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Abstract Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence (‘wearing-off’) before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab’s effect on MS-related fatigue. Forty-five relapsing–remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Highlights Following in vitro ischemia, the nerve growth factor receptor TrkB is activated in the presence of the TrkB agonist 7,8-DHF only in female and not in male cultured hippocampal neurons, leading to increased neuronal survival. Expression of ERα is increased following in vitro ischemia in female but not male hippocampal neurons. The female hippocampal neuronal specific responses to in vitro ischemia are blocked by pre-treatment with testosterone. The data support a model for a female-specific a neuroprotective pathway in hippocampal neurons. The pathway is activated by a TrkB agonist, dependent on ERα and blocked by testosterone.

Abstract Background Neonatal hypoxia ischemia (HI) related brain injury is one of the major causes of life-long neurological morbidities that result in learning and memory impairments. Evidence suggests that male neonates are more susceptible to the detrimental effects of HI, yet the mechanisms mediating these sex-specific responses to neural injury in neonates remain poorly understood. We previously tested the effects of treatment with a small molecule agonist of the tyrosine kinase B receptor (TrkB), 7,8-dihydroxyflavone (DHF) following neonatal HI and determined that females, but not males exhibit increased phosphorylation of TrkB and reduced apoptosis in their hippocampi. Moreover, these female-specific effects of the TrkB agonist were found to be dependent upon the expression of $$\text{ER}\alpha$$ ER α . These findings demonstrated that TrkB activation in the presence of $$\text{ER}\alpha$$ ER α comprises one pathway by which neuroprotection may be conferred in a female-specific manner. The goal of this study was to determine the role of $$\text{ER}\alpha$$ ER α -dependent TrkB-mediated neuroprotection in memory and anxiety in young adult mice exposed to HI during the neonatal period. Methods In this study, we used a unilateral hypoxic ischemic (HI) mouse model. $$\text{ER}\alpha$$ ER α +/+ or $$\text{ER}\alpha$$ ER α −/− mice were subjected to HI on postnatal day (P) 9 and mice were treated with either vehicle control or the TrkB agonist, DHF, for 7 days following HI. When mice reached young adulthood, we used the novel object recognition, novel object location and open field tests to assess long-term memory and anxiety-like behavior. The brains were then assessed for tissue damage using immunohistochemistry. Results Neonatal DHF treatment prevented HI-induced decrements in recognition and location memory in adulthood in females, but not in males. This protective effect was absent in female mice lacking $$\text{ER}\alpha$$ ER α . The female-specific improved recognition and location memory outcomes in adulthood conferred by DHF therapy after neonatal HI tended to be or were $$\text{ER}\alpha$$ ER α -dependent, respectively. Interestingly, DHF triggered anxiety-like behavior in both sexes only in the mice that lacked $$\text{ER}\alpha$$ ER α . When we assessed the severity of injury, we found that DHF therapy did not decrease the percent tissue loss in proportion to functional recovery. We additionally observed that the presence of $$\text{ER}\alpha$$ ER α significantly reduced overall HI-associated mortality in both sexes. Conclusions These observations provide evidence for a therapeutic role for DHF in which TrkB-mediated sustained recovery of recognition and location memories in females are $$\text{ER}\alpha$$ ER α -associated and dependent, respectively. However, the beneficial effects of DHF therapy did not include reduction of gross tissue loss but may be derived from the enhanced functioning of residual tissues in a cell-specific manner.

The intraoral scanner represents an important innovation in the world of dentistry, capable of transforming and digitizing conventional workflows and significantly improving communication with the patient, especially in pediatric age. The aim of this study is to investigate how digital dentistry, using the intraoral scanner, can interact in the communicative trinomial dentist–pediatric patient–parents and how this tool can be useful in communicating and understanding the received message. The value of the introduction of digital dentistry on communication schemes is evaluated by administering a questionnaire of 17 questions. A sample of 100 children aged between 6 and 12 years was studied. Of the sample of children/parents included in the study, 50 were re-examined 4 weeks after the first visit to re-administer the questionnaire. Internal consistency, assessed through Cronbach’s alpha, was adequate, being alpha equal to 0.728. Test–retest reliability was assessed with Cohen’s kappa index for dichotomous variables (percentage of agreement was >85.71%), and for the discrete variables it was assessed with the Intraclass Correlation Coefficient (ICC). The reliability was moderate (0.5 < ICC < 0.75) for Q4, Q9, Q11 and Q1; for the other answers, the reliability was poor (ICC < 0.5) and not statistically significant. The digital approach is confirmed not only as a powerful innovation from an engineering or clinical point of view, but also as a useful tool for a more effective communication in the approach to pediatric patients.

IntroductionHospitalized children diagnosed with SARS-CoV-2-related conditions are at risk for new or persistent symptoms and functional impairments. Our objective was to analyze post-hospital symptoms, healthcare utilization, and outcomes of children previously hospitalized and diagnosed with acute SARS-CoV-2 infection or Multisystem Inflammatory Syndrome in Children (MIS-C).MethodsProspective, multicenter electronic survey of parents of children

The current hypothesis on the pathophysiology of multiple sclerosis (MS) suggests the involvement of both inflammatory and neurodegenerative mechanisms. Disease Modifying Therapies (DMTs) effectively decrease relapse rates, thus reducing relapse-associated disability in people with MS. In some patients, disability progression, however, is not solely linked to new lesions and clinical relapses but can manifest independently. Progression Independent of Relapse Activity (PIRA) significantly contributes to long-term disability, stressing the urge to unveil biomarkers to forecast disease progression. Twenty-five adult patients with relapsing–remitting multiple sclerosis (RRMS) were enrolled in a cohort study, according to the latest McDonald criteria, and tested before and after high-efficacy Disease Modifying Therapies (DMTs) (6–24 months). Through Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells. Multivariate logistic and linear models with interactions were generated. Robustness was assessed by randomization tests in R. A subset of miRNAs, correlated with PIRA, and the Expanded Disability Status Scale (EDSS), was selected. To refine the patient stratification connected to the disease trajectory, we computed a robust logistic classification model derived from baseline miRNA expression to predict PIRA status (AUC = 0.971). We built an optimal multilinear model by selecting four other miRNA predictors to describe EDSS changes compared to baseline. Multivariate modeling offers a promising avenue to uncover potential biomarkers essential for accurate prediction of disability progression in early MS stages. These models can provide valuable insights into developing personalized and effective treatment strategies.

Fixed appliance (FA) therapy predisposes patients to white spot lesions (WSLs). The F-ACP complex (amorphous calcium phosphate nanoparticles enriched with carbonate and fluorine and coated with citrate) has been effective for in vitro enamel remineralization. The aim of this study was to evaluate the efficacy of the F-ACP complex in remineralizing WSLs after FA therapy. One hundred and six adolescents (aged 12–20 years) were randomized into study and control groups after FA therapy. Patients in the study group were advised to use dental mousse containing F-ACP applied within Essix retainers for six months. The presence of WSLs was recorded at baseline (T0), 3 months (T1), and 6 months (T2) according to the International Caries Detection and Assessment System (ICDAS). Visual Plaque Index (VPI) and Gingival Bleeding Index (GBI) were recorded. Among 106 study participants, 91 (52 and 39 in study and control groups, respectively) completed the study. The results showed that the ICDAS score was significantly lower (p < 0.001) in the study group than in the control group between T0 and T2. The application of mousse containing the F-ACP complex inside Essix retainers for six months is effective in remineralizing white spot lesions in patients after FA therapy without side effects.

One of the most promising areas of research in palaeomicrobiology is the study of the human microbiome. In particular, ancient dental calculus helps to reconstruct a substantial share of oral microbiome composition by mapping together human evolution with its state of health/oral disease. This review aims to trace microbial characteristics in ancient dental calculus to describe the evolution of the human host-oral microbiome relationship in oral health or disease in children and adults. Following the PRISMA-Extension for Scoping Reviews guidelines, the main scientific databases (PubMed, Scopus, Lilacs, Cochrane Library) have been drawn upon. Eligibility criteria were established, and all the data collected on a purpose-oriented collection form were analysed descriptively. From the initial 340 records, only 19 studies were deemed comprehensive enough for the purpose of this review. The knowledge of the composition of ancient oral microbiomes has broadened over the past few years thanks to increasingly well-performing decontamination protocols and additional analytical avenues. Above all, metagenomic sequencing, also implemented by state-of-the-art bioinformatics tools, allows for the determination of the qualitative-quantitative composition of microbial species associated with health status and caries/periodontal disease. Some microbial species, especially periodontal pathogens, do not appear to have changed in history, while others that support caries disease or oral health could be connected to human evolution through lifestyle and environmental contributing factors.

Background and objectivesMultiple sclerosis (MS) is a chronic, progressive neurological disease characterized by early-stage neuroinflammation, neurodegeneration, and demyelination that involves a spectrum of heterogeneous clinical manifestations in terms of disease course and response to therapy. Even though several disease-modifying therapies (DMTs) are available to prevent MS-related brain damage—acting on the peripheral immune system with an indirect effect on MS lesions—individualizing therapy according to disease characteristics and prognostic factors is still an unmet need. Given that deregulated miRNAs have been proposed as diagnostic tools in neurodegenerative/neuroinflammatory diseases such as MS, we aimed to explore miRNA profiles as potential classifiers of the relapsing–remitting MS (RRMS) patients’ prospects to gain a more effective DMT choice and achieve a preferential drug response.MethodsA total of 25 adult patients with RRMS were enrolled in a cohort study, according to the latest McDonald criteria before (pre-cladribine, pre-CLA; pre-ocrelizumab, pre-OCRE, time T0) and after high-efficacy DMTs, time T1, 6 months post-CLA (n = 10, 7 F and 3 M, age 39.0 ± 7.5) or post-OCRE (n = 15, 10 F and 5 M, age 40.5 ± 10.4) treatment. A total of 15 age- and sex-matched healthy control subjects (9 F and 6 M, age 36.3 ± 3.0) were also selected. By using Agilent microarrays, we analyzed miRNA profiles from peripheral blood mononuclear cells (PBMC). miRNA–target networks were obtained by miRTargetLink, and Pearson’s correlation served to estimate the association between miRNAs and outcome clinical features.ResultsFirst, the miRNA profiles of pre-CLA or pre-OCRE RRMS patients compared to healthy controls identified modulated miRNA patterns (40 and seven miRNAs, respectively). A direct comparison of the two pre-treatment groups at T0 and T1 revealed more pro-inflammatory patterns in the pre-CLA miRNA profiles. Moreover, both DMTs emerged as being capable of reverting some dysregulated miRNAs toward a protective phenotype. Both drug-dependent miRNA profiles and specific miRNAs, such as miR-199a-3p, miR-29b-3p, and miR-151a-3p, emerged as potentially involved in these drug-induced mechanisms. This enabled the selection of miRNAs correlated to clinical features and the related miRNA–mRNA network.DiscussionThese data support the hypothesis of specific deregulated miRNAs as putative biomarkers in RRMS patients’ stratification and DMT drug response.

Background: The injection of local anesthetics is the procedure that still causes the most fear and anxiety in a dental session; to minimize this problem, we can use topical anesthesia. The aim of this study is to analyze the tolerability and the clinical efficacy in the control of pain, during the subsequent injection of the local anesthetic, of an experimental anesthetic patch with a new formulation, which was previously tested in gel formula. Methods: A total of 150 children, aged 4 to 9 years, were included in the study. Each patient was treated using three different pre-anesthesia methods (placebo gel, experimental gel, and experimental patch), according to a split-mouth procedure, within a week of each other. The injection pain was analyzed using the WBFPRS and FLACC scales. Patients’ caregivers’ satisfaction was recorded at the end of the procedures. The data were analyzed using one-way ANOVA-RM, Wilcoxon–Mann–Whitney, Mann–Whitney U, and χ2 tests. Results: In this study, significantly higher pain ratings were observed with the topical placebo gel and lower pain ratings were observed with the experimental patch. Conclusion: The use of the patch proved to be very effective in reducing pain both subjectively and objectively, in the absence of both local and systemic side effects, validating its use in the oral mucosa.

Multiple sclerosis (MS) is a debilitating neurological disease that has been classified as an immune-mediated attack on myelin, the protective sheath of nerves. Some aspects of its pathogenesis are still unclear; nevertheless, it is generally established that viral infections influence the course of the disease. Cytomegalovirus (CMV) is a major pathogen involved in alterations of the immune system, including the expansion of highly differentiated cytotoxic CD8+ T cells and the accumulation of adaptive natural killer (NK) cells expressing high levels of the NKG2C receptor. In this study, we evaluated the impact of latent CMV infection on MS patients through the characterization of peripheral NK cells, CD8+ T cells, and NKT-like cells using flow cytometry. We evaluated the associations between immune cell profiles and clinical features such as MS duration and MS progression, evaluated using the Expanded Disability Status Scale (EDSS). We showed that NK cells, CD8+ T cells, and NKT-like cells had an altered phenotype in CMV-infected MS patients and displayed high levels of the NKG2C receptor. Moreover, in MS patients, increased NKG2C expression levels were found to be associated with higher EDSS scores. Overall, these results support the hypothesis that CMV infection imprints the immune system by modifying the phenotype and receptor repertoire of NK and CD8+ T cells, suggesting a detrimental role of CMV on MS progression.

BackgroundSlow pathway (SP) ablation is the cornerstone for atrioventricular nodal reentry tachycardia (AVNRT) treatment, and a low-voltage bridge offers a good target during mapping using low x-ray exposure. We aimed to assess a new tool to identify SP by activation mapping using the last CARTO3® version, i.e., CARTO PRIME® V7 (Biosense Webster, Diamond Bar, CA, USA)Methods and resultsRight atrial septum and triangle of Koch 3D-activation map were obtained from intracardiac contact mapping during low x-ray CARTO 3® procedure. In 60 patients (mean age 60.3 ± 14.7, 61% females) undergoing ablation for AVNRT, an automatic activation map using a DECANAV® mapping catheter and CARTO® Confidense™, Coherent, and FAM DX software modules were obtained. The SP was identified in all patients as the latest atrioventricular node activation area; RF catheter ablation (RFCA) in that region elicited junctional beats. The mean procedural time was 150.3 ± 48.3 min, the mean fluoroscopy time exposure was 2.9 ± 2 min, the mean dose-area product (DAP) was 16.5 ± 2.7 cGy/cm2. The mean number of RF applications was 3.9 ± 2, the mean ablation index was 428.6 ± 96.6, and the mean contact force was 8 ± 2.8 g. There were no adverse event during the procedure, and no AVNRT recurrences occurred during a mean follow-up of 14.3 ± 8.3 months.ConclusionAblation of the SP by automatic mapping using Confidense™, Coherent, and FAM DX software modules is an innovative, safe, and effective approach to AVNRT ablation. The CARTO3® V7 system shows on a 3D map the latest AV node activation area during sinus rhythm allowing low fluoroscopy time and highly effective RFCA.

Abstract One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long‐acting GnRH antagonist degarelix in various biologic media by the tailor‐made HPLC method, which allows precise determination of 5‐Aph(Hyd)‐degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.

Motor fatigue is one of the most common symptoms in multiple sclerosis (MS) patients. Previous studies suggested that increased motor fatigue in MS may arise at the central nervous system level. However, the mechanisms underlying central motor fatigue in MS are still unclear.This paper investigated whether central motor fatigue in MS reflects impaired corticospinal transmission or suboptimal primary motor cortex (M1) output (supraspinal fatigue). Furthermore, we sought to identify whether central motor fatigue is associated with abnormal M1 excitability and connectivity within the sensorimotor network.Twenty-two patients affected by relapsing-remitting MS and 15 healthy controls (HCs) performed repeated blocks of contraction at different percentages of maximal voluntary contraction with the right first dorsal interosseus muscle until exhaustion. Peripheral, central, and supraspinal components of motor fatigue were quantified by a neuromuscular assessment based on the superimposed twitch evoked by peripheral nerve and transcranial magnetic stimulation (TMS). Corticospinal transmission, excitability and inhibition during the task were tested by measurement of motor evoked potential (MEP) latency, amplitude, and cortical silent period (CSP). M1 excitability and connectivity was measured by TMS-evoked electroencephalography (EEG) potentials (TEPs) elicited by M1 stimulation before and after the task.Patients completed fewer blocks of contraction and showed higher values of central and supraspinal fatigue than HCs. We found no MEP or CSP differences between MS patients and HCs. Patients showed a post-fatigue increase in TEPs propagation from M1 to the rest of the cortex and in source-reconstructed activity within the sensorimotor network, in contrast to the reduction observed in HCs. Post-fatigue increase in source-reconstructed TEPs correlated with supraspinal fatigue values.To conclude, MS-related motor fatigue is caused by central mechanisms related explicitly to suboptimal M1 output rather than impaired corticospinal transmission. Furthermore, by adopting a TMS-EEG approach, we proved that suboptimal M1 output in MS patients is associated with abnormal task-related modulation of M1 connectivity within the sensorimotor network. Our findings shed new light on the central mechanisms of motor fatigue in MS by highlighting a possible role of abnormal sensorimotor network dynamics. These novel results may point to new therapeutical targets for fatigue in MS.

Botulinum toxin (BoNT) is an effective and safe therapy for the symptomatic treatment of several neurological disturbances. An important line of research has provided numerous pieces of evidence about the mechanisms of action of BoNT in the central nervous system, especially in the context of dystonia and spasticity. However, only a few studies focused on the possible central effects of BoNT in Parkinson’s disease (PD). We performed a systematic review to describe and discuss the evidence from studies focused on possible central effects of BoNT in PD animal models and PD patients. To this aim, a literature search in PubMed and SCOPUS was performed in May 2023. The records were screened according to title and abstract by two independent reviewers and relevant articles were selected for full-text review. Most of the papers highlighted by our review report that the intrastriatal administration of BoNT, through local anticholinergic action and the remodulation of striatal compensatory mechanisms secondary to dopaminergic denervation, induces an improvement in motor and non-motor symptoms in the absence of neuronal loss in animal models of PD. In human subjects, the data are scarce: a single neurophysiological study in tremulous PD patients found that the change in tremor severity after peripheral BoNT administration was associated with improved sensory–motor integration and intracortical inhibition measures. Further clinical, neurophysiological, and neuroimaging studies are necessary to clarify the possible central effects of BoNT in PD.

Novel foods, including edible insects, are emerging because of their nutritional characteristics and low environmental impacts and could represent a valid alternative source of food in a more sustainable way. Edible insects have been shown to have beneficial effects on human health. Insect-derived bioactive peptides exert antihypertensive, antioxidant, anti-inflammatory, and antimicrobial properties and have protective effects against common metabolic conditions. In this review, the roles of edible insects in human health are reported, and the possible applications of these peptides in clinical practice are discussed. A special mention is given to the role of antimicrobial peptides and their potential applications in controlling infections in orthodontic procedures. In this context, insects’ antimicrobial peptides might represent a potential tool to face the onset of infective endocarditis, with a low chance to develop resistances, and could be manipulated and optimized to replace common antibiotics used in clinical practice so far. Although some safety concerns must be taken into consideration, and the isolation and production of insect-derived proteins are far from easy, edible insects represent an interesting source of peptides, with beneficial effects that may be, in the future, integrated into clinical and orthodontic practice.

The growing applications of peptide-based therapeutics require the development of efficient protocols from the perspective of an industrial scale-up. T3P® (cyclic propylphosphonic anhydride) promotes amidation in the solution-phase through a biomimetic approach, similar to the activation of carboxylic moiety catalyzed by ATP-grasp enzymes in metabolic pathways. The T3P® induced coupling reaction was applied in this study to the solution-phase peptide synthesis (SolPPS). Peptide bond formation occurred in a few minutes with high efficiency and no epimerization, generating water-soluble by-products, both using N-Boc or N-Fmoc amino acids. The optimized protocol, which was successfully applied to the iterative synthesis of a pentapeptide, also allowed for a decrease in the solvent volume, thus improving process sustainability. The protocol was finally extended to the liquid-phase peptide synthesis (LPPS), where the isolation of the peptide was performed using precipitation, thus also showing the suitability of this coupling reagent to this emerging technique.

OBJECTIVE:There is no consensus on the optimal timing and specific brain MRI sequences in the evaluation and management of severe pediatric traumatic brain injury (TBI), and information on current practices is lacking. The authors performed a survey of MRI practices among sites participating in a multicenter study of severe pediatric TBI to provide information for designing future clinical trials using MRI to assess brain injury after severe pediatric TBI. METHODS:Information on current imaging practices and resources was collected from 27 institutions participating in the Approaches and Decisions after Pediatric TBI Trial. Multiple-choice questions addressed the percentage of patients with TBI who have MRI studies, timing of MRI, MRI sequences used to investigate TBI, as well as the magnetic field strength of MR scanners used at the participating institutions and use of standardized MRI protocols for imaging after severe pediatric TBI. RESULTS:Overall, the reported use of MRI in pediatric patients with severe TBI at participating sites was high, with 40% of sites indicating that they obtain MRI studies in > 95% of this patient population. Differences were observed in the frequency of MRI use between US and international sites, with the US sites obtaining MRI in a higher proportion of their pediatric patients with severe TBI (94% of US vs 44% of international sites reported MRI in at least 70% of patients with severe TBI). The reported timing and composition of MRI studies was highly variable across sites. Sixty percent of sites reported typically obtaining an MRI study within the first 7 days postinjury, with the remainder of responses distributed throughout the first 30-day postinjury period. Responses indicated that MRI sequences sensitive for diffuse axonal injury and ischemia are frequently obtained in patients with TBI, whereas perfusion imaging and spectroscopy techniques are less common. CONCLUSIONS:Results from this survey suggest that despite the lack of consensus or guidelines, MRI is commonly obtained during the acute clinical setting after severe pediatric TBI. The variation in MRI practices highlights the need for additional studies to determine the utility, optimal timing, and composition of clinical MRI studies after TBI. The information in this survey describes current clinical MRI practices in children with severe TBI and identifies important challenges and objectives that should be considered when designing future studies.

Timely diagnosis of secondary progressive multiple sclerosis (SPMS) represents a clinical challenge. The Frailty Index, a quantitative frailty measure, and the Neurophysiological Index, a combined measure of sensorimotor cortex inhibitory mechanism parameters, have recently emerged as promising tools to support SPMS diagnosis. The aim of this study was to explore the possible relationship between these two indices in MS. MS participants underwent a clinical evaluation, Frailty Index administration, and neurophysiological assessment. Frailty and Neurophysiological Index scores were found to be higher in SPMS and correlated with each other, thus suggesting that they may capture similar SPMS-related pathophysiological mechanisms.

The intraoral scanner represents an important innovation in the world of dentistry, capable of transforming and digitizing conventional workflows and significantly improving communication with the patient, especially in pediatric age. The aim of this study is to investigate how digital dentistry, using the intraoral scanner, can interact in the communicative trinomial dentist–pediatric patient–parents and how this tool can be useful in communicating and understanding the received message. The value of the introduction of digital dentistry on communication schemes is evaluated by administering a questionnaire of 17 questions. A sample of 100 children aged between 6 and 12 years was studied. Of the sample of children/parents included in the study, 50 were re-examined 4 weeks after the first visit to re-administer the questionnaire. Internal consistency, assessed through Cronbach's alpha, was adequate, being alpha equal to 0.728. Test–retest reliability was assessed with Cohen's kappa index for dichotomous variables (percentage of agreement was >85.71%), and for the discrete variables it was assessed with the Intraclass Correlation Coefficient (ICC). The reliability was moderate (0.5 < ICC < 0.75) for Q4, Q9, Q11 and Q1; for the other answers, the reliability was poor (ICC < 0.5) and not statistically significant. The digital approach is confirmed not only as a powerful innovation from an engineering or clinical point of view, but also as a useful tool for a more effective communication in the approach to pediatric patients. [ABSTRACT FROM AUTHOR]

IntroductionFunctional Motor Disorders (FMDs) represent nosological entities with no clear phenotypic characterization, especially in patients with multiple (combined FMDs) motor manifestations. A data-driven approach using cluster analysis of clinical data has been proposed as an analytic method to obtain non-hierarchical unbiased classifications. The study aimed to identify clinical subtypes of combined FMDs using a data-driven approach to overcome possible limits related to “a priori” classifications and clinical overlapping.MethodsData were obtained by the Italian Registry of Functional Motor Disorders. Patients identified with multiple or “combined” FMDs by standardized clinical assessments were selected to be analyzed. Non-hierarchical cluster analysis was performed based on FMDs phenomenology. Multivariate analysis was then performed after adjustment for principal confounding variables.ResultsFrom a study population of n = 410 subjects with FMDs, we selected n = 188 subjects [women: 133 (70.7%); age: 47.9 ± 14.4 years; disease duration: 6.4 ± 7.7 years] presenting combined FMDs to be analyzed. Based on motor phenotype, two independent clusters were identified: Cluster C1 (n = 82; 43.6%) and Cluster C2 (n = 106; 56.4%). Cluster C1 was characterized by functional tremor plus parkinsonism as the main clinical phenotype. Cluster C2 mainly included subjects with functional weakness. Cluster C1 included older subjects suffering from anxiety who were more treated with botulinum toxin and antiepileptics. Cluster C2 included younger subjects referring to different associated symptoms, such as pain, headache, and visual disturbances, who were more treated with antidepressants.ConclusionUsing a data-driven approach of clinical data from the Italian registry, we differentiated clinical subtypes among combined FMDs to be validated by prospective studies.

Imaging-based quantitative measures from diffusion-weighted MRI (dMRI) offer the ability to non-invasively extract microscopic information from human brain tissues. Group-level comparisons of such measures represent an important approach to investigate abnormal brain conditions. These types of analyses are especially useful when the regions of abnormality spatially coincide across subjects. When this is not true, approaches for individualized analyses are necessary. Here we present a framework for single-subject multidimensional analysis based on the Mahalanobis distance. This is conducted along specific white matter pathways represented by tractography-derived streamline bundles. A definition for abnormality was constructed from Wilk's criterion, which accounts for normative sample size, number of features used in the Mahalanobis distance, and multiple comparisons. One example of a condition exhibiting high heterogeneity across subjects is traumatic brain injury (TBI). Using the Mahalanobis distance computed from the three eigenvalues of the diffusion tensor along the cingulum, uncinate, and parcellated corpus callosum tractograms, 8 severe TBI patients were individually compared to a normative sample of 49 healthy controls. For all TBI patients, the analyses showed statistically significant deviations from the normative data at one or multiple locations along the analyzed bundles. The detected anomalies were widespread across the analyzed tracts, consistent with the expected heterogeneity that is hallmark of TBI. Each of the controls subjects was also compared to the remaining 48 subjects in the control group in a leave-one-out fashion. Only two segments were identified as abnormal out of the entire analysis in the control group, thus the method also demonstrated good specificity.

Background: The anti-CD20 monoclonal antibody ocrelizumab has been widely employed in the treatment of people with multiple sclerosis (pwMS). However, its B-cell-depleting effect may induce a higher risk of infectious events and alterations in the secretion of B-cell-activating factors, such as BAFF, APRIL and CD40L. Methods: The aim of this study was to investigate plasma BAFF, APRIL and CD40L levels and their relationship with infectious risk in ocrelizumab-treated pwMS at baseline (T0), at 6 months (T6) and at 12 months (T12) after starting the treatment. As a control group, healthy donors (HD) were enrolled too. Results: A total of 38 pwMS and 26 HD were enrolled. At baseline, pwMS showed higher plasma BAFF (p < 0.0001), APRIL (p = 0.0223) and CD40L (p < 0.0001) levels compared to HD. Compared to T0, plasma BAFF levels were significantly increased at both T6 and T12 (p < 0.0001 and p < 0.0001, respectively). Whereas plasma APRIL and CD40L levels were decreased at T12 (p = 0.0003 and p < 0.0001, respectively). When stratifying pwMS according to the development of an infectious event during the 12-month follow-up period in two groups—with (14) and without an infectious event (24)—higher plasma BAFF levels were observed at all time-points; significantly, in the group with an infectious event compared to the group without an infectious event (T0: p < 0.0001, T6: p = 0.0056 and T12: p = 0.0400). Conclusions: BAFF may have a role as a marker of immune dysfunction and of infectious risk.

Summary: The difficulty to unambiguously identify the various subsets of mononuclear phagocytes (MNPs) of the intestinal lamina propria has hindered our understanding of the initial events occurring after mucosal exposure to HIV-1.Here, we compared the composition and function of MNP subsets at steady-state and following ex vivo and in vivo viral exposure in human and macaque colorectal tissues.Combined evaluation of CD11c, CD64, CD103, and CX3CR1 expression allowed to differentiate lamina propria MNPs subsets common to both species. Among them, CD11c+ CX3CR1+ cells expressing CCR5 migrated inside the epithelium following ex vivo and in vivo exposure of colonic tissue to HIV-1 or SIV. In addition, the predominant population of CX3CR1high macrophages present at steady-state partially shifted to CX3CR1low macrophages as early as three days following in vivo SIV rectal challenge of macaques.Our analysis identifies CX3CR1+ MNPs as novel players in the early events of HIV-1 and SIV colorectal transmission.

Dystonia is thought to be a network disorder due to abnormalities in the basal ganglia-thalamo-cortical circuit. We aimed to investigate the white matter (WM) microstructural damage of bundles connecting pre-defined subcortical and cortical regions in cervical dystonia (CD) and blepharospasm (BSP). Thirty-five patients (17 with CD and 18 with BSP) and 17 healthy subjects underwent MRI, including diffusion tensor imaging (DTI). Probabilistic tractography (BedpostX) was performed to reconstruct WM tracts connecting the globus pallidus, putamen and thalamus with the primary motor, primary sensory and supplementary motor cortices. WM tract integrity was evaluated by deriving their DTI metrics. Significant differences in mean, radial and axial diffusivity between CD and HS and between BSP and HS were found in the majority of the reconstructed WM tracts, while no differences were found between the two groups of patients. The observation of abnormalities in DTI metrics of specific WM tracts suggests a diffuse and extensive loss of WM integrity as a common feature of CD and BSP, aligning with the increasing evidence of microstructural damage of several brain regions belonging to specific circuits, such as the basal ganglia-thalamo-cortical circuit, which likely reflects a common pathophysiological mechanism of focal dystonia.

The aim of the present study was to test a new topical anesthetic gel with a different formulation (10% lidocaine, 10% prilocaine) to analyze its effectiveness in pain control, during the subsequent injection of local anesthetic, and the presence of any side effects. Methods: The study’s research design was a randomized controlled clinical trial on 300 children, aged 5–8 years, divided into two groups, each of 150 patients, according to pre-injection procedures (presence or absence of topical anesthesia). The injection pain was analyzed using the Wong-Baker Faces Pain Rating Scale (PRS) and the Face, Legs, Activity, Cry, Consolability Scale (FLACC). At the end of the procedures, patients’ parents’ satisfaction was recorded. The data were analyzed using the Student’s T test, Mann–Whitney U test and Chi-square test. Results: There were statistically significant differences between the two groups both in the PRS and FLACC ratings. Both in subjective and objective pain evaluations, significantly higher pain ratings were observed in the group without topical anesthesia. There was also a statistically significant difference in terms of patients’ parents’ judgment, as in the group with the use of topical anesthetic the level of parental satisfaction is statistically higher. Conclusion: The experimental anesthetic has proved very effective in its use as a topical gel in both pain measurement scales, thus validating its use on the oral mucosa, for its pharmacological and psychological effect, in the total absence of local and systemic side effects.

The aim of this study was to compare the positional information transfer accuracy of palatal temporary anchorage devices (TADs) of two different brands of transfer caps: PSM and Leone. Thirty plaster casts of maxillary dental arches were chosen for master models. A couple of Leone TADs were inserted in each master model. For each master model, two analysis models were created: using two transfer caps, Leone and PSM, the impressions were taken, the analogues were connected on the transfer caps, and the casts were poured. Using digital methods and equipment, such as a 3D scanner, a 3D analysis and a comparison of the accuracy of the two transfer caps in transferring the positional information of the TADs was then made. The data obtained were analyzed using the Mann–Whitney U-test at a significance level of α = 0.05. PSM transfer caps showed higher error frequency in almost all measurements. Only two measurements had a larger error in the analysis models made with Leone transfer caps. The Mann–Whitney U-test found a significant difference between the error levels of TADs found in the analysis models created with PSM transfer caps. Leone transfer caps showed greater reliability in TADs positional information transmission.

One of the most promising areas of research in palaeomicrobiology is the study of the human microbiome. In particular, ancient dental calculus helps to reconstruct a substantial share of oral microbiome composition by mapping together human evolution with its state of health/oral disease. This review aims to trace microbial characteristics in ancient dental calculus to describe the evolution of the human host-oral microbiome relationship in oral health or disease in children and adults. Following the PRISMA-Extension for Scoping Reviews guidelines, the main scientific databases (PubMed, Scopus, Lilacs, Cochrane Library) have been drawn upon. Eligibility criteria were established, and all the data collected on a purpose-oriented collection form were analysed descriptively. From the initial 340 records, only 19 studies were deemed comprehensive enough for the purpose of this review. The knowledge of the composition of ancient oral microbiomes has broadened over the past few years thanks to increasingly well-performing decontamination protocols and additional analytical avenues. Above all, metagenomic sequencing, also implemented by state-of-the-art bioinformatics tools, allows for the determination of the qualitative-quantitative composition of microbial species associated with health status and caries/periodontal disease. Some microbial species, especially periodontal pathogens, do not appear to have changed in history, while others that support caries disease or oral health could be connected to human evolution through lifestyle and environmental contributing factors. [ABSTRACT FROM AUTHOR]

Recent trends in Human Research Protection Programs (HRPPs) have contributed to the rising emphasis on prospective monitoring of clinical research and education programs. Therefore, internal efforts and resources to monitor investigator compliance and site performance have become an important focus in the conduct of clinical research. Once the science and ethics of the research is approved by the Institutional Review Board (IRB), the investigator has the overall responsibility for conducting the research, protecting human subjects, and providing periodic reports and updates related to the research to the IRB. Any potential non-compliance issues that arise during the conduct of the study will be reported to the IRB and potentially prompt decisions about the continuation of the study. Nevertheless, institutions should recognize that IRB review processes, investigations of noncompliance and prospective monitoring are distinct components within an HRPP. The Center for Clinical Research and Technology (CCRT) at University Hospitals Case Medical Center (UHCMC) recently implemented a prospective monitoring and education program and collected data to evaluate the program's development. Trends associated with resource utilization, monitoring procedures and educational activities of the program will be presented, as well as an analysis of the impact of the program. (Contains 3 tables and 1 figure.)

Dental caries is a public health problem in children and is more prevalent in low-socioeconomic-status groups. The aim of this study is to assess the association between migrant families and the prevalence of caries among young children in Italy. This is a cross-sectional study. In the age range of 3 to 5 years, a total of 266 migrant children and 301 nonmigrant children were examined in three Italian charity dental centers. All children had families with low SES. The dmft was determined by intraoral examination performed by six pediatric dentist specialists to assess their dental health. In this study, the prevalence of caries (71%) and the mean dmft (3.68; SD: 1.52) of migrant children were statistically significantly higher than the percentage (52%) and the mean dmft of the nonmigrant control group (3.10; SD: 1.65) with no differences between genders. For the migrant children, the mean (0.49; SD: 0.32) of restorations (filled teeth) was statistically significantly lower than that of nonmigrant children (1.20; SD: 0.48). This study highlights that dmft values and the prevalence of caries are higher in migrant children than in nonmigrant children. In addition, the control group shows a higher level of dental caries than the national mean.