Functional gradients reveal cortical hierarchy changes in multiple sclerosis.

Functional gradient (FG) analysis represents an increasingly popular methodological perspective for investigating brain hierarchical organization but whether and how network hierarchy changes concomitant with functional connectivity alterations in multiple sclerosis (MS) has remained elusive. Here, we analyzed FG components to uncover possible alterations in cortical hierarchy using resting-state functional MRI (rs-fMRI) data acquired in 122 MS patients and 97 healthy control (HC) subjects. Cortical hierarchy was assessed by deriving regional FG scores from rs-fMRI connectivity matrices using a functional parcellation of the cerebral cortex. The FG analysis identified a primary (visual-to-sensorimotor) and a secondary (sensory-to-transmodal) component. Results showed a significant alteration in cortical hierarchy as indexed by regional changes in FG scores in MS patients within the sensorimotor network and a compression (i.e., a reduced standard deviation across all cortical parcels) of the sensory-transmodal gradient axis, suggesting disrupted segregation between sensory and cognitive processing. Moreover, FG scores within limbic and default mode networks were significantly correlated ( ρ = 0.30 $$ \rho =0.30 $$ , p < .005 after Bonferroni correction for both) with the symbol digit modality test (SDMT) score, a measure of information processing speed commonly used in MS neuropsychological assessments. Finally, leveraging supervised machine learning, we tested the predictive value of network-level FG features, highlighting the prominent role of the FG scores within the default mode network in the accurate prediction of SDMT scores in MS patients (average mean absolute error of 1.22 ± 0.07 points on a hold-out set of 24 patients). Our work provides a comprehensive evaluation of FG alterations in MS, shedding light on the hierarchical organization of the MS brain and suggesting that FG connectivity analysis can be regarded as a valuable approach in rs-fMRI studies across different MS populations.

Patient Blood Management in Microsurgical Procedures for Reconstructive Surgery.

Introduction: The main purpose of reconstructive surgery (RS) is to restore the integrity of soft tissues damaged by trauma, surgery, congenital deformity, burns, or infection. Microsurgical techniques consist of harvesting tissues that are separated from the vascular sources of the donor site and anastomosed to the vessels of the recipient site. In these procedures, there are some preoperative modifiable factors that have the potential to influence the outcome of the flap transfer and its anastomosis. The management of anemia, which is always present in the postoperative period and plays a decisive role in the implantation of the flap, covers significant importance, and is associated with clinical and laboratory settings of chronic inflammation. Methods: Chronic inflammatory anemia (ACD) is a constant condition in patients who have undergone RS and correlates with the perfusion of the free flap. The aim of this treatment protocol is to reduce the transfusion rate by maintaining both a good organ perfusion and correction of the patient's anemic state. From January 2017 to September 2019, we studied 16 patients (16 males, mean age 38 years) who underwent microsurgical procedures for RS. Their hemoglobin (Hb) levels, corpuscular indexes, transferrin saturation (TSAT) ferritin concentrations and creatinine clearance were measured the first day after surgery (T0), after the first week (T1), and after five weeks (T2). At T0, all the patients showed low hemoglobin levels (average 7.4 g/dL, STD 0.71 range 6.2-7.4 g dL-1), with an MCV of 72, MCH of 28, MCHC of 33, RDW of 16, serum iron of 35, ferritin of 28, Ret% of 1.36, TRF of 277, creatinine clearance of 119 and high ferritin levels (range 320-560 ng mL-1) with TSAT less than 20%. All the patients were assessed for their clinical status, medical history and comorbidities before the beginning of the therapy. Results: A collaboration between the two departments (Department of Transfusion Medicine and Department of Reconstructive Surgery) resulted in the application of a therapeutic protocol with erythropoietic stimulating agents (ESAs) (Binocrit 6000 UI/week) and intravenous iron every other day, starting the second day after surgery. Thirteen patients received ESAs and FCM (ferric carboxymaltose, 500-1000 mg per session), three patients received ESAs and iron gluconate (one vial every other day). No patients received blood transfusions. No side effects were observed, and most importantly, no limb or flap rejection occurred. Conclusions: Preliminary data from our protocol show an optimal therapeutic response, notwithstanding the very limited scientific literature and data available in this specific surgical field. The enrollment of further patients will allow us to validate this therapeutic protocol with statistically sound data.

Arterial spin labeling MRI applied to migraine: current insights and future perspectives.

INTRODUCTION: Advanced neuroimaging techniques have extensively contributed to elucidate the complex mechanisms underpinning the pathophysiology of migraine, a neurovascular disorder characterized by episodes of headache associated with a constellation of non-pain symptoms. The present manuscript, summarizing the most recent progresses of the arterial spin labelling (ASL) MRI techniques and the most significant findings from ASL studies conducted in migraine, is aimed to clarify how ASL investigations are contributing to the evolving insight on migraine pathophysiology and their putative role in migraine clinical setting. ASL techniques, allowing to quantitatively demonstrate changes in cerebral blood flow (CBF) both during the attacks and in the course of interictal period, could represent the melting point between advanced neuroimaging investigations, conducted with pure scientific purposes, and conventional neuroimaging approaches, employed in the diagnostic decision-making processes. MAIN BODY: Converging ASL evidences have demonstrated that abnormal CBF, exceeding the boundaries of a single vascular territory, with biphasic trend dominated by an initial hypoperfusion (during the aura phenomenon but also in the first part of the headache phase) followed by hyperperfusion, characterizes migraine with aura attack and can represent a valuable clinical tool in the differential diagnosis from acute ischemic strokes and epileptic seizures. Studies conducted during migraine without aura attacks are converging to highlight the involvement of dorsolateral pons and hypothalamus in migraine pathophysiology, albeit not able to disentangle their role as "migraine generators" from mere attack epiphenomenon. Furthermore, ASL findings tend to support the presence of perfusion abnormalities in brain regions known to be involved in aura ignition and propagation as well as in areas involved in multisensory processing, in both patients with migraine with aura and migraine without aura. CONCLUSION: Although ASL studies have dramatically clarified quality and timing of perfusion abnormalities during migraine with aura attacks, the same cannot be said for perfusion changes during migraine attacks without aura and interictal periods. Future studies with more rigorous methodological approaches in terms of study protocol, ASL technique and sample selection and size are mandatory to exploit the possibility of better understanding migraine pathophysiology and identifying neuroimaging biomarkers of each migraine phase in different migraine phenotypes.

Benefits of pre-operative oral Sucrosomial® iron supplementation in cardiac surgery: influence of patient's baseline hemoglobin and gender.

BACKGROUND: The prevalence of low pre-operative hemoglobin (Hb) among cardiac surgery patients is high. As iron homeostasis is often impaired in these patients, restoration of iron availability might over-ride iron-restricted erythropoiesis. This post-hoc analysis of a previously published, large, randomized clinical trial (ClincalTrials.gov NCT03560687; n=1,000) assesses which sub-cohort of patients benefits the most from pre-operative Hb optimization with oral Sucrosomial® iron. MATERIALS AND METHODS: Patients without baseline Hb (n=349) or receiving >5 red blood cell units (n=57) were excluded from the study. Data from the remaining 594 were reanalyzed according to treatment, baseline anemia (Hb <13 g/dL) or gender. Patients (pt) received a one-month course of 60 mg/day Sucrosomial® iron (Iron group, n=309) or routine care (Control group, n=285) prior to elective cardiac surgery. Main end-point variables were increase in Hb from randomization to hospital admission, transfusion requirements, and cost-effectiveness of Sucrosomial® iron administration. RESULTS: At hospital admission, Hb had increased 0.7 g/dL and 0.1 g/dL, for Iron and Control groups, respectively (p<0.001), with no gender-related differences, leading to a decrease in transfusion rate (30 vs 59%, respectively; p<0.001) and transfusion index (0.5 units/patient vs 1.2 units/pt, respectively; p<0.001). Sucrosomial® iron administration was well-tolerated, and yielded cost-savings of €92/pt (p<0.001), particularly in those presenting with baseline Hb <13 g/dL. CONCLUSIONS: This post-hoc analysis confirms pre-operative Sucrosomial® iron administration is a safe and cost-effective strategy to increase preoperative Hb and decrease transfusion requirements in elective cardiac surgery, especially in those anemic at baseline.

Resting-state functional MRI in multicenter studies on multiple sclerosis: a report on raw data quality and functional connectivity features from the Italian Neuroimaging Network Initiative.

The Italian Neuroimaging Network Initiative (INNI) is an expanding repository of brain MRI data from multiple sclerosis (MS) patients recruited at four Italian MRI research sites. We describe the raw data quality of resting-state functional MRI (RS-fMRI) time-series in INNI and the inter-site variability in functional connectivity (FC) features after unified automated data preprocessing. MRI datasets from 489 MS patients and 246 healthy control (HC) subjects were retrieved from the INNI database. Raw data quality metrics included temporal signal-to-noise ratio (tSNR), spatial smoothness (FWHM), framewise displacement (FD), and differential variation in signals (DVARS). Automated preprocessing integrated white-matter lesion segmentation (SAMSEG) into a standard fMRI pipeline (fMRIPrep). FC features were calculated on pre-processed data and harmonized between sites (Combat) prior to assessing general MS-related alterations. Across centers (both groups), median tSNR and FWHM ranged from 47 to 84 and from 2.0 to 2.5, and median FD and DVARS ranged from 0.08 to 0.24 and from 1.06 to 1.22. After preprocessing, only global FC-related features were significantly correlated with FD or DVARS. Across large-scale networks, age/sex/FD-adjusted and harmonized FC features exhibited both inter-site and site-specific inter-group effects. Significant general reductions were obtained for somatomotor and limbic networks in MS patients (vs. HC). The implemented procedures provide technical information on raw data quality and outcome of fully automated preprocessing that might serve as reference in future RS-fMRI studies within INNI. The unified pipeline introduced little bias across sites and appears suitable for multisite FC analyses on harmonized network estimates.

An Integrated Taxonomic Approach Points towards a Single-Species Hypothesis for Santolina (Asteraceae) in Corsica and Sardinia.

Santolina is a plant genus of dwarf aromatic shrubs that includes about 26 species native to the western Mediterranean Basin. In Corsica and Sardinia, two of the main islands of the Mediterranean, Santolina corsica (tetraploid) and S. insularis (hexaploid) are reported. Along with the cultivated pentaploid S. chamaecyparissus, these species form a group of taxa that is hard to distinguish only by morphology. Molecular (using ITS, trnH-psbA, trnL-trnF, trnQ-rps16, rps15-ycf1, psbM-trnD, and trnS-trnG), cypsela morpho-colorimetric, morphometric, and niche similarity analyses were conducted to investigate the diversity of plants belonging to this species group. Our results confute the current taxonomic hypothesis and suggest considering S. corsica and S. insularis as a single species. Moreover, molecular and morphometric results highlight the strong affinity between S. chamaecyparissus and the Santolina populations endemic to Corsica and Sardinia. Finally, the populations from south-western Sardinia, due to their high differentiation in the studied plastid markers and the different climatic niche with respect to all the other populations, could be considered as an evolutionary significant unit.

Preoperative Sucrosomial Iron Supplementation Increases Haemoglobin and Reduces Transfusion Requirements in Elective Heart Surgery Patients: A Prospective Randomized Study.

BACKGROUND: Low preoperative haemoglobin is frequently observed in heart surgery patients and is associated with a significant decrease in haemoglobin between post-operative days 2 and 3, known as haemoglobin drift. Overall, these patients tend to receive many RBC transfusions. Since iron homeostasis is often impaired in these patients, restoration of iron availability might override iron-restricted erythropoiesis. However, reduced tolerance to oral iron salts has limited this strategy to intravenous iron administration. STUDY DESIGN AND METHODS: The purpose of this study was to assess whether preoperative supplementation with oral sucrosomial iron, a new iron-delivery technology with improved tolerance and bioavailability, might be an effective strategy for this patient population. One thousand consecutive patients were randomized and received either a one-month course of sucrosomial iron (60 mg/day) or no treatment prior to elective heart surgery at a single high-volume centre (ClinicalTrials.gov NCT03560687). Primary end-points were haemoglobin concentration on the day of hospital admittance and number of blood transfusions. Secondary end-points were haemoglobin drift, tolerance of treatment and cost-effectiveness of sucrosomial iron administration. RESULTS: Baseline haemoglobin in the treatment group was higher (by 0.67 g/dL; p<0.001) than that in the control group. The percentage of patients in the treatment group who required transfusion (35.4%) was half that in the control group (64.6%). The average number of transfused units per operation was 0.95 vs. 2.03 in the treatment and control groups, respectively. Haemoglobin drift was substantially similar in the two groups, and the tolerability of treatment was excellent (98%). The overall cost of treatment was 156 Euros less in the treatment group, expressed as a raw cost of transfusion. CONCLUSION: In elective heart surgery, routine preoperative sucrosomial iron administration seems to be a safe, well-tolerated and cost-effective strategy to increase preoperative haemoglobin and reduce the need for allogeneic blood transfusions.

Blood Oxygenation Level Dependent Magnetic Resonance Imaging (MRI), Dynamic Contrast Enhanced MRI, and Diffusion Weighted MRI for Benign and Malignant Breast Cancer Discrimination: A Preliminary Experience.

PURPOSE: To combine blood oxygenation level dependent magnetic resonance imaging (BOLD-MRI), dynamic contrast enhanced MRI (DCE-MRI), and diffusion weighted MRI (DW-MRI) in differentiation of benign and malignant breast lesions. METHODS: Thirty-seven breast lesions (11 benign and 21 malignant lesions) pathologically proven were included in this retrospective preliminary study. Pharmaco-kinetic parameters including Ktrans, kep, ve, and vp were extracted by DCE-MRI; BOLD parameters were estimated by basal signal S0 and the relaxation rate R2*; and diffusion and perfusion parameters were derived by DW-MRI (pseudo-diffusion coefficient (Dp), perfusion fraction (fp), and tissue diffusivity (Dt)). The correlation coefficient, Wilcoxon-Mann-Whitney U-test, and receiver operating characteristic (ROC) analysis were calculated and area under the ROC curve (AUC) was obtained. Moreover, pattern recognition approaches (linear discrimination analysis and decision tree) with balancing technique and leave one out cross validation approach were considered. RESULTS: R2* and D had a significant negative correlation (-0.57). The mean value, standard deviation, Skewness and Kurtosis values of R2* did not show a statistical significance between benign and malignant lesions (p > 0.05) confirmed by the 'poor' diagnostic value of ROC analysis. For DW-MRI derived parameters, the univariate analysis, standard deviation of D, Skewness and Kurtosis values of D* had a significant result to discriminate benign and malignant lesions and the best result at the univariate analysis in the discrimination of benign and malignant lesions was obtained by the Skewness of D* with an AUC of 82.9% (p-value = 0.02). Significant results for the mean value of Ktrans, mean value, standard deviation value and Skewness of kep, mean value, Skewness and Kurtosis of ve were obtained and the best AUC among DCE-MRI extracted parameters was reached by the mean value of kep and was equal to 80.0%. The best diagnostic performance in the discrimination of benign and malignant lesions was obtained at the multivariate analysis considering the DCE-MRI parameters alone with an AUC = 0.91 when the balancing technique was considered. CONCLUSIONS: Our results suggest that the combined use of DCE-MRI, DW-MRI and/or BOLD-MRI does not provide a dramatic improvement compared to the use of DCE-MRI features alone, in the classification of breast lesions. However, an interesting result was the negative correlation between R2* and D.

Pain control and functional improvement in patients treated by autologous conditioned serum after failure of platelet rich plasma treatments in knee osteoarthritis.

OBJECTIVE: To assess the efficacy of autologous conditioned serum (ACS) for the treatment of patients with knee osteoarthritis after failure of medical treatments and platelet rich plasma (PRP) injections. BACKGROUND: Knee osteoarthritis is the most common form of arthritis. Prior to prosthetic surgery these patients might benefit from medical treatments, physiotherapy, and in case of their ineffectiveness, from autologous blood component injections. METHODOLOGY: We have treated 30 patients with Kellgren-Lawrence I-III knee osteoarthritis with ACS after failure of standard medical treatments/physiotherapy and platelet rich plasma (PRP) injections for a full cycle, within the previous year from enrollment. RESULTS: ACS administration was performed in all patients with mild side effects and produced prompt (1 month) improvements of VAS and Lequesne scales in 67% of patients and this result persisted at 6 and 12 months. No relationship between the rate of response and Kellgren-Lawrence scale at enrollment was observed whilst responders had a significantly higher amount of interleukin-1 receptor antagonist (IL1-RA) in ACS as compared to nonresponders. CONCLUSION: The present study confirms the efficacy of ACS in pain control and functional recovery of patients with knee osteoarthritis resistant to medical and PRP treatment. These results were obtained in a well-defined cohort of resistant patients and seem to be related with IL1-RA content in injected ACS.

UV-C Irradiation as a Tool to Reduce Biofilm Growth on Pompeii Wall Paintings.

This study focuses on the experimentation of a method based on the use of UV-C irradiation to eliminate the biofilms present in a tomb located in the necropolis of Porta Nocera, in Pompeii. For this study, the autotrophic component of the biofilm was isolated in the laboratory, while, contemporarily, the characterization of the composition of the pigments of the frescoes took place on original fragments, which had already detached from the tomb and were examined in situ. These preliminary analyses were necessary for the recreation of test samples in the laboratory, which closely matched the original surfaces. Artificial biofilms were used for experimental exposure to UV-C radiation. The exposure to UV-C radiation was carried out at different distances for a fixed time interval. The effectiveness of the biocidal action was assessed by employing optical microscopy techniques, through a careful visual assessment of the area occupied by the biofilm on the different test samples, using a photographic survey, as well as by means of colorimetric measurements using spectrometric techniques. In order to obtain an additional parameter to evaluate the death rate of microorganism cultures exposed to the UV-C radiation, the concentrations of the photosynthetic pigments were also measured by spectrophotometry. Results showed that biofilms were completely eradicated by radiation, and no change in pigment color was observed.

In vitro release and expansion of mesenchymal stem cells by a hyaluronic acid scaffold used in combination with bone marrow.

Articular cartilage injuries of the knee are difficult to treat due to the poor healing ability of cartilage and conventional treatment methods often give unsatisfactory results. Mesenchymal Stem Cells (MSCs) have generated interest as an alternative source of cells for cartilage tissue engineering due to their chondrogenic potential and their easy isolation from bone marrow. It has been reported that the use of scaffold in cartilage engineering acts as a support for cell adhesion, keeping the cells in the cartilage defects and therefore facilitating tissue formation, and that Hyaluronic acid (HA) is a molecule of particular interest for producing scaffold for tissue engineering. In this study we evaluated the in vitro selection and expansion of Bone Marrow MSCs (BM-MSCs) and by residual BM+HA membrane (BM-HA-MSCs) used as scaffold. Sixty mL of BM have been aspirated by the posterior iliac crest and HA membrane (Hyalograft-C, Fidia Advanced Biopolimers) was used as scaffold. BM-MSCs were cultured with D-MEM supplemented with Desamethasone, Ascorbic Acid, ß-Transforming Growth Factor and Insulin. When cultured in chondrogenic selective medium MSCs from both BM and HA membrane were able to differentiate into chondrogenesis, but BM-HA-MSCs showed a higher staining intensity than BM-MSCs when they were stained with Toluidine blue. The interaction of MSCs with the HA-scaffold seems to promote by itself chondrogenesis.