Complete-arch accuracy of four intraoral scanners: An in vitro study

The purpose of this study is to define the accuracy of four intraoral scanners (IOS) through the analysis of digital impressions of a complete dental arch model. Eight metal inserts were placed on the model as reference points and then it was scanned with a laboratory scanner in order to obtain the reference model. Subsequently, the reference model was scanned with four IOS (Carestream 3600, CEREC Omnicam, True Definition Scanner, Trios 3Shape). Linear measurements were traced on an STL file between the chosen reference points and divided into four categories: three-element mesiodistal, five-element mesiodistal, diagonal, and contralateral measurements. The digital reference values for the measurements were then compared with the values obtained from the scans to analyze the accuracy of the IOS using ANOVA. There were no statistically significant differences between the measurements of the digital scans obtained with the four IOS systems for any of the measurement groups tested

International Evidence Based Reappraisal of Genes Associated With Arrhythmogenic Right Ventricular Cardiomyopathy Using the Clinical Genome Resource Framework

Background - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease characterized by ventricular arrhythmias and progressive ventricular dysfunction. Genetic testing is recommended and a pathogenic variant in an ARVC-associated gene is a major criterion for diagnosis according to the 2010 Task Force Criteria (TFC). As incorrect attribution of a gene to ARVC can contribute to misdiagnosis, we assembled an international multidisciplinary ARVC ClinGen Gene Curation Expert Panel to reappraise all reported ARVC genes. / Methods - Following a comprehensive literature search, six two-member teams conducted blinded independent curation of reported ARVC genes using the semi-quantitative ClinGen framework. /Results - Of 26 reported ARVC genes, only six (PKP2, DSP, DSG2, DSC2, JUP, TMEM43) had strong evidence and were classified as definitive for ARVC causation. There was moderate evidence for two genes, DES and PLN. The remaining 18 genes had limited or no evidence. RYR2 was refuted as an ARVC gene since clinical data and model systems exhibited a catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype. In ClinVar, only 5 pathogenic / likely pathogenic (P/LP) variants (1.1%) in limited evidence genes had been reported in ARVC cases in contrast to 450 desmosome gene variants (97.4%). / Conclusions - Using the ClinGen approach to gene-disease curation, only eight genes, (PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN, DES) had definitive or moderate evidence for ARVC and these genes accounted for nearly all P/LP ARVC variants in ClinVar. Therefore, only P/LP variants in these eight genes should yield a major criterion for ARVC diagnosis. P/LP variants identified in other genes in a patient should prompt further phenotyping as variants in many of these genes are associated with other cardiovascular conditions

Efficient clofilium tosylate-mediated rescue of POLG-related disease phenotypes in zebrafish

The DNA polymerase gamma (Polg) is a nuclear-encoded enzyme involved in DNA replication in animal mitochondria. In humans, mutations in the POLG gene underlie a set of mitochondrial diseases characterized by mitochondrial DNA (mtDNA) depletion or deletion and multiorgan defects, named POLG disorders, for which an effective therapy is still needed. By applying antisense strategies, ENU- and CRISPR/Cas9-based mutagenesis, we have generated embryonic, larval-lethal and adult-viable zebrafish Polg models. Morphological and functional characterizations detected a set of phenotypes remarkably associated to POLG disorders, including cardiac, skeletal muscle, hepatic and gonadal defects, as well as mitochondrial dysfunctions and, notably, a perturbed mitochondria-to-nucleus retrograde signaling (CREB and Hypoxia pathways). Next, taking advantage of preliminary evidence on the candidate molecule Clofilium tosylate (CLO), we tested CLO toxicity and then its efficacy in our zebrafish lines. Interestingly, at well tolerated doses, the CLO drug could successfully rescue mtDNA and Complex I respiratory activity to normal levels, even in mutant phenotypes worsened by treatment with Ethidium Bromide. In addition, the CLO drug could efficiently restore cardio-skeletal parameters and mitochondrial mass back to normal values. Altogether, these evidences point to zebrafish as a valuable vertebrate organism to faithfully phenocopy multiple defects detected in POLG patients. Moreover, this model represents an excellent platform to screen, at the whole-animal level, candidate molecules with therapeutic effects in POLG disorders

The genetic architecture of Plakophilin 2 cardiomyopathy

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position

Correction to:The genetic architecture of Plakophilin 2 cardiomyopathy (Genetics in Medicine, (2021), 23, 10, (1961-1968), 10.1038/s41436-021-01233-7)

Due to a processing error Cynthia James, Brittney Murray, and Crystal Tichnell were assigned to the wrong affiliation. Cynthia James, Brittney Murray, and Crystal Tichnell have as their affiliation 5 Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA. In addition Hana Zouk, Megan Hawley, and Birgit Funke were assigned only to affiliation 3; they also have affiliation 4 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. The original article has been corrected

Applying the Theory of Affective Intelligence to Support for Authoritarian Policies and Parties

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148346/1/pops12571.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148346/2/pops12571_am.pd

Conscious \u2013 unconscious dissociations in visual perception: clues from hemianopic patients

DISSOCIAZIONE CONSAPEVOLE-INCONSAPEVOLE NELLA PERCEZIONE VISIVA: INDIZI DA PAZIENTI EMIANOPTICI. Lesioni lungo la via visiva producono difetti caratteristici nel campo visivo. Il tipo pi\uf9 comune di disturbo del campo visivo omonimo (HVFD) \ue8 l\u2019emianopsia. La probabilit\ue0 del verificarsi di HVFDs in seguito ad ictus, trauma o intervento \ue8 elevata, circa il 20-30 %. Nei pazienti con HVFDs sono seriamente compromesse le attivit\ue0 quotidiane a causa della disabilit\ue0 acquisita in nell\u2019orientamento visivo e di esplorazione spaziale. Il recupero della funzione visiva \ue8 possibile, ma \ue8 raramente completo. Tuttavia, negli anni settanta del secolo scorso Poeppel et al e successivamente Weiskrantz et al hanno descritto la presenza di comportamento guidato dalla visione nel campo cieco di pazienti emianopsici (\u201cblindsight\u201d). Questa Tesi \ue8 incentrata sul tentativo di gettare nuova luce su questo importante fenomeno. In particolare, lo scopo del presente progetto di ricerca \ue8 molteplice: i) si propone di studiare le implicazioni del concetto di numerosit\ue0 e di percezione Gestaltica nei normali e il ruolo di queste caratteristiche nel fenomeno del Blindsight in pazienti con emianopsia ; ii) vuole indagare le propriet\ue0 psicofisiche della visione residua (consapevole e inconsapevole) nel campo cieco e iii ) si propone di studiare l'anatomia e la funzionalit\ue0 degli emisferi intatti e danneggiati attraverso l\u2019uso dell\u2019elettroencefalografia e della neuroimmagine funzionale. Nel primo progetto, abbiamo impiegato il paradigma di ridondanza del segnale (RSE), in soggetti normali ed in pazienti emianopsici, al fine di indagare le caratteristiche percettive dell\u2019emicampo intatto e cieco, e l'interazione tra loro. Come prima cosa, abbiamo testato 18 partecipanti sani (et\ue0 media : 31.1 ) per osservare se la RSE aumenta con 4 vs 1 stimoli. Abbiamo usato due differenti configurazioni di stimoli, nella prima i quattro stimoli formano una figura gestalt simile a una forma di diamante, mentre nell'altra la posizione degli stimoli \ue8 stata randomizzata. Ai partecipanti era richiesto di mantenere la fissazione su un piccolo stimolo centrale e, dopo l\u2019arrivo di un segnale acustico, dovevano premere un pulsante il pi\uf9 rapidamente possibile alla presentazione degli stimoli visivi. I risultati hanno mostrato un aumento della RSE (cio\ue8 pi\uf9 rapidi tempi di reazione) quando gli stimoli erano quadrupli rispetto a quando erano singoli, indipendentemente dalla configurazione proposta. Un\u2019ulteriore analisi ha mostrato che l\u2019RSE con stimoli semplici e con stimoli che formano una configurazione Gestaltica \ue8 spiegata da una coattivazione neurale, piuttosto che da una teoria probabilistica, in quanto si osserva una violazione del modello di Miller. Al contrario, il risultato ottenuto nella presentazione di stimuli quadrupli in posizione randomizzata potrebbe essere spiegabile alla luce di una teoria probabilistica. Nella seconda parte, abbiamo studiato se tale paradigma modificato era pi\uf9 efficace nel rilevare il fenomeno del Blindsight (un comportamento inconscio guidato visivamente) in pazienti emianoptici e nei pazienti emisferectomizzati. Abbiamo testato sei pazienti con emianopsia (et\ue0 media : 45,83 ) a seguito di lesione del tratto corticale o ottico e un paziente emisferectomizzato. La procedura era la stessa dell\u2019esperimento precedente. I risultati hanno mostrato una maggiore efficacia del metodo con stimoli numerosi, tenendo conto della misurazione della RSE con pi\uf9 stimoli presentati contemporaneamente nell\u2019emicampo intatto e cieco rispetto alla presentazione singola nel campo intatto. \uc8 interessante notare che la RSE nei pazienti era pi\uf9 pronunciata per la configurazione gestaltica. Inoltre i risultati osservati con l\u2019analisi di risonanza magnetica funzionale hanno mostrato un'attivazione di aree visive localizzate a livello della via visiva ventrale. Nel secondo progetto, ci siamo proposti di capire quale dei due emisferi media il comportamento guidato visivamente dopo la presentazione di stimoli nell\u2019emicampo cieco di pazienti con emianopsia. Abbiamo testato 9 pazienti (et\ue0 media : 44.5 ) con il paradigma di Poffenberger ( PP ): si tratta di un compito di Tempo di Reazione che prevede la presentazione dello stimolo visivo lateralizzato e una risposta unimanuale. I risultati hanno mostrato che nell\u2019emicampo intatto tutti i pazienti mostrano una CUD positiva (cio\ue8 normale) mentre i risultati nell\u2019emicampo cieco erano pi\uf9 variabili con una CUD positiva in alcuni pazienti e negativa in altri. Quest\u2019ultimo dato significa che la risposta nel campo cieco era mediata dall\u2019emisfero intatto e questo potrebbe essere correlato alla estensione delle singole lesioni. Inoltre, abbiamo usato un nuovo metodo per indagare il Blindsight, abbiamo confrontato le frequenze di distribuzione cumulative (CDF) dei temi di reazione a seguito della presentazione dello stimolo nel campo intatto e cieco in condizioni normali e con gli occhi chiusi. Abbiamo testato 6 pazienti di cui due mostrano il fenomeno del blindsight mentre ad occhi chiusi non c\u2019erano risposte sopra al caso. Infine, abbiamo usato la risonanza magnetica funzionale (fMRI) per valutare il coinvolgimento delle specifiche strutture cerebrali in IT delle informazioni visuo-motorie e il ruolo dell\u2019emisfero intatto. Abbiamo testato il ben noto paziente con blindsight GY con il paradigma di Poffenberger . I risultati comportamentali hanno registrato una CUD positiva quando il paziente era stimolato visivamente nel campo intatto, e una CUD negativa quando stimolato nel campo cieco, suggerendo che sia l'emisfero intatto a mediare il blindsight. I risultati dell\u2019analisi funzionale hanno mostrato l'attivazione di aree corticali (aree visive ventrali , aree visive dorsali, aree senso- motorie e premotorie) e le aree del corpo calloso, differenziato nella condizione di stimolazione consapevole e inconsapevole (anteriore vs medio -posteriore, rispettivamente). Nel terzo progetto, abbiamo misurato la risposta elettrofisiologica alla stimolazione visiva del campo visivo cieco e intatto sempre nel paradigma di Poffenberger (PP) in 12 soggetti sani e in tre pazienti emianoptici. Lo scopo dell'indagine \ue8 stato quello di indagare sulla natura e la funzionalit\ue0 dell'emisfero leso, cos\uec come cercare di capire l'efficienza della trasmissione inter-emisferica. In entrambi gli emisferi abbiamo trovato una assenza di risposta ERP per la stimolazione del campo cieco mentre per la stimolazione dell\u2019 emicampo intatto abbiamo trovato una buona risposta diretta nell'emisfero controlaterale. \uc8 interessante notare una risposta differente nei tre pazienti per la risposta commissurale indiretta. Infatti, la risposta registrata nell'emisfero lesionato \ue8 assente o molto debole in siti posteriori per il paziente EA e il paziente PC, mentre per la paziente SL la risposta registrata nell'emisfero leso era paragonabile a quella dei soggetti sani. Ci\uf2 sembrerebbe suggerire che il trasferimento interemisferico e l'integrazione di informazioni visive tra l\u2019emisfero danneggiato e quello intatto dei pazienti emianoptici sembra avvenire nella fase percettiva e necessita dell'integrit\ue0 funzionale e anatomica dello splenium del Corpo Calloso. In breve, l\u2019interesse dell\u2019intera ricerca \ue8 multiplo. In primo luogo, utilizzando il RSE si \ue8 constatato che vi \ue8 una sostanziale interazione tra i due emisferi nei pazienti e che la visione inconscia \ue8 sensibile alla numerosit\ue0 e mostra una sorta di organizzazione percettiva gestaltica. In secondo luogo, ho descritto i risultati di un nuovo metodo per registrare la presenza di abilit\ue0 residue di rilevamento di stimoli inconsci nei pazienti emianoptici, probabilmente innescato da antiche aree evolutive sottocorticali. Infine, utilizzando il paradigma di Poffenberger, con l\u2019uso delle registrazioni ERP e della neuroimmagine, \ue8 stato possibile avere indizi utili a capire l'importanza dell'emisfero intatto nella mediazione della visione cieca.CONSCIOUS \u2013 UNCONSCIOUS DISSOCIATIONS IN VISUAL PERCEPTION: CLUES FROM HEMIANOPIC PATIENTS. Lesions along the visual pathway produce characteristic gaps in the visual field. The most common type of homonymous field disorder (HVFD) is hemianopia. The probability of occurrence of HVFDs following a stroke, trauma or surgery is high, around 20-30%. Patients with HVFDs are seriously impaired in everyday activities and this is because of the acquired disability in visual orienting and exploration. Recovery of visual function is possible but is rarely complete. However, in the seventies of last century it has been shown by Poeppel et al. and subsequently by Weiskrantz et al. that some hemianopic patients retain some form of visually guided behaviour in the blind hemifield in absence of perceptual awareness (\u201cblindsight\u201d). This Thesis is mainly based on casting new light on this intriguing phenomenon. In particular, the purpose of the present research project is multifold: i) To investigate whether higher-order perceptual effects like Numerosity detection and Gestalt phenomena are present in the blind hemifield of hemianopic patients; ii) To investigate the basic psychophysical properties of conscious as well as unconscious (blindsight) residual vision in the blind field and iii) To study the anatomy and functionality of the intact and damaged hemispheres through electrophysiological recordings and functional imaging. In the first project, we employed a redundant signal effect (RSE) paradigm, in healthy participants and in patients, to investigate the perceptual characteristics of the intact and blind hemifield, and the interaction between them. Initially, we tested in healthy participants whether the RSE increases with 4 vs 1 stimuli. We used two different configurations of stimuli, in one the four redundant stimuli formed a gestalt-like figure in the shape of a diamond, while in the other the position of stimuli was randomized. We tested 18 participants (mean age: 31.1). They were required to keep their fixation steady on a central fixation point and, following onset of an acoustic warning signal, to press a button as quickly as possible upon presentation of the visual stimuli. Results showed an increase of the RSE (i.e. faster reaction times) with four with respect to single stimuli independently from the configuration proposed. The analysis of the present data showed that the RSE effect in the Single bilateral presentation and in the Quadruple Gestalt bilateral presentation is attributable to neural coactivation rather than probability summation, in that there was a violation of Miller\u2019s race inequality. Conversely, the result obtained in the Quadruple Random bilateral presentation was attributable to a probability summation, in that there was no violation of the race inequality. In the second part of this project, we investigated if this procedure was more likely to increase the probability to detect blindsight in hemianopic patients and in hemisperectomized patients. We tested six patients with hemianopia (mean age: 45.83) as a result of cortical or optic tract lesion and one hemisperectomized patient. The procedure and design were the same as in the previous experiment. The results showed a trend toward an increase of speed of reaction time as measured by the RSE with multiple stimuli presented simultaneously to the intact and blind hemifield in comparison to stimuli to the intact field only. It is interesting to point out that the RSE in hemianopics and in the hemisperectomized patient was more pronounced for the gestalt-like configuration and this suggests the presence of gestalt-like perception in blindsight and provides important clues for rehabilitation. Moreover the functional magnetic resonance imaging results showed as expected an activation of visual areas localized at the level of the ventral visual pathway. In the second project, we tried to understand which of the two hemispheres mediates visually guided behavior following stimulus presentation to the blind hemifield of patients with hemianopia. We tested 9 patients (mean age:44.5) with the Poffenberger paradigm (PP): a RT task that involves a lateralized visual stimulus presentation in the intact and in the blind hemifield and a unimanual response. The crossed-uncrossed difference (CUD), a behavioural estimate of callosal interhemispheric transfer (IT) time for stimuli presented to the intact hemifield of all patients was positive and this can be interpreted as related to the lesioned hemisphere subserving the response whilst in the blind hemifield the results were more variable with some patients showing a positive and others a negative CUD (i.e. the response was subserved by the intact hemisphere) and this could be related to the extension of the individual lesions. In the second part, we used a new method for testing blindsight, namely to compare the cumulative distribution frequency (CDF) of RT for stimulus presentation to the intact and the blind field under normal or occluded viewing conditions. We tested 6 patients and the results were that two of them showed blindsight. We also used functional magnetic resonance (fMRI) to assess the involvement of specific brain structures in the IT of visuomotor information and the role of the intact hemisphere. We tested with the Poffenberger paradigm the well known blindsight patient GY. Behavioural results showed a positive CUD for the stimulation of the intact hemifield, and a negative CUD for the stimulation of the blind hemifield, suggesting that the intact hemisphere mediates the blindsight responses. Functional results showed activation of cortical areas (ventral visual areas, dorsal visual areas, sensori-motor and premotor areas) and callosal areas, with interesting differences in the conscious and unconscious conditions (anterior vs. middle-posterior, respectively). In the third project, we measured the electrophysiological response to visual stimulation of blind and intact visual field in the Poffenberger Paradigm (PP) in 12 healthy subjects and in three hemianopic patients. The purpose of the investigation was to inquire into the nature and the functionality of the lesioned hemisphere as well as try to understand the efficiency of IT. In both hemispheres we found an absence of ERP responses for stimulation of the hemianopic field while for stimulation of the intact hemifield we found a good direct response in the contralateral hemisphere. Interestingly, we observed a different response in the three patients for the indirect commissural response: the response recorded in the lesioned hemisphere was absent or very weak in posterior sites for patient EA and patient PC while for patient SL the response recorded in the lesioned hemisphere was comparable to that of healthy participants. This suggests that IT and integration of visual information from the intact to the damaged hemisphere of hemianopic patients seems to occur at the perceptual stage depending on the functional and anatomical integrity of the splenium of the CC. In short, the thrust of this entire Thesis is multifold. First, by using the Redundant Signal Effect it was found that there is a substantial cross-talk between the two hemispheres in hemianopic patients, including one hemispherectomy patient, and that unconscious vision is sensitive to stimulus numerosity and shows a sort of gestaltic perceptual organization. Second, I described the results of a new method to assess a reliable detection of unconscious stimuli in hemianopic patients probably triggered by evolutionary ancient subcortical areas. Finally, by using the Poffenberger paradigm, associated or not with ERP recordings, it was possible to have clues as to the importance of the intact hemisphere in mediating blindsight