Hepatitis C epidemiology and treatment outcomes in Italy: Impact of the DAA era and the COVID-19 pandemic.

HCV infection poses a global health threat, with significant morbidity and mortality. This study examines HCV trends in a large Italian region from 2015 to 2022, considering demographic changes, evolving clinical profiles, treatment regimens and outcomes, including the impact of the COVID-19 pandemic. This multicentre retrospective study analysed demographics, clinical histories and risk factors in 6882 HCV patients. The study spanned before and after the direct-acting antiviral (DAA) era, and the COVID-19 period, focusing on treatment outcomes (SVR12, non-SVR12 and patients lost to follow-up). Statistical methods included ANOVA, multinomial logistic regression, Kruskal-Wallis test and chi-square analysis, and were conducted adhering to the intention-to-treat (ITT) principle. The cohort, mainly Italian males (average age 58.88), showed Genotype 1 dominance (56.6%) and a high SVR12 rate (97.5%). The pandemic increased follow-up losses, yet SVR12 rates remained stable, influenced by factors like age, gender, cirrhosis and comorbidities. Despite COVID-19 challenges, the region sustained high SVR12 rates in HCV care, emphasising the importance of sustained efforts in HCV care. Continuous screening and targeted interventions in high-risk populations are crucial for achieving WHO elimination targets. The study highlights the resilience of HCV care during the pandemic and provides insights for future public health strategies.

Pointing in cervical dystonia patients.

Introduction: The normal hemispheric balance can be altered by the asymmetric sensorimotor signal elicited by Cervical Dystonia (CD), leading to motor and cognitive deficits. Methods: Directional errors, peak velocities, movement and reaction times of pointing towards out-of-reach targets in the horizontal plane were analysed in 18 CD patients and in 11 aged-matched healthy controls. Results: CD patients displayed a larger scatter of individual trials around the average pointing direction (variable error) than normal subjects, whatever the arm used, and the target pointed. When pointing in the left hemispace, all subjects showed a left deviation (constant error) with respect to the target position, which was significantly larger in CD patients than controls, whatever the direction of the abnormal neck torsion could be. Reaction times were larger and peak velocities lower in CD patients than controls. Discussion: Deficits in the pointing precision of CD patients may arise from a disruption of motor commands related to the sensorimotor imbalance, from a subtle increase in shoulder rigidity or from a reduced agonists activation. Their larger left bias in pointing to left targets could be due to an increased right parietal dominance, independently upon the direction of head roll/jaw rotation which expands the left space representation and/or increases left spatial attention. These deficits may potentially extend to tracking and gazing objects in the left hemispace, leading to reduced skills in spatial-dependent motor and cognitive performance.

Trigeminal Stimulation and Visuospatial Performance: The Struggle between Chewing and Trigeminal Asymmetries.

Chewing improves visuospatial performance through locus coeruleus (LC) activation. The effects of bilateral and unilateral mastication were investigated in subjects showing different degrees of asymmetry in masseter electromyographic (EMG) activity during clenching and in pupil size at rest (anisocoria), which is a proxy of LC imbalance. Correlations between performance changes and asymmetry values were found in males, but not in females. Among males, subjects with low asymmetry values (balanced-BAL) were more sensitive than those with high asymmetry values (imbalanced-IMB) to bilateral and unilateral chewing on the side with higher EMG activity (hypertonic). The opposite was true for hypotonic side chewing. BAL subjects were sensitive to unilateral chewing on both sides, while in IMB subjects, hypertonic side chewing did not influence performance in either males or females. Bilateral chewing elicited larger effects in BAL subjects than in IMB subjects, exceeding the values predicted from unilateral chewing in both groups. Finally, pupil size and anisocoria changes elicited by chewing were correlated with asymmetry values, independent of sex. Data confirmed the facilitation of visuospatial performance exerted by chewing. Trigeminal asymmetries modulate the chewing effects, making occlusal rebalancing an appropriate strategy to improve performance.

Effects of a short period of postural training on postural stability and vestibulospinal reflexes.

The effects of postural training on postural stability and vestibulospinal reflexes (VSRs) were investigated in normal subjects. A period (23 minutes) of repeated episodes (n = 10, 50 seconds) of unipedal stance elicited a progressive reduction of the area covered by centre of pressure (CoP) displacement, of average CoP displacement along the X and Y axes and of CoP velocity observed in this challenging postural task. All these changes were correlated to each other with the only exception of those in X and Y CoP displacement. Moreover, they were larger in the subjects showing higher initial instability in unipedal stance, suggesting that they were triggered by the modulation of sensory afferents signalling body sway. No changes in bipedal stance occurred soon and 1 hour after this period of postural training, while a reduction of CoP displacement was apparent after 24 hours, possibly due to a beneficial effect of overnight sleep on postural learning. The same period of postural training also reduced the CoP displacement elicited by electrical vestibular stimulation (EVS) along the X axis up to 24 hours following the training end. No significant changes in postural parameters of bipedal stance and VSRs could be observed in control experiments where subjects were tested at identical time points without performing the postural training. Therefore, postural training led to a stricter control of CoP displacement, possibly acting through the cerebellum by enhancing feedforward mechanisms of postural stability and by depressing the VSR, the most important reflex mechanism involved in balance maintenance under challenging conditions.

Sleep Deprivation-Induced Changes in Baseline Brain Activity and Vigilant Attention Performance.

Sleep deprivation (SD) negatively affects several aspects of cognitive performance, and one of the most widely-used tools to evaluate these effects is the Psychomotor Vigilance Test (PVT). The present study investigated the possibility of predicting changes induced by SD in vigilant attention performance by evaluating the baseline electroencephalographic (EEG) activity immediately preceding the PVT stimuli onset. All participants (n = 10) underwent EEG recordings during 10 min of PVT before and after a night of SD. For each participant, the root mean square (RMS) of the baseline EEG signal was evaluated for each 1 s time window, and the respective average value was computed. After SD, participants showed slower (and less accurate) performance in the PVT task. Moreover, a close relationship between the changes in the baseline activity with those in cognitive performance was identified at several electrodes (Fp2, F7, F8, P3, T6, O1, Oz, O2), with the highest predictive power at the occipital derivations. These results indicate that vigilant attention impairments induced by SD can be predicted by the pre-stimulus baseline activity changes.

Automatic Cyclic Alternating Pattern (CAP) analysis: Local and multi-trace approaches.

The Cyclic Alternating Pattern (CAP) is composed of cycles of two different electroencephalographic features: an activation A-phase followed by a B-phase representing the background activity. CAP is considered a physiological marker of sleep instability. Despite its informative nature, the clinical applications remain limited as CAP analysis is a time-consuming activity. In order to overcome this limit, several automatic detection methods were recently developed. In this paper, two new dimensions were investigated in the attempt to optimize novel, efficient and automatic detection algorithms: 1) many electroencephalographic leads were compared to identify the best local performance, and 2) the global contribution of the concurrent detection across several derivations to CAP identification. The developed algorithms were tested on 41 polysomnographic recordings from normal (n = 8) and pathological (n = 33) subjects. In comparison with the visual CAP analysis as the gold standard, the performance of each algorithm was evaluated. Locally, the detection on the F4-C4 derivation showed the best performance in comparison with all other leads, providing practical suggestions of electrode montage when a lean and minimally invasive approach is preferable. A further improvement in the detection was achieved by a multi-trace method, the Global Analysis-Common Events, to be applied when several recording derivations are available. Moreover, CAP time and CAP rate obtained with these algorithms positively correlated with the ones identified by the scorer. These preliminary findings support efficient automated ways for the evaluation of the sleep instability, generalizable to both normal and pathological subjects affected by different sleep disorders.

Effect of the Trigeminal Nerve Stimulation on Auditory Event-Related Potentials.

Trigeminal sensorimotor activity stimulates arousal and cognitive performance, likely through activation of the locus coeruleus (LC). In this study we investigated, in normal subjects, the effects of bilateral trigeminal nerve stimulation (TNS) on the LC-dependent P300 wave, elicited by an acoustic oddball paradigm. Pupil size, a proxy of LC activity, and electroencephalographic power changes were also investigated. Before TNS/sham-TNS, pupil size did not correlate with P300 amplitude across subjects. After TNS but not sham-TNS, a positive correlation emerged between P300 amplitude and pupil size within frontal and median cortical regions. TNS also reduced P300 amplitude in several cortical areas. In both groups, before and after TNS/sham-TNS, subjects correctly indicated all the target stimuli. We propose that TNS activates LC, increasing the cortical norepinephrine release and the dependence of the P300 upon basal LC activity. Enhancing the signal-to-noise ratio of cortical neurons, norepinephrine may improve the sensory processing, allowing the subject to reach the best discriminative performance with a lower level of neural activation (i.e., a lower P300 amplitude). The study suggests that TNS could be used for improving cognitive performance in patients affected by cognitive disorders or arousal dysfunctions.

The path from trigeminal asymmetry to cognitive impairment: a behavioral and molecular study.

Trigeminal input exerts acute and chronic effects on the brain, modulating cognitive functions. Here, new data from humans and animals suggest that these effects are caused by trigeminal influences on the Locus Coeruleus (LC). In humans subjects clenching with masseter asymmetric activity, occlusal correction improved cognition, alongside with reductions in pupil size and anisocoria, proxies of LC activity and asymmetry, respectively. Notably, reductions in pupil size at rest on the hypertonic side predicted cognitive improvements. In adult rats, a distal unilateral section of the trigeminal mandibular branch reduced, on the contralateral side, the expression of c-Fos (brainstem) and BDNF (brainstem, hippocampus, frontal cortex). This counterintuitive finding can be explained by the following model: teeth contact perception loss on the lesioned side results in an increased occlusal effort, which enhances afferent inputs from muscle spindles and posterior periodontal receptors, spared by the distal lesion. Such effort leads to a reduced engagement of the intact side, with a corresponding reduction in the afferent inputs to the LC and in c-Fos and BDNF gene expression. In conclusion, acute effects of malocclusion on performance seem mediated by the LC, which could also contribute to the chronic trophic dysfunction induced by loss of trigeminal input.

Chewing and Cognitive Improvement: The Side Matters.

Chewing improves cognitive performance, which is impaired in subjects showing an asymmetry in electromyographic (EMG) masseter activity during clenching. In these subjects, the simultaneous presence of an asymmetry in pupil size (anisocoria) at rest indicates an imbalance in Ascending Reticular Activating System (ARAS) influencing arousal and pupil size. The aim of the present study was to verify whether a trigeminal EMG asymmetry may bias the stimulating effect of chewing on cognition. Cognitive performance and pupil size at rest were recorded before and after 1 min of unilateral chewing in 20 subjects with anisocoria, showing an EMG asymmetry during clenching. Unilateral chewing stimulated performance mainly when it occurred on the side of lower EMG activity (and smaller pupil size). Following chewing on the hypotonic side, changes in cognitive performance were negatively and positively correlated with those in anisocoria and pupil size, respectively. We propose that, following chewing on the hypotonic side, the arousing effects of trigeminal stimulation on performance are enhanced by a rebalancing of ARAS structures. At variance, following chewing on the hypertonic side, the arousing effect of trigeminal stimulation could be partially or completely prevented by the simultaneous increase in ARAS imbalance.

Trigeminal input, pupil size and cognitive performance: From oral to brain matter.

It has been observed that, in patients affected by temporomandibular disorders (TMDs) and edentulism, a left-right asymmetry in electromyographic (EMG) activity of masseter muscles during clenching and in pupil size at rest (anisocoria) is present. Both are greatly reduced by an orthotic-prosthetic correction. In parallel, the correction significantly improves cognitive performance. These effects are possibly due to the recovery of a cortical balance, via Locus Coeruleus (LC) modulation, whose activity is powerfully affected by the sensorimotor trigeminal input. The role of this functional axis was further investigated in subjects without overt occlusal or dental problems. In these individuals, the EMG asymmetry was significantly correlated to anisocoria at rest, with the dental arches open or in contact. Also in normal subjects, both the EMG and the pupil asymmetry during clenching could be significantly reduced by an orthotic (bite) correction. Closing the arches without bite increased anisocoria and reduced performance in the Spinnler-Tognoni matrices test, as well as the mydriasis induced by a haptic task. When the bite was interposed, anisocoria was reduced, while both performance and task-related mydriasis were enhanced. Since pupil size is considered a proxy of the LC activity, these results suggest that asymmetric occlusion biases the LC discharge and the hemispheric excitability, possibly via a sensorimotor trigeminal imbalance. Removing the anisocoria through bite correction re-establishes a symmetric LC discharge, improving performance and enhancing task-related mydriasis. Therefore, occlusal balancing may represent a tool for improving subjective performance and may be exploited for training and rehabilitative purposes.

Unbalanced Occlusion Modifies the Pattern of Brain Activity During Execution of a Finger to Thumb Motor Task.

In order to assess possible influences of occlusion on motor performance, we studied by functional magnetic resonance imaging (fMRI) the changes in the blood oxygenation level dependent (BOLD) signal induced at brain level by a finger to thumb motor task in a population of subjects characterized by an asymmetric activation of jaw muscles during clenching (malocclusion). In these subjects, appropriate occlusal correction by an oral orthotic (bite) reduced the masticatory asymmetry. The finger to thumb task was performed while the subject's dental arches were touching, in two conditions: (a) with the teeth in direct contact (Bite OFF) and (b) with the bite interposed between the arches (Bite ON). Both conditions required only a very slight activation of masticatory muscles. Maps of the BOLD signal recorded during the movement were contrasted with the resting condition (activation maps). Between conditions comparison of the activation maps (Bite OFF/Bite ON) showed that, in Bite OFF, the BOLD signal was significantly higher in the trigeminal sensorimotor region, the premotor cortex, the cerebellum, the inferior temporal and occipital cortex, the calcarine cortex, the precuneus on both sides, as well as in the right posterior cingulate cortex. These data are consistent with the hypothesis that malocclusion makes movement performance more difficult, leading to a stronger activation of (a) sensorimotor areas not dealing with the control of the involved body part, (b) regions planning the motor sequence, and (c) the cerebellum, which is essential in motor coordination. Moreover, the findings of a higher activation of temporo-occipital cortex and precuneus/cingulus, respectively, suggest that, during malocclusion, the movement occurs with an increased visual imagery activity, and requires a stronger attentive effort.

Short-Term Effects of Chewing on Task Performance and Task-Induced Mydriasis: Trigeminal Influence on the Arousal Systems.

Trigeminal input to the ascending activating system is important for the maintenance of arousal and may affect the discharge of the noradrenergic neurons of the locus coeruleus (LC), whose activity influences both vigilance state and pupil size, inducing mydriasis. For this reason, pupil size evaluation is now considered an indicator of LC activity. Since mastication activates trigeminal afferent neurons, the aims of the present study, conducted on healthy adult participants, were to investigate whether chewing a bolus of different hardness may: (1) differentially affect the performance on a cognitive task (consisting in the retrieval of specific target numbers within numerical matrices) and (2) increase the dilatation of the pupil (mydriasis) induced by a haptic task, suggesting a change in LC activation. Results show that chewing significantly increased both the velocity of number retrieval (without affecting the number of errors) and the mydriasis associated with the haptic task, whereas simple task repetition did not modify either retrieval or mydriasis. Handgrip exercise, instead, significantly decreased both parameters. Effects were significantly stronger and longer lasting when subjects chewed hard pellets. Finally, chewing-induced improvements in performance and changes in mydriasis were positively correlated, which suggests that trigeminal signals enhanced by chewing may boost the cognitive performance by increasing LC activity.

Oral Implant-Prostheses: New Teeth for a Brighter Brain.

Several studies have demonstrated that chewing can be regarded as a preventive measure for cognitive impairment, whereas masticatory deficiency, associated with soft-diet feeding, is a risk factor for the development of dementia. At present the link between orofacial sensorimotor activity and cognitive functions is unknown. In subjects with unilateral molar loss we have shown asymmetries in both pupil size and masticatory muscles electromyographic (EMG) activity during clenching: the molar less side was characterized by a lower EMG activity and a smaller pupil. Since implant-prostheses, greatly reduced both the asymmetry in EMG activity and in pupil's size, trigeminal unbalance, leading to unbalance in the activity of the Locus Coeruleus (LC), may be responsible for the pupil's asymmetry. According to the findings obtained in animal models, we propose that the different activity of the right and left LC may induce an asymmetry in brain activity, thus leading to cognitive impairment. According to this hypothesis, prostheses improved the performance in a complex sensorimotor task and increased the mydriasis associated with haptic tasks. In conclusion, the present study indicates that the implant-prosthesis therapy, which reduces the unbalance of trigeminal proprioceptive afferents and the asymmetry in pupil's size, may improve arousal, boosting performance in a complex sensorimotor task.