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Abstract Background The gut microbiota (GM) plays a critical role in regulating human physiology, with dysbiosis linked to various diseases, including heart failure (HF). HF is a complex syndrome with a significant global health impact, as its incidence doubles with each decade of life, and its prevalence peaks in individuals over 80 years. A bidirectional interaction exists between GM and HF, where alterations in gut health can worsen the disease’s progression. Main body The “gut hypothesis of HF” suggests that HF-induced changes, such as reduced intestinal perfusion and altered gut motility, negatively impact GM composition, leading to increased intestinal permeability, the release of GM-derived metabolites into the bloodstream, and systemic inflammation. This process creates a vicious cycle that further deteriorates heart function. GM-derived metabolites, including trimethylamine N-oxide (TMAO), short-chain fatty acids (SCFAs), and secondary bile acids (BAs), can influence gene expression through epigenetic mechanisms, such as DNA methylation and histone modifications. These epigenetic changes may play a crucial role in mediating the effects of dysbiotic gut microbial metabolites, linking them to altered cardiac health and contributing to the progression of HF. This process is particularly relevant in older individuals, as the aging process itself has been associated with both dysbiosis and cumulative epigenetic alterations, intensifying the interplay between GM, epigenetic changes, and HF, and further increasing the risk of HF in the elderly. Conclusion Despite the growing body of evidence, the complex interplay between GM, epigenetic modifications, and HF remains poorly understood. The dynamic nature of epigenetics and GM, shaped by various factors such as age, diet, and lifestyle, presents significant challenges in elucidating the precise mechanisms underlying this complex relationship. Future research should prioritize innovative approaches to overcome these limitations. By identifying specific metabolite-induced epigenetic modifications and modulating the composition and function of GM, novel and personalized therapeutic strategies for the prevention and/or treatment of HF can be developed. Moreover, targeted research focusing specifically on older individuals is crucial for understanding the intricate connections between GM, epigenetics, and HF during aging.

Abstract Affective Touch is characterized by both emotional and arousing dimensions that rely on specific features of a gentle human caress. In this study, we investigated whether and how both the nature of the touching effector (Human hand vs. Artificial hand) and touch type (Dynamic vs. Static) influenced the participants’ pupil dilation and their subjective experience during tactile stimulation. We observed that when participants received a dynamic touch, their pupil dilation increased more when the touch was produced by a human compared to an artificial hand. This discrimination was not present for static touch. Also, dynamic touch given by a human hand invoked a supralinear enhancement of pupil dilation indicating that the combination of these two features induced a stronger autonomic activation than the summed effects of each separately. Moreover, this specific type of touch was perceived as the most pleasant compared to all other tactile stimulations. Overall, our results suggest that pupil dilation could reflect the pleasant experience of human-to-human tactile interactions, supporting the notion that the autonomic nervous system is responsive to the emotional and hedonic aspects associated with Affective Touch as a part of a complex and holistic social experience, rather than solely reacting to its low-level sensory properties.

Key Clinical Message Posterior glottic lesions resembling granulomas unresponsive to conservative treatment should raise suspicion of a neoplastic condition. Although surgery is rarely recommended for arytenoid granulomas due to their high recurrence rate, histological evaluation is mandatory in cases of uncertain diagnosis. Clinicians should be aware that, although very rare, a laryngeal neuroendocrine tumor occurring in the posterior glottis can mimic the appearance of an idiopathic granuloma, presenting a diagnostic challenge.

Abstract Accessible SARS-CoV-2-specific immunoassays may inform clinical management in people with HIV, particularly in case of persisting immunodysfunction. We prospectively studied their application in vaccine recipients with HIV, purposely including participants with a history of advanced HIV infection. Participants received one (n = 250), two (n = 249) or three (n = 42) doses of the BNT162b2 vaccine. Adverse events were documented through questionnaires. Sample collection occurred pre-vaccination and a median of 4 weeks post-second dose and 14 weeks post-third dose. Anti-spike and anti-nucleocapsid antibodies were measured with the Roche Elecsys chemiluminescence immunoassays. Neutralising activity was evaluated using the GenScript cPass surrogate virus neutralisation test, following validation against a Plaque Reduction Neutralization Test. T-cell reactivity was assessed with the Roche SARS-CoV-2 IFNγ release assay. Primary vaccination (2 doses) was well tolerated and elicited measurable anti-spike antibodies in 202/206 (98.0%) participants. Anti-spike titres varied widely, influenced by previous SARS-CoV-2 exposure, ethnicity, intravenous drug use, CD4 counts and HIV viremia as independent predictors. A third vaccine dose significantly boosted anti-spike and neutralising responses, reducing variability. Anti-spike titres > 15 U/mL correlated with neutralising activity in 136/144 paired samples (94.4%). Three participants with detectable anti-S antibodies did not develop cPass neutralising responses post-third dose, yet displayed SARS-CoV-2 specific IFNγ responses. SARS-CoV-2 vaccination is well-tolerated and immunogenic in adults with HIV, with responses improving post-third dose. Anti-spike antibodies serve as a reliable indicator of neutralising activity. Discordances between anti-spike and neutralising responses were accompanied by detectable IFN-γ responses, underlining the complexity of the immune response in this population.

Summary: Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. Funding: The Wellcome Trust, the MRC.

Abstract Sound localization is essential to perceive the surrounding world and to interact with objects. This ability can be learned across time, and multisensory and motor cues play a crucial role in the learning process. A recent study demonstrated that when training localization skills, reaching to the sound source to determine its position reduced localization errors faster and to a greater extent as compared to just naming sources’ positions, despite the fact that in both tasks, participants received the same feedback about the correct position of sound sources in case of wrong response. However, it remains to establish which features have made reaching to sound more effective as compared to naming. In the present study, we introduced a further condition in which the hand is the effector providing the response, but without it reaching toward the space occupied by the target source: the pointing condition. We tested three groups of participants (naming, pointing, and reaching groups) each while performing a sound localization task in normal and altered listening situations (i.e. mild-moderate unilateral hearing loss) simulated through auditory virtual reality technology. The experiment comprised four blocks: during the first and the last block, participants were tested in normal listening condition, while during the second and the third in altered listening condition. We measured their performance, their subjective judgments (e.g. effort), and their head-related behavior (through kinematic tracking). First, people’s performance decreased when exposed to asymmetrical mild-moderate hearing impairment, more specifically on the ipsilateral side and for the pointing group. Second, we documented that all groups decreased their localization errors across altered listening blocks, but the extent of this reduction was higher for reaching and pointing as compared to the naming group. Crucially, the reaching group leads to a greater error reduction for the side where the listening alteration was applied. Furthermore, we documented that, across blocks, reaching and pointing groups increased the implementation of head motor behavior during the task (i.e., they increased approaching head movements toward the space of the sound) more than naming. Third, while performance in the unaltered blocks (first and last) was comparable, only the reaching group continued to exhibit a head behavior similar to those developed during the altered blocks (second and third), corroborating the previous observed relationship between the reaching to sounds task and head movements. In conclusion, this study further demonstrated the effectiveness of reaching to sounds as compared to pointing and naming in the learning processes. This effect could be related both to the process of implementing goal-directed motor actions and to the role of reaching actions in fostering the implementation of head-related motor strategies.

Abstract Spatial perspective and identity of visual bodily stimuli are two key cues for the self-other distinction. However, how they emerge into visual awareness is largely unknown. Here, self- or other-hands presented in first- or third-person perspective were compared in a breaking-Continuous Flash Suppression paradigm (Experiment 1) measuring the time the stimuli need to access visual awareness, and in a Binocular Rivalry paradigm (Experiment 2), measuring predominance in perceptual awareness. Results showed that, irrespectively of identity, first-person perspective speeded up the access, whereas the third-person one increased the dominance. We suggest that the effect of first-person perspective represents an unconscious prioritization of an egocentric body coding important for visuomotor control. On the other hand, the effect of third-person perspective indicates a conscious advantage of an allocentric body representation fundamental for detecting the presence of another intentional agent. Summarizing, the emergence of self-other distinction into visual awareness would strongly depend on the interplay between spatial perspectives, with an inverse prioritization before and after conscious perception. On the other hand, identity features might rely on post-perceptual processes.

Abstract Interpersonal touch is intrinsically reciprocal since it entails a person promoting and another receiving the touch. While several studies have investigated the beneficial effects of receiving affective touch, the affective experience of caressing another individual remains largely unknown. Here, we investigated the hedonic and autonomic responses (skin conductance and heart rate) in the person promoting affective touch. We also examined whether interpersonal relationship, gender, and eye contact modulate these responses. As expected, caressing the partner was perceived as more pleasant than caressing a stranger, especially if the affective touch occurred together with mutual eye contact. Promoting affective touch to the partner also resulted in a decrease of both autonomic responses and anxiety levels, suggesting the occurrence of a calming effect. Additionally, these effects were more pronounced in females compared to males, indicating that hedonic and autonomic aspects of affective touch are modulated by both social relationship and gender. These findings show for the first time that caressing a beloved one is not only pleasant but also reduces autonomic responses and anxiety in the person promoting the touch. This might suggest that affective touch has an instrumental role for romantic partners in promoting and reinforcing their affective bonding.

Abstract Resting-state functional magnetic resonance imaging (rs-fMRI) has become an increasingly popular technique. This technique can assess several features of brain connectivity, such as inter-regional temporal correlation (functional connectivity), from which graph measures of network organization can be derived. However, these measures are prone to a certain degree of variability depending on the analytical steps during preprocessing. Many studies have investigated the effect of different preprocessing steps on functional connectivity measures; however, no study investigated whether different structural reconstructions lead to different functional connectivity metrics. Here, we evaluated the impact of different structural segmentation strategies on functional connectivity outcomes. To this aim, we compared different metrics computed after two different registration strategies. The first strategy used structural information from the 3D T1-weighted image (unimodal), while the second strategy implemented a multimodal approach, where an additional registration step used the information from the T2-weighted image. The impact of these different approaches was evaluated on a sample of 58 healthy adults. As expected, different approaches led to significant differences in structural measures (i.e., cortical thickness, volume, and gyrification index), with the maximum impact on the insula cortex. However, these differences were only slightly translated to functional metrics. We reported no differences in graph measures and seed-based functional connectivity maps, but slight differences in the insula when we compared the mean functional strength for each parcel. Overall, these results suggested that functional metrics are only slightly different when using a unimodal compared to a multimodal approach, while the structural output can be significantly affected.

Abstract Spontaneous brain activity, measured with resting state fMRI (R-fMRI), is correlated among regions that are co-activated by behavioral tasks. It is unclear, however, whether spatial patterns of spontaneous activity within a cortical region correspond to spatial patterns of activity evoked by specific stimuli, actions, or mental states. The current study investigated the hypothesis that spontaneous activity in motor cortex represents motor patterns commonly occurring in daily life. To test this hypothesis 15 healthy participants were scanned while performing four different hand movements. Three movements (Grip, Extend, Pinch) were ecological involving grip and grasp hand movements; one control movement involving the rotation of the wrist was not ecological and infrequent (Shake). They were also scanned at rest before and after the execution of the motor tasks (resting-state scans). Using the task data, we identified movement-specific patterns in the primary motor cortex. These task-defined patterns were compared to resting-state patterns in the same motor region. We also performed a control analysis within the primary visual cortex. We found that spontaneous activity patterns in the primary motor cortex were more like task patterns for ecological than control movements. In contrast, there was no difference between ecological and control hand movements in the primary visual area. These findings provide evidence that spontaneous activity in human motor cortex forms fine-scale, patterned representations associated with behaviors that frequently occur in daily life.

Key Clinical Message Baricitinib, a Janus kinase inhibitor (JAK‐inhibitor), seems to contribute to an improvement of a child affected by Aicardi‐Goutières syndrome (AGS), reducing the interferon score and determining a recovery of cognitive, communicative, and relational dysfunctions, while the gross motor deficit persisted. Abstract We report the treatment response to baricitinib, a JAK‐inhibitor, in a 4‐year‐old girl affected by Aicardi‐Goutières syndrome (AGS2, RNASEH2B mutation). Using quantitative measures, we detected a significant amelioration characterized by a complete recovery of cognitive, communicative, and relational skills after 8 and 16 months from the beginning of therapy.

Key clinical message The recurrence of respiratory symptoms without a clear clinical reason in children can be secondary to the presence of an unknown foreign body of the airways. In such cases, endoscopy of the airways is always necessary, regardless of the patient's age. Abstract The management of foreign bodies of the pediatric airway can be challenging. The clinical presentation may vary and, in case of recurrent respiratory symptoms without a clear clinical cause, the presence of a foreign body of the airway should be suspected. We describe the case of a 13‐month‐old patient, weight 11 kg, with a misdiagnosed subglottic foreign body causing dysphonia and worsening respiratory distress, removed by means of a direct laryngotracheoscopy in tubeless general anesthesia in spontaneous breathing.

Abstract Vegetables represent a major source of Ni exposure. Environmental contamination and cultural practices can increase Ni amount in tomato posing significant risk for human health. This work assesses the tomato (Solanum lycopersicum L.) response to Ni on the agronomic yield of fruits and the related production of allergens. Two cultivars were grown in pots amended with Ni 0, 30, 60, 120, and 300 mg kg−1, respectively. XRF and ICP-MS analyses highlighted the direct increase of fruit Ni content compared to soil Ni, maintaining a stable biomass. Leaf water content increased at Ni 300 mg kg−1. Total protein content and individual allergenic components were investigated using biochemical (RP-HPLC and N-terminal amino acid sequencing) and immunological (inhibition tests of IgE binding by SPHIAa assay on the FABER testing system) methodologies. Ni affected the fruit tissue concentration of pathogenesis-related proteins and relevant allergens (LTP, profilin, Bet v 1-like protein and TLP). This study elucidates for the first time that tomato reacts to exogenous Ni, uptaking the metal while changing its allergenic profiles, with potential double increasing of exposure risks for consumers. This evidence highlighted the importance of adequate choice of low-Ni tomato cultivars and practices to reduce Ni uptake by potentially contaminated matrices.

We report on findings from the first randomized controlled pilot trial of virtual reality exposure therapy (VRET) developed specifically for reducing social anxiety associated with stuttering. People who stutter with heightened social anxiety were recruited from online adverts and randomly allocated to receive VRET (n = 13) or be put on a waitlist (n = 12). Treatment was delivered remotely using a smartphone-based VR headset. It consisted of three weekly sessions, each comprising both performative and interactive exposure exercises, and was guided by a virtual therapist. Multilevel model analyses failed to demonstrate the effectiveness of VRET at reducing social anxiety between pre- and post-treatment. We found similar results for fear of negative evaluation, negative thoughts associated with stuttering, and stuttering characteristics. However, VRET was associated with reduced social anxiety between post-treatment and one-month follow-up. These pilot findings suggest that our current VRET protocol may not be effective at reducing social anxiety amongst people who stutter, though might be capable of supporting longer-term change. Future VRET protocols targeting stuttering-related social anxiety should be explored with larger samples. The results from this pilot trial provide a solid basis for further design improvements and for future research to explore appropriate techniques for widening access to social anxiety treatments in stuttering.

Abstract Background As often seen in many chronic diseases, the disease impact on patients also induces a significant impact on the quality of life (QoL) of caregivers. Caregivers are the ones who are really willing to offer care in the general approach of many aspects of the disease, including the awareness of the diseases itself, the daily management of therapy, and all the potential challenges that living with a chronic disease can include. The main objectives of the study were to explore the perspectives and views of caregivers of Behçet’s syndrome (BS) patients, to study their level of awareness on the disease and the impact that BS may have on their lives by means of a survey co-designed with caregivers and patients with this purpose. A survey was entirely co-designed with a panel of caregivers of patients living with BS patients. Results Results show that BS caregivers organise their life according to the needs of the patient, that they (79%) considered themselves as helpful for the patient and 53% of them replied that they can freely express their emotions. Notably, 70% and 68% of the respondents reported they renounced with a variable frequency to sexual relationships due to concerns regarding the health of the partner or to the partner’s illness, respectively. The majority (79%) of respondents indicated that they are familiar with the treatment taken by the patients and that 68% deal with the administration of some medicines. In terms of awareness, a good percentage (64%) of respondents reported to understand the illness and, in terms of education, 68% of participants are willing to take part in training programmes dedicated to BS. Conclusions The results of this survey contribute to provide new information on BS caregivers and on their important role, and to identify areas in which new initiatives could provide BS caregivers (and therefore patients) with tools and knowledge that can empower them in reducing the burden of the disease on their lives, on families, and on the patient.

Abstract We conducted a cross-sectional study to assess the likelihood of returning for routine breast cancer screening among women who have experienced a false-positive result (FPR) and to describe the possible individual and organizational factors that could influence subsequent attendance to the screening program. Several information were collected on demographic and clinical characteristics data. Electronic data from 2014 to 2016 related to breast screening program of the Local Health Authority (LHA) of Bologna (Italy) of women between 45 and 74 years old were reviewed. A total of 4847 women experienced an FPR during mammographic screening and were recalled to subsequent round; 80.2% adhered to the screening. Mean age was 54.2 ± 8.4 years old. Women resulted to be less likely to adhere to screening if they were not-Italian (p = 0.001), if they lived in the Bologna district (p

Abstract This case report describes a peculiar and innovative fixing procedure with a Poly‐D,L‐lactic acid (PDLLA) polymer in the unusual case of magnet dislodgment and rupture of the cochlear implant (CI) silicone sheath holding the magnet.

Abstract Clinical data provided by the patient are not always reliable or could be difficult to collect. In this case, a difficult history collection resulted in a diagnostic delay. Major complications were avoided performing an urgent surgical intervention.

Abstract We tested the hypothesis that circulating CXCL10 and IL-6 in donor after brain death provide independent additional predictors of graft outcome. From January 1, 2010 to June 30, 2012 all donors after brain death managed by the NITp (n = 1100) were prospectively included in this study. CXCL10 and IL-6 were measured on serum collected for the crossmatch at the beginning of the observation period. Graft outcome in recipients who received kidney (n = 1325, follow-up 4.9 years), liver (n = 815, follow-up 4.3 years) and heart (n = 272, follow-up 5 years) was evaluated. Both CXCL-10 and IL-6 showed increased concentration in donors after brain death. The intensive care unit stay, the hemodynamic instability, the cause of death, the presence of risk factors for cardiovascular disease and the presence of ongoing infection resulted as significant determinants of IL-6 and CXCL10 donor concentrations. Both cytokines resulted as independent predictors of Immediate Graft Function. Donor IL-6 or CXCL10 were associated with graft failure after liver transplant, and acted as predictors of recipient survival after kidney, liver and heart transplantation. Serum donor IL-6 and CXCL10 concentration can provide independent incremental prediction of graft outcome among recipients followed according to standard clinical practice.

Abstract An increased incidence of narcolepsy type 1 (NT1) was observed in Scandinavia following the 2009–2010 influenza Pandemrix vaccination. The association between NT1 and HLA-DQB1*06:02:01 supported the view of the vaccine as an etiological agent. A/H1N1 hemagglutinin (HA) is the main antigenic determinant of the host neutralization antibody response. Using two different immunoassays, the Luciferase Immunoprecipitation System (LIPS) and Radiobinding Assay (RBA), we investigated HA antibody levels and affinity in an exploratory and in a confirmatory cohort of Swedish NT1 patients and healthy controls vaccinated with Pandemrix. HA antibodies were increased in NT1 patients compared to controls in the exploratory (LIPS p = 0.0295, RBA p = 0.0369) but not in the confirmatory cohort (LIPS p = 0.55, RBA p = 0.625). HA antibody affinity, assessed by competition with Pandemrix vaccine, was comparable between patients and controls (LIPS: 48 vs. 39 ng/ml, p = 0.81; RBA: 472 vs. 491 ng/ml, p = 0.65). The LIPS assay also detected higher HA antibody titres as associated with HLA-DQB1*06:02:01 (p = 0.02). Our study shows that following Pandemrix vaccination, HA antibodies levels and affinity were comparable NT1 patients and controls and suggests that HA antibodies are unlikely to play a role in NT1 pathogenesis.

Abstract The current framework of radiological protection of occupational exposed medical workers reduced the eye-lens equivalent dose limit from 150 to 20 mSv per year requiring an accurate dosimetric evaluation and an increase understanding of radiation induced effects on Lens cells considering the typical scenario of occupational exposed medical operators. Indeed, it is widely accepted that genomic damage of Lens epithelial cells (LEC) is a key mechanism of cataractogenesis. However, the relationship between apoptosis and cataractogenesis is still controversial. In this study biological and physical data are combined to improve the understanding of radiation induced effects on LEC. To characterize the occupational exposure of medical workers during angiographic procedures an INNOVA 4100 (General Electric Healthcare) equipment was used (scenario A). Additional experiments were conducted using a research tube (scenario B). For both scenarios, the frequencies of binucleated cells, micronuclei, p21-positive cells were assessed with different doses and dose rates. A Monte-Carlo study was conducted using a model for the photon generation with the X-ray tubes and with the Petri dishes considering the two different scenarios (A and B) to reproduce the experimental conditions and validate the irradiation setups to the cells. The simulation results have been tallied using the Monte Carlo code MCNP6. The spectral characteristics of the different X-ray beams have been estimated. All irradiated samples showed frequencies of micronuclei and p21-positive cells higher than the unirradiated controls. Differences in frequencies increased with the delivered dose measured with Gafchromic films XR-RV3. The spectrum incident on eye lens and Petri, as estimated with MCNP6, was in good agreement in the scenario A (confirming the experimental setup), while the mean energy spectrum was higher in the scenario B. Nevertheless, the response of LEC seemed mainly related to the measured absorbed dose. No effects on viability were detected. Our results support the hypothesis that apoptosis is not responsible for cataract induced by low doses of X-ray (i.e. 25 mGy) while the induction of transient p21 may interfere with the disassembly of the nuclear envelop in differentiating LEC, leading to cataract formation. Further studies are needed to better clarify the relationship we suggested between DNA damage, transient p21 induction and the inability of LEC enucleation.

Abstract Silent sinus syndrome (SSS) is a rare clinical condition, commonly unilateral, secondary to the obstruction of the osteomeatal complex, subsequent negative pressure in the maxillary sinus, and collapse of the orbit floor and sinus walls. We describe a case of unilateral SSS treated by means of functional endoscopic sinus surgery.

Introduction: International guidelines include transoral robotic surgery (TORS) as an option for selected oropharyngeal squamous cell carcinomas (OPSCCs). In the perspective of treatment de-intensification, many surgeons have started recommending and performing TORS preferentially in p16- positive OPSCC in order to reduce the long-term morbidity related to chemoradiotherapy. The aim of the present review is to analyze the current evidence supporting the above-cited strategy. Materials and Methods: The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results: Twenty-two studies were included in this review, with a total of 3992 patients treated with primary TORS. The majority of patients were classified as HPV+ (n = 3655, 91.6%), and 8.2% (n = 327) as HPV−. The HPV status was unknown in only 10 (0.3%) patients. In particular, only five of the included studies compared survival outcomes of HPV−positive patients with HPV−negative ones treated with primary TORS, and only two of these found a significant improvement in survival in the HPV−driven cohort. Discussion: The current literature does not clarify whether HPV+ OPSCCs treated with TORS, alone or with adjuvant treatments, are associated with a better oncologic and/or functional outcome compared to those treated with radio- or chemoradiotherapy. However, TORS alone obtained good oncological outcomes in a high percentage of cases in the reviewed series. Recent data, on the other hand, suggest that TORS could represent a promising strategy for intensifying treatments in HPV− OPSCC.

Abstract Congenital dacryocystocele is a rare clinical condition, more commonly unilateral, secondary to the defective canalization of the nasolacrimal duct. In case of failure of conservative treatment, surgical marsupialization is recommended. We describe the case of a 40‐day‐old male newborn treated by means of microdebrider marsupialization.

Older children and teenagers with bilateral cochlear implants often have poor spatial hearing because they cannot fuse sounds from the two ears. This deficit jeopardizes speech and language development, education, and social well-being. The lack of protocols for fitting bilateral cochlear implants and resources for spatial-hearing training contribute to these difficulties. Spatial hearing develops with bilateral experience. A large body of research demonstrates that sound localisation can improve with training, underpinned by plasticity-driven changes in the auditory pathways. Generalizing training to non-trained auditory skills is best achieved by using a multi-modal (audio-visual) implementation and multi-domain training tasks (localisation, speech-in-noise, and spatial music). The goal of this work was to develop a package of virtual-reality games (BEARS, Both EARS) to train spatial hearing in young people (8–16 years) with bilateral cochlear implants using an action-research protocol. The action research protocol used formalized cycles for participants to trial aspects of the BEARS suite, reflect on their experiences, and in turn inform changes in the game implementations. This participatory design used the stakeholder participants as co-creators. The cycles for each of the three domains (localisation, spatial speech-in-noise, and spatial music) were customized to focus on the elements that the stakeholder participants considered important. The participants agreed that the final games were appropriate and ready to be used by patients. The main areas of modification were: the variety of immersive scenarios to cover age range and interests, the number of levels of complexity to ensure small improvements were measurable, feedback, and reward schemes to ensure positive reinforcement, and an additional implementation on an iPad for those who had difficulties with the headsets due to age or balance issues. The effectiveness of the BEARS training suite will be evaluated in a large-scale clinical trial to determine if using the games lead to improvements in speech-in-noise, quality of life, perceived benefit, and cost utility. Such interventions allow patients to take control of their own management reducing the reliance on outpatient-based rehabilitation. For young people, a virtual-reality implementation is more engaging than traditional rehabilitation methods, and the participatory design used here has ensured that the BEARS games are relevant.

Abstract Management of upper retropharyngeal abscesses in children is challenging. In surgical cases, ultrasound‐assisted intra‐operative procedures may be helpful to reach peculiar locations, thus reducing surgical morbidity and complications rate.

Abstract Surgical procedures requiring close contact with saliva, such as salivary gland surgery, may determine the risk of spreading the SARS‐CoV‐2 infection. The use of PPE and isolation settings are mandatory to protect health workers.

Extracellular vesicles (EVs) are implicated in the crosstalk between adipocytes and other metabolic organs, and an altered biological cargo has been observed in EVs from human obese adipose tissue (AT). Yet, the role of adipocyte-derived EVs in pancreatic β cells remains to be determined. Here, we explored the effects of EVs released from adipocytes isolated from both rodents and humans and human AT explants on survival and function of pancreatic β cells and human pancreatic islets. EVs from healthy 3T3-L1 adipocytes increased survival and proliferation and promoted insulin secretion in INS-1E β cells and human pancreatic islets, both those untreated or exposed to cytokines or glucolipotoxicity, whereas EVs from inflamed adipocytes caused β cell death and dysfunction. Human lean adipocyte-derived EVs produced similar beneficial effects, whereas EVs from obese AT explants were harmful for human EndoC-βH3 β cells. We observed differential expression of miRNAs in EVs from healthy and inflamed adipocytes, as well as alteration in signaling pathways and expression of β cell genes, adipokines, and cytokines in recipient β cells. These in vitro results suggest that, depending on the physiopathological state of AT, adipocyte-derived EVs may influence β cell fate and function.

This research note introduces a new global dataset, the Citizenship, Migration and Mobility in a Pandemic (CMMP). The dataset features systematic information on border closures and domestic lockdowns in response to the COVID-19 outbreak in 211 countries and territories worldwide from 1 March to 1 June 2020. It documents the evolution of the types and scope of international travel bans and exceptions to them, as well as internal measures including limitations of non-essential movement and curfews in 27 countries. CMMP can be used to study causes and effects of policy restrictions to migration and mobility during the COVID-19 pandemic. The dataset is available through Cadmus and will be regularly updated until the last pandemic-related restriction has been lifted or become long-term.

Eukaryotes have evolved various quality control mechanisms to promote proteostasis in the endoplasmic reticulum (ER). Selective removal of certain ER domains via autophagy (termed as ER-phagy) has emerged as a major quality control mechanism. However, the degree to which ER-phagy is employed by other branches of ER-quality control remains largely elusive. Here, we identify a cytosolic protein, C53, that is specifically recruited to autophagosomes during ER-stress, in both plant and mammalian cells. C53 interacts with ATG8 via a distinct binding epitope, featuring a shuffled ATG8 interacting motif (sAIM). C53 senses proteotoxic stress in the ER lumen by forming a tripartite receptor complex with the ER-associated ufmylation ligase UFL1 and its membrane adaptor DDRGK1. The C53/UFL1/DDRGK1 receptor complex is activated by stalled ribosomes and induces the degradation of internal or passenger proteins in the ER. Consistently, the C53 receptor complex and ufmylation mutants are highly susceptible to ER stress. Thus, C53 forms an ancient quality control pathway that bridges selective autophagy with ribosome-associated quality control in the ER.

Abstract Background Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing. Results In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8–51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6). Conclusions Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.

The increase in the number of people who choose to have medical procedures done to improve their appearance may be due to changed social and cultural factors in modern society, as well to the ease of access and affordable costs of these cosmetic treatments.

Abstract Laryngeal granulomas are ascribed to laryngopharyngeal reflux, voice abuse, and endotracheal intubation, but their pathogenesis is controversial. A recurrent giant granuloma causing dyspnea occurred after a severe psychological stress and was successfully treated by surgery, steroid injection, and psychotherapy. This case highlights the role of psychological stress in granulomas pathogenesis.

When treating children with Cerebral Palsy (CP), computational simulations based on musculoskeletal models have a great potential in assisting the clinical decision-making process towards the most promising treatments. In particular, predictive simulations could be used to predict and compare the functional outcome of a series of candidate interventions. In order to be able to benefit from these predictive simulations however, it is important to know how much information about the post-treatment patient's motor control could be gathered from data available before the intervention. Within this paper, we quantified how much of the muscle activity measured after a treatment could be explained by subject-specific muscle synergies computed from EMG data collected before the intervention. We also investigated whether generic synergies could be used, in case no EMG data is available when running predictive simulations, to reproduce both pre- and post-treatment muscle activity in children with CP. Subject-specific synergies proved to be a good indicator of the patient's post-treatment motor control, explaining on average more than 85% of the post-treatment muscle activity, compared to an average of 94% when applied to the original pre-treatment data. Generic synergies explained 84% of the pre-treatment and 83% of the post-treatment muscle activity on average, but performed relatively well for patients with low selective motor control and poorly in patients with more selectivity. Our results suggest that subject-specific muscle synergies computed from pre-treatment EMG data could be used with confidence to represent the post-treatment motor control of children with CP during walking. In addition, when performing simulations involving patients with a low selective motor control, generic synergies could be a valid alternative.

Multi-scale simulations, combining muscle and joint contact force (JCF) from musculoskeletal simulations with adaptive mechanobiological finite element analysis, allow to estimate musculoskeletal loading and predict femoral growth in children. Generic linearly scaled musculoskeletal models are commonly used. This approach, however, neglects subject- and age-specific musculoskeletal geometry, e.g. femoral neck-shaft angle (NSA) and anteversion angle (AVA). This study aimed to evaluate the impact of proximal femoral geometry, i.e. altered NSA and AVA, on hip JCF and femoral growth simulations. Musculoskeletal models with NSA ranging from 120° to 150° and AVA ranging from 20° to 50° were created and used to calculate muscle and hip JCF based on the gait analysis data of a typically developing child. A finite element model of a paediatric femur was created from magnetic resonance images. The finite element model was morphed to the geometries of the different musculoskeletal models and used for mechanobiological finite element analysis to predict femoral growth trends. Our findings showed that hip JCF increase with increasing NSA and AVA. Furthermore, the orientation of the hip JCF followed the orientation of the femoral neck axis. Consequently, the osteogenic index, which is a function of cartilage stresses and defines the growth rate, barely changed with altered NSA and AVA. Nevertheless, growth predictions were sensitive to the femoral geometry due to changes in the predicted growth directions. Altered NSA had a bigger impact on the growth results than altered AVA. Growth simulations based on mechanobiological principles were in agreement with reported changes in paediatric populations.

Objective: The effects of botulinum toxin injections (BoNT) on health-related quality of life along the complex spectrum of spasticity needs further characterization to guide practitioners in a real-life therapeutic environment. Methods: In this study, we analyzed 50 consecutive and unselected patients with spasticity before and four weeks after re-injection of botulinum toxin. Health-related quality of life in terms of the EuroQol (EQ) as well as further motor and non-motor characteristics were assessed. Results: BoNT improved the EQ visual analog scale (EQ VAS). In addition, state of health and pain maxima improved. The EQ VAS improvement correlated with pre-injection characteristics of the EQ VAS and life satisfaction in the “movement disorders” domain. Conclusion: EQ VAS is sensitive for monitoring HR-QoL outcomes in an unselected real life observational cohort. This study may inform future studies intended to validate prediction variables that could inform on HR-QoL effects of BoNT treatment in spasticity.

The 3D Tune-In Toolkit (3DTI Toolkit) is an open-source standard C++ library which includes a binaural spatialiser. This paper presents the technical details of this renderer, outlining its architecture and describing the processes implemented in each of its components. In order to put this description into context, the basic concepts behind binaural spatialisation are reviewed through a chronology of research milestones in the field in the last 40 years. The 3DTI Toolkit renders the anechoic signal path by convolving sound sources with Head Related Impulse Responses (HRIRs), obtained by interpolating those extracted from a set that can be loaded from any file in a standard audio format. Interaural time differences are managed separately, in order to be able to customise the rendering according the head size of the listener, and to reduce comb-filtering when interpolating between different HRIRs. In addition, geometrical and frequency-dependent corrections for simulating near-field sources are included. Reverberation is computed separately using a virtual loudspeakers Ambisonic approach and convolution with Binaural Room Impulse Responses (BRIRs). In all these processes, special care has been put in avoiding audible artefacts produced by changes in gains and audio filters due to the movements of sources and of the listener. The 3DTI Toolkit performance, as well as some other relevant metrics such as non-linear distortion, are assessed and presented, followed by a comparison between the features offered by the 3DTI Toolkit and those found in other currently available open- and closed-source binaural renderers.

When we successfully achieve willed actions, the feeling that our moving body parts belong to the self (i.e., body ownership) is barely required. However, how and to what extent the awareness of our own body contributes to the neurocognitive processes subserving actions is still debated. Here we capitalized on immersive virtual reality in order to examine whether and how body ownership influences motor performance (and, secondly, if it modulates the feeling of voluntariness). Healthy participants saw a virtual body either from a first or a third person perspective. In both conditions, they had to draw continuously straight vertical lines while seeing the virtual arm doing the same action (i.e., drawing lines) or deviating from them (i.e., drawing ellipses). Results showed that when there was a mismatch between the intended and the seen movements (i.e., participants had to draw lines but the avatar drew ellipses), motor performance was strongly "attracted" towards the seen (rather than the performed) movement when the avatar's body part was perceived as own (i.e., first person perspective). In support of previous studies, here we provide direct behavioral evidence that the feeling of body ownership modulates the interference of seen movements to the performed movements.

Background: New sources of insulin-secreting cells are strongly in demand for treatment of diabetes. Induced pluripotent stem cells (iPSCs) have the potential to generate insulin-producing cells (iβ). However, the gene expression profile and secretory function of iβ still need to be validated in comparison with native β cells. Methods: Two clones of human iPSCs, reprogrammed from adult fibroblasts through integration-free Sendai virus, were differentiated into iβ and compared with donor pancreatic islets and EndoC-βH1, an immortalized human β cell line. Results: Both clones of iPSCs differentiated into insulin + cells with high efficiency (up to 20%). iβ were negative for pluripotency markers (Oct4, Sox2, Ssea4) and positive for Pdx1, Nkx6.1, Chromogranin A, PC1/3, insulin, glucagon and somatostatin. iβ basally secreted C-peptide, glucagon and ghrelin and released insulin in response either to increasing concentration of glucose or a depolarizing stimulus. The comparison revealed that iβ are remarkably similar to donor derived islets in terms of gene and protein expression profile and similar level of heterogeneity. The ability of iβ to respond to glucose instead was more related to that of EndoC-βH1. Discussion: We demonstrated that insulin-producing cells generated from iPSCs recapitulate fundamental gene expression profiles and secretory function of native human β cells.

Objectives Surgical management of children with chronic otitis media with effusion (OME) includes tympanostomy tube insertion or adenoidectomy, alone or with myringotomy and tube insertion. The aim of this study was to compare the effectiveness of transoral microdebrider endoscopic-assisted adenoidectomy (TOMEA) and traditional adenoidectomy in the management of children with mild hearing loss due to OME and chronic adenoiditis. Methods This prospective, double-blind and controlled study involved 120 consecutive patients aged 4–12 years, who were randomised 1:1 to undergo TOMEA or traditional adenoidectomy under general anesthesia. All the patients underwent a complete otolaryngological examination, including nasopharyngeal fibre endoscopy (NFE), pneumatic otoscopy, otomicroscopy, tympanometry and supraliminar tonal audiometry, upon enrolment, and three and nine months postoperatively. Results There were no statistically significant differences in age or gender distribution between the TOMEA group (mean age, 4.9±1.1 years; 53.3% males) and the traditional adenoidectomy group (mean age, 5.3±0.9 years; 56.7% males). Both procedures led to a significant improvement in choanal patency (P

Hepatitis B virus (HBV) genotype E almost exclusively occurs in African people, and its presence is more commonly associated with the development of chronic HBV (CHB) infection. Moreover, an epidemiological link has been found between the distribution of HBV genotype E infection and African countries with high incidences of hepatocellular carcinoma. As part of a programme for the health assessment of migrants, we evaluated 358 young African subjects for HBV infection; 58.1% (208/358) were positive for an HBV marker, and 54 (25.5%) had CHB. Eighty-one percent of the CHB subjects were infected with HBV genotype E, with a median serum HBV-DNA of 3.2 (IQR: 2.7-3.6) logIU/ml. All patients had high serum HBsAg titres (10,899 [range 5,359-20,272] IU/ml), and no correlation was found between HBsAg titres and HBV-DNA plasma levels. RT sequence analysis showed the presence of a number of immune escape mutations: strains from all of the patients had a serine at HBsAg position 140; 3 also had T116N, Y100C, and P142L+S143L substitutions; and 1 had a G112R substitution. Six (18%) patients had stop-codons at position 216. In 5 of the 9 (26.5%) CHB patients, ultrasound liver biopsy, quantification of total intrahepatic HBV-DNA and cccDNA, and RT/HBsAg sequencing were performed. The median (IQR) total intrahepatic HBV-DNA was 766 (753-1139) copies/1000 cells, and the median (IQR) cccDNA was 17 (10-27) copies/1000 cells. Correlations were observed for both total intrahepatic HBV-DNA and cccDNA with serum HBV-DNA, while no correlation was found for the HBsAg titres. A difference of 2.5/1,000 nucleotides was found in the HBsAg sequences obtained from plasma and from liver tissue, with 3 cases of possible viral anatomical compartmentalization. In conclusion, a high rate of CHB infection due to the E genotype was demonstrated in a group of immigrants from Western Africa. An analysis of the viral strains obtained showed the virological characteristics of immune escape, which may be the cause of viral replication persistence. Moreover, a fair percentage of stop codon mutations were found. The lack of correlation between HBsAg titres and plasma or intrahepatic HBV-DNA found in these subjects suggests a pathway of virus production that is not linked to HBsAg secretion. Studies with a larger number of patients with CHB due to the E genotype are advisable to corroborate these observations.

This study showed that in adult Drosophila melanogaster, the type of sugar-either present within the crop lumen or in the bathing solution of the crop-had no effect on crop muscle contraction. What is important, however, is the volume within the crop lumen. Electrophysiological recordings demonstrated that exogenous applications of serotonin on crop muscles increases both the amplitude and the frequency of crop contraction rate, while adipokinetic hormone mainly enhances the crop contraction frequency. Conversely, octopamine virtually silenced the overall crop activity. The present study reports for the first time an analysis of serotonin effects along the gut-brain axis in adult D. melanogaster. Injection of serotonin into the brain between the interocellar area shows that brain applications of serotonin decrease the frequency of crop activity. Based on our results, we propose that there are two different, opposite pathways for crop motility control governed by serotonin: excitatory when added in the abdomen (i.e., directly bathing the crop) and inhibitory when supplied within the brain (i.e., by injection). Finally, our results point to a double brain-gut serotonergic circuitry suggesting that not only the brain can affect gut functions, but the gut can also affect the central nervous system. On the basis of our results, and data in the literature, a possible mechanism for these two discrete serotonergic functions is suggested.

Islet volume and endocrine pancreas architecture (islet size distribution) may be independent determinants of β-cell function. Furthermore, the accuracy of homeostatic model assessment (HOMA) indexes in predicting β-cell mass has never been assessed. Here we investigated the relationships between islet volume, islet density, and islet size distribution, estimated after pancreatic tissue digestion, with established indexes of β-cell function in humans. We included in this study 42 patients who were candidates for islet autotransplantation and had well-characterized glucose metabolism. Indexes of insulin secretion were calculated and compared with the islet volume, as a surrogate of β-cell mass, obtained after digestion of pancreas. Islet counting analysis showed considerable interindividual variation in islet density and size. Islet volume, but not density nor size, was the only independent determinant of β-cell function assessed by insulin HOMA β-cell. Islet volume was significantly reduced in the patients with overt hyperglycemia, but not in patients with impaired fasting glucose. Insulin HOMA β-cell predicted islet volume better than other measures of fasting insulin secretion. In conclusion, the present study documented a close direct relationship between indexes of β-cell function and islet volume in humans. The insulin HOMA β-cell provides a more reliable estimate of pancreatic islet volume than fasting glucose before islet isolation.

To investigate the effect of diabetes mellitus (DM) on disease-free and overall post-resection survival of patients with pancreatic ductal adenocarcinoma (PDAC).Prospective observational study on patients admitted for pancreatic disease from January 2008 to October 2012. DM was classified as recent-onset (

Islet transplantation is one of the most promising and effective therapies for restoring normoglycemia in type 1 diabetes (T1D) patients, but islet engraftment is one of the main obstacles hampering long-term success. Monitoring graft loss, caused either by immunological or nonimmunological events, occurring in the first phase after transplantation and at later stages of a patient's life is a very important issue. Among the imaging approaches previously applied, magnetic resonance imaging (MRI) monitoring of islet fate following labeling with superparamagnetic iron oxide agents yielded promising results. The aim of this study was to translate into patients the method of islet labeling and MRI monitoring developed in our preclinical setting and to compare imaging results with graft clinical outcome. Three T1D patients and one nondiabetic patient undergoing autotransplantation following subtotal pancreatectomy received Endorem ® -labeled islets. Patients were monitored by MRI and metabolically (HbA1c, exogenous insulin requirement, and C-peptide, TEF) at 1, 3, and 7 days following transplantation and once a month up to 10 months. Labeled transplanted islets appeared as hypointense areas scattered within the liver parenchyma, whose absolute number at 24 h after transplantation reflected the labeling efficiency. In patients #1 and #3 with good midterm graft function, MRI follow-up showed an important early loss of hypointense spots followed by a slow and progressive disappearance at later timepoints. Graft loss of function in patient #2 4 weeks after transplantation was associated with the complete disappearance of all hypointense signals. The autotransplanted patient, stably insulin free, showed no significant signal reduction during the first 3 days, followed by loss of spots similar to a patient with good midterm graft function. These results suggest that MRI monitoring of islet transplantation at early time points could represent a meaningful readout for helping in predicting transplant failure or success, but its relevance for mid/long-term islet function assessment appears evanescent.

Few long-term studies have yet described neuropsychological outcome in preterm twins. Our aim was to assess, by long-term evaluation, neuropsychological outcome in preterm twins in order to define a correct follow-up program. Our study was a cohort one, with an index and a comparison group. Neonatal medical records of all preterm newborns admitted to our centre between 1991 and 1997 were reviewed and selected patients were recalled. The sample population included two matched groups of children aged 6—12 years, 86 twins and 86 singletons, submitted to paediatric, neurological, psychological, and ophthalmological examinations. Inclusion criteria were twin pregnancy and gestational age 27—36 weeks for index group; same gestational age, but single pregnancy, for the comparison group. All children underwent paediatric and neuropsychiatric examinations, cognitive assessment, and psychological evaluation by standardized tests for screening of learning specific disorders and language difficulties, and finally, ophthalmological examination. In order to study their role in predicting neuropsychological outcome, we examined some perinatal prognostic factors by statistical analysis. Unfavourable neuropsychological outcome was observed in 55/172 (32%) children, with different prevalence in the two groups, 42/172 (24%) in twins and 13/172 (8%) in singletons. Statistical analysis performed for examined prognostic factors showed significant differences in neuropsychological outcome with regard only to gestational age < 32 weeks, low birth weight, intraventricular haemorrhage, and periventricular leukomalacia. The incidence of neuropsychological diseases in the two groups showed significant difference about language and learning difficulties. Our data suggest that preterm twins represent a particular high-risk category of premature babies, mostly regarding the risk of so-called “minimal brain dysfunction”, so a careful follow-up is recommended.

Hyperfamiliarity for unknown faces is a rare selective disorder that consists of the disturbing and abnormal feeling of familiarity for unknown faces, while recognition of known faces is normal. In one such patient we investigated with a multimodal neuroimaging design the hitherto undescribed neural signature associated with hyperfamiliarity feelings. Behaviorally, signal detection methods revealed that the patient's discrimination sensitivity between familiar and unfamiliar faces was significantly lower than that of matched controls, and her response criterion for familiarity decisions was significantly more liberal. At the neural level, while morphometric analysis and single-photon emission CT (SPECT) showed the atrophy and hypofunctioning of the left temporal regions, functional magnetic resonance imaging (fMRI) revealed that hyperfamiliarity feelings were selectively associated to enhanced activity in the right medial and inferior temporal cortices. We therefore characterize the neurofunctional signature of hyperfamiliarity for unknown faces as related to the loss of coordinated activity between the complementary face processing functions of the left and right temporal lobes.

ObjectiveThe aim of this study was to investigate whether Transcranial Magnetic Stimulation (TMS) applied over the medial line of the scalp affects the subjective perception of continuous pain induced by means of electric stimulation. In addition, we wanted to identify the point of stimulation where this effect was maximum.MethodsSuperficial electrical stimulation was used to induce continuous pain on the dominant hand. At the beginning of the experiment we reached a pain rating of 5 on an 11-point numeric rating scale (NRS; 0 = no pain and 10 = maximum tolerable pain) for each subject by setting individually the current intensity. The TMS (five pulses at increasing intensities) was applied on 5 equidistant points (one per session) over the medial line of the scalp in 13 healthy volunteers using a double-cone coil to stimulate underlying parts of the brain cortex. In every experimental session the painful stimulation lasted 45 minutes, during which pain and distress intensities NRS were recorded continuously. We calculated the effect of adaptation and the immediate effect of the TMS stimulation for all locations. Additionally, an ALE (Activation Likelihood Estimation) meta-analysis was performed to compare our results with the neuroimaging literature on subjective pain rating.ResultsTMS stimulation temporarily decreased the pain ratings, and pain adaptation was suppressed when applying the TMS over the FCz site on the scalp. No effect was found for distress ratings.ConclusionsThe present data suggest that the medial cortex in proximity of the cingulated gyrus has a causal role in adaptation mechanisms and in processing ongoing pain and subjective sensation of pain intensity.

A question still debated within cognitive neuroscience is whether signals present during actions significantly contribute to the emergence of human's body ownership. In the present study, we aimed at answer this question by means of a neuropsychological approach. We administered the classical rubber hand illusion paradigm to a group of healthy participants and to a group of neurological patients affected by a complete left upper limb hemiplegia, but without any propriceptive/tactile deficits. The illusion strength was measured both subjectively (i.e., by a self-report questionnaire) and behaviorally (i.e., the location of one's own hand is shifted towards the rubber hand). We aimed at examining whether, and to which extent, an enduring absence of movements related signals affects body ownership. Our results showed that patients displayed, respect to healthy participants, stronger illusory effects when the left (affected) hand was stimulated and no effects when the right (unaffected) hand was stimulated. In other words, hemiplegics had a weaker/more flexible sense of body ownership for the affected hand, but an enhanced/more rigid one for the healthy hand. Possible interpretations of such asymmetrical distribution of body ownership, as well as limits of our results, are discussed. Broadly speaking, our findings suggest that the alteration of the normal flow of signals present during movements impacts on human's body ownership. This in turn, means that movements have a role per se in developing and maintaining a coherent body ownership.

The cross-talk between beta cells and endothelium plays a key role in islet physiopathology and in the revascularization process after islet transplantation. However, the molecular mechanisms involved in this cross-talk are not fully elucidated. Extracellular vesicles (EVs) are secreted membrane nanoparticles involved in inter-cellular communication through the transfer of proteins and nucleic acids. The aims of this study were: 1) isolation and characterization of EVs from human islets; 2) evaluation of the pro-angiogenic effect of islet-derived EVs on human islet endothelial cells (IECs). EVs were isolated by ultracentrifugation from conditioned medium of human islets and characterized by nanotrack analysis (Nanosight), FACS, western blot, bioanalyzer, mRNA/microRNA RT-PCR array. On IECs, we evaluated EV-induced insulin mRNA transfer, proliferation, resistance to apoptosis, in vitro angiogenesis, migration, gene and protein profiling. EVs sized 236±54 nm, expressed different surface molecules and islet-specific proteins (insulin, C-peptide, GLP1R) and carried several mRNAs (VEGFa, eNOS) and microRNAs (miR-27b, miR-126, miR-130 and miR-296) involved in beta cell function, insulin secretion and angiogenesis. Purified EVs were internalized into IECs inducing insulin mRNA expression, protection from apoptosis and enhancement of angiogenesis. Human islets release biologically active EVs able to shuttle specific mRNAs and microRNAs (miRNAs) into target endothelial cells. These results suggest a putative role for islet-derived EVs in beta cell-endothelium cross-talk and in the neoangiogenesis process which is critical for engraftment of transplanted islets.