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We report the analysis of 1 year of data from the first cohort of 15 patients enrolled in an open-label, first-in-human, dose-escalation phase I study (ClinicalTrials.gov: NCT03282760, EudraCT2015-004855-37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of secondary progressive multiple sclerosis. Participants were treated with hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed. All participants displayed stability of clinical and laboratory outcomes, as well as lesion load and brain activity (MRI), compared with the study entry. Longitudinal metabolomics and lipidomics of biological fluids identified time- and dose-dependent responses with increased levels of acyl-carnitines and fatty acids in the cerebrospinal fluid (CSF). The absence of AEs and the stability of functional and structural outcomes are reassuring and represent a milestone for the safe translation of stem cells into regenerative medicines., Competing Interests: Declaration of interests S.P. is founder, CSO, and shareholder (>5%) of CITC Ltd. and Chair of the Scientific Advisory Board at ReNeuron plc., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the diagnostic performance of Whole Body (WB)-MRI in comparison with 18F-Fluorodeoxyglucose-PET/CT (18F-FDG-PET/CT) in lymphoma staging and to assess whether quantitative metabolic parameters from 18F-FDG-PET/CT and Apparent Diffusion Coefficient (ADC) values are related., Materials and Methods: We prospectively enrolled patients with a histologically proven primary nodal lymphoma to  undergo 18F-FDG-PET/CT and WB-MRI, both performed within 15 days one from the other, either before starting treatment (baseline) or during treatment (interim). Positive and negative predictive values of WB-MRI for the identification of nodal and extra-nodal disease were measured. The agreement between WB-MRI and 18F-FDG-PET/CT for the identification of lesions and staging was assessed through Cohen's coefficient k and observed agreement. Quantitative parameters of nodal lesions derived from 18F-FDG-PET/CT and WB-MRI (ADC) were measured and the Pearson or Spearman correlation coefficient was used to assess the correlation between them. The specified level of significance was p ≤ 0.05., Results: Among the 91 identified patients, 8 refused to participate and 22 met exclusion criteria, thus images from 61 patients (37 men, mean age 30.7 years) were evaluated. The agreement between 18F-FDG-PET/CT and WB-MRI for the identification of nodal and extra-nodal lesions was 0.95 (95% CI 0.92 to 0.98) and 1.00 (95% CI NA), respectively; for staging it was 1.00 (95% CI NA). A strong negative correlation was found between ADCmean and SUVmean of nodal lesions in patients evaluated at baseline (Spearman coefficient r s  = - 0.61, p = 0.001)., Conclusion: WB-MRI has a good diagnostic performance for staging of patients with lymphoma in comparison with 18F-FDG-PET/CT and is a promising technique for the quantitative assessment of disease burden in these patients., (© 2023. The Author(s).)

Pancreatic neuroendocrine neoplasms (panNENs) are part of a large family of tumors arising from the neuroendocrine system. PanNENs show low-intermediate tumor grade and generally high somatostatin receptor (SSTR) expression. Therefore, panNENs benefit from functional imaging with 68 Ga-somatostatin analogues (SSA) for diagnosis, staging, and treatment choice in parallel with morphological imaging. This narrative review aims to present conventional imaging techniques and new perspectives in the management of panNENs, providing the clinicians with useful insight for clinical practice. The 68 Ga-SSA PET/CT is the most widely used in panNENs, not only fr diagnosis and staging purpose but also to characterize the biology of the tumor and its responsiveness to SSAs. On the contrary, the 18 F-Fluordeoxiglucose (FDG) PET/CT is not employed systematically in all panNEN patients, being generally preferred in G2-G3, to predict aggressiveness and progression rate. The combination of 68 Ga-SSA PET/CT and 18 F-FDG PET/CT can finally suggest the best therapeutic strategy. Other radiopharmaceuticals are 68 Ga-exendin-4 in case of insulinomas and 18 F-dopamine (DOPA), which can be helpful in SSTR-negative tumors. New promising but still-under-investigation radiopharmaceuticals include radiolabeled SSTR antagonists and 18 F-SSAs. Conventional imaging includes contrast enhanced CT and multiparametric MRI. There are now enriched by radiomics, a new non-invasive imaging approach, very promising to early predict tumor response or progression.

Diagnosis of etiology in early-stage ischemic heart disease (IHD) and dilated cardiomyopathy (DCM) patients may be challenging. We aimed at investigating, by means of classification and regression tree (CART) modeling, the predictive power of heart rate variability (HRV) features together with clinical parameters to support the diagnosis in the early stage of IHD and DCM. The study included 263 IHD and 181 DCM patients, as well as 689 healthy subjects. A 24 h Holter monitoring was used and linear and non-linear HRV parameters were extracted considering both normal and ectopic beats (heart rate total variability signal). We used a CART algorithm to produce classification models based on HRV together with relevant clinical (age, sex, and left ventricular ejection fraction, LVEF) features. Among HRV parameters, MeanRR, SDNN, pNN50, LF, LF/HF, LFn, FD, Beta exp were selected by the CART algorithm and included in the produced models. The model based on pNN50, FD, sex, age, and LVEF features presented the highest accuracy (73.3%). The proposed approach based on HRV parameters, age, sex, and LVEF features highlighted the possibility to produce clinically interpretable models capable to differentiate IHD, DCM, and healthy subjects with accuracy which is clinically relevant in first steps of the IHD and DCM diagnostic process., (© 2022. The Author(s).)

Background: Sjögren’s syndrome (SS) is a progressive autoimmune disease characterized by local mononuclear cell infiltration of the salivary and lachrymal glands. Labial biopsy demonstrates local infiltration by Th1 cells that produce pro-inflammatory cytokines, such as interleukin-2 (IL2). The aim of this study was to assess the utility of 99mTc-labelled-IL2 (99mTc-IL2) in evaluating in vivo the extent and severity of lympho-mononuclear cell infiltration in the salivary glands of patients with SS. Methods: We investigated 48 patients with primary SS and 27 control subjects using 99mTc-IL2 scintigraphy. Furthermore, in a subgroup of 30 patients, we also performed 99mTc-pertechnetate scintigraphy (99mTcO4−) for evaluation of the salivary gland function. Results: 99mTc-IL2 uptake in the salivary glands of SS patients was higher than in the control subjects (1.30 ± 0.16 vs. 0.83 ± 0.08 for parotids and 1.36 ± 0.15 vs. 1.16 ± 0.07 for submandibular glands; p < 0.0001). The salivary gland uptake of 99mTc-IL2 in patients with a longer history of disease was lower compared with the recently diagnosed patients. A significant direct correlation was found between the uptake of 99mTc-IL2 and histology. Conclusions: 99mTc-IL2 scintigraphy showed that the degree of lymphocytic infiltration of major salivary glands is variable in patients with different disease durations. Patients with a high 99mTc-IL2 uptake could be efficiently treated with immuno-modulatory drugs and the efficacy of treatment could be followed-up by 99mTc-IL2 scintigraphy.

Lesbian, gay, bisexual, transgender, intersex, queer people and minority gender identities and sexualities (LGBTIQ+) are often stigmatized and experience discrimination in health care settings, leading to poorer mental health outcomes and unmet needs compared to heterosexual and cisgendered peers. It is thus imperative that mental health providers consider and address structural challenges in order to reduce mental health inequalities of this population. This narrative review assessed the barriers that may prevent access to care and the pathways for care in LGBTIQ + communities. PubMed, PsycInfo, Embase, and Scopus were searched for papers published between December 2021 and February 2022. A total of 107 papers were included with studies reflecting five themes: (1) Unmet mental health needs; (2) Young people; (3) Substance abuse and addiction; (4) Barriers and pathways to care; and (5) Interventions. Findings demonstrate that LGBTIQ + people experience stigmatization and higher rates of substance misuse and mental ill health, which may lead to barriers in accessing health care services, and fewer tailored interventions being provided. These findings have implications for policy, health care screening, and how specialist services are structured. Substantial gaps in the evidence-base exist, and future research should examine how mental health care providers can challenge social issues that maintain discriminatory and stigmatizing practices, and support LGBTIQ + individuals to sustain their resilience.

Circadian heart rate (HR) is influenced by hypertension and other cardiovascular risk factors particularly smoking, obesity and dyslipidemia. Until now, to evaluate the HR changes due to presence of these risk factors, a single HR office measure or a mean evaluated on day time or night time or 24h was used. However, since HR shows a circadian behavior, a single value represents only a rough approximation of this behavior. In this study, we analyzed the influence of smoking, obesity and dyslipidemia on the circadian rhythm in normotensive and hypertensive subject groups presenting only one of these risk factors. The 24h HR recordings of 170 normotensive (83 without risk factors, 20 smokers, 44 with dyslipidemia, 23 obese) and 353 hypertensive (169 without risk factors, 32 smokers, 99 with dyslipidemia, 53 obese) subjects were acquired using a Holter Blood Pressure Monitor. Results highlighted a specific circadian behavior with three characteristic periods presenting different HR means and rates of HR change in the eight subject groups. The slopes could be used both to estimate the morning HR surge associated with acute cardiovascular effects in the awakening and to evaluate the decline during the night. Moreover, we suggest to use three HR mean values (one for each identified period of the day) rather than two HR values to better describe the circadian HR behavior. Furthermore, smoking increased and dyslipidemia decreased mean HR values from 10:00 to 04:00, both in normotensive and hypertensive subjects in comparison with subjects without risk factors. In this time interval, hypertensive obese subjects showed higher values while normotensive ones presented quite similar values than subjects without risk factors. During the awakening (05:00-10:00) the slopes were similar among all groups with no significant difference among the mean HR values., Competing Interests: The authors have declared that no competing interests exist.

Background: Sublingual varices (SV) are dilatations of tortuous veins that increased with age. Previous studies showed that this pathology could be correlated to some risk factors such as hypertension, age, gender and diabetes mellitus. In this study we evaluated, on a large number of subjects, the relationship between SV and different grades of hypertension as well as some risk factors extending the analysis to new risk factors such as dyslipidemia, obesity and antihypertensive therapy, modelling a possible dependence of SV on all these factors., Methods: In the study 1008 subjects, 284 with and 724 without SV, were examined. The blood pressure was measured in office condition and, to exclude subjects with white coat syndrome or masked hypertension, also using a 24 h Holter pressure monitor. Hypertensive subjects were divided in resistant, drugs controlled (compensated) and patients with prior unknown hypertension (new diagnosed) groups. The presence or absence of SV as well as of the risk factors was assessed clinically. We tested the influence of age on the presence of SV by using the chi-square test and the relation between each risk factor and SV by the Cochran-Mantel-Haenszel test. Finally, we carried out a multivariate regression tree analysis in order to predict the presence of SV., Results: We confirmed the influence of age on SV and found a significant relationship between SV and both the compensated and resistant hypertension grades. We highlighted a relationship between SV and dyslipidemia in subjects with new diagnosed hypertension, and between SV and smoking in subjects with compensated hypertension grade. The regression tree showed a classification accuracy of about 75% using as variables hypertension grades, age and antihypertensive treatment., Conclusions: We confirmed the SV dependence on age, resistant hypertension and smoking, highlighting a new association with dyslipidemia in new diagnosed hypertensive subjects and new relations depending on the hypertension grades. Thus, the SV inspection could be used to suggest a lipidologist as well as a hypertension specialist visit for a pharmacological and pressure check particularly in subjects presenting SV and dyslipidemia. However, further parameters are to be considered to improve the sensitivity of the prognostic tree model.

Background: The analysis of the circadian rhythm of heart rate variability (HRV) represents a relevant physiological tool to assess the vagal system. However, the influence of age (mostly >75 years) on HRV is not widely known., Aims: The aim of this study was to evaluate the influence of age on HRV, particularly in the elderly and to identify a model of this relationship. The study was carried out by examining linear and nonlinear parameters extracted from HRV, including individuals over 75 years for which there is no research available., Methods: Data from 140 healthy subjects were sex matched and divided into young (young group: 15-39 years old), adult (adult group: 40-64 years old) and senior (senior group: 65-90 years old) groups. 24-h Holter monitoring was used and several HRV parameters were extracted from time, and spectral and nonlinear analyses were examined., Results: Time-domain parameters, mainly standard deviation of the NN interval (SDNN) and number of successive differences of intervals which differ by more than 50 ms, presented significant differences between the young group and the other two groups during the 24-h period, while normalized spectral parameters (LFn, HFn and low frequency/high frequency), as well as nonlinear parameters, mainly β exponent and fractal dimension, showed significant difference between the senior group and the other two groups. All these parameters showed a similar circadian rhythm with significant differences between the mean day and night values, especially in young and adult group cohorts. Moreover, a parabolic relationship between these parameters and age was highlighted with an opposite trend over about 60 years compared with younger people., Conclusion: A progressive physiological autonomic imbalance is present in ageing. The inverse trend in the relation between HRV parameters and age found in the senior group could be mainly due to a faster fluctuation of RR. This should be considered when studying changes in the cardiac autonomic nervous control., (Copyright © 2020 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Background and Objective: The input data distributions of EEG-based BCI systems can change during intra-session transitions due to nonstationarity caused by features covariate shifts, thus compromising BCI performance. We aimed to identify the most robust spatial filtering approach, among most used methods, testing them on calibration dataset, and test dataset recorded 30 min afterwards. In addition, we also investigated if their performance improved after application of Stationary Subspace Analysis (SSA)., Methods: We have recorded, in 17 healthy subjects, the calibration set at the beginning of the upper limb motor imagery BCI experiment and testing set separately 30 min afterwards. Both the calibration and test data were pre-processed and the BCI models were produced by using several spatial filtering approaches on the calibration set. Those models were subsequently evaluated on a test set. The differences between the accuracy estimated by cross-validation on the calibration dataset and the accuracy on the test dataset were investigated. The same procedure was performed with, and without SSA pre-processing step., Results: A significant reduction in accuracy on the test dataset was observed for CSP, SPoC and SpecRCSP approaches. For SLap and SpecCSP only a slight decreasing trend was observed, while FBCSP and FBCSPT largely maintained moderately high median accuracy >70%. In the case of application of SSA pre-processing, the differences between accuracy observed on calibration and test dataset were reduced. In addition, accuracy values both on calibration and test set were slightly higher in case of SSA pre-processing and also in this case FBCSP and FBCSPT presented slightly better performance compared to other methods., Conclusion: The intrinsic signal nonstationarity characteristics, caused by covariance shifts of power features, reduced the accuracy of BCI model, therefore, suggesting that this evaluation framework should be considered for testing and simulating real life performance. FBCSP and FBSCPT approaches showed to be more robust to feature covariance shift. SSA can improve the models performance and reduce accuracy decline from calibration to test set., Competing Interests: Declaration of Competing Interest The 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 © 2020. Published by Elsevier B.V.)

Objective : Ischemic heart disease (IHD), in its chronic stable form, is a subtle pathology due to its silent behavior before developing in unstable angina, myocardial infarction or sudden cardiac death. The clinical assessment is based on typical symptoms and finally confirmed, invasively, by coronary angiography. Recently, heart rate variability (HRV) analysis as well as some machine learning algorithms like artificial neural networks (ANNs) were used to identify cardiovascular arrhythmias and, only in few cases, to classify IHD segments in a limited number of subjects. The goal of this study was the identification of the ANN structure and the HRV parameters producing the best performance to identify IHD patients in a non-invasive way, validating the results on a large sample of subjects. Moreover, we examined the influence of a clinical non-invasive parameter, the left ventricular ejection fraction (LVEF), on the classification performance. Approach : To this aim, we extracted several linear and non-linear parameters from 24 h RR signal, considering both normal and ectopic beats (heart rate total variability), of 251 normal and 245 IHD subjects, matched by age and gender. ANNs using several different combinations of these parameters together with age and gender were tested. For each ANN, we varied the number of hidden neurons from 2 to 7 and simulated 100 times, changing randomly the training and test dataset. Main results : The HRTV parameters showed significant greater variability in IHD than in normal subjects. The ANN applied to mean RR, LF, LF/HF, beta exponent, SD2 together with age and gender reached a maximum accuracy of 71.8% and, by adding as input LVEF, an accuracy of 79.8%. Significance : The study provides a deep insight into how a combination of some HRTV parameters and LVEF could be exploited to reliably detect the presence of subjects affected by IHD., (© 2020 Institute of Physics and Engineering in Medicine.)

The study reports the performance of Parkinson's disease (PD) patients to operate Motor-Imagery based Brain-Computer Interface (MI-BCI) and compares three selected pre-processing and classification approaches. The experiment was conducted on 7 PD patients who performed a total of 14 MI-BCI sessions targeting lower extremities. EEG was recorded during the initial calibration phase of each session, and the specific BCI models were produced by using Spectrally weighted Common Spatial Patterns (SpecCSP), Source Power Comodulation (SPoC) and Filter-Bank Common Spatial Patterns (FBCSP) methods. The results showed that FBCSP outperformed SPoC in terms of accuracy, and both SPoC and SpecCSP in terms of the false-positive ratio. The study also demonstrates that PD patients were capable of operating MI-BCI, although with lower accuracy.