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Background: Family history of Parkinson's disease (PD) is a common finding in PD patients. However, a few studies have systematically examined this aspect., Objectives: We investigated the family history of PD patients, comparing demographic and clinical features between familial PD (fPD) and sporadic PD (sPD)., Methods: A cross-sectional study enrolling 2035 PD patients was conducted in 28 Italian centers. Clinical data and family history up to the third degree of kinship were collected., Results: Family history of PD was determined in 21.9% of patients. fPD patients had earlier age at onset than sporadic patients. No relevant differences in the prevalence of motor and nonmotor symptoms were detected. Family history of mood disorders resulted more prevalently in the fPD group., Conclusions: fPD was found to recur more frequently than previously reported. Family history collection beyond the core family is essential to discover disease clusters and identify novel risk factors for PD., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

A framework for electrolyte-gated organic transistors (EGOTs) that unifies the view of interfacial capacitive coupling of electrolyte-gated organic field-effect transistors (EGOFETs) with the volumetric capacitive coupling in organic electrochemical transistors (OECTs) is proposed. The EGOT effective capacitance arises from in-series capacitances of the electrolyte/gate electrode and electrolyte/channel interfaces, and the chemical capacitance of the organic semiconductor channel whose weight with respect to the interfacial capacitance is modulated by the charge carrier density, hence by the gate voltage. The expression for chemical capacitance is derived from the DOS of the organic semiconductor, which it is assumed to exhibit exponential energy disorder in the HOMO-LUMO gap. The analytical expression of the EGOT current is assessed on experimental data and shown to accurately predict the shape of the whole transfer curve of an EGOT thus allowing to extract accurate values for the switch-on voltage and the interfacial transconductance, without assumptions on specific response regime and, in OECT, without invoking the volumetric capacitance. Interestingly, the EGOT model recovers EGOFET and OECT as limit cases and, in the latter case, explicitly represents the volumetric capacitance in terms of the energy disorder and the bandgap of the organic semiconductor., (© 2024 The Author(s). Advanced Materials published by Wiley‐VCH GmbH.)

Background: Midline Tremor is defined as an isolated or combined tremor that affects the neck, trunk, jaw, tongue, and/or voice and could be part of Essential Tremor (ET), or dystonic tremor. The clinical efficacy of deep brain stimulation for Midline Tremor has been rarely reported. The Ventral Intermediate Nucleus and Globus Pallidus Internus are the preferred targets, but with variable outcomes. Thalamic Ventral-Oralis (VO) complex and Zona Incerta (ZI) are emerging targets for tremor control in various etiologies., Objective: To report on neuroradiological, neurophysiological targeting and long-term efficacy of thalamic Ventral-Oralis complex and Zona Incerta deep brain stimulation in Midline Tremor., Methods: Three patients (two males and one female) with Midline Tremor in dystonic syndromes were recruited for this open-label study. Clinical, surgical, neurophysiological intraoperative testing and long-term follow-up data are reported., Results: Intraoperative testing and reconstruction of volume of tissue activated confirmed the position of the electrodes in the area stimulated between the thalamic Ventral-Oralis complex and Zona Incerta in all patients. All three patients showed optimal control of both tremor and dystonic features at short-term (6 months) and long-term follow-up (up to 6 years). No adverse events occurred., Conclusion: In the syndromes of Midline Tremor of various origins, the best target for DBS might be difficult to identify. Our results showed that thalamic Ventral-Oralis complex/Zona Incerta may be a viable and safe option even in specific forms of tremor with axial distribution., (© 2024. The Author(s).)

Periodic travelling waves (PTW) are a common solution type of partial differential equations. Such models exhibit multistability of PTWs, typically visualised through the Busse balloon, and parameter changes typically lead to a cascade of wavelength changes through the Busse balloon. In the past, the stability boundaries of the Busse balloon have been used to predict such wavelength changes. Here, motivated by anecdotal evidence from previous work, we provide compelling evidence that the Busse balloon provides insufficient information to predict wavelength changes due to a delayed loss of stability phenomenon. Using two different reaction-advection-diffusion systems, we relate the delay that occurs between the crossing of a stability boundary in the Busse balloon and the occurrence of a wavelength change to features of the essential spectrum of the destabilised PTW. This leads to a predictive framework that can estimate the order of magnitude of such a time delay, which provides a novel "early warning sign" for pattern destabilisation. We illustrate the implementation of the predictive framework to predict under what conditions a wavelength change of a PTW occurs., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background/Objectives : Cognitive impairment in spinocerebellar ataxia patients has been reported since the early-disease stage. We aimed to assess cognitive differences in SCA1 and SCA2 patients. Methods : We performed neuropsychological (NPS) and neurophysiological (auditory event-related potentials, aERPs) assessments in 16 SCA1 and 18 SCA2 consecutive patients. Furthermore, clinical information (age at onset, disease duration, motor disability) was collected. Results : NPS tests yielded scores in the normal range in both groups but with lower scores in the Frontal Assessment Battery ( p < 0.05) and Visual Analogue Test for Anosognosia for motor impairment ( p < 0.05) in SCA1, and the Trail Making Test ( p < 0.01), Raven's progressive matrices ( p < 0.01), Stroop ( p < 0.05), and emotion attribution tests ( p < 0.05) in SCA2. aERPs showed lower N100 amplitude ( p < 0.01) and prolonged N200 latency ( p < 0.01) in SCA1 compared with SCA2. Clinically, SCA2 had more severe motor disability than SCA1 in the Assessment and Rating of Ataxia Scale. Conclusions : SCA2 showed more significant difficulties in attentional, visuospatial, and emotional function, and greater motor impairment. In contrast, SCA1 showed less cognitive flexibility/phasic ability, probably affected by a more severe degree of dysarthria. The same group revealed less neural activity during nonconscious attentional processing (N100-N200 data), suggesting greater involvement of sensory pathways in discriminating auditory stimuli. NFS did not correlate with NPS findings, implying an independent relationship. However, the specific role of the cerebellum and cerebellar symptoms in NPS test results deserves more focus.

Usually, positive neurological symptoms are considered as the consequence of a mere, afinalistic and abnormal increase in function of specific brain areas. However, according to the Theory of Active Inference, which argues that action and perception constitute a loop that updates expectations according to a Bayesian model, the brain is rather an explorer that formulates hypotheses and tests them to assess the correspondence between internal models and reality. Moreover, the cerebral cortex is characterised by a continuous "conflict" between different brain areas, which constantly attempt to expand in order to acquire more of the limited available computational resources, by means of their dopamine-induced neuroplasticity. Thus, it has recently been suggested that dreams, during rapid eye movement sleep (REMS), protect visual brain areas (deprived of their stimuli during rest) from being conquered by other normally stimulated ones. It is therefore conceivable that positive symptoms also have a functional importance for the brain. We evaluate supporting literature data of a 'defensive' role of positive symptoms and the relevance of dopamine-induced neuroplasticity in the context of neurodegenerative and psychiatric diseases. Furthermore, the possible functional significance of idiopathic REMS-related behavioural disorder as well as phantom limb syndrome is examined. We suggest that positive neurological symptoms are not merely a passive expression of a damage, but active efforts, related to dopamine-induced plasticity, to maintain a correct relationship between the external world and its brain representation, thus preventing healthy cortical areas from ousting injured ones., (© 2024. The Author(s).)

We extend the N-intertwined mean-field approximation (NIMFA) for the susceptible-infectious-susceptible (SIS) epidemiological process to time-varying networks. Processes on time-varying networks are often analyzed under the assumption that the process and network evolution happen on different timescales. This approximation is called timescale separation. We investigate timescale separation between disease spreading and topology updates of the network. We introduce the transition times [under T]̲(r) and T[over ¯](r) as the boundaries between the intermediate regime and the annealed (fast changing network) and quenched (static network) regimes, respectively, for a fixed accuracy tolerance r. By analyzing the convergence of static NIMFA processes, we analytically derive upper and lower bounds for T[over ¯](r). Our results provide insights and bounds on the time of convergence to the steady state of the static NIMFA SIS process. We show that, under our assumptions, the upper-transition time T[over ¯](r) is almost entirely determined by the basic reproduction number R&#95;{0} of the network. The value of the upper-transition time T[over ¯](r) around the epidemic threshold is large, which agrees with the current understanding that some real-world epidemics cannot be approximated with the aforementioned timescale separation.

Purpose: Non-motor symptoms, such as sleep disturbances, fatigue, neuropsychiatric manifestations, cognitive impairment, and sensory abnormalities, have been widely reported in patients with idiopathic cervical dystonia (ICD). This study aimed to clarify the autonomic nervous system (ANS) involvement in ICD patients, which is still unclear in the literature., Methods: We conducted a pilot case-control study to investigate ANS in twenty ICD patients and twenty age-sex-matched controls. The Composite Autonomic System Scale 31 was used for ANS clinical assessment. The laser Doppler flowmetry quantitative spectral analysis, applied to the skin and recorded from indices, was used to measure at rest, after a parasympathetic activation (six deep breathing) and two sympathetic stimuli (isometric handgrip and mental calculation), the power of high-frequency and low-frequency oscillations, and the low-frequency/high-frequency ratio., Results: ICD patients manifested higher clinical dysautonomic symptoms than controls (p < 0.05). At rest, a lower high-frequency power band was detected among ICD patients than controls, reaching a statistically significant difference in the age group of ≥ 57-year-olds (p < 0.05). In the latter age group, ICD patients showed a lower low-frequency/high-frequency ratio than controls at rest (p < 0.05) and after mental calculation (p < 0.05). Regardless of age, during handgrip, ICD patients showed (i) lower low-frequency/high-frequency ratio (p < 0.05), (ii) similar increase of the low-frequency oscillatory component compared to controls, and (iii) stable high-frequency oscillatory component, which conversely decreased in controls. No differences between the two groups were detected during deep breathing., Conclusion: ICD patients showed ANS dysfunction at clinical and neurophysiological levels, reflecting an abnormal parasympathetic-sympathetic interaction likely related to abnormal neck posture and neurotransmitter alterations., (© 2023. The Author(s).)

Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution during disease progression along a 9-year clinical course in a patient with advanced disseminated melanoma who received different treatments, including trametinib, ipilimumab, radiation, vemurafenib, surgical tumor debulking and a second ipilimumab course, ultimately achieving complete long-term disease remission.Longitudinal analyses of therapies-resistant metastatic tumors revealed the effects of different treatments on tumor's microenvironment and immunogenicity, ultimately creating a milieu favorable to immunotherapy response. Monitoring of the temporal dynamics of T cells by analysis of the T cell receptor (TCR) repertoire in the tumor and peripheral blood during disease evolution indicated that T-cell clones with common TCR rearrangements, present at low levels at baseline, were maintained and expanded after immunotherapy, and that TCR diversity increased. Analysis of genetic, molecular, and cellular components of the tumor depicted a multistep process in which treatment with kinase inhibitors strongly conditioned the immune microenvironment creating an inflamed milieu converting cold into hot tumors, while ipilimumab impacted and increased the TCR repertoire, a requirement for tumor rejection.Since the optimal sequencing of treatment with antibodies targeting immune checkpoints and kinase inhibitors for advanced melanoma is still clinically debated, this case indicates that immunotherapy success is possible even after progression on targeted therapy., 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.)

AFG3-like matrix AAA peptidase subunit 2 gene (AFG3L2, OMIM * 604,581) biallelic mutations lead to autosomal recessive spastic ataxia-5 SPAX5, OMIM # 614,487), a rare hereditary form of ataxia. The clinical spectrum includes early-onset cerebellar ataxia, spasticity, and progressive myoclonic epilepsy (PME). In Italy, the epidemiology of the disease is probably underestimated. The advent of next generation sequencing (NGS) technologies has speeded up the diagnosis of hereditary diseases and increased the percentage of diagnosis of rare disorders, such as the rare hereditary ataxia groups. Here, we describe two patients from two different villages in the province of Ferrara, who manifested a different clinical ataxia-plus history, although carrying the same biallelic mutation in AFG3L2 (p.Met625Ile) identified through NGS analysis., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer (TC). Several genomic and transcriptomic studies explored the molecular landscape of follicular cell-derived TCs, and BRAF V600E, RAS mutations, and gene fusions are well-established drivers. DICER1 mutations were described in specific sets of TC patients but represent a rare event in adult TC patients., Methods: Here, we report the molecular characterization of 30 retrospective follicular cell-derived thyroid tumors, comprising PTCs (90%) and poorly differentiated TCs (10%), collected at our Institute. We performed DNA whole-exome sequencing using patient-matched control for somatic mutation calling, and targeted RNA-seq for gene fusion detection. Transcriptional profiles established in the same cohort by microarray were investigated using three signaling-related gene signatures derived from The Cancer Genome Atlas (TCGA)., Results: The occurrence of BRAF V600E (44%), RAS mutations (13%), and gene fusions (13%) was confirmed in our cohort. In addition, in two patients lacking known drivers, mutations of the DICER1 gene (p.D1709N and p.D1810V) were identified. DICER1 mutations occur in two adult patients with follicular-pattern lesions, and in one of them a second concurrent DICER1 mutation (p.R459*) is also observed. Additional putative drivers include ROS1 gene (p.P2130A mutation), identified in a patient with a rare solid-trabecular subtype of PTC. Transcriptomics indicates that DICER1 tumors are RAS-like, whereas the ROS1 -mutated tumor displays a borderline RAS-/BRAF-like subtype. We also provide an overview of DICER1 and ROS1 mutations in thyroid lesions by investigating the COSMIC database., Conclusion: Even though small, our series recapitulates the genetic background of PTC. Furthermore, we identified DICER1 mutations, one of which is previously unreported in thyroid lesions. For these less common alterations and for patients with unknown drivers, we provide signaling information applying TCGA-derived classification., Competing Interests: GP received honoraria from Lilly, AstraZeneca, Novartis, Illumina, and Roche and is part of the advisory board of ADS Biotec. 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 © 2023 Minna, Devecchi, Pistore, Paolini, Mauro, Penso, Pagliardini, Busico, Pruneri, De Cecco, Borrello, Sensi and Greco.)

Objective: Opicapone (OPC) is a third-generation peripheral catechol-O-methyl transferase inhibitor (COMT-i) approved as add-on therapy to levodopa/DOPA decarboxylase inhibitors (DDCI) combinations in Parkinson's disease (PD) patients with end-of-dose motor fluctuations. While the OPC effectiveness on motor symptoms is well known, there is still uncertainty about the timing of introduction, the management of levodopa dose, and the efficacy on non-motor symptoms (NMS)., Subjects and Methods: A group of PD experts participated in a consensus activity composed of the Nominal Group Technique (NGT) and the Delphi method to better define the role of OPC. A list of statements was defined with the NGT and voted on through an online Delphi process by a panel of 85 Italian clinicians., Results: 24 statements were selected for the Delphi voting. Most statements (n=15, 62%) reached a consensus. A wide agreement was reached about the efficacy of OPC in treating motor fluctuations, including early morning akinesia and nocturnal akinesia. The panel widely agreed about the effectiveness of OPC in early fluctuating patients. The long-lasting inhibitory effect of OPC was recognized as an advantage over other COMT-i, resulting in a single daily dose and greater ease of introduction into the levodopa therapeutic regimen., Conclusions: The efficacy of OPC observed in the clinical trials for the management of PD patients with motor fluctuations is also experienced in clinical practice. The review of the current positioning of OPC from the late to early stages of the disease may represent an important step in the evolution of the PD therapeutic approach.

The advent of immunotherapies with biological drugs has revolutionized the treatment of cancers and auto-immune diseases. However, in some patients, the production of anti-drug antibodies (ADAs) hampers the drug efficacy. The concentration of ADAs is typically in the range of 1-10 pm; hence their immunodetection is challenging. ADAs toward Infliximab (IFX), a drug used to treat rheumatoid arthritis and other auto-immune diseases, are focussed. An ambipolar electrolyte-gated transistor (EGT) immunosensor is reported based on a reduced graphene oxide (rGO) channel and IFX bound to the gate electrode as the specific probe. The rGO-EGTs are easy to fabricate and exhibit low voltage operations (≤ 0.3 V), a robust response within 15 min, and ultra-high sensitivity (10 am limit of detection). A multiparametric analysis of the whole rGO-EGT transfer curves based on the type-I generalized extreme value distribution is proposed. It is demonstrated that it allows to selectively quantify ADAs also in the co-presence of its antagonist tumor necrosis factor alpha (TNF-α), the natural circulating target of IFX., (© 2023 The Authors. Advanced Materials published by Wiley-VCH GmbH.)

Porcine Reproductive and Respiratory Syndrome (PRRS) caused by the PRRS virus affects farmed pigs worldwide, causing direct and indirect losses. The most severe manifestations of PRRS infection are observed in piglets and pregnant sows. The clinical outcome of the infection depends on the PRRSV strain's virulence, the pregnancy state of the female, environmental factors, the presence of protective antibodies due to previous infections, and the host's genetic susceptibility. The latter aspect was investigated in this study, in particular, evaluating the most significant polymorphisms (SNPs) of the CD163 gene in slaughtered pigs reared in Central Italy. Total RNAs were extracted from 377 swine samples and subjected to RT-PCR targeted to the CD163 gene, followed by sequencing analysis. Contextually, the viral RNA was detected by RT-qPCR in order to phenotypically categorize animals into infected and not infected. In particular, 36 haplotypes were found, and their frequencies ranged from 0.13% to 35.15%. There were 62 resulting genotypes, three of which were associated with a putative resistance to the disease. Both the haplotypes and genotypes were inferred by PHASE v.2.1 software. To the best of our knowledge, this type of investigation was conducted for the first time on pig livestock distributed in different regions of Central Italy. Thus, the obtained findings may be considered very important since they add useful information about swine genetic background in relation to PRRS infection, from the perspective of adopting Marker-Assisted Selection (MAS) as a possible and alternative strategy to control this still widespread disease.

In this survey, we propose an overview on Lyapunov functions for a variety of compartmental models in epidemiology. We exhibit the most widely employed functions, and provide a commentary on their use. Our aim is to provide a comprehensive starting point to readers who are attempting to prove global stability of systems of ODEs. The focus is on mathematical epidemiology, however some of the functions and strategies presented in this paper can be adapted to a wider variety of models, such as prey-predator or rumor spreading., Competing Interests: Conflict of interestOn behalf of all authors, the corresponding author states that there is no conflict of interest., (© The Author(s) 2023.)

Telemedicine provides healthcare services remotely and represents a fundamental resource for the management of rare and fragile patients. Tele-health implementation is a main objective of the European Reference Networks (ERNs) mission to accelerate diagnosis for rare diseases. TeleNewCARe is a pilot case-control project which evaluates the efficacy and satisfaction of telegenetics for neuromuscular and cardiac adult patients, compared to face-to-face genetic counselling. The virtual sessions were co-hosted by a medical geneticist and a neurologist/cardiologist. Specific questionnaires (Clinical Genetics Satisfaction Questionnaire (CGS), Telemedicine Satisfaction Questionnaire (TSQ) and a Satisfaction Questionnaire for medical geneticists) were used to assess the effectiveness and fulfilment of telecounselling, both for patients and health care providers. Satisfaction expressed for telegenetics did not significantly differ from face-to-face counselling. The virtually enrolled patients declared they had the possibility to relate confidentially with the specialists, to share information and to be informed in an exhaustive way about their disease. Almost all patients declared themselves willing to reuse the telecounselling in the future. The multidisciplinary care was perceived as a significant added value. No overt technical problems were reported although the need for digital skills and tools can limit patients' compliance. Our experience supports telegenetics as a valid alternative to traditional genetic counselling in cardiac and neuromuscular patients. This innovative approach facilitates multidisciplinary care, grants a periodical follow up, without forcing patients to discomfortable travelling, and allows to maintain expert care. This result meets the ERNs needs to reduce patients' burden to access and monitor their healthcare., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2023. Published by Elsevier Masson SAS.)

The interplay between disease spreading and personal risk perception is of key importance for modelling the spread of infectious diseases. We propose a planar system of ordinary differential equations (ODEs) to describe the co-evolution of a spreading phenomenon and the average link density in the personal contact network. Contrary to standard epidemic models, we assume that the contact network changes based on the current prevalence of the disease in the population, i.e. the network adapts to the current state of the epidemic. We assume that personal risk perception is described using two functional responses: one for link-breaking and one for link-creation. The focus is on applying the model to epidemics, but we also highlight other possible fields of application. We derive an explicit form for the basic reproduction number and guarantee the existence of at least one endemic equilibrium, for all possible functional responses. Moreover, we show that for all functional responses, limit cycles do not exist. This means that our minimal model is not able to reproduce consequent waves of an epidemic, and more complex disease or behavioural dynamics are required to reproduce epidemic waves., Competing Interests: Conflict of interestThe authors have no relevant financial or non-financial interests to disclose., (© The Author(s) 2023.)

Background: Event-related potentials (ERPs) reflect cognitive processing: negative early components (N100, N200) are involved in the sensory and perceptual processing of a stimulus, whereas late positive component P300 requires conscious attention. Both neuropsychological and affective disorders are present in patients with spinocerebellar ataxia type 1 (SCA1), but the underlying mechanisms need further clarification., Materials and Methods: In this pilot study, we assessed cognitive processing by recording auditory ERPs in 16 consecutive SCA1 patients and 16 healthy controls (HC) matched for age and sex. Motor and nonmotor symptoms were evaluated using the Scale for the Assessment and Rating of Ataxia (SARA) and an extensive neuropsychological battery. ERPs were recorded using an oddball paradigm, and peak latency and amplitude of N100, N200, and P300 were measured in the averaged responses to target tones., Results: We found in SCA1 significantly increased latencies of N200 and P300 (p=0.033, p=0.007) and decreased amplitudes of N100 and P300 (p=0.024, p=0.038) compared with HC. Furthermore, P300 latency had the highest AUC in the discrimination of SCA1 in ROC analysis. The expansion of trinucleotide repeats correlated with P300 latency (r=-0.607, p=0.048), whereas both P300 and N100 amplitudes correlated with the severity of motor symptoms (r=-0.692, p=0.003; r=-0.621; p=0.010). Significant correlations between P300 latency and the scores of Emotion Attribution Task (r=-0.633, p=0.027), as well as between N200 latency and the scores of Frontal Assessment Battery and Stroop test (r=-0.520, p=0.047; r=0.538, p=0.039), were observed., Conclusions: This research provides for the first time an extensive characterization of ERPs as useful electrophysiological markers to identify early cognitive dysfunction in SCA1., (© 2023. The Author(s).)

Background: Effects of dopaminergic medications used to treat Parkinson's disease (PD) may be compared with each other by using conversion factors, calculated as Levodopa equivalent dose (LED). However, current LED proposals on MAO-B inhibitors (iMAO-B) safinamide and rasagiline are still based on empirical approaches., Objectives: To estimate LED of safinamide 50 and 100 mg., Methods: In this multicenter, longitudinal, case-control study, we retrospectively reviewed clinical charts of 500 consecutive PD patients with motor complications and treated with (i) safinamide 100 mg ( N  = 130), safinamide 50 mg ( N  = 144), or rasagiline 1 mg ( N  = 97) for 9 ± 3 months and a control group of patients never treated with any iMAO-B ( N  = 129)., Results: Major baseline features (age, sex, disease duration and stage, severity of motor signs and motor complications) were similar among the groups. Patients on rasagiline had lower UPDRS-II scores and Levodopa dose than control subjects. After a mean follow-up of 8.8-to-10.1 months, patients on Safinamide 50 mg and 100 mg had lower UPDRS-III and OFF-related UPDRS-IV scores than control subjects, who in turn had larger increase in total LED than the three iMAO-B groups. After adjusting for age, disease duration, duration of follow-up, baseline values and taking change in UPDRS-III scores into account (sensitivity analysis), safinamide 100 mg corresponded to 125 mg LED, whereas safinamide 50 mg and rasagiline 1 mg equally corresponded to 100 mg LED., Conclusions: We used a rigorous approach to calculate LED of safinamide 50 and 100 mg. Large prospective pragmatic trials are needed to replicate our findings., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The genetic landscape of melanoma resistance to targeted therapy with small molecules inhibiting BRAF and MEK kinases is still largely undefined. In this study, we portrayed in detail the somatic alterations of resistant melanoma and explored the associated biological processes and their integration with transcriptional profiles. By targeted next-generation sequencing and whole-exome sequencing analyses, a list of 101 genes showing imbalance in metastatic tumors from patients with a complete/durable response or disease progression during therapy with vemurafenib or with dabrafenib and trametinib was defined. Classification of altered genes in functional categories indicated that the mutational pattern of both resistant tumors and melanoma cell lines was enriched in gene families involved in oncogenic signaling pathways and in DNA repair. Integration of genomic and transcriptomic features showed that the enrichment of mutations in gene sets associated with anabolic processes, chromatin alterations, and IFN-α response determined a significant positive modulation of the same gene signatures at the transcriptional level. In particular, MTORC1 signaling was enriched in tumors from poorly responsive patients and in resistant tumors excised from treated patients. Results indicate that genetic patterns are associated with melanoma resistance to targeted therapy and disclose the underlying key molecular pathways to define drug combinations for improved personalized therapies., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Biallelic intronic AAGGG repeat expansion in the replication factor C subunit 1 (RFC1) gene was recently identified in two/third of patients with cerebellar ataxia, sensory neuropathy, and bilateral vestibular areflexia syndrome (CANVAS). The phenotypic spectrum has expanded since (i.e., parkinsonism, motor neuron involvement, cognitive decline); no behavioral symptoms have been reported yet., Case Report: We report an Italian family that met the diagnostic criteria for CANVAS, and RFC1-expansion was detected in five of seven. All the affected members presented behavioral-psychiatric symptoms (anxiety, panic attacks, alcohol abuse) before the multisystemic RFC1-expansion manifestation. The disease course was progressive, with ataxia and behavioral-cognitive aspects as the most disabling symptoms., Conclusion: These behavioral-cognitive observations may broaden the RFC1-expansion phenotypic spectrum and highlight the importance of investigating the whole non-motor symptoms in ataxic patients., (© 2022. Fondazione Società Italiana di Neurologia.)

Background: Circulating microRNAs (ct-miRs) are promising cancer biomarkers. This study focuses on platform comparison to assess performance variability, agreement in the assignment of a miR signature classifier (MSC), and concordance for the identification of cancer-associated miRs in plasma samples from non-small cell lung cancer (NSCLC) patients., Methods: A plasma cohort of 10 NSCLC patients and 10 healthy donors matched for clinical features and MSC risk level was profiled for miR expression using two sequencing-based and three quantitative reverse transcription PCR (qPCR)-based platforms. Intra- and inter-platform variations were examined by correlation and concordance analysis. The MSC risk levels were compared with those estimated using a reference method. Differentially expressed ct-miRs were identified among NSCLC patients and donors, and the diagnostic value of those dysregulated in patients was assessed by receiver operating characteristic curve analysis. The downregulation of miR-150-5p was verified by qPCR. The Cancer Genome Atlas (TCGA) lung carcinoma dataset was used for validation at the tissue level., Results: The intra-platform reproducibility was consistent, whereas the highest values of inter-platform correlations were among qPCR-based platforms. MSC classification concordance was >80% for four platforms. The dysregulation and discriminatory power of miR-150-5p and miR-210-3p were documented. Both were significantly dysregulated also on TCGA tissue-originated profiles from lung cell carcinoma in comparison with normal samples., Conclusion: Overall, our studies provide a large performance analysis between five different platforms for miR quantification, indicate the solidity of MSC classifier, and identify two noninvasive biomarkers for NSCLC., Competing Interests: GS and MB are coinventors for three patent applications licensed to Gensignia Life Sciences and regarding the miR MSC signature used in this article. 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 © 2022 Gargiuli, De Cecco, Mariancini, Iannò, Micali, Mancinelli, Boeri, Sozzi, Dugo and Sensi.)

We present an SI epidemic model whereby a continuous structuring variable captures variability in proliferative potential and resistance to infection among susceptible individuals. The occurrence of heritable, spontaneous changes in these phenotypic characteristics and the presence of a fitness trade-off between resistance to infection and proliferative potential are explicitly incorporated into the model. The model comprises an ordinary differential equation for the number of infected individuals that is coupled with a partial integrodifferential equation for the population density function of susceptible individuals through an integral term. The expression for the basic reproduction number [Formula: see text] is derived, the disease-free equilibrium and endemic equilibrium of the model are characterised and a threshold theorem involving [Formula: see text] is proved. Analytical results are integrated with the results of numerical simulations of a calibrated version of the model based on the results of artificial selection experiments in a host-parasite system. The results of our mathematical study disentangle the impact of different evolutionary parameters on the spread of infectious diseases and the consequent phenotypic adaption of susceptible individuals. In particular, these results provide a theoretical basis for the observation that infectious diseases exerting stronger selective pressures on susceptible individuals and being characterised by higher infection rates are more likely to spread. Moreover, our results indicate that heritable, spontaneous phenotypic changes in proliferative potential and resistance to infection can either promote or prevent the spread of infectious diseases depending on the strength of selection acting on susceptible individuals prior to infection. Finally, we demonstrate that, when an endemic equilibrium is established, higher levels of resistance to infection and lower degrees of phenotypic heterogeneity among susceptible individuals are to be expected in the presence of infections which are characterised by lower rates of death and exert stronger selective pressures., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We study a fast-slow version of an SIRS epidemiological model on homogeneous graphs, obtained through the application of the moment closure method. We use GSPT to study the model, taking into account that the infection period is much shorter than the average duration of immunity. We show that the dynamics occurs through a sequence of fast and slow flows, that can be described through 2-dimensional maps that, under some assumptions, can be approximated as 1-dimensional maps. Using this method, together with numerical bifurcation tools, we show that the model can give rise to periodic solutions, differently from the corresponding model based on homogeneous mixing., (© 2021. The Author(s).)

The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.

In population-based screens, tissue biopsy remains the standard practice for women with imaging that suggests breast cancer. We examined circulating microRNAs as minimally invasive diagnostic biomarkers to discriminate malignant from benign breast lesions. miRNAs were analyzed by OpenArray in a retrospective cohort of plasma samples including 100 patients with malignant (T), 89 benign disease (B), and 99 healthy donors (HD) divided into training and testing sets and a prospective cohort (BABE) of 289 women with suspicious imaging findings who underwent tissue biopsy. miRNAs associated with disease status were identified by univariate analysis and then combined into signatures by multivariate logistic regression models. By combining 16 miRNAs differentially expressed in the T vs. HD comparison, 26 signatures were also able to significantly discriminate T from B disease. Seven of them, involving 5 specific miRNAs (miR-625, miR-423-5p, miR-370-3p, miR-181c, and miR-301b), were statistically validated in the testing set. Among the 7 signatures, the discriminatory performances of 5 were confirmed in the prospective BABE Cohort. This study identified 5 circulating miRNAs that, properly combined, distinguish malignant from benign breast disease in women with a high likelihood of malignancy.

Single- and group-housed pregnant sows were assessed during 8 weeks (4th and 8th to 14th) with regard to physiological, reproductive, welfare indicators and gene expression profiling. Compared to single-housed sows, group-housed sows had decreased non-return to estrus at 56 days after artificial insemination (AI) (83% vs 92%) and farrowing rate (78% vs 88%), respectively. Furthermore, group-housed sows showed a higher degree ( p  < 0.01) of advantageous physiological indicators, such as albumin (odds ratio [OR] = 4.4), alkaline phosphatase (OR = 1.5), bactericidal (OR = 3.2) and complement (OR = 24.3), and disadvantageous for alanine amino transferase (OR = 0.5), bilirubin (OR = 0.4), lysozyme (OR = 0.3) and C-reactive protein compared to single-housed. Eighty-seven genes related to immune response were underexpressed (log fold change ≤ 1.5; p  < 0.05) during the 8th to 14th weeks in the group compared to single-housed sows, which in turn showed an immunomodulatory reduction on the expression of 43 genes during the 11th to 14th compared to the 4th week. Overall, the results were interpreted as indicative of greater comfort state of the group compared to single-housed sows.

We report a dual gate/common channel organic transistor architecture designed for quantifying the concentration of one of the strands of miRNA-21 in solution. The device allows one to measure the differential response between two gate electrodes, viz. one sensing and one reference, both immersed in the electrolyte above the transistor channel. Hybridization with oligonucleotide in the picomolar regime induces a sizable reduction of the current flowing through the transistor channel. The device signal is reported at various gate voltages, showing maximum sensitivity in the sublinear regime, with a limit of detection as low as 35 pM. We describe the dose curves with an analytical function derived from a thermodynamic model of the reaction equilibria relevant in our experiment and device configuration, and we show that the apparent Hill dependence on analyte concentration, whose exponent lies between 0.5 and 1, emerges from the interplay of the different equilibria. The binding free energy characteristic of the hybridization on the device surface is found to be approximately 20% lower with respect to the reaction in solution, hinting to partially inhibiting effect of the surface and presence of competing reactions. Impedance spectroscopy and surface plasmon resonance (SPR) performed on the same oligonucleotide pair were correlated to the electronic current transduced by the EGOFET, and confirmed the selectivity of the biorecognition probe covalently bound on the gold surface., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Collecting duct carcinoma (CDC) is a rare and highly aggressive kidney cancer subtype with poor prognosis and no standard treatments. To date, only a few studies have examined the transcriptomic portrait of CDC. Through integration of multiple datasets, we compared CDC to normal tissue, upper-tract urothelial carcinomas, and other renal cancers, including clear cell, papillary, and chromophobe histologies. Association between CDC gene expression signatures and in vitro drug sensitivity data was evaluated using the Cancer Therapeutic Response Portal, Genomics of Drug Sensitivity in Cancer datasets, and connectivity map. We identified a CDC-specific gene signature that predicted in vitro sensitivity to different targeted agents and was associated to worse outcome in clear cell renal cell carcinoma. We showed that CDC are transcriptionally related to the principal cells of the collecting ducts providing evidence that this tumor originates from this normal kidney cell type. Finally, we proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signaling, metabolic and immune-related alterations. Our findings elucidate the molecular features of CDC providing novel biological and clinical insights. The identification of distinct CDC subtypes and their transcriptomic traits provides the rationale for patient stratification and alternative therapeutic approaches.

Objectives: Levodopa-Carbidopa Intrajejunal gel (LCIG) infusion is an effective intervention for people with advanced Parkinson's disease (PD). Although age may not be a limiting factor for LCIG implant, no data are available on late elderly PD (LE-PD) subjects. In this cross-sectional, we aimed to demonstrate if older age may impact on quality of life (QoL), motor and non-motor symptoms severity, and profile of side effects in PD treated with LCIG., Methods: Out of 512 PD subjects treated with LCIG at 9 Italian PD centers, we selected 25 LE-PD defined as age ≥ 80 years at last follow-up who were available to attend the study visit. Twenty-five PD patients (Control-PD, defined as age < 75 years at last follow-up) matched to LE-PD by disease and LCIG duration served as control group. The following motor and non-motor variables were ascertained: quality of life (PDQ-8), time spent in ON, wearing-off Questionnaire, Unified PD Rating Scale, freezing of gait questionnaire, Parkinson's disease sleep scale-2, Non Motor Symptoms Scale (NMSS), and MOCA., Results: No statistically significant differences were found between LE-PD and Control-PD on PDQ-8 and several motor and non-motor variables. LE-PD had less frequent and milder impulsive-compulsive behaviors and milder dyskinesia. At multivariable regression, worse quality of life was associated with UPDRS-III and NMSS scores but not to age at study visit and age at LICG implant. Rate of adverse effects was similar in both groups. Drop-out rate calculated in the whole PD cohort was comparable between the two groups., Conclusion: Our data provide evidence that valuable LCIG infusion might be achieved in late elderly PD.

The efficacy of immunotherapy can be undermined by the development of an immune response against a drug/antibody mediated by anti-drug antibodies (ADAs) in treated patients. We present the first label-free EGOFET immunosensor that integrates a biological drug, Nivolumab (Opdivo©), as a specific recognition moiety to quantitatively and selectively detect ADAs against the drug. The limit of detection is 100 fM. This demonstration is a prelude to the detection of ADAs in a clinical setting in the treatment of different pathologies, and it also enables rapid screening of biological drugs for immunogenicity.

In view of the depletion of fossil fuel reserves and climatic effects of greenhouse gas emissions, Ni,Fe-containing carbon monoxide dehydrogenase (Ni-CODH) enzymes have attracted increasing interest in recent years for their capability to selectively catalyze the reversible reduction of CO 2 to CO (CO 2 + 2H + + 2e - ⇌ CO + H 2 O). The possibility of converting the greenhouse gas CO 2 into useful materials that can be used as synthetic building blocks or, remarkably, as carbon fuels makes Ni-CODH a very promising target for reverse-engineering studies. In this context, in order to provide insights into the chemical principles underlying the biological catalysis of CO 2 activation and reduction, quantum mechanics calculations have been carried out in the framework of density functional theory (DFT) on different-sized models of the Ni-CODH active site. With the aim of uncovering which stereoelectronic properties of the active site (known as the C-cluster) are crucial for the efficient binding and release of CO 2 , different coordination modes of CO 2 to different forms and redox states of the C-cluster have been investigated. The results obtained from this study highlight the key role of the protein environment in tuning the reactivity and the geometry of the C-cluster. In particular, the protonation state of His93 is found to be crucial for promoting the binding or the dissociation of CO 2 . The oxidation state of the C-cluster is also shown to be critical. CO 2 binds to C red2 according to a dissociative mechanism (i.e., CO 2 binds to the C-cluster after the release of possible ligands from Fe u ) when His93 is doubly protonated. CO 2 can also bind noncatalytically to C red1 according to an associative mechanism (i.e., CO 2 binding is preceded by the binding of H 2 O to Fe u ). Conversely, CO 2 dissociates when His93 is singly protonated and the C-cluster is oxidized at least to the C int redox state.

Introduction: The GLORIA registry included 375 advanced Parkinson's disease (PD) patients and evaluated the efficacy and safety of a 24-month levodopa-carbidopa intestinal gel (LCIG) treatment in routine medical care. This analysis focuses on the Italian population, 60 patients treated with LCIG in 7 specialised PD care centres., Methods: Hours of "Off" and "On" time were assessed with a modified version of the Unified Parkinson's Disease Rating Scale (UPDRS) part IV items 39 and 32. Motor fluctuations, dyskinesia, non-motor symptoms, quality of life and safety were evaluated., Results: Overall, 42 (70%) out of 60 patients completed the registry. LCIG treatment reduced "Off" time (- 3.3 ± 2.7 h at month 24 (M24), P < 0.0001), increased "On" time with dyskinesia (- 2.6 ± 5.2 h at M12, P = 0.0160), and improved UPDRS II and UPDRS III total scores at M24 (- 4.5 ± 10.6, P = 0.0333 and - 4.9 ± 11.7, P = 0.0229, respectively), Non-Motor Symptom Scale (NMSS) total score (- 21.8 ± 28.5, P < 0.0001) and Parkinson's Disease Questionnaire-8 item (PDQ-8) total score (- 12.5 ± 23.9, P = 0.0173) versus previous oral therapy. Adverse drug reactions (ADR) possibly or probably related to treatment were reported in 16 (28.6%) patients. Decreased weight (7.1%), polyneuropathy (7.1%) and abdominal pain (5.4%) were the most frequent ADRs while device malfunction (5.4%) and medical device change (5.4%) were the most reported device complaints., Conclusions: LCIG improved motor fluctuations, non-motor symptoms and quality of life over 24 months while tolerability was consistent with the established safety profile.

Background: Targeted therapy with BRAF and MEK inhibitors has improved the survival of patients with BRAF-mutated metastatic melanoma, but most patients relapse upon the onset of drug resistance induced by mechanisms including genetic and epigenetic events. Among the epigenetic alterations, microRNA perturbation is associated with the development of kinase inhibitor resistance. Here, we identified and studied the role of miR-146a-5p dysregulation in melanoma drug resistance., Methods: The miR-146a-5p-regulated NFkB signaling network was identified in drug-resistant cell lines and melanoma tumor samples by expression profiling and knock-in and knock-out studies. A bioinformatic data analysis identified COX2 as a central gene regulated by miR-146a-5p and NFkB. The effects of miR-146a-5p/COX2 manipulation were studied in vitro in cell lines and with 3D cultures of treatment-resistant tumor explants from patients progressing during therapy., Results: miR-146a-5p expression was inversely correlated with drug sensitivity and COX2 expression and was reduced in BRAF and MEK inhibitor-resistant melanoma cells and tissues. Forced miR-146a-5p expression reduced COX2 activity and significantly increased drug sensitivity by hampering prosurvival NFkB signaling, leading to reduced proliferation and enhanced apoptosis. Similar effects were obtained by inhibiting COX2 by celecoxib, a clinically approved COX2 inhibitor., Conclusions: Deregulation of the miR-146a-5p/COX2 axis occurs in the development of melanoma resistance to targeted drugs in melanoma patients. This finding reveals novel targets for more effective combination treatment. Video Abstract.

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Electrolyte gated organic transistors can operate as powerful ultrasensitive biosensors, and efforts are currently devoted to devising strategies for reducing the contribution of hardly avoidable, nonspecific interactions to their response, to ultimately harness selectivity in the detection process. We report a novel lab-on-a-chip device integrating a multigate electrolyte gated organic field-effect transistor (EGOFET) with a 6.5 μL microfluidics set up capable to provide an assessment of both the response reproducibility, by enabling measurement in triplicate, and of the device selectivity through the presence of an internal reference electrode. As proof-of-concept, we demonstrate the efficient operation of our pentacene based EGOFET sensing platform through the quantification of tumor necrosis factor alpha with a detection limit as low as 3 pM. Sensing of inflammatory cytokines, which also include TNFα, is of the outmost importance for monitoring a large number of diseases. The multiplexable organic electronic lab-on-chip provides a statistically solid, reliable, and selective response on microliters sample volumes on the minutes time scale, thus matching the relevant key-performance indicators required in point-of-care diagnostics.

The TANDEM investigation was carried out in 17 Italian Movement Disorder centers on behalf of a joint initiative of neurologist members of the Italian Academy for Parkinson's disease and Movement Disorders (LIMPE-DISMOV Academy) and gastroenterologist members of the Italian Society of Digestive Endoscopy (SIED) to evaluate the efficacy and tolerability of levodopa-carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) in routine medical care. Motor scores in "ON" and OFF" state (UPDRS-III), complications of therapy (UPDRS-IV), activities of daily living, sleep disorders and quality of life were evaluated at baseline and at two follow-up assessments (FUV1 and FUV2) within the initial 12-month LCIG treatment. In 159 patients (55% males) with a mean age of 69.1 ± 6.6 years and a diagnosis of PD since 13.6 ± 5.5 years, the UPDRS-III total score (in "OFF") decreased from baseline (45.8 ± 13.2) to FUV1 (41.0 ± 17.4; p < 0.001) and FUV2 (40.5 ± 15.5; p < 0.001), the UPDRS-IV total score decreased from baseline (8.8 ± 2.9) to FUV1 (5.1 ± 3.4; p < 0.001) and FUV2 (5.5 ± 3.2; p < 0.001). The percentage of patients exhibiting freezing, dystonia, gait/walking disturbances, falls, pain and sleep disorders was significantly reduced. Twenty-eight device complications were reported and 11 (6.9%) patients prematurely terminated the study. LCIG after 12-month treatment led to sustained improvement of time spent in "OFF", complications of therapy, PD-associated symptoms and sleep disorders. LCIG tolerability was consistent with the established safety profile of LCIG.

In multiple myeloma, novel treatments with proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs) have prolonged survival but the disease remains incurable. At relapse, next-generation sequencing has shown occasional mutations of drug targets but has failed to identify unifying features that underlie chemotherapy resistance. We studied 42 patients refractory to both PIs and IMiDs. Whole-exome sequencing was performed in 40 patients, and RNA sequencing (RNA-seq) was performed in 27. We found more mutations than were reported at diagnosis and more subclonal mutations, which implies ongoing evolution of the genome of myeloma cells during treatment. The mutational landscape was different from that described in published studies on samples taken at diagnosis. The TP53 pathway was the most frequently inactivated (in 45% of patients). Conversely, point mutations of genes associated with resistance to IMiDs were rare and were always subclonal. Refractory patients were uniquely characterized by having a mutational signature linked to exposure to alkylating agents, whose role in chemotherapy resistance and disease progression remains to be elucidated. RNA-seq analysis showed that treatment or mutations had no influence on clustering, which was instead influenced by karyotypic events. We describe a cluster with both amp(1q) and del(13) characterized by CCND2 upregulation and also overexpression of MCL1, which represents a novel target for experimental treatments. Overall, high-risk features were found in 65% of patients. However, only amp(1q) predicted survival. Gene mutations of IMiD and PI targets are not a preferred mode of drug resistance in myeloma. Chemotherapy resistance of the bulk tumor population is likely attained through differential, yet converging evolution of subclones that are overall variable from patient to patient and within the same patient., (© 2020 by The American Society of Hematology.)

We carried out a prospective observational study to evaluate whether Monocyte Distribution Width (MDW) may play a role in identifying patients with sepsis in comparison with Procalcitonin (PCT). We prospectively enrolled all consecutive patients hospitalized at the Infectious Diseases Unit of Pescara General Hospital for bacterial infection or sepsis. MDW values were collected for all patients. Clinical characteristics, demographic data, past and present medical history, microbiological results, PCT, as well as neutrophil and monocytes indices at entry were compared in the 2 groups. Two-hundred-sixty patients were enrolled, 63.5% males, aged 59.1±19.5 years. Sepsis was diagnosed in 105 (40.4%); in 60 (57.1%) at least 1 microorganism was isolated from blood cultures. In multivariate models, MDW as a continuous variable (OR:1.57 for each unit increase; 95%CI: 1.31-1.87, p<0.001) and PCT˃1 ng/mL (OR: 48.5; 95%CI: 14.7-160.1, p<0.001) were independently associated with sepsis. Statistical best cut points associated with sepsis were 22.0 for MDW and 1.0 ng/mL for PCT whereas MDW values<20 were invariably associated with negative blood cultures. At ROC curve analysis, the AUC of MDW (0.87) was nearly overlapping that of PCT (0.88). Our data suggest that incorporating MDW within current routine WBC counts and indices may be of remarkable use for detection of sepsis. Further research is warranted., Competing Interests: The authors have declared that no competing interests exist

High grade serous ovarian cancer (HGSOC) retains high molecular heterogeneity and genomic instability, which currently limit the treatment opportunities. HGSOC patients receiving complete cytoreduction (R0) at primary surgery and platinum-based therapy may unevenly experience early disease relapse, in spite of their clinically favorable prognosis. To identify distinctive traits of the genomic landscape guiding tumor progression, we focused on the R0 patients of The Cancer Genome Atlas (TCGA) ovarian serous cystadenocarcinoma (TCGA-OV) dataset and classified them according to their time to relapse (TTR) from surgery. We included in the study two groups of R0-TCGA patients experiencing substantially different outcome: Resistant (R; TTR ≤ 12 months; n = 11) and frankly Sensitive (fS; TTR ≥ 24 months; n = 16). We performed an integrated clinical, RNA-Sequencing, exome and somatic copy number alteration (sCNA) data analysis. No significant differences in mutational landscape were detected, although the lack of BRCA-related mutational signature characterized the R group. Focal sCNA analysis showed a higher frequency of amplification in R group and deletions in fS group respectively, involving cytobands not commonly detected by recurrent sCNA analysis. Functional analysis of focal sCNA with a concordantly altered gene expression identified in R group a gain in Notch, and interferon signaling and fatty acid metabolism. We are aware of the constraints related to the low number of OC cases analyzed. It is worth noting, however, that the sCNA identified in this exploratory analysis and characterizing Pt-resistance are novel, deserving validation in a wider cohort of patients achieving complete surgical debulking., Competing Interests: The authors declare no conflict of interest. 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.

Introduction: The GREENFIELD observational study assessed the effect of levodopa/carbidopa intestinal gel (LCIG) on motor and non-motor symptoms, and the related impact on patient quality of life and caregiver burden up to 8 years., Methods: Final results of a large Italian cohort of patients who started LCIG in routine care between 2007 and 2014 are presented. Comparison between baseline (before LCIG) and follow-up visits on yearly basis (visit 2/3) is reported. Primary endpoint was Unified Parkinson's Disease Rating Scale (UPDRS-IV) Item 39; secondary endpoints were UPDRS I and II, dyskinesia items, PD Quality of Life Questionnaire-39, Parkinson's Disease Sleep Scale-2, Gait and Falls Questionnaire, Questionnaire on Impulsive Disorders, and Relative Stress Scale., Results: Overall, 145 patients from 14 centers were assessed with a mean time since LCIG start of 2.8 ± 1.7 years at visit 2. The mean UPDRS-IV item 39 score showed significant reductions compared to baseline (mean score 2.0 ± 0.81) at visit 2 (mean score 0.9 ± 0.69; - 55%; p < 0.001) and at visit 3 (mean score 1.0 ± 0.75; - 50%; p < 0.001). At visit 3, significant reductions were observed for dyskinesia duration score (- 28%; p < 0.001), dyskinesia disability (- 40%; p < 0.001), and painful dyskinesia (- 50%; p < 0.001). Overall, 40 (27.6%) patients experienced 49 serious adverse events which were considered related to PEG/J procedure or to device in 16.3% of the cases., Conclusions: The results of this study support the long-term efficacy of LCIG on PD symptoms as well as on activities of daily living. The adverse events were consistent with the established LCIG safety profile.

Background: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive, and poorly investigated simple sarcoma with a low frequency of genetic deregulation other than an Ewing sarcoma RNA binding protein 1 (EWSR1)-Wilm's tumor suppressor (WT1) translocation. We used whole-exome sequencing to interrogate six consecutive pre-treated DSRCTs whose gene expression was previously investigated., Methods: DNA libraries were prepared from formalin-fixed, paraffin-embedded archival tissue specimens following the Agilent SureSelectXT2 target enrichment protocol and sequenced on Illumina NextSeq 500. Raw sequence data were aligned to the reference genome with Burrows-Wheeler Aligner algorithm. Somatic mutations and copy number alterations (CNAs) were identified using MuTect2 and EXCAVATOR2, respectively. Biological functions associated with altered genes were investigated through Ingenuity Pathway Analysis (IPA) software., Results: A total of 137 unique somatic mutations were identified: 133 mutated genes were case-specific, and 2 were mutated in two cases but in different positions. Among the 135 mutated genes, 27% were related to two biological categories: DNA damage-response (DDR) network that was also identified through IPA and mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) already demonstrated to be relevant in DSRCT. The mutated genes in the DDR network were involved in various steps of transcription and particularly affected pre-mRNA. Half of these genes encoded RNA-binding proteins or DNA/RNA-binding proteins, which were recently recognized as a new class of DDR players. CNAs in genes/gene families, involved in MErT/EMT and DDR, were recurrent across patients and mostly segregated in the MErT/EMT category. In addition, recurrent gains of regions in chromosome 1 involving many MErT/EMT gene families and loss of one arm or the entire chromosome 6 affecting relevant immune-regulatory genes were recorded., Conclusions: The emerging picture is an extreme inter-tumor heterogeneity, characterized by the concurrent deregulation of the DDR and MErT/EMT dynamic and plastic programs that could favour genomic instability and explain the refractory DSRCT profile.

Introduction: Caring for a person with Parkinson's disease (PD) is associated with an increased risk of psychiatric morbidity and persistent distress. The objective of this study was to describe the burden and the related factors of caregivers of advanced PD (APD) patients either treated with continuous dopaminergic delivery systems or standard therapy., Methods: This cross-sectional, epidemiologic study conducted in 13 Italian sites enrolled PD patients treated with continuous dopaminergic delivering systems [either levodopa/carbidopa intestinal gel (LCIG) infusion or continuous subcutaneous apomorphine infusion (CSAI)] or continuation of standard of care (SOC) with a caregiver. Patient quality of life (QoL) and caregiver burden were assessed using the Parkinson's Disease Questionnaire (PDQ-8) and Zarit Burden Inventory (ZBI), respectively., Results: 126 patients (mean age 69.3 ± 8 years) and their caregivers (mean age 57.9 ± 12.9) were enrolled. Most caregivers were spouses. Fifty-three patients were treated with LCIG, 19 with CSAI, and 54 with SOC. Mean ZBI scores were 29.6 ± 14.4 for LCIG, 35.8 ± 20.2 for CSAI, and 31.4 ± 16.0 for SOC. Caregivers of LCIG, CSAI, and SOC patients showed no burden or mild/moderate burden in 74, 53, and 63% of the cases, respectively. Mean PDQ-8 scores were 11.25 ± 5.67, 11.26 ± 5.55, and 14.22 ± 6.51 in LCIG, CSAI, and SOC patients. Neurologists considered patients "very much or much improved" in 89, 58, and 13% of the LCIG, CSAI, and SOC groups using the Clinical Global Impression-Global Improvement Scale. Predictors significantly associated with caregiver burden were patients and caregivers' judgment of QoL and caregivers' need to change work., Conclusions: Caregiver burden showed a tendency to be lower when patients are treated with LCIG than with CSAI or SOC.

FeFe hydrogenases catalyze H 2 oxidation and production using an "H-cluster", where two Fe ions are bound by an aza-dithiolate (adt) ligand. Various hypotheses have been proposed (by us and others) to explain that the enzyme reversibly inactivates under oxidizing, anaerobic conditions: intramolecular binding of the N atom of adt, formation of the so-called "Hox/inact" state or nonproductive binding of H 2 to isomers of the H-cluster. Here, we show that none of the above explains the new finding that the anaerobic, oxidative, H 2 -dependent reversible inactivation is strictly dependent on the presence of Cl - or Br - . We provide experimental evidence that chloride uncompetitively inhibits the enzyme: it reversibly binds to catalytic intermediates of H 2 oxidation (but not to the resting "Hox" state), after which oxidation locks the active site into a stable, saturated, inactive form, the structure of which is proposed here based on DFT calculations. The halides interact with the amine group of the H-cluster but do not directly bind to iron. It should be possible to stabilize the inhibited state in amounts compatible with spectroscopic investigations to explore further this unexpected reactivity of the H-cluster of hydrogenase.