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Background and Overview Severely molar-incisor hypomineralization (MIH)–affected teeth are prone to develop early posteruptive enamel breakdown (PEB) and caries. A novel conservative interim approach for the prevention of this complication is presented. Case Description A 6-year-old boy with strong hypersensitivity and extensive brown opacities in the partially erupted mandibular permanent first molars (PFMs) was diagnosed with MIH. Constant hygiene and dietary counseling were followed by the application of luted orthodontic bands and glass ionomer sealants to protect PFMs from caries and PEB until the complete eruption of the teeth. After 36 months, the PFMs were completely erupted, with no caries and PEB, and the cooperation of the child increased. Conclusions and Practical Implications Temporary strategies are useful to preserve MIH-affected PFMs. With the methodology described, the hypersensitivity decreased and the patient reached a good degree of cooperation, making possible definitive rehabilitative considerations.

OBJECTIVE To evaluate the factor age at the surgery on long-term postoperative outcomes in patients with postprostatectomy incontinence (PPI) after AdVance XP transobturator male sling implantation. METHODS A total of 115 male patients with PPI, who had undergone AdVance XP sling implantation, were included. Patients had PPI with endoscopically confirmed good sphincteric-contractility and a positive coaptive response. Kruskal-Wallis test with Dunn post-hoc tests were used to analyze the postoperative outcome differences between the patient groups aged less than 66, 66-75, and over greater than 75 years. Outcome measures were the 24 h pad test, the number of daily pads used, the International Consultation on Incontinence Questionnaire short form (ICIQ-SF), International Quality of Life Score (IQOL), Patient Global Impression of Improvement (PGI-I), International Index of Erectile Function-5 (IIEF-5), International Prostate Symptom Score (IPSS), and Visual Analog Scale scores. Observation time points were 3, 6, 12, 24, 36, 48, 60, and 84 months after surgery. RESULTS Between the age groups, there was no difference in the success rate of the procedure (defined as 0 pads/24 h and less than 5 g in the 24-h pad test) at any point in time. Subjective parameters measures using the ICIQ-SF, PGI-I, IQOL, and IPSS scores showed no differences between the two cohorts. Only erectile function (IIEF-5 score) was lower in older patients in comparison to the cohort aged less than 66 years (p

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism., Autism spectrum disorder (ASD) is characterised by synaptic surplus and atypical functional connectivity. Here, the authors show that synaptic pathology in Tsc2 haploinsufficient mice is associated with autism-like behavior and cortico-striatal hyperconnectivity, and that analogous functional hyperconnectivity signatures can be linked to mTOR-pathway dysfunction in subgroups of children with idiopathic ASD.

Background Recent guidelines suggested a wider use of long-acting injectable antipsychotics (LAI) than previously, but naturalistic data on the consequences of LAI use in terms of discontinuation rates and associated factors are still sparse, making it hard for clinicians to be informed on plausible treatment courses. Objective Our objective was to assess, under real-world clinical circumstances, LAI discontinuation rates over a period of 12 months after a first prescription, reasons for discontinuation, and associated factors. Methods The STAR Network ‘Depot Study’ was a naturalistic, multicentre, observational prospective study that enrolled subjects initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centres were assessed at baseline and at 6 and 12 months of follow-up. Psychopathology, drug attitude and treatment adherence were measured using the Brief Psychiatric Rating Scale, the Drug Attitude Inventory and the Kemp scale, respectively. Results The study followed 394 participants for 12 months. The overall discontinuation rate at 12 months was 39.3% (95% confidence interval [CI] 34.4–44.3), with paliperidone LAI being the least discontinued LAI (33.9%; 95% CI 25.3–43.5) and olanzapine LAI the most discontinued (62.5%; 95% CI 35.4–84.8). The most frequent reason for discontinuation was onset of adverse events (32.9%; 95% CI 25.6–40.9) followed by participant refusal of the medication (20.6%; 95% CI 14.6–27.9). Medication adherence at baseline was negatively associated with discontinuation risk (hazard ratio [HR] 0.853; 95% CI 0.742–0.981; p = 0.026), whereas being prescribed olanzapine LAI was associated with increased discontinuation risk compared with being prescribed paliperidone LAI (HR 2.156; 95% CI 1.003–4.634; p = 0.049). Conclusions Clinicians should be aware that LAI discontinuation is a frequent occurrence. LAI choice should be carefully discussed with the patient, taking into account individual characteristics and possible obstacles related to the practicalities of each formulation. Supplementary Information The online version contains supplementary material available at 10.1007/s40263-021-00809-w.

Objective: The aim of this study was to assess the security, value, and efficacy of the second-generation AdVance male sling XP (Boston Scientific®), after implementation in 2010 with advantageous modifications in the sling structure and needle shape, in a prospective multicenter long-term follow-up study. Methods: In total, 115 patients were included. Exclusion criteria were earlier incontinence (UI) surgery, nocturnal UI, former radiotherapy, or night-time incontinence. We also excluded patients with a functional urethra Results: The 24-month follow-up (114 patients) revealed 64.0% cured and 28.8% improved patients. Mean urine loss was reduced significantly to 19.0 g (p < 0.001). A mean PGI score of 1.5 and a mean VAS score of 0.2 were obtained. The 60-month follow-up (59 patients) revealed 57.6% cured and 25.4% improved patients. Mean urine loss was reduced significantly to 18.3 g (p < 0.001). A mean PGI score of 1.6 and a mean VAS score of 0.2 were obtained. Conclusions: The AdVance XP displays excellent continence results and secure effectiveness over a 5-year period. Moreover, these data are demonstrating low complication rates and improved quality of life in the long-term use of AdVance XP.

American trypanosomiasis, also named Chagas disease (CD), is an anthropozoonosis caused by the protozoan parasite Trypanosoma cruzi. The disease affects millions of people worldwide, leading yearly to approximately 50,000 deaths. COVID-19, generated by SARS-CoV-2, can lead to lymphopenia and death. We hereby describe the first report of two patients with CD and COVID-19 coinfection, from hospitalization until patients’ death.

The study was performed to evaluate the impact of cardiological disorders on the outcome of myasthenic crisis (MC) requiring ventilation. The study includes 90 cases admitted to the Neurology Unit of Modena, Italy (January 2000 - September 2020). All patients were eligible for a non-invasive ventilation (NIV) trial. We analyzed the effect of cardiac comorbidities on the outcomes, which were the need of invasive ventilation, the risk tracheostomy for weaning failure and the duration of intensive care unit (ICU) stay Females were 58.9% and males 41.1%. Median age at diagnosis was 59 and at MC was 65. Patients were classified as early (EOMG) or late (LOMG), 34.4 and 65.6% respectively, according to age above or below 50; 85% of patients were anti- AChR antibody positive. Hypertension and cardiac diseases occurred at the diagnosis in 61 and 44.4%, respectively. Invasive mechanical ventilation (MV) was needed in 34% of cases. Nine subjects (10%) underwent tracheostomy because of weaning failure. Independent predictors of NIV failure were atrial fibrillation (AF), either parossistic or persistent (OR 3.05, p < 0.01), hypertensive cardiopathy (HHD) (OR 2.52, p < 0.01) and ischaemic heart disease (IHD) (OR 3.08, p < 0.01). Hypertension (HT) had no statistical effect on the outcomes. HHD was a predictor of weaning failure (OR 4.01, p = 0.017). Our study shows that HHD, AF and IHD increase the risk of NIV failure in MC receiving ventilation.

The “Hypogeum of the Garlands” is a sepulchral site, recently found in Grottaferrata (Lazio, Italy), dating back to the first-second century AD. Two sarcophagi were discovered inside, hosting the human remains of Aebutia Quarta, a rich Roman woman, and her son Carvilius Gemellus. While the body of Carvilius is exceptionally well-preserved, following its embalming and perfect sealing of the sarcophagus, in the case of Aebutia only the bones were preserved because of the sarcophagus’s seal breaking down, although she was covered with perfectly preserved flower garlands. Embalming of the body was a rare ritual in the Imperial Roman times when corpses were more often cremated. The remains of Aebutia showed possible traces of heating. Burned bones from a third individual were discovered on the chamber’s floor and preliminary anthropological survey showed that this individual was a male of 40–50 years old. Here, a combination of spectroscopic techniques, including non-destructive inelastic neutron scattering and Raman spectroscopy, and minimally destructive Fourier transform infrared spectroscopy, were applied to the analysis of these bone samples to give information about ancient Roman funerary practices. The temperature and burning conditions were thus determined, showing that Aebutia Quarta was exposed to mild temperatures (200 °C) only in the upper part of the body, while the third individual was likely cremated as its bones were exposed to temperatures up to 900 °C in quasi-anaerobic conditions.

Purpose. To describe the clinical features of acute nongranulomatous anterior uveitis (NGAU) patients and to estimate the prevalence of concomitant spondyloarthritis (SpA). Methods. Retrospective study of consecutive patients affected by NGAU referred to the Ocular Immunology Unit of the AUSL-IRCCS di Reggio Emilia, Italy, between January 2016 and January 2019. All patients underwent ophthalmic evaluation and blood test with HLA-B27 typing and were referred to a rheumatologist to identify any undiagnosed SpA. SpA was classified according to the Assessment of SpondyloArthritis international Society (ASAS) criteria in axial or peripheral SpA. Patients were divided into two groups: NGAU with associated SpA (SpA+) and NGAU without SpA (SpA-). Clinical and demographic features of the two groups, including sex, HLA-B27, family history of rheumatic disease, uveitis laterality, course, and severity of ocular inflammation, complications, and treatment, were compared. Results. Ninety-nine patients with NGAU were enrolled, of whom 36 (36%) with a diagnosis of SpA: 14 with peripheral SpA and 22 with axial SpA. The prevalence of SpA was higher in HLA-B27-positive patients than in HLA-B27-negative patients (50% vs. 15%, p < 0.0001 ). The multivariate logistic regression ( R 2 = 0.28 ) for SpA diagnosis identified as significant predictive factors: age at diagnosis ( odds ratio OR = 0.95 , 95% confidence interval [CI]: 0.91-0.99) and HLA-B27+ ( OR = 5.32 , 95% CI: 1.80-15.70). Conclusions. Our results confirmed the high prevalence of undiagnosed SpA in patients with NGAU, suggesting that, regardless of HLA-B27 status, in the presence of IBP and/or peripheral arthritis, patients with NGAU must be referred to the rheumatologist to allow earlier diagnosis.

This study, based on the 'Servizi Territoriali Associati per la Ricerca' (STAR) Network Depot Study nationwide baseline data, explored whether individual symptoms severity and clusters might influence the prescription of paliperidone palmitate 1-month (PP1M) vs. aripiprazole monohydrate. The Brief Psychiatric Rating Scale (BPRS) was used to assess psychopathology and relevant symptoms clusters. Drug Attitude Inventory, 10 items, was used to test attitude towards medications. Adherence to treatments was rated according to the Kemp seven-point scale. We assessed for eligibility 451 individuals and, among them, we included 195 subjects (n = 117 who started PPM1 and n = 78 aripiprazole monohydrate). Individuals were comparable in terms of age, gender, treatment years, recent hospitalizations, previous long-acting injectable antipsychotic treatments, additional oral treatments, attitude toward drugs, medication adherence, and alcohol/substance-related comorbidities. Subjects starting PP1M presented higher BPRS overall (P = 0.009), positive (P = 0.015), and negative (P = 0.010) symptom scores compared to subjects starting aripiprazole monohydrate. Results were confirmed by appropriate regression models and propensity score matching analysis. No differences were found comparing the other BPRS subscale scores: affect, resistance, and activation. Clinicians may be more prone to prescribe PPM1, rather than aripiprazole monohydrate, to subjects showing higher overall symptom severity, including positive and negative symptoms. No additional clinical factors influenced prescribing attitudes in our sample.

Abnormal hippocampal neural plasticity has been implicated in behavioural abnormalities and complex neuropsychiatric conditions, including bipolar disorder (BD). However, the determinants of this neural alteration remain unknown. This work tests the hypothesis that the neurotransmitter serotonin (5-HT) is a key determinant of hippocampal neuroplasticity, and its absence leads to maladaptive behaviour relevant for BD. Depletion of brain 5-HT in Tph2 mutant mice resulted in reduced behavioural despair, reduced anxiety, marked aggression and lower habituation in novel environments, reminiscent of bipolar-associated manic behaviour. Treatment with valproate produced a substantial improvement of the mania-like behavioural phenotypes displayed by Tph2 mutants. Brain-wide fMRI mapping in mutants revealed functional hippocampal hyperactivity in which we also observed dramatically increased neuroplasticity. Importantly, remarkable correspondence between the transcriptomic profile of the Tph2 mutant hippocampus and neurons from bipolar disorder patients was observed. Chronic stress reversed the emotional phenotype and the hippocampal transcriptional landscape of Tph2 mutants. These changes were associated with inappropriate activation of transcriptional adaptive response to stress as assessed by gene set enrichment analyses in the hippocampus of Tph2 mutant mice. These findings delineate 5-HT as a critical determinant in BD associated maladaptive emotional responses and aberrant hippocampal neuroplasticity, and support the use of Tph2−/− mice as a new research tool for mechanistic and therapeutic research in bipolar disorder.

The aim of the study was to identify possible predictors of neurological worsening and need of non-invasive ventilation (NIV) in individuals affected by myotonic dystrophy type 1 (DM1), the most common form of adult-onset muscular dystrophy. Methods A retrospective observational cohort study was undertaken. Thirty-three patients with genetic diagnosis of DM1 were followed at our Neuromuscular unit in Modena. Abnormal trinucleotide repeat (CTG) expansion of dystrophy protein kinase gene (MDPK) on chromosome 19q 13.3 was the prerequisite for inclusion. The number of CTG repeats was determined. All the participants were older than 14 at the time of enrolment, therefore they could be included into the juvenile or adult form of the disease. Participants were neurologically evaluated every 6-8 months up to 18 years. Neurological impairment was assessed by Muscular Impairment Rating (MIRS), Medical Research Council (MRC), and modified Rankin (mRS) scales. The independent variables considered for prognosis were age at first evaluation, duration of the disease, CTG repeat number, gender, and presence of cardiac and vascular morbidities. Male patients were 51.5% and female patients 48.5%. Sixteen patients were younger than the mean age of 30.1 years, while the remaining 17 were up to 65. Twelve subjects (36.4%) underwent NIV before the end of follow-up. Muscle force and disability scores showed statistically significant deterioration (p < 0.001) during follow-up. The worsening was significantly higher among patients carrying higher number of CTG repeats and of younger age. The presence of cardio-vascular involvement has significant impact on neurological and respiratory progression. Neurological worsening is predicted by CTG expansion size, young age and presence of cardio-vascular morbidities.

The immune system of patients infected by SARS-CoV-2 is severely impaired. Detailed investigation of T cells and cytokine production in patients affected by COVID-19 pneumonia are urgently required. Here we show that, compared with healthy controls, COVID-19 patients’ T cell compartment displays several alterations involving naïve, central memory, effector memory and terminally differentiated cells, as well as regulatory T cells and PD1+CD57+ exhausted T cells. Significant alterations exist also in several lineage-specifying transcription factors and chemokine receptors. Terminally differentiated T cells from patients proliferate less than those from healthy controls, whereas their mitochondria functionality is similar in CD4+ T cells from both groups. Patients display significant increases of proinflammatory or anti-inflammatory cytokines, including T helper type-1 and type-2 cytokines, chemokines and galectins; their lymphocytes produce more tumor necrosis factor (TNF), interferon-γ, interleukin (IL)-2 and IL-17, with the last observation implying that blocking IL-17 could provide a novel therapeutic strategy for COVID-19., COVID-19 is a serious pandemic threat to public health, but insights on the pathophysiological and immunological conditions are only emerging. Here the authors use multi-color flow cytometry to characterize CD4+ and CD8+ T cells in peripheral blood from 39 COVID-19 patients in Italy to report altered T cell activation, function and polarization.

Introduction Chronic Critical Illness (chronic CI) is a condition associated to patients surviving an episode of acute respiratory failure (ARF). The prevalence and the factors associated with the development of chronic CI in the population admitted to a Respiratory Intensive Care Unit (RICU) have not yet been clarified. Methods An observational prospective cohort study was undertaken at the RICU of the University Hospital of Modena (Italy). Patients mechanically ventilated with ARF in RICU were enrolled. Demographics, severity scores (APACHEII, SOFA, SAPSII), and clinical condition (septic shock, pneumonia, ARDS) were recorded on admission. Respiratory mechanics and inflammatory-metabolic blood parameters were measured both on admission and over the first week of stay. All variables were tested as predictors of chronic CI through univariate and multivariate analysis. Results Chronic CI occurred in 33 out of 100 patients observed. Higher APACHEII, the presence of septic shock, diaphragmatic dysfunction (DD) at sonography, multidrug-resistant (MDR) bacterial infection, the occurrence of a second infection during stay, and a C-reactive protein (CRP) serum level inceasing 7 days over admission were associated with chronic CI. Septic shock was the strongest predictor of chronic CI (AUC = 0.92 p Conclusions Chronic CI is frequent in patients admitted to RICU and mechanically ventilated due to ARF. Infection-related factors seem to play a major role as predictors of this syndrome.

Background The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery. Methods In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery. Results Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2–5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1–0.7) or in OT (HR = 0.1, 95% CI = 0.0–0.8) treated with tocilizumab. Conclusion To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.

Background Focal brain lesions can lend insight into the causal neuroanatomical substrate of depression in the human brain. However, studies of lesion location have led to inconsistent results. Methods Five independent datasets with different lesion etiologies and measures of postlesion depression were collated (N = 461). Each 3-dimensional lesion location was mapped to a common brain atlas. We used voxel lesion symptom mapping to test for associations between depression and lesion locations. Next, we computed the network of regions functionally connected to each lesion location using a large normative connectome dataset (N = 1000). We used these lesion network maps to test for associations between depression and connected brain circuits. Reproducibility was assessed using a rigorous leave-one-dataset-out validation. Finally, we tested whether lesion locations associated with depression fell within the same circuit as brain stimulation sites that were effective for improving poststroke depression. Results Lesion locations associated with depression were highly heterogeneous, and no single brain region was consistently implicated. However, these same lesion locations mapped to a connected brain circuit, centered on the left dorsolateral prefrontal cortex. Results were robust to leave-one-dataset-out cross-validation. Finally, our depression circuit derived from brain lesions aligned with brain stimulation sites that were effective for improving poststroke depression. Conclusions Lesion locations associated with depression fail to map to a specific brain region but do map to a specific brain circuit. This circuit may have prognostic utility in identifying patients at risk for poststroke depression and therapeutic utility in refining brain stimulation targets.

Nasopharyngeal carcinoma, one of the most common head and neck cancers in Southeast Asia, is uncommon in Western countries and it is frequently diagnosed in advanced stage. Chemotherapy given with radiation therapy, followed by more chemotherapy, is the standard of care of stage IV nasopharyngeal carcinoma but Cetuximab, an epidermal growth factor (EGFR) inhibitor, is now making its way in the treatment of locoregionally advanced nasopharyngeal carcinoma. We report a case of 58 years old patient with metastatic nasopharyngeal carcinoma with an astonishing response to Cetuximab. At the time of writing, the patient is still in treatment with Cetuximab with excellent disease control.

Non-infectious uveitis are intraocular inflammatory conditions caused by dysregulated activation of the immune response without any detectable infectious agents. The aim of this study was to explore potential markers and therapeutic targets for two distinct types of non-infectious uveitis associated with Behçet's disease (BD) and Vogt Koyanagi Harada (VKH) disease. Concentrations of 27 cytokines were investigated in aqueous humor (AH) samples from patients with active uveitis vs. healthy controls (HC) (n = 10 patients with BD-associated uveitis; n = 10 patients with VKH-associated uveitis; n = 10 HC) using the Bio-Plex ProTM human cytokine group I panel. Additionally, leukocytes in AH samples were counted with hemocytometers and characterized by flow cytometry. Eleven cytokines were differentially expressed between patients with uveitis and HC with a median concentration greater than 10 pg/ml. IL-6, IP-10, G-CSF, and IFNγ showed higher concentrations in AH samples from both BD and VKH patients while IL-2, IL-8, IL-13, TNFα, eotaxin, IL-1ra showed statistically significant higher concentrations only in AH samples from BD patients. GM-CSF was the sole cytokine with an opposite profile showing decreased levels in AH samples from BD patients. IL-1ra and IL-6 were detected at higher frequencies in AH samples from BD and VKH patients compared with those from HC while IFNγ and TNFα were not detected in HC. The concentrations of IL-6, IL-8, IP-10, G-CSF, IFNγ, TNFα, eotaxin, IL-1ra positively correlated with the concentrations of leukocytes in AH, suggesting that such cytokines can be produced by immune cells and/or attract and/or promote proliferation and survival of immune cells in these types of uveitis. The correlation matrix of cytokine concentrations in AH samples revealed that IFNγ, TNFα, eotaxin, IL-6, G-CSF highly correlated each other. The ratios of cytokine concentrations between AH and plasma intra-individuals showed that IL-2, IL-6, IP-10, GM-CSF were increased intraocularly. In conclusion, AH sampling followed by multiplex analysis of cytokines should be fostered in non-infectious uveitis to identify cytokines dysregulated intraocularly in each individual laying the groundwork for precision medicine.

The aim of this study is to validate the Italian version of the Mental Health Knowledge Schedule (MAKS-I). The validation process included: linguistic validation; analysis of the feasibility; face validity; internal consistency; floor and the ceiling effects; divergent validity. Multiple linear regression was performed to examine the relationship between mental health knowledge and independent variables. MAKS-I was administered to 453 people. The linguistic validation was successful and face validity of the questionnaire showed no critical issues. The estimated composite reliability was 0.638. Divergent validity was supported by lack of statistical significant correlation between MAKS-I and RIBS-I with a positive correlation index. Participation in seminars or conferences related to the issue of mental health stigma, gender, qualification and having a first or second-degree relatives with a psychiatric disorder can be considered possible predictors of the MAKS-I score. MAKS-I is a reliable questionnaire to assess mental health knowledge and familiarity with psychiatric clinical conditions in Italian language.

About 20% of patients with myasthenia gravis (MG) may develop myasthenic crisis (MC) requiring ventilation, either invasive (MV) or non-invasive (NIV) and intensive unit care (ICU). NIV failure in patients with MC can occur up to 60% of cases admitted to ICU. Moreover it is not known the outcome of MC receiving NIV. Purpose of this study was to identify predictors of outcome in MC who underwent non-invasive ventilator support outside ICU setting. We enrolled 90 patients, 53 females and 37 males admitted to University Hospital of Modena (Italy) between January 2000 and September 2020. Median age at MC was 65 years. Thirty-four patients (37.8%) required MV. Thymectomy was performed in 45 cases, associated with thymoma in 55%, with hyperplastic thymus in 33%. First-line treatment was plasmaexchange (38.8%) or intravenous immunoglobulins (45.6%). Males exhibited higher risk of MV than females .Patients in MV were treated with plasmaexchange as first-line therapy . Our in-hospital mortality rate was low. Nine patients underwent tracheostomy which was significantly related to male gender. Comorbidities had significant effect on length of ICU .Our study confirms as predictors of prognosis in our patients male gender, older age at onset, infections as trigger, pneumonia.

The pathophysiology of autism has been suggested to involve a combination of both macroscale connectome miswiring and microcircuit anomalies. Here, we combine connectome-wide manifold learning with biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. We studied neuroimaging and phenotypic data in 47 individuals with autism and 37 typically developing controls obtained from the Autism Brain Imaging Data Exchange initiative. Our analysis establishes significant differences in structural connectome organization in individuals with autism relative to controls, with strong between-group effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models reveal that the degree of macroscale anomalies is related to atypical increases of recurrent excitation/inhibition, as well as subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic association analysis based on postmortem datasets identifies genes expressed in cortical and thalamic areas from childhood to young adulthood. Finally, supervised machine learning finds that the macroscale perturbations are associated with symptom severity scores on the Autism Diagnostic Observation Schedule. Together, our analyses suggest that atypical subcortico-cortical interactions are associated with both microcircuit and macroscale connectome differences in autism., Autism is increasingly recognized to impact multiple scales of neural organization. Here, the authors show alterations in individuals with autism relative to typically developing controls, with findings particularly pointing to atypically organized subcortical-cortical networks.

OBJECTIVE To evaluate the efficacy and safety of the AdVance XP male sling in a midterm follow-up for the treatment of male urinary incontinence in a selected patient cohort. MATERIALS AND METHODS In all, 115 patients with postprostatectomy incontinence were prospectively enrolled. A previous endoscopic evaluation of a sufficient coaptive zone in the repositioning test was mandatory. Patients with urine leakage in supine position or previous incontinence surgery were excluded. Postoperatively a standardized 24-hour pad test and pad usage were evaluated. To compare pre- and postoperative continence status nonparametric t test was used. A P-value of

This trial (20010168) studied how body weight (BW) and body mass index (BMI) influenced the pharmacokinetics (PK) of anakinra. Subjects (n = 32) were assigned to four groups (n = 8) according to BW and BMI. Randomization was according to a four‐treatment, four‐period, four‐sequence crossover design. The four anakinra injections were 100, 150, and 300 mg s.c. and 100 mg i.v. Plasma samples were measured by enzyme‐linked immunosorbent assay and noncompartmental PK parameters estimated. BW demonstrated the following effects: after i.v. administration, significant effects (P 100 kg) obese (BMI > 36) vs. larger (> 100 kg) less obese (BMI

This study evaluated whether the impairment in cooperation that characterizes individuals with borderline personality disorder (BPD) can be explained by the difficulty to use emotion regulation strategies and to accurately perceive the fairness of others' behavior. Forty-one patients with BPD and 41 sex and age matched healthy controls (HC) played the responder's role in a Modified Ultimatum Game during which they were asked to apply 3 different emotion regulation strategies: look, distancing, and reappraisal. Offer rejection rates were used as an index of punishment behavior. After the experiment, participants also rated the degree of perceived equity of the offers after receiving fair and unfair offers. Reappraisal was effective in decreasing punishment behaviors for unfair offers in both the BPD and HC groups. By contrast, BPD patients displayed a different behavior than HC when making decisions upon fair offers, independently from the regulation strategies adopted. In fact, they rejected higher rates of fair offers than HC. Further, BPD patients judged fair offers as less fair than HC. This indicates an altered judgment and decision making on fair interpersonal exchanges. In conclusion, BPD patients exhibit increased punishment behavior during fair, "favorable" social exchanges, which they tend to perceive as less fair than controls. Thus, BPD patients may be biased toward underestimating positive feedback from others. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Sepsis is an overwhelming systemic inflammation resulting from an uncontrolled infection that causes extensive tissue damage, organ dysfunction and eventually death. A growing body of evidence indicates that impaired neutrophil migration to the site of infection is associated with poor outcome in sepsis. Here we show that galectin-3 (Gal-3), an endogenous glycan-binding protein, plays a critical role in sepsis outcome. We found that serum Gal-3 concentration increased in patients with septic shock and mice undergoing sepsis induced by cecal ligation and puncture (CLP). Mice deficient in Gal-3 (Gal-3 KO) are more resistant to sepsis induced by CLP, showing lower levels of biochemical markers and neutrophil infiltration for organ injury/dysfunction than those observed in wild-type mice (WT). Furthermore, Gal-3 KO mice show an increased number of neutrophils in the primary focus of infection and reduced bacterial loads in the peritoneal cavity, blood, and lungs. Mechanistically, blood neutrophils from septic mice show higher levels of surface-bound Gal-3 than neutrophils from naive mice. The deficiency of Gal-3 was associated with increased rolling and adhesion of these cells in mesenteric venules. Our results indicate that Gal-3, secreted during sepsis, inhibits neutrophil migration into the infectious focus, which promotes the bacterial spread and worsens the outcome of sepsis.

Background The main clinical consequences of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) infection are pneumonia and respiratory failure even requiring mechanical ventilation. In this context, the lung parenchyma is highly prone to ventilator-related injury, with pneumothorax and persistent air leak as the most serious adverse events. So far, endobronchial valve (EBV) positioning has proved efficacious in treating air leaks with a high success rate. Case presentation We report, for the first time, two cases of patients affected by SARS-CoV-2-related pneumonia complicated with bacterial super-infection, experiencing pneumothorax and persistent air leaks after invasive mechanical ventilation. Despite the severity of respiratory failure both patients underwent rigid interventional bronchoscopy and were successfully treated through EBV positioning. Conclusions Persistent air leaks may result from lung tissue damage due to a complex interaction between inflammation and ventilator-related injury (VILI), especially in the advanced stages of ARDS. EBV positioning seems to be a feasible and effective minimally invasive therapeutic option for treating this subset of patients.

(1) Background: Due to its richness in chlorogenic acids (CGAs), Mat&eacute, (Ilex paraguariensis A. St.-Hil.) could be of interest in the prevention of cardiometabolic diseases, however clinical evidence are lacking. This trial aimed to evaluate the impact of mat&eacute, CGAs, consumed in a daily dose achievable through traditional mat&eacute, beverages, on parameters related to cardiometabolic risk. (2) Design: Thirty-four male volunteers aged 45&ndash, 65 years and with at most one criteria of metabolic syndrome, were recruited for a randomized, double-blind, placebo-controlled, and crossover study. The volunteers were assigned to consume an encapsulated dry mat&eacute, extract for four-weeks, providing 580 mg of caffeoyl quinic acid derivatives (CQAs) daily, or a placebo, with a two weeks washout between intervention periods. Anthropometric variables, blood pressure, plasma glucose, lipids, endothelial, and inflammatory biomarkers were measured in overnight-fasted subjects and after a glucose load. (3) Results: We found no significant effects of treatment on these parameters and the response to the glucose load was also similar between the two interventions. However, a significant decrease in fasting glucose was observed between day 0 and day 28 for the mat&eacute, group only (&minus, 0.57 &plusmn, 0.11 mmol/L, p &lt, 0.0002). In subjects with an intermediate to high Framingham risk score, consumption of mat&eacute, extract induced a 10% increase of high-density lipoprotein (HDL)-c from baseline. In a subgroup representative of the study population, significant decreases in the C-reactive protein (CRP) (&minus, 50%) and interleukin-6 (IL-6) (&minus, 19%) levels were observed. (4) Conclusions: These clinical observations suggest that mat&eacute, naturally rich in CGAs, could improve some cardiometabolic markers in subjects with a higher predisposition to metabolic syndrome, even if that remains to be confirmed in new trials specifically targeting this population.

In a previous trial in Mali, we showed that traditional pearl millet couscous and thick porridge delayed gastric emptying (about 5 h half-emptying times) in a normal-weight population compared with non-traditional carbohydrate-based foods (pasta, potatoes, white rice; about 3 h half-emptying times), and in a gastric simulator we showed millet couscous had slower digestion than wheat couscous. In light of these findings, we tested the hypothesis in a normal-weight US population (n 14) that millet foods would reduce glycaemic response (continuous glucose monitor), improve appetitive sensations (visual analogue scale ratings), as well as reduce gastric emptying rate (13C-octanoic acid breath test). Five carbohydrate-based foods (millet couscous – commercial and self-made, millet thick porridge, wheat couscous, white rice) were fed in a crossover trial matched on available carbohydrate basis. Significantly lower overall glycaemic response was observed for all millet-based foods and wheat couscous compared with white rice (P ≤ 0·05). Millet couscous (self-made) had significantly higher glycaemic response than millet couscous (commercial) and wheat couscous (P P

Background For many years, long-acting intramuscular (LAI) antipsychotics have been prescribed predominantly to chronic and severe patients, as a last resort when other treatments failed. Recently, a broader and earlier use of LAIs, particularly second-generation LAIs, has been emphasized. To date, few studies attempted to frame how this change in prescribing took place in real-world practice. Therefore, this study aimed to describe the clinical features of patients prescribed with LAIs, and to explore possible prescribing differences between first- and second-generations LAIs under ordinary clinical practice in Italy. Methods The STAR Network "Depot" Study is an observational, longitudinal, multicenter study involving 35 centers in Italy. In the cross-sectional phase, patients prescribed with LAIs were consecutively recruited and assessed over a period of 12 months. Descriptive statistics and multivariable logistic regression analyses were employed. Results Of the 451 recruited patients, 61% were males. The level of social and working functioning was heterogeneous, as was the severity of disease. Seventy-two per cent of the patients had a diagnosis of the schizophrenia spectrum. Seventy per cent were prescribed with second-generation antipsychotic (SGA) LAIs (mostly paliperidone, aripiprazole and risperidone). Compared to first-generation antipsychotic (FGA) LAIs, patients prescribed with SGA LAIs were more often younger; employed; with a diagnosis of the schizophrenia spectrum or bipolar disorder; with higher levels of affective symptoms; with fewer LAI prescriptions in the past. Discussion LAIs' prescribing practices appear to be more flexible as compared to the past, although this change is mostly restricted to SGA LAIs.

Vogt–Koyanagi–Harada (VKH) is an autoimmune disease characterized by inflammation in tissues that contain melanocytes. We aimed to increase the knowledge regarding immunological pathways deregulated in VKH disease. We compared the percentages of circulating natural killer (NK), NK T and T cells expressing the activatory markers: CD16, CD69, NK group 2D (NKG2D), natural cytotoxicity triggering receptor 3 (Nkp30), natural cytotoxicity triggering receptor 1 (Nkp46) and the inhibitory marker: NK group 2 member A (NKG2A) in 10 active VKH patients, 20 control subjects (CTR) and seven patients with Behçet disease (BD) by flow cytometry. Cytotoxic potential of NK cells was determined through the degranulation marker CD107a expression after contact with K562 cells by flow cytometry. Moreover, plasmatic levels of 27 cytokines were determined with a multiplex bead‐based assay. VKH patients showed higher percentages of NKG2D(pos) NK and NK T cells versus CTR. The cytotoxic potential of NK cells induced by K562 cells was comparable between VKH patients and CTR. Finally, higher concentrations of interleukin (IL)‐4, IL‐5, IL‐7, IL‐17 and platelet‐derived growth factor‐subunits B (PDGF‐bb) were detected in plasma of VKH patients versus CTR. The immune profile of VKH patients was similar to that of BD patients.

Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently., eLife digest Autism is a condition that is usually diagnosed early in life that affects how a person communicates and socializes, and is often characterized by repetitive behaviors. One key theory of autism is that it reflects an imbalance in levels of excitation and inhibition in the brain. Excitatory signals are those that make other brain cells more likely to become active; inhibitory signals have the opposite effect. In non-autistic individuals, inhibitory activity outweighs excitatory activity. In people with autism, by contrast, an increase in excitatory activity is believed to produce an imbalance in excitation and inhibition. Most of the evidence to support this excitation-inhibition imbalance theory has come from studies of rare mutations that cause autism. Many of these mutations occur on the sex chromosomes or are influenced by androgen hormones (hormones that usually play a role on typically male traits). However, most people with autism do not possess these particular mutations. It was thus unclear whether the theory could apply to everyone with autism or, for example, whether it may better apply to specific groups of individuals based on their sex or gender. This is especially important given that about four times as many men and boys compared to women and girls are diagnosed with autism. Trakoshis, Martínez-Cañada et al. have now found a way to ask whether any imbalance in excitation and inhibition in the brain occurs differently in men and women. Using computer modeling, they identified a signal in brain scans that corresponds to an imbalance of excitation and inhibition. After showing that the technique works to identify real increases in excitation in the brain scans of mice, Trakoshis, Martínez-Cañada et al. looked for this signal, or biomarker, in brain scans of people with and without autism. All the people in the study identified with the gender that matched the sex they were assigned at birth. The results revealed differences between the men and women with autism. Men with autism showed an imbalance in excitation and inhibition in specific ‘social brain' regions including the medial prefrontal cortex, but women with autism did not. Notably, many of these brain regions are strongly affected by androgen hormones. Previous studies have found that women with autism are sometimes better at hiding or ‘camouflaging’ their difficulties when socializing or communicating than men with autism. Trakoshis, Martínez-Cañada et al. showed that the better a woman was at camouflaging her autism, the more her brain activity in this region resembled that of non-autistic women. Excitation-inhibition imbalance may thus affect specific brain regions involved in socializing and communication more in men who have autism than in women with the condition. Balanced excitation and inhibition in these brain areas may enable some women with autism to camouflage their difficulties socializing or communicating. Being able to detect imbalances in activity using standard brain imaging could be useful for clinical trials. Future studies could use this biomarker to monitor responses to drug treatments that aim to adjust the balance between excitation and inhibition.

BackgroundThe exposure and consumption of information during epidemic outbreaks may alter people’s risk perception and trigger behavioral changes, which can ultimately affect the evolution of the disease. It is thus of utmost importance to map the dissemination of information by mainstream media outlets and the public response to this information. However, our understanding of this exposure-response dynamic during the COVID-19 pandemic is still limited.ObjectiveThe goal of this study is to characterize the media coverage and collective internet response to the COVID-19 pandemic in four countries: Italy, the United Kingdom, the United States, and Canada.MethodsWe collected a heterogeneous data set including 227,768 web-based news articles and 13,448 YouTube videos published by mainstream media outlets, 107,898 user posts and 3,829,309 comments on the social media platform Reddit, and 278,456,892 views of COVID-19–related Wikipedia pages. To analyze the relationship between media coverage, epidemic progression, and users’ collective web-based response, we considered a linear regression model that predicts the public response for each country given the amount of news exposure. We also applied topic modelling to the data set using nonnegative matrix factorization.ResultsOur results show that public attention, quantified as user activity on Reddit and active searches on Wikipedia pages, is mainly driven by media coverage; meanwhile, this activity declines rapidly while news exposure and COVID-19 incidence remain high. Furthermore, using an unsupervised, dynamic topic modeling approach, we show that while the levels of attention dedicated to different topics by media outlets and internet users are in good accordance, interesting deviations emerge in their temporal patterns.ConclusionsOverall, our findings offer an additional key to interpret public perception and response to the current global health emergency and raise questions about the effects of attention saturation on people’s collective awareness and risk perception and thus on their tendencies toward behavioral change.

Contains fulltext : 219632.pdf (Publisher’s version ) (Open Access) Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naive B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM- plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.

To report long term results of biologic treatment of severe and refractory Behçet's uveitis (BU) choosing a different biologic agent according to the uveitis clinical features.Retrospective cohort of patients with BU refractory to conventional therapy, who received Interferon (IFN) alpha-2a or Infliximab (IFX) for at least 3 months.Twenty-two patients were included (mean age 29 ± 10 years, 63% males); Fifteen received IFN and 7 IFX, for a mean treatment period of 30 ± 24(SD) months. Twenty (90%) patients discontinued treatment, in most cases for complete remission (77%). Seven patients (32%) showed relapses during treatment and five (23%) after discontinuation. Visual acuity improved significantly in IFN group and all eyes showed a significant decrease in central macular thickness at 12 months.Both IFX and IFN Alpha-2a were effective and well tolerated in the treatment of refractory BU using a customized approach based on the uveitis features.

In this study, we compared the fecal microbiota and metabolomes of 26 healthy subjects before (HS) and after (HSB) 2 months of diet intervention based on the administration of durum wheat flour and whole-grain barley pasta containing the minimum recommended daily intake (3 g) of barley β-glucans. Metabolically active bacteria were analyzed through pyrosequencing of the 16S rRNA gene and community-level catabolic profiles. Pyrosequencing data showed that levels of Clostridiaceae ( Clostridium orbiscindens and Clostridium sp.), Roseburia hominis , and Ruminococcus sp. increased, while levels of other Firmicutes and Fusobacteria decreased, from the HSB samples to the HS fecal samples. Community-level catabolic profiles were lower in HSB samples. Compared to the results for HS samples, cultivable lactobacilli increased in HSB fecal samples, while the numbers of Enterobacteriaceae , total coliforms, and Bacteroides , Porphyromonas , Prevotella , Pseudomonas , Alcaligenes , and Aeromonas bacteria decreased. Metabolome analyses were performed using an amino acid analyzer and gas chromatography-mass spectrometry solid-phase microextraction. A marked increase in short-chain fatty acids (SCFA), such as 2-methyl-propanoic, acetic, butyric, and propionic acids, was found in HSB samples with respect to the HS fecal samples. Durum wheat flour and whole-grain barley pasta containing 3% barley β-glucans appeared to be effective in modulating the composition and metabolic pathways of the intestinal microbiota, leading to an increased level of SCFA in the HSB samples.

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.

We aimed to assess the effectiveness of 'Paesaggi di Prevenzione', a school-based prevention program delivered by trained teachers and designed to tackle smoking, alcohol misuse, dietary risks, and physical inactivity in adolescence. We evaluated the program between 2010 and 2013 with a two-arm, parallel-group, multicentre cluster randomized controlled trial in which schools were the units of randomization. We collected data on health-compromising behaviours using self-reported measurements of behaviour frequency administered before and after program implementation. We used multivariable mixed-effects logistic regression models to estimate program effects on health-compromising behaviours. The analysis sample included 3410 middle school students and 1651 high school students. Among middle school students, mean age at baseline was 12 years (standard deviation [SD] 0.5 years), 51% were boys, and 41% had high socioeconomic status [SES] (defined as having at least one parent/guardian with university level education). In high school students, mean age at baseline was 14 years (SD 0.7 years), 56% were boys, and 31% had high SES. The program did not have effects on smoking, alcohol misuse, and physical activity. The program had iatrogenic effects in regard to some eating behaviours, resulting in (i) lower odds of fruit consumption among middle-school students (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.68-0.99) and (ii) lower odds of having breakfast every day in high-school students at the post-intervention measurement (OR 0.76; 95%CI 0.58-0.99) but not at one-year follow-up (OR 0.94; 95%CI 0.69-1.28). Due to the possibility of unintended effects, we advise against disseminating 'Paesaggi di Prevenzione' in its present form. TRIAL REGISTRATION: ISRCTN00953701.

Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such asFmr1(fragile X mental retardation protein 1).Fmr1knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity inEngrailed-2knock-out (En2−/−) adult mice, which show a lower expression ofFmr1and anatomical defects common toFmr1knock-outs. MRI-based resting-state functional connectivity in adultEn2−/−mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test,En2−/−but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation.En2−/−mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze,En2−/−and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved inEn2mutants. Therefore, fearful responses to somatosensory stimuli inEn2−/−mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes.SIGNIFICANCE STATEMENTOverreactivity to tactile stimuli is a common symptom in autism spectrum disorder (ASD) patients. Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here, we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related geneEngrailed-2(En2−/−mice). Compared with WT controls,En2−/−mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations.

Mutations in the synaptic scaffolding protein SHANK3 are a major cause of autism and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher-order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in adult male mice, here we show that loss of Shank3 (Shank3B(−/−)) results in disrupted local and long-range prefrontal and frontostriatal functional connectivity. We document that prefrontal hypoconnectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity. SIGNIFICANCE STATEMENT Mutations in the synaptic scaffolding protein SHANK3 are commonly associated with autism, intellectual, and language deficits. Previous research has linked SHANK3 deficiency to basal ganglia dysfunction, motor stereotypies, and social deficits. However, the neural mechanism whereby Shank3 gene mutations affects cortical functional connectivity and higher-order socio-communicative functions remain unclear. Here we show that loss of SHANK3 in mice results in largely disrupted functional connectivity and abnormal gray matter anatomy in prefrontal areas. We also show that prefrontal connectivity disruption is tightly linked to socio-communicative deficits. Our findings suggest that SHANK3 is a critical orchestrator of frontocortical function, and that disrupted connectivity of prefrontal areas may underpin socio-communicative impairments observed in SHANK3 mutation carriers.

The presence of networks of correlation between regional gray matter volume as measured across subjects in a group of individuals has been consistently described in several human studies, an approach termed structural covariance MRI (scMRI). Complementary to prevalent brain mapping modalities like functional and diffusion-weighted imaging, the approach can provide precious insights into the mutual influence of trophic and plastic processes in health and pathological states. To investigate whether analogous scMRI networks are present in lower mammal species amenable to genetic and experimental manipulation such as the laboratory mouse, we employed high resolution morphoanatomical MRI in a large cohort of genetically-homogeneous wild-type mice (C57Bl6/J) and mapped scMRI networks using a seed-based approach. We show that the mouse brain exhibits robust homotopic scMRI networks in both primary and associative cortices, a finding corroborated by independent component analyses of cortical volumes. Subcortical structures also showed highly symmetric inter-hemispheric correlations, with evidence of distributed antero-posterior networks in diencephalic regions of the thalamus and hypothalamus. Hierarchical cluster analysis revealed six identifiable clusters of cortical and sub-cortical regions corresponding to previously described neuroanatomical systems. Our work documents the presence of homotopic cortical and subcortical scMRI networks in the mouse brain, thus supporting the use of this species to investigate the elusive biological and neuroanatomical underpinnings of scMRI network development and its derangement in neuropathological states. The identification of scMRI networks in genetically homogeneous inbred mice is consistent with the emerging view of a key role of environmental factors in shaping these correlational networks.

To use Pharmacokinetic (PK) simulations to illustrate potential differences in clinical outcomes between prophylaxis with conventional recombinant factor VIII (rFVIII) and rFVIIIFc, an extended half-life rFVIII covalently fused to the Fc domain of human IgG1.Population PK estimates from 180 (rFVIIIFc) and 46 (rFVIII) severe haemophilia A patients were used to simulate FVIII activity over time at various rFVIIIFc dosing regimens compared to rFVIII 30 IU kg(-1) three times weekly in a typical adult patient.rFVIII dosed 3x30 IU kg(-1) weekly gave trough levels of 2.7, 2.8 and 0.7 IU dL(-1) , and time spent below 1, 3 and 5 IU dL(-1) of 0.2/1.2/2.3 days week(-1) . rFVIIIFc 2 x 45 IU kg(-1) gave higher troughs (4.4 and 1.7 IU dL(-1) ) and shorter time spent below 1, 3 and 5 IU dL(-1) (0/0.6/1.3 days week(-1) ), with same total factor consumption. rFVIIIFc 2 x 30 IU kg(-1) gave similar troughs (3.0 and 1.2 IU kg(-1) ) and time spent below 1, 3 and 5 IU dL(-1) (0/1.0/2.1 days week(-1) ), despite total factor consumption being reduced by one-third. The same dose and interval of rFVIIIFc (3 x 30 IU kg(-1) ) gave substantially higher troughs (7.8, 8.5 and 3.3 IU dL(-1) ) and markedly shorter time spent below 1, 3 and 5 IU dL(-1) (0/0/0.4 days week(-1) ).The lower clearance of rFVIIIFc compared to conventional rFVIII gives rFVIIIFc the potential of improved bleed prevention and reduced injection frequency at similar factor consumption. Although additional clinical data are required to confirm the conclusions, the simulations clearly show the potential of rFVIIIFc of increased flexibility to tailor treatment to the individual patient, and to advance the standard of care in haemophilia.

Mesoionic compounds have shown antitumor and citotoxic activity against different tumor cells lines, which has been attributed to their physical and chemical characteristics. Among these compounds, the 1,3,4-thiadiazolium-2-phenylamine derivatives have been highlighted due to their important anti-melanoma activity. In this work, the effects of three derivatives that belong this class, MI-J, MI-4F and MI-2,4diF, on the oxidative stress parameters were evaluated using rat liver mitochondria. All the derivatives prevented natural and calcium induced oxidation of pyridine nucleotides at lower concentrations (6.5 and 32.5 nmol/mg protein). The calcium uptake was inhibited by all the derivatives at higher concentrations (65 and 130 nmol/mg protein), whereas the cation efflux was inhibited only by the MI-J (52%) and MI-4F (50%), possibly by inhibiting the formation of the permeability transition pore (PTP) by 100% and 50%, respectively, as observed in the same experimental conditions. MI-2,4diF did not inhibit the mitochondrial permeability transition or calcium efflux. The enzymatic activity of glutathione reductase, glutathione peroxidase and catalase was not affected by any derivative, but superoxide dismutase was inhibited by all the derivatives. MI-J inhibited enzyme activity significantly (85%) at the highest concentration (130 nmol/mg protein); on the other hand, their activity was less affected by fluorine derivatives (MI-4F-20% and MI-2,4diF-32%). These results suggest that these derivatives exert antioxidant effects on isolated mitochondria.

For the treatment of persistent post-prostatectomy incontinence (PPI), several surgical treatment options including male slings are available. In 2010, the second generation of the retrourethral male sling Advance, AdVanceXP, was introduced. Aim of the study was to examine in a prospective multicentre study the outcome of AdVanceXP in the treatment of PPI.Ninety-four patients were treated with AdVanceXP. Patients with nocturnal incontinence, previous incontinence surgery, with coaptive zone1 cm and irradiated patients were excluded. Measurements included: daily pad usage, 24-h pad weight test, post-operative pain in the visual analogue scale, International Quality of Life questionnaire, International Consultation on Incontinence Questionnaire short form, IEEF5 and Patient Global Impression of Improvement. Adverse events were recorded. All patients with no pads and 0-5 g in the 24-h pad test were defined as cured and those with a reduction in urine loss50 % as improved.Preoperatively, the median 24-h pad weight test was 274 g and daily pad usage was 3. At 1-year follow-up, 66.3 % of patients could be classified as cured and 25.3 % as improved. After 2 years, 73.1 % could be classified as cured and 19.6 % as improved. Urine loss decreased (p 0.001), and quality of life improved significantly (p 0.001). Mean PGI was 1.5 after 1 year and 1.4 after 2 years. Majority of complications were minor. No intraoperative complications and five serious post-operative events occurred (grade IIIB complications). No explantation was necessary.AdVanceXP, when correctly indicated, shows good effectiveness and low complication rates after up to 2 years.

Rationale: Choroidal metastasis is a rare metastatic location although the most common intraocular neoplasm. In general, choroidal metastases respond favorably to systemic therapy targeted toward the primary neoplasm. In patients with choroidal metastasis of ALK rearranged non small cell lung cancer (NSCLC), targeted therapy using Alk inhibitors gradually replaced radiotherapy as the best treatment. Alectinib is a second-generation ALK inhibitors. Here we describe 2 clinical cases of patients with choroidal metastasis of ALK rearranged NSCLC who received Alectinib as first-line therapy achieving disease control and quality of life improvement. Patients concerns: In case report 1, 62-year-old man presented with scintillated scotomas at the level of the right eye; in case report 2, 69-year-old man presented with respiratory distress, persistent cough resistant to medical therapy, pain, and blurred vision. Diagnoses: In case report 1, fundus and ultrasonographic examination showed circumscribed choroid thickening with dome-like appearance compatible with repetitive lesion. Computed tomographic/y (CT) showed multiple bilateral pulmonary nodular formations and adenocarcinoma of the lung was diagnosed by a transbronchial biopsy. In case report 2, CT showed a primary lesion of 36 × 27 mm in the middle lobe with bilateral lung metastases and lymphadenopathies. Multiple hepatic metastases and minor suspicious bone repetitions. A liver biopsy made a diagnosis of adenocarcinoma compatible with pulmonary primitiveness. An ocular fluoroangiography evidenced a left choroidal metastasis. Interventions: Case report 1, 2, medical treatment with Alectinib 1200 mg/day was initiated. Outcomes: In case report 1, a few days after beginning the treatment, both systemic symptoms like respiratory distress and low vision were palliated. Reassessment by CT confirmed treatment response. In case report 2, clinically, visus disorders had already improved 2 weeks after beginning treatment. CT showed pulmonary, nodal, and hepatic response. Stability of bone metastases occurred after 2 months. In addition, ocular ultrasonography documented the regression of previously reported lesions confirmed treatment response. Lessons: Alectinib works very well in intracranial metastases and is assumed to be so on the ocular ones as well, with benefit for the patient in quality of life.

We aimed to assess the effectiveness of ‘Paesaggi di Prevenzione’, a school-based prevention program delivered by trained teachers and designed to tackle smoking, alcohol misuse, dietary risks, and physical inactivity in adolescence. We evaluated the program between 2010 and 2013 with a two-arm, parallel-group, multicentre cluster randomized controlled trial in which schools were the units of randomization. We collected data on health-compromising behaviours using self-reported measurements of behaviour frequency administered before and after program implementation. We used multivariable mixed-effects logistic regression models to estimate program effects on health-compromising behaviours. The analysis sample included 3410 middle school students and 1651 high school students. Among middle school students, mean age at baseline was 12 years (standard deviation [SD] 0.5 years), 51% were boys, and 41% had high socioeconomic status [SES] (defined as having at least one parent/guardian with university level education). In high school students, mean age at baseline was 14 years (SD 0.7 years), 56% were boys, and 31% had high SES. The program did not have effects on smoking, alcohol misuse, and physical activity. The program had iatrogenic effects in regard to some eating behaviours, resulting in (i) lower odds of fruit consumption among middle-school students (odds ratio [OR] 0.82; 95% confidence interval [CI] 0.68–0.99) and (ii) lower odds of having breakfast every day in high-school students at the post-intervention measurement (OR 0.76; 95%CI 0.58–0.99) but not at one-year follow-up (OR 0.94; 95%CI 0.69–1.28). Due to the possibility of unintended effects, we advise against disseminating ‘Paesaggi di Prevenzione’ in its present form. Trial registration ISRCTN00953701

Understanding the population of Central Italy during the 1

Human genetic studies are rapidly identifying variants that increase risk for neurodevelopmental disorders. However, it remains unclear how specific mutations impact brain function and contribute to neuropsychiatric risk. Chromosome 16p11.2 deletion is one of the most common copy number variations in autism and related neurodevelopmental disorders. Using resting state functional MRI data from the Simons Variation in Individuals Project (VIP) database, we show that 16p11.2 deletion carriers exhibit impaired prefrontal connectivity, resulting in weaker long-range functional coupling with temporal-parietal regions. These functional changes are associated with socio-cognitive impairments. We also document that a mouse with the same genetic deficiency exhibits similarly diminished prefrontal connectivity, together with thalamo-prefrontal miswiring and reduced long-range functional synchronization. These results reveal a mechanistic link between specific genetic risk for neurodevelopmental disorders and long-range functional coupling, and suggest that deletion in 16p11.2 may lead to impaired socio-cognitive function via dysregulation of prefrontal connectivity.

To evaluate the outcome of the retrourethral transobturator sling (RTS) by functional magnetic resonance imaging (MRI) and to identify parameters associated with sling failure. Of thirty recruited men with postprostatectomy stress urinary incontinence (SUI), 26 consecutively underwent functional MRI before sling procedure and 12 months thereafter in a prospective clinical cohort observational study. Periurethral/urethral fibrosis and sling visualization were evaluated on static sequences. The angle of the membranous urethra, position of the bladder neck and external urethral sphincter were assessed during Valsalva’s maneuver and voiding. Sling success was defined as no or one dry “security” pad. The success and failure rates were 58 % (15/26 patients) and 42 % (11/26 patients), respectively. The sling leads to reduction in the membranous urethra angle during Valsalva’s maneuver (39.55° vs. 36.82°, p = 0.025) and voiding (38.25° vs. 34.83°, p = 0.001) and elevation of the external urethral sphincter (2.9 vs. 4.8 mm, p = 0.017). Preoperative wider angle of the membranous urethra was significantly correlated with severe preoperative incontinence. Sling failure (p = 0.001) and severe preoperative incontinence (p = 0.001) were significantly related to only small changes of the membranous urethra angle. The interrater and intrarater reliability for membranous urethra angle was excellent (intraclass correlation coefficient ≥0.75). The RTS leads to reduction in the membranous urethra angle. The extent of the changes in the membranous urethra angle is associated with RTS outcome. Functional MRI is a reliable noninvasive visualization tool of interactions between the sling and pelvic floor for further research on the complex nature of postprostatectomy SUI.