R mutation presence.

ObjectivesThis study aimed at exploring (1) the motor and non-motor correlates of counterfactual thinking (CFT) abilities in non-demented amyotrophic lateral sclerosis (ALS) patients and (2) the ability of CFT measures to discriminate these patients from healthy controls (HCs) and patients with and without cognitive impairment.MethodsN = 110 ALS patients and N = 51 HCs were administered two CFT tasks, whose sum, resulting in a CFT Index (CFTI), was addressed as the outcome. Patients further underwent an in-depth cognitive, behavioral, and motor-functional evaluation. Correlational analyses were run to explore the correlates of the CFTI in patients. Logistic regressions were performed to test whether the CFTI could discriminate patients from HCs.ResultsThe CFTI was selectively associated (p ≤ 0.005) with fluency and memory subscales of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), but not with other variables. CFTI scores discriminated patients from HCs (p < 0.001) with high accuracy (82%), but not patients with a normal vs. defective performance on the ECAS-Total.ConclusionCFT measures in non-demented ALS patients were associated with verbal fluency and memory functions, and they were also able to discriminate them from HCs.