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Abstract Background Over 20% of hospital bed use is inappropriate, implying a waste of resources and the increase of patient iatrogenic risk. Methods This is a cluster, pragmatic, randomised controlled trial, carried out in a large University Hospital of Northern Italy, aiming to evaluate the effect of a strategy to reduce unnecessary hospital days. The primary outcome was the percentage of patient-days compatible with discharge. Among secondary objectives, to describe the strategy’s effect in the long-term, as well as on hospital readmissions, considered to be a marker of the quality of hospital care. The 12 medical wards with the longest length of stay participated. Effectiveness was measured at the individual level on 3498 eligible patients during monthly index days. Patients admitted or discharged on index days, or with stay >90 days, were excluded. All ward staff was blinded to the index days, while staff in the control arm and data analysts were blinded to the trial’s objectives and interventions. The strategy comprised the distribution to physicians of the list of their patients whose hospital stay was compatible with discharge according to a validated Delay Tool, and of physician length of stay profiles, followed by audits managed autonomously by the physicians of the ward. Results During the 12 months of data collection, over 50% of patient-days were judged to be compatible with discharge. Delays were mainly due to problems with activities under medical staff control. Multivariate analysis considering clustering showed that the strategy reduced patient-days compatible with discharge by 16% in the intervention vs control group, (OR=0.841; 95% CI, 0.735 to 0.963; P=0.012). Follow-up at 1 year did not yield a statistically significant difference between the percentages of patient-days judged to be compatible with discharge between the two arms (OR=0.818; 95% CI, 0.476 to 1.405; P=0.47). There was no significant difference in 30-day readmission and mortality rates for all eligible patients (N=3498) between the two arms. Conclusions Results indicate that a strategy, involving physician direct accountability, can reduce unnecessary hospital days. Relatively simple interventions, like the one assessed in this study, should be implemented in all hospitals with excessive lengths of stay, since unnecessary prolongation may be harmful to patients. Trial registration ClinicalTrials.gov, identifier NCT01422811. more...

Dysphagia is a frequent and life-threatening complication of multiple sclerosis (MS). Swallowing disturbances may be present at all stages of MS, although their prevalence increases with age, with disease duration, and in progressive phenotypes. The pathophysiology of dysphagia in MS is likely due to a combination of factors, including the involvement of corticobulbar tracts, the cerebellum, and the brainstem. Accurate diagnosis and early management of swallowing disorders improve quality of life and may delay complications or invasive therapeutic interventions. Here we provide an overview of the pathophysiology, the assessment, and the management of MS dysphagia, also examining the possible role of novel therapeutic strategies. Although studies using imaging and neurophysiological techniques have contributed to better characterize swallowing alterations in MS, the treatment of dysphagia is still challenging. Rehabilitation represents the main therapeutic approach for swallowing disorders. Recently, some innovative neurophysiological approaches, such as pharyngeal electrical stimulation (PES), repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS), have been proposed as a supplement to swallowing therapy in different neurological conditions. However, only few studies have explored the role of neuromodulation for MS dysphagia., Competing Interests: Diego Centonze is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme and Teva. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Restivo, Quartarone, Bruschetta, Alito, Milardi, Marchese-Ragona, Iezzi, Peter, Centonze and Stampanoni Bassi.) more...

The big bud mite Phytoptus avellanae is a resurgent pest of hazelnut, Corylus avellana , causing substantial yields reductions in many productive areas. Mites colonise and develop within healthy buds which become swollen, with subsequent alteration to the plant's development. To date, there has been limited knowledge on how the cultivar and pest management strategies affect infestations. This study explored these aspects through two ad hoc experiments carried out in central Italy. In the first experiment, the susceptibility of 11 cultivars with different geographic origins was tested in a germplasm hazelnut collection. The second experiment assessed the infestation level in orchards with integrated pest management (IPM) and organic pest management strategies and in a renaturalised environment (a former agricultural area now converted in a natural park). The results showed that the most and the least susceptible cultivars were Tonda Gentile and Nocchione, respectively. No significant differences were found between IPM and organic management, but they were both different to the renaturalised environment. The outcomes of this research can serve as a valuable reference and can be applied to all current or potential hazelnut cultivation areas characterised by the same environmental conditions. more...

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.) more...

Background and Purpose: Loss of long-term potentiation (LTP) expression has been associated with a worse disease course in relapsing-remitting multiple sclerosis (RR-MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP-like plasticity in patients with multiple sclerosis (MS)., Methods: In 46 newly diagnosed RR-MS patients, we explored the impact of preventive exercise on LTP-like plasticity as assessed by intermittent theta-burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8-week inpatient neurorehabilitation program on clinical scores and LTP-like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects., Results: Reduced LTP expression was found in RR-MS patients compared with controls. Exercising RR-MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity., Conclusions: Both preventive exercise and physical rehabilitation may enhance the expression of LTP-like synaptic plasticity in MS, with potential beneficial effects on disability accumulation., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.) more...

Background: Elevated levels of specific proinflammatory molecules in the cerebrospinal fluid (CSF) have been associated with disability progression, enhanced neurodegeneration and higher incidence of mood disorders in people with multiple sclerosis (MS). Studies in animal models of MS suggest that preventive exercise may play an immunomodulatory activity, with beneficial effects on both motor deficits and behavioral alterations. Here we explored the impact of lifestyle physical activity on clinical presentation and associated central inflammation in a large group of newly diagnosed patients with MS. Furthermore, we addressed the causal link between exercise-mediated immunomodulation and mood symptoms in the animal setting., Methods: A cross-sectional study was conducted on 235 relapsing-remitting MS patients at the time of the diagnosis. Patients were divided into 3 groups ("sedentary", "lifestyle physical activity" and "exercise") according to the level of physical activity in the six months preceding the evaluation. Patients underwent clinical, neuropsychological and psychiatric evaluation, magnetic resonance imaging and lumbar puncture for diagnostic purposes. The CSF levels of proinflammatory and anti-inflammatory cytokines were analyzed and compared with a group of 80 individuals with non-inflammatory and non-degenerative diseases. Behavioral and electrophysiological studies were carried out in control mice receiving intracerebral injection of IL-2 or vehicle. Behavior was also assessed in mice with experimental autoimmune encephalomyelitis (EAE), animal model of MS, reared in standard (sedentary group) or running wheel-equipped (exercise group) cages., Results: In exercising MS patients, depression and anxiety were reduced compared to sedentary patients. The CSF levels of the interleukin-2 and 6 (IL-2, IL-6) were increased in MS patients compared with control individuals. In MS subjects exercise was associated with normalized CSF levels of IL-2. In EAE mice exercise started before disease onset reduced both behavioral alterations and striatal IL-2 expression. Notably, a causal role of IL-2 in mood disorders was shown. IL-2 administration in control healthy mice induced anxious- and depressive-like behaviors and impaired type-1 cannabinoid (CB1) receptor-mediated neurotransmission at GABAergic synapses, mimicking EAE-induced synaptic dysfunction., Conclusions: Our results indicate an immunomodulatory effect of exercise in MS patients, associated with reduced CSF expression of IL-2, which might result in reduced mood disorders. These data suggest that exercise in the early stages may act as a disease-modifying therapy in MS although further longitudinal studies are needed to clarify this issue., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...

In multiple sclerosis (MS), fatigue is a frequent symptom that negatively affects quality of life. The pathogenesis of fatigue is multifactorial and inflammation may play a specific role. To explore the association between fatigue, central inflammation and disease course in MS in 106 relapsing-remitting (RR)-MS patients, clinical characteristics, including fatigue and mood, were explored at the time of diagnosis. NEDA (no evidence of disease activity)-3 status after one-year follow up was calculated. Cerebrospinal fluid (CSF) levels of a set of proinflammatory and anti-inflammatory molecules and peripheral blood markers of inflammation were also analyzed. MRI structural measures were explored in 35 patients. A significant negative correlation was found at diagnosis between fatigue measured with the Modified Fatigue Impact Scale (MFIS) and the CSF levels of interleukin (IL)-10. Conversely, no significant associations were found with peripheral markers of inflammation. Higher MFIS scores were associated with reduced probability to reach NEDA-3 status after 1-year follow up. Finally, T2 lesion load showed a positive correlation with MFIS scores and a negative correlation with CSF IL-10 levels at diagnosis. CSF inflammation, and particularly the reduced expression of the anti-inflammatory molecule IL-10, may exacerbate fatigue. Fatigue in MS may reflect subclinical CSF inflammation, predisposing to greater disease activity., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: TP has been an advisor or speaker for Sanofi-Genzyme, Medis, Hemofarm, Merck, Teva, and Roche. JD has been an advisor or speaker for Bayer HealthCare, Sanofi-Genzyme, Medis, Merck, Teva, Novartis, Hemofarm, Biogen and Roche. FB acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Bio-gen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. RF received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novar-tis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. LG, LP, EI, GG, ED, FA, ABr, ABo, MS, AF, GM, DF, VV, MSB: nothing to report. more...

(1) Background: The clinical course of multiple sclerosis (MS) is critically influenced by the expression of different pro-inflammatory and anti-inflammatory cytokines. Interleukin 6 (IL-6) represents a major inflammatory molecule previously associated with exacerbated disease activity in relapsing remitting MS (RR-MS); however, the role of single-nucleotide polymorphisms (SNPs) in the IL-6 gene has not been fully elucidated in MS. (2) Methods: We explored in a cohort of 171 RR-MS patients, at the time of diagnosis, the associations between four IL-6 SNPs ( rs1818879 , rs1554606, rs1800797 , and rs1474347 ), CSF inflammation, and clinical presentation. (3) Results: Using principal component analysis and logistic regression analysis we identified an association between rs1818879 , radiological activity, and a set of cytokines, including the IL-1 β , IL-9, IL-10, and IL-13. No significant associations were found between other SNPs and clinical or inflammatory parameters. (4) Conclusions: The association between the rs1818879 polymorphism and subclinical neuroinflammatory activity suggests that interindividual differences in the IL-6 gene might influence the immune activation profile in MS. more...

The clinical course of multiple sclerosis (MS) is critically influenced by the interplay between inflammatory and neurodegenerative processes. The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism (rs6265), one of the most studied single-nucleotide polymorphisms (SNPs), influences brain functioning and neurodegenerative processes in healthy individuals and in several neuropsychiatric diseases. However, the role of this polymorphism in MS is still controversial. In 218 relapsing-remitting (RR)-MS patients, we explored, at the time of diagnosis, the associations between the Val66Met polymorphism, clinical characteristics, and the cerebrospinal fluid (CSF) levels of a large set of pro-inflammatory and anti-inflammatory molecules. In addition, associations between Val66Met and structural MRI measures were assessed. We identified an association between the presence of Met and a combination of cytokines, identified by principal component analysis (PCA), including the pro-inflammatory molecules MCP-1, IL-8, TNF, Eotaxin, and MIP-1b. No significant associations emerged with clinical characteristics. Analysis of MRI measures evidenced reduced cortical thickness at the time of diagnosis in patients with Val66Met. We report for the first time an association between the Val66Met polymorphism and central inflammation in MS patients at the time of diagnosis. The role of this polymorphism in both inflammatory and neurodegenerative processes may explain its complex influence on the MS course. more...

Background : Astrocytes and microglia play an important role in the inflammatory process of multiple sclerosis (MS). We investigated the associations between the cerebrospinal fluid (CSF) levels of glial fibrillary acid protein (GFAP) and soluble triggering receptors expressed on myeloid cells-2 (sTREM-2), inflammatory molecules, and clinical characteristics in a group of patients with relapsing-remitting MS (RRMS). Methods : Fifty-one RRMS patients participated in the study. Clinical evaluation and CSF collection were performed at the time of diagnosis. The CSF levels of GFAP, sTREM-2, and of a large set of inflammatory and anti-inflammatory molecules were determined. MRI structural measures (cortical thickness, T2 lesion load, cerebellar volume) were examined. Results : The CSF levels of GFAP and sTREM-2 showed significant correlations with inflammatory cytokines IL-8, G-CSF, and IL-5. Both GFAP and sTREM-2 CSF levels positively correlated with age at diagnosis. GFAP was also higher in male MS patients, and was associated with an increased risk of MS progression, as evidenced by higher BREMS at the onset. Finally, a negative association was found between GFAP CSF levels and cerebellar volume in RRMS at diagnosis. Conclusions : GFAP and sTREM-2 represent suitable biomarkers of central inflammation in MS. Our results suggest that enhanced CSF expression of GFAP may characterize patients with a higher risk of progression. more...

Importance: Many patients with cancer who would benefit from psychosocial care do not receive it. Implementation strategies may favor the integration of psychosocial care into practice and improve patient outcomes., Objective: To evaluate the effectiveness of the Humanization in Cancer Care (HuCare) Quality Improvement Strategy vs standard care as improvement of at least 1 of 2 domains (emotional or social function) of patient health-related quality of life at baseline and 3 months. A key secondary aim included investigation of the long-term effect., Design, Setting, and Participants: HuCare2 was a multicenter, incomplete, stepped-wedge cluster randomized clinical trial, conducted from May 30, 2016, to August 28, 2019, in three 5-center clusters of cancer centers representative of hospital size and geographic location in Italy. The study was divided into 5 equally spaced epochs. Implementation sequence was defined by a blinded statistician; the nature of the intervention precluded blinding for clinical staff. Participants included consecutive adult outpatients with newly diagnosed cancer of any type and stage starting medical cancer treatment., Interventions: The HuCare Quality Improvement Strategy comprised (1) clinician communication training, (2) on-site visits for context analysis and problem-solving, and (3) implementation of 6 evidence-based recommendations., Main Outcomes and Measures: The primary outcome was the difference between the means of changes of individual scores in emotional or social functions of health-related quality of life detected at baseline and 3-month follow-up (within each group) and during the postintervention epoch compared with control periods (between groups). Long-term effect of the intervention (at 12 months) was assessed as a secondary outcome. Intention-to-treat analysis was used., Results: A total of 762 patients (475 [62.3%] women) were enrolled (400 HuCare Quality Improvement Strategy and 362 usual care); mean (SD) age was 61.4 (13.1) years. The HuCare Quality Improvement Strategy significantly improved emotional function during treatment (odds ratio [OR], 1.13; 95% CI, 1.04-1.22; P = .008) but not social function (OR, 0.99; 95% CI, 0.89-1.09; P = .80). Effect on emotional function persisted at 12 months (OR, 1.05; 95% CI, 1.00-1.10; P = .04)., Conclusions and Relevance: In this trial, the HuCare Quality Improvement Strategy significantly improved the emotional function aspect of health-related quality of life during cancer treatment and at 12 months, indicating a change in clinician behavior and in ward organization. These findings support the need for strategies to introduce psychosocial care; however, more research is needed on factors that may maximize the effects., Trial Registration: ClinicalTrials.gov Identifier: NCT03008993. more...

Age at onset is the main risk factor for disease progression in patients with relapsing-remitting multiple sclerosis (RR-MS). In this cross-sectional study, we explored whether older age is associated with specific disease features involved in the progression independent of relapse activity (PIRA). In 266 patients with RR-MS, the associations between age at onset, clinical characteristics, cerebrospinal fluid (CSF) levels of lactate, and that of several inflammatory molecules were analyzed. The long-term potentiation (LTP)-like plasticity was studied using transcranial magnetic stimulation (TMS). Older age was associated with a reduced prevalence of both clinical and radiological focal inflammatory disease activity. Older patients showed also increased CSF levels of lactate and that of the pro-inflammatory molecules monocyte chemoattractant protein 1 (MCP-1)/CCL2, macrophage inflammatory protein 1-alpha (MIP-1α)/CCL3, and interleukin (IL)-8. Finally, TMS evidenced a negative correlation between age and LTP-like plasticity. In newly diagnosed RR-MS, older age at onset is associated with reduced acute disease activity, increased oxidative stress, enhanced central inflammation, and altered synaptic plasticity. Independently of their age, patients with multiple sclerosis (MS) showing similar clinical, immunological, and neurophysiological characteristics may represent ideal candidates for early treatments effective against PIRA., Competing Interests: RFu received honoraria for serving on scientific advisory boards or as a speaker from Biogen, Novartis, Roche, and Merck and funding for research from Merck. DC is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme and Teva. FB acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Stampanoni Bassi, Gilio, Iezzi, Moscatelli, Pekmezovic, Drulovic, Furlan, Finardi, Mandolesi, Musella, Galifi, Fantozzi, Bellantonio, Storto, Centonze and Buttari.) more...

Background and Aims: Interferon beta (IFNb) is a safe first-line drug commonly used for relapsing-remitting (RR)-MS. Nevertheless, a considerable proportion of patients do not respond to IFNb treatment. Therefore, until now, a number of studies have investigated various markers that could predict the patients who would respond to IFNb therapy. The objective of this study was to identify reliable biomarkers to predict the efficacy of IFNb treatment in MS., Methods: In a group of 116 patients with clinically isolated syndrome (CIS) and RR-MS, we explored the association between CSF detectability of a large set of proinflammatory and anti-inflammatory molecules at the time of diagnosis and response to IFNb after the first year of treatment. The absence of clinical relapses, radiological activity and disability progression (NEDA-3) was assessed at the end of 1-year follow up. The results were compared with those obtained in additional groups of CIS and RR-MS patients treated with other first-line drugs (dimethyl fumarate and glatiramer acetate)., Results: CSF undetectability of macrophage inflammatory protein (MIP)-1α was the main predictor of reaching NEDA-3 status after 1 year of IFNb treatment. Moreover, detectable platelet-derived growth factor (PDGF) was associated with higher probability of reaching NEDA-3. Conversely, no associations with the CSF molecules were found in the two other groups of patients treated either with dimethyl fumarate or with glatiramer acetate., Conclusion: MIP-1α and PDGF could potentially represent suitable CSF biomarkers able to predict response to IFNb in MS., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.S. acted as Advisory Board members of Novartis, Biogen and Merck Serono. R.Fu. has received honoraria as speaker or for research support from Biogen, Novartis, Merck, Roche, Genzyme. G.A.M. received honoraria for speaking, consultation fees and travel funding from Roche, Almirall, Bayer Schering, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Mylan and Teva. She is the principal investigator in clinical trials for Actelion, Biogen Idec, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, Teva. D.C. is an Advisory Board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva and received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck Serono, Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme and Teva. F.B. acted as Advisory Board members of Teva and Roche and received honoraria for speaking or consultation fees from Merck Serono, Teva, Biogen Idec, Sanofi, and Novartis and non-financial support from Merck Serono, Teva, Biogen Idec, and Sanofi. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. M.S.B., E.I., J.D., T.P., L.G., A.F., A.G., A.M., G.M., R.Fa., P.B. declare no conflict of interest., (© The Author(s), 2020.) more...

In multiple sclerosis (MS), inflammation alters synaptic transmission and plasticity, negatively influencing the disease course. In the present study, we aimed to explore the influence of the proinflammatory cytokine IL-1β on peculiar features of associative Hebbian synaptic plasticity, such as input specificity, using the paired associative stimulation (PAS). In 33 relapsing remitting-MS patients and 15 healthy controls, PAS was performed on the abductor pollicis brevis (APB) muscle. The effects over the motor hot spot of the APB and abductor digiti minimi (ADM) muscles were tested immediately after PAS and 15 and 30 min later. Intracortical excitability was tested with paired-pulse transcranial magnetic stimulation (TMS). The cerebrospinal fluid (CSF) levels of IL-1β were calculated. In MS patients, PAS failed to induce long-term potentiation (LTP)-like effects in the APB muscle and elicited a paradoxical motor-evoked potential (MEP) increase in the ADM. IL-1β levels were negatively correlated with the LTP-like response in the APB muscle. Moreover, IL-1β levels were associated with synaptic hyperexcitability tested with paired-pulse TMS. Synaptic hyperexcitability caused by IL-1β may critically contribute to alter Hebbian plasticity in MS, inducing a loss of topographic specificity. more...

Competing Interests: Competing interests: The authors declare no conflict of Interest.

Transcranial magnetic stimulation (TMS) has been employed in multiple sclerosis (MS) to assess the integrity of the corticospinal tract and the corpus callosum and to explore some physiological properties of the motor cortex. Specific alterations of TMS measures have been strongly associated to different pathophysiological mechanisms, particularly to demyelination and neuronal loss. Moreover, TMS has contributed to investigate the neurophysiological basis of MS symptoms, particularly those not completely explained by conventional structural damage, such as fatigue. However, variability existing between studies suggests that alternative mechanisms should be involved. Knowledge of MS pathophysiology has been enriched by experimental studies in animal models (i.e., experimental autoimmune encephalomyelitis) demonstrating that inflammation alters synaptic transmission, promoting hyperexcitability and neuronal damage. Accordingly, TMS studies have demonstrated an imbalance between cortical excitation and inhibition in MS. In particular, cerebrospinal fluid concentrations of different proinflammatory and anti-inflammatory molecules have been associated to corticospinal hyperexcitability, highlighting that inflammatory synaptopathy may represent a key pathophysiological mechanism in MS. In this perspective article, we discuss whether corticospinal excitability alterations assessed with TMS in MS patients could be useful to explain the pathophysiological correlates and their relationships with specific MS clinical characteristics and symptoms. Furthermore, we discuss evidence indicating that, in MS patients, inflammatory synaptopathy could be present since the early phases, could specifically characterize relapses, and could progressively increase during the disease course., (Copyright © 2020 Stampanoni Bassi, Buttari, Gilio, De Paolis, Fresegna, Centonze and Iezzi.) more...

Specific proinflammatory and anti-inflammatory molecules could represent useful cerebrospinal fluid (CSF) biomarkers to predict the clinical course of multiple sclerosis (MS). The proinflammatory molecule interleukin (IL)-6 has been investigated in the pathophysiology of MS and has been associated in previous smaller studies to increased disability and disease activity. Here, we wanted to further address IL-6 as a possible CSF biomarker of MS by investigating its detectability in a large cohort of 534 MS patients and in 103 individuals with other non-inflammatory neurological diseases. In these newly diagnosed patients, we also explored correlations between IL-6 detectability, MS phenotypes, and disease characteristics. We found that IL-6 was more frequently detectable in the CSF of MS patients compared with their control counterparts as significant differences emerged between patients with Clinically isolated syndrome (CIS), Relapsing-remitting (RR), and secondary progressive and primary progressive MS compared to non-inflammatory controls. IL-6 was equally present in the CSF of all MS phenotypes. In RR MS patients, IL-6 detectability was found to signal clinically and/or radiologically defined disease activity, among all other clinical characteristics. Our results add further evidence that CSF proinflammatory cytokines could be useful for the identification of those MS patients who are prone to increased disease activity. In particular, IL-6 could represent an interesting prognostic biomarker of MS, as also demonstrated in other diseases where CSF IL-6 was found to identify patients with worse disease severity., (Copyright © 2020 Stampanoni Bassi, Iezzi, Drulovic, Pekmezovic, Gilio, Furlan, Finardi, Marfia, Sica, Centonze and Buttari.) more...

Introduction: Nursing home residents represent a particularly vulnerable population experiencing high risk of unplanned hospital admissions, but few interventions have proved effective in reducing this risk. The aim of this research will be to verify the effects of a hospital-based multidisciplinary mobile unit (MMU) team intervention delivering urgent care to nursing home residents directly at their bedside., Methods and Analysis: Four nursing homes based in the Parma province, in Northern Italy, will be involved in this prospective, pragmatic, multicentre, 18-month quasiexperimental study (sequential design with two cohorts). The residents of two nursing homes will receive the MMU team care intervention. In case of urgent care needs, the nursing home physician will contact the hospital physician responsible for the MMU team by phone. The case will be triaged as (a) manageable by phone advice, (b) requiring urgent assessment by the MMU team or (c) requiring immediate emergency department (ED) referral. MMU team is composed of one senior physician and one emergency-medicine resident chosen within the staff of Internal Medicine and Critical Subacute Care Unit of Parma University-Hospital, usually with different specialty background, and equipped with portable ultrasound, set of drugs and devices useful in urgency. The MMU visits patients in nursing homes, with the mission to stabilise clinical conditions and avoid hospital admission. Residents of the other two nursing homes will receive usual care, that is, ED referral in every case of urgency. Study endpoints include unplanned hospital admissions (primary), crude all-cause mortality, hospital mortality, length of stay and healthcare-related costs (secondary)., Ethics and Dissemination: The study protocol was approved by the Ethics Committee of Area Vasta Emilia Nord (Emilia-Romagna region). Informed consent will be collected from patients or legal representatives. The results will be actively disseminated through peer-reviewed journals and conference presentations, in compliance with the Italian law., Trial Registration Number: ClinicalTrials.gov Registry (NCT04085679); Pre-results., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelinating white matter lesions and neurodegeneration, with a variable clinical course. Brain network architecture provides efficient information processing and resilience to damage. The peculiar organization characterized by a low number of highly connected nodes (hubs) confers high resistance to random damage. Anti-homeostatic synaptic plasticity, in particular long-term potentiation (LTP), represents one of the main physiological mechanisms underlying clinical recovery after brain damage. Different types of synaptic plasticity, including both anti-homeostatic and homeostatic mechanisms (synaptic scaling), contribute to shape brain networks. In MS, altered synaptic functioning induced by inflammatory mediators may represent a further cause of brain network collapse in addition to demyelination and grey matter atrophy. We propose that impaired LTP expression and pathologically enhanced upscaling may contribute to disrupting brain network topology in MS, weakening resilience to damage and negatively influencing the disease course. more...

Studies of brain network connectivity improved understanding on brain changes and adaptation in response to different pathologies. Synaptic plasticity, the ability of neurons to modify their connections, is involved in brain network remodeling following different types of brain damage (e.g., vascular, neurodegenerative, inflammatory). Although synaptic plasticity mechanisms have been extensively elucidated, how neural plasticity can shape network organization is far from being completely understood. Similarities existing between synaptic plasticity and principles governing brain network organization could be helpful to define brain network properties and reorganization profiles after damage. In this review, we discuss how different forms of synaptic plasticity, including homeostatic and anti-homeostatic mechanisms, could be directly involved in generating specific brain network characteristics. We propose that long-term potentiation could represent the neurophysiological basis for the formation of highly connected nodes (hubs). Conversely, homeostatic plasticity may contribute to stabilize network activity preventing poor and excessive connectivity in the peripheral nodes. In addition, synaptic plasticity dysfunction may drive brain network disruption in neuropsychiatric conditions such as Alzheimer's disease and schizophrenia. Optimal network architecture, characterized by efficient information processing and resilience, and reorganization after damage strictly depend on the balance between these forms of plasticity. more...

Background: Synaptic plasticity helps in reducing the clinical expression of brain damage and represents a useful mechanism to compensate the negative impact of new brain lesions in multiple sclerosis (MS). Inflammation, altering synaptic plasticity, could negatively influence the disease course in relapsing-remitting MS (RR-MS). Objective: In the present study, we explored whether interleukin (IL)-6, a major proinflammatory cytokine involved in MS pathogenesis, alters synaptic plasticity and affects the ability to compensate for ongoing brain damage. Methods: The effect of IL-6 incubation on long-term potentiation (LTP) induction was explored in vitro , in mice hippocampal slices. We also explored the correlation between the cerebrospinal fluid (CSF) levels of this cytokine and the LTP-like effect induced by the paired associative stimulation (PAS) in a group of RR-MS patients. Finally, we examined the correlation between the CSF levels of IL-6 at the time of diagnosis and the prospective disease activity in a cohort of 150 RR-MS patients. Results: In vitro LTP induction was abolished by IL-6. Consistently, in patients with MS, a negative correlation emerged between IL-6 CSF concentrations and the effect of PAS. In MS patients, longer disease duration before diagnosis was associated with higher IL-6 CSF concentrations. In addition, elevated CSF levels of IL-6 were associated with greater clinical expression of new inflammatory brain lesions, unlike in patients with low or absent IL-6 concentrations, who had a better disease course. Conclusions: IL-6 interfering with synaptic plasticity mechanisms may impair the ability to compensate the clinical manifestation of new brain lesions in RR-MS patients. more...

Introduction: Disease course of multiple sclerosis (MS) is negatively influenced by proinflammatory molecules released by activated T and B lymphocytes and local immune cells. The endovanilloid system plays different physiological functions, and preclinical data suggest that transient receptor potential vanilloid type 1 (TRPV1) could modulate neuroinflammation in this disorder. Methods: The effect of TRPV1 activation on the release of two main proinflammatory cytokines, tumor necrosis factor (TNF) and interleukin (IL)-6, was explored in activated microglial cells. Furthermore, in a group of 132 MS patients, the association between the cerebrospinal fluid (CSF) levels of TNF and IL-6 and a single nucleotide polymorphisms (SNP) influencing TRPV1 protein expression and function (rs222747) was assessed. Results: In in vitro experiments, TRPV1 stimulation by capsaicin significantly reduced TNF and IL-6 release by activated microglial cells. Moreover, the anti-inflammatory effect of TRPV1 activation was confirmed by another TRPV1 agonist, the resiniferatoxin (RTX), whose effects were significantly inhibited by the TRPV1 antagonist, 5-iodoresiniferatoxin (5-IRTX). Vice versa, BV2 pre-treatment with 5-IRTX increased the inflammatory response induced by LPS. Moreover, in MS patients, a significant association emerged between TRPV1 SNP rs222747 and CSF TNF levels. In particular, the presence of a G allele, known to result in increased TRPV1 protein expression and function, was associated to lower CSF levels of TNF. Conclusions: Our results indicate that TRPV1 influences central inflammation in MS by regulating cytokine release by activated microglial cells. The modulation of the endovanilloid system may represent a useful approach to contrast neuroinflammation in MS. more...

The endocannabinoid system (ECS) has been recently recognized as a prominent promoter of the emotional homeostasis, mediating the effects of different environmental signals including rewarding and stressing stimuli. The ECS modulates the rewarding effects of environmental stimuli, influencing synaptic transmission in the dopaminergic projections to the limbic system, and mediates the neurophysiological and behavioral consequences of stress. Notably, the individual psychosocial context is another key element modulating the activity of the ECS. Finally, inflammation represents an additional factor that could alter the cannabinoid signaling in the CNS inducing a "sickness behavior," characterized by anxiety, anhedonia, and depressive symptoms. The complex influences of the ECS on both the environmental and internal stimuli processing, make the cannabinoid-based drugs an appealing option to treat different psychiatric conditions. Although ample experimental evidence shows beneficial effects of ECS modulation on mood, scarce clinical indication limits the use of cannabis-based treatments. To better define the possible clinical indications of cannabinoid-based drugs in psychiatry, a number of issues should be better addressed, including genetic variability and psychosocial factors possibly affecting the individual response. In particular, better knowledge of the multifaceted effects of cannabinoids could help to understand how to boost their therapeutic use in anxiety and depression treatment. more...

Background: In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS., Methods: At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up., Results: CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system., Conclusions: Our results suggest that PDGF could promote a more prolonged relapse-free period during the course of RR-MS, without influencing inflammation reactivation and inflammation-driven neuronal damage and likely enhancing adaptive plasticity. more...

Neurons in the central nervous system are organized in functional units interconnected to form complex networks. Acute and chronic brain damage disrupts brain connectivity producing neurological signs and/or symptoms. In several neurological diseases, particularly in Multiple Sclerosis (MS), structural imaging studies cannot always demonstrate a clear association between lesion site and clinical disability, originating the "clinico-radiological paradox." The discrepancy between structural damage and disability can be explained by a complex network perspective. Both brain networks architecture and synaptic plasticity may play important roles in modulating brain networks efficiency after brain damage. In particular, long-term potentiation (LTP) may occur in surviving neurons to compensate network disconnection. In MS, inflammatory cytokines dramatically interfere with synaptic transmission and plasticity. Importantly, in addition to acute and chronic structural damage, inflammation could contribute to reduce brain networks efficiency in MS leading to worse clinical recovery after a relapse and worse disease progression. These evidence suggest that removing inflammation should represent the main therapeutic target in MS; moreover, as synaptic plasticity is particularly altered by inflammation, specific strategies aimed at promoting LTP mechanisms could be effective for enhancing clinical recovery. Modulation of plasticity with different non-invasive brain stimulation (NIBS) techniques has been used to promote recovery of MS symptoms. Better knowledge of features inducing brain disconnection in MS is crucial to design specific strategies to promote recovery and use NIBS with an increasingly tailored approach. more...

Background and Purpose: Public campaigns to increase stroke preparedness have been tested in different contexts, showing contradictory results. We evaluated the effectiveness of a stroke campaign, designed specifically for the Italian population in reducing prehospital delay., Methods: According to an SW-RCT (Stepped-Wedge Cluster Randomized Controlled Trial) design, the campaign was launched in 4 provinces in the northern part of the region Emilia Romagna at 3-month intervals in randomized sequence. The units of analysis were the patients admitted to hospital, with stroke and transient ischemic attack, over a time period of 15 months, beginning 3 months before the intervention was launched in the first province to allow for baseline data collection. The proportion of early arrivals (within 2 hours of symptom onset) was the primary outcome. Thrombolysis rate and some behavioral end points were the secondary outcomes. Data were analyzed using a fixed-effect model, adjusting for cluster and time trends., Results: We enrolled 1622 patients, 912 exposed and 710 nonexposed to the campaign. The proportion of early access was nonsignificantly lower in exposed patients (354 [38.8%] versus 315 [44.4%]; adjusted odds ratio, 0.81; 95% confidence interval, 0.60-1.08; P =0.15). As for secondary end points, an increase was found for stroke recognition, which approximated but did not reach statistical significance ( P =0.07)., Conclusions: Our campaign was not effective in reducing prehospital delay. Even if some limitations of the intervention, mainly in terms of duration, are taken into account, our study demonstrates that new communication strategies should be tested before large-scale implementation., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01881152., (© 2017 American Heart Association, Inc.) more...

Cognitive deficits are frequently observed in multiple sclerosis (MS), mainly involving processing speed and episodic memory. Both demyelination and gray matter atrophy can contribute to cognitive deficits in MS. In recent years, neuroinflammation is emerging as a new factor influencing clinical course in MS. Inflammatory cytokines induce synaptic dysfunction in MS. Synaptic plasticity occurring within hippocampal structures is considered as one of the basic physiological mechanisms of learning and memory. In experimental models of MS, hippocampal plasticity is profoundly altered by proinflammatory cytokines. Although mechanisms of inflammation-induced hippocampal pathology in MS are not completely understood, alteration of Amyloid-β (Aβ) metabolism is emerging as a key factor linking together inflammation, synaptic plasticity and neurodegeneration in different neurological diseases. We explored the correlation between concentrations of Aβ 1-42 and the levels of some proinflammatory and anti-inflammatory cytokines (interleukin-1β (IL-1β), IL1-ra, IL-8, IL-10, IL-12, tumor necrosis factor α (TNFα), interferon γ (IFNγ)) in the cerebrospinal fluid (CSF) of 103 remitting MS patients. CSF levels of Aβ 1-42 were negatively correlated with the proinflammatory cytokine IL-8 and positively correlated with the anti-inflammatory molecules IL-10 and interleukin-1 receptor antagonist (IL-1ra). Other correlations, although noticeable, were either borderline or not significant. Our data show that an imbalance between proinflammatory and anti-inflammatory cytokines may lead to altered Aβ homeostasis, representing a key factor linking together inflammation, synaptic plasticity and cognitive dysfunction in MS. This could be relevant to identify novel therapeutic approaches to hinder the progression of cognitive dysfunction in MS. more...

Introduction: Our group previously demonstrated the feasibility of the HuCare Quality Improvement Strategy (HQIS), aimed at integrating into practice six psychosocial interventions recommended by international guidelines. This trial will assess whether the introduction of the strategy in oncology wards improves patient's health-related quality of life (HRQoL)., Methods and Analysis: Multicentre, incomplete stepped-wedge cluster randomised controlled trial, conducted in three clusters of five centres each, in three equally spaced time epochs. The study also includes an initial epoch when none of the centres are exposed to the intervention, and a final epoch when all centres will have implemented the strategy. The intervention is applied at a cluster level, and assessed at an individual level with cross-sectional model. A total of 720 patients who received a cancer diagnosis in the previous 2 months and about to start medical treatment will be enrolled. The primary aim is to evaluate the effectiveness of the HQIS versus standard care in terms of improvement of at least one of two domains (emotional and social functions) of HRQoL using the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items) questionnaire, at baseline and at 3 months. This outcome was chosen because patients with cancer generally exhibit low HRQoL, particularly at certain stages of care, and because it allows to assess the strategy's impact as perceived by patients themselves. The HQIS comprises three phases: (1) clinician training-to improve communication-relational skills and instruct on the project; (2) centre support-four on-site visits by experts of the project team, aimed to boost motivation, help with context analysis and identification of solutions; (3) implementation of Evidence-Based Medicine (EBM) recommendations at the centre., Ethics and Dissemination: Ethics committee review approval has been obtained from the Ethics Committee of Parma. Results will be disseminated at conferences, and in peer-reviewed and professional journals intended for policymakers and managers., Trial Registration Number: NCT03008993; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.) more...

Background: Vinflunine is the only chemotherapeutic agent shown to improve survival in platinum-refractory patients with metastatic transitional cell carcinoma of the urothelium (TCCU) in a phase III clinical trial, which led to product registration for this indication in Europe. The aim of this study was to assess the efficacy of vinflunine and to evaluate the prognostic significance of risk factors in a large, unselected cohort of patients with metastatic TCCU treated according to routine clinical practice., Methods: This was a retrospective multicenter study. Italian cancer centers were selected if, according to the Registry of the Italian Medicines Agency (AIFA), at least four patients had been treated with vinflunine between February 2011 and June 2014, after first- or second-line platinum-based chemotherapy. The primary objective was to test whether the efficacy measured by overall survival (OS) in the registration study could be confirmed in routine clinical practice. Multivariate analysis was carried out using Cox proportional hazard model., Results: A total of 217 patients were treated in 28 Italian centers. Median age was 69 years (IQR 62-76) and 84% were male; Eastern Cooperative Oncology Group performance status (ECOG PS) was ≥ 1 in 53% of patients. The median number of cycles was 4 (IQR 2-6); 29%, 35%, and 36% received an initial dose of 320 mg/m 2 , 280 mg/m 2 or a lower dose, respectively. Median progression-free survival (PFS) and OS for the entire population was 3.2 months (2.6-3.7) and 8.1 months (6.3-8.9). A complete response was observed in six patients, partial response in 21, stable disease in 60, progressive disease in 108, with a disease control rate of 40%. Multivariate analysis showed that ECOG PS, number of metastatic sites and liver involvement were unfavorable prognostic factors for OS. Toxicity was mild, and grade 3-4 adverse effects were mainly: neutropenia (9%), anemia (6%), asthenia/fatigue (7%) and constipation (5%)., Conclusions: In routine clinical practice the results obtained with VFL seem to be better than the results of the registration trial and reinforce evidence supporting its use after failure of a platinum-based chemotherapy. more...

Background: Systematic reviews call for well-designed trials with clearly described intervention components to support the effectiveness of educational campaigns to reduce patient delay in stroke presentation. We herein describe the systematic development process of a campaign aimed to increase stroke awareness and preparedness., Methods: Campaign development followed Intervention Mapping (IM), a theory- and evidence-based tool, and was articulated in two phases: needs assessment and intervention development. In phase 1, two cross-sectional surveys were performed, one aiming to measure stroke awareness in the target population and the other to analyze the behavioral determinants of prehospital delay. In phase 2, a matrix of proximal program objectives was developed, theory-based intervention methods and practical strategies were selected and program components and materials produced., Results: In phase 1, the survey on 202 citizens highlighted underestimation of symptom severity, as in only 44% of stroke situations respondents would choose to call the emergency service (EMS). In the survey on 393 consecutive patients, 55% presented over 2 hours after symptom onset; major determinants were deciding to call the general practitioner first and the reaction of the first person the patient called. In phase 2, adult individuals were identified as the target of the intervention, both as potential "patients" and witnesses of stroke. The low educational level found in the patient survey called for a narrative approach in cartoon form. The family setting was chosen for the message because 42% of patients who presented within 2 hours had been advised by a family member to call EMS. To act on people's tendency to view stroke as an untreatable disease, it was decided to avoid fear-arousal appeals and use a positive message providing instructions and hope. Focus groups were used to test educational products and identify the most suitable sites for message dissemination., Conclusions: The IM approach allowed to develop a stroke campaign integrating theories, scientific evidence and information collected from the target population, and enabled to provide clear explanations for the reasons behind key decisions during the intervention development process., Trial Registration: NCT01881152 . Retrospectively registered June 7 2013. more...

The endocannabinoid system plays a regulatory role in a number of physiological processes and has been found altered in different pathological conditions, including movement disorders. The interactions between cannabinoids and dopamine in the basal ganglia are remarkably complex and involve both the modulation of other neurotransmitters (γ-aminobutyric acid, glutamate, opioids, peptides) and the activation of different receptors subtypes (cannabinoid receptor type 1 and 2). In the last years, experimental studies contributed to enrich this scenario reporting interactions between cannabinoids and other receptor systems (transient receptor potential vanilloid type 1 cation channel, adenosine receptors, 5-hydroxytryptamine receptors). The improved knowledge, adding new interpretation on the biochemical interaction between cannabinoids and other signaling pathways, may contribute to develop new pharmacological strategies. A number of preclinical studies in different experimental Parkinson's disease (PD) models demonstrated that modulating the cannabinoid system may be useful to treat some motor symptoms. Despite new cannabinoid-based medicines have been proposed for motor and nonmotor symptoms of PD, so far, results from clinical studies are controversial and inconclusive. Further clinical studies involving larger samples of patients, appropriate molecular targets, and specific clinical outcome measures are needed to clarify the effectiveness of cannabinoid-based therapies., Competing Interests: No competing financial interests exist. more...

Background: Research capacity is a prerequisite for any health care institution intending to provide high-quality care, yet, few clinicians engage in research, and their work is rarely recognized. To make research an institutional activity, it could be helpful to measure health care professionals' research performance. However, a comprehensive approach to do this is lacking., Methods: We conducted a literature analysis to determine how best to assess research performance. Our method was not restricted to bibliometric and citation parameters, as is usually the case, but also including "hidden" activities, generally not considered in research performance evaluations., Results: A set of 12 easily retrievable indicators was used and corresponding points assigned according to a weighting system intended to reflect the effort estimated to perform each activity. We observed a highly skewed score distribution, with a minority of health care professionals performing well across the indicators. The highest score was recorded for scientific papers (768/1098 points, 70%). Twenty percent of researchers at our institution generated 50% of points., Conclusions: We develop a simple method for measuring research performance, which could be rapidly implemented in health care institutions. It is hoped that the proposed method might be useful for promoting research and guiding resource allocation, although further evaluations are needed to confirm the method's utility. more...

Mirror movements (MMs) occur on the contralateral side of a limb being used intentionally. Because few families with congenital MMs and no other neurological signs have been reported, the underlying mechanisms of MMs are still not entirely clear. We report on the clinical, genetic, neurophysiological and neuroimaging findings of 10 of 26 living members of a novel four-generation family with congenital MMs. DCC and RAD51 were sequenced in affected members of the family. Five of the ten subjects with MMs underwent neurophysiological and neuroimaging evaluations. The neurophysiological evaluation consisted of electromyographic (EMG) mirror recordings, investigations of corticospinal excitability, and analysis of interhemispheric inhibition using transcranial magnetic stimulation techniques. The neuroimaging evaluation included functional MRI during finger movements. Eight (all females) of the ten members examined presented MMs of varying degrees at the clinical assessment. Transmission of MMs appears to have occurred according to an autosomal-dominant fashion with variable expression. No mutation in DCC or RAD51 was identified. EMG mirror activity was higher in MM subjects than in healthy controls. Short-latency interhemispheric inhibition was reduced in MM subjects. Ipsilateral motor-evoked potentials were detectable in the most severe case. The neuroimaging evaluation did not disclose any significant abnormalities in MM subjects. The variability of the clinical features of this family, and the lack of known genetic abnormalities, suggests that MMs are heterogeneous disorders. The pathophysiological mechanisms of MMs include abnormalities of transcallosal inhibition and corticospinal decussation. more...

Financial incentives in primary care have been introduced with the purpose of improving appropriateness of care and containing demand. We usually observe pay-for-performance programs, but alternatives, such as pay-for-participation in improvement activities and pay-for-compliance with clinical guidelines, have also been implemented. Here, we assess the influence of different programs that ensure extra payments to GPs for containing avoidable hospitalisations. Our dataset covers patients and GPs of the Italian region Emilia-Romagna for the year 2005. By separating pay-for-performance from pay-for-participation and pay-for-compliance programs, we estimate the impact of different financial incentives on the probability of avoidable hospitalisations. As dependent variable, we consider two different sets of conditions for which timely and effective primary care should be able to limit the need for hospital admission. The first is based on 27 medical diagnostic related groups that Emilia-Romagna identifies as at risk of inappropriateness in primary care, while the second refers to the internationally recognised ambulatory care-sensitive conditions. We show that pay-for-performance schemes may have a significant effect over aggregate indicators of appropriateness, while the effectiveness of pay-for-participation schemes is adequately captured only by taking into account subpopulations affected by specific diseases. Moreover, the same scheme produces different effects on the two sets of indicators used, with performance improvements limited to the target explicitly addressed by the Italian policy maker. This evidence is consistent with the idea that a "tunnel vision" effect may occur when public authorities monitor specific sets of objectives as proxies for more general improvements in the quality of health care delivered. more...