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Background: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs. Methods: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6–65) was divided into six successive 6–10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients. Results: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6–13 and adults aged 50–65 with OCD taking SRIs (Cohen's d = −0.24 to −0.74). Volumes of putamen, pallidum (d = 0.18–0.40), and ventricles (d = 0.31–0.66) were greater in patients aged 20–29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = −0.27 to −1.31). Conclusions: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20–29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response.

The original version of this Article omitted from the author list the 212th author Patrizia Mecocci, who is from the Institute of Gerontology and Geriatrics, Department of Medicine, University of Perugia, Perugia, Italy. Consequently, the “Sample Contribution” section of Author Contributions was updated to add “P.M” between “P.D.” and “R.C.”. Additionally, the original version of this Article contained the incorrect affiliation for author Patrick Gavin Kehoe, which incorrectly read “German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany”. The correct version replaces this affiliation with “Bristol Medical School (THS), University of Bristol, Southmead Hospital, Bristol, UK”. This has been corrected in both the PDF and HTML versions of the Article. CA extern

Objective: The observers use the optic flow to control self-motion. However, the current state of knowledge indicates that it is difficult to understand how optic flow is used by the visual system without a direct measurement of the changes in the flow patterns caused by eye movements during natural behaviour. The purpose of this literature review is to highlight the importance of the integration between optic flow and eye movements for postural control. Methods: A literature review of the electronic papers through July 2022 was independently performed by three investigators. The selection of the studies was made by a search on PubMed, Scopus, and Google Scholar with two groups of selected keywords. We excluded papers performed on subjects with pathologies, children, and the elderly. Results: The results of this literature analysis highlight that eye movements are required to drive visual motion processing and heading perception in both static and dynamic contexts. Conclusion: Although we now know many neural mechanisms that process heading direction from the optic flow field, a consideration of optic flow patterns relative to gaze direction provides more detailed information on how the retinal flow field is used to control body balance. Doi: 10.28991/ESJ-2022-06-06-020 Full Text: PDF

BACKGROUND Dupilumab has been demonstrated to be an effective treatment for patients with moderate-to-severe atopic dermatitis (AD) in clinical trials. However, evidence of real-world experience with dupilumab in a broader population is limited to date. METHODS Adult patients with moderate-to-severe AD, defined as an Eczema Area Severity Index (EASI) score of 24 or higher, treated with dupilumab at ten Italian academic centers, were included in the study. Physician-reported outcome measures (EASI), patient-reported outcome measures (pruritus and sleep score, Dermatology Life Quality Index, DLQI) and serological markers [immunoglobulin (Ig) E and eosinophil count] after 16 weeks were analyzed. RESULTS We enrolled 543 patients with moderate-to-severe AD. Two patients (0.4%) discontinued treatment. The median ± interquartile percentage change from baseline to 16 weeks of treatment in the EASI score was -87.5±22.0 (p

Forests are vital for ecological, economic, and social reasons, and adopting sustainable forest management practices is necessary. While traditional forest monitoring techniques provide detailed data, they are time-consuming; conversely, geomatic techniques can provide more detailed data for forest resource management. This study aims to assess the suitability of Mobile Mapping Systems (MMS) with simultaneous localisation and mapping (SLAM) technology for precision forestry purposes in challenging environments. We compared the performance of MMS data with Terrestrial Laser Scanning (TLS) data and evaluated the Forest Structural Complexity Tool (FSCT), which was developed for TLS datasets, on MMS data. The case study area is a highly sloped coniferous forest in the Italian Alps affected by a severe fire in 2017. Data were processed using a fully automated open-source Python tool that detects each tree's position, Diameter at Breast Height (DBH), and height. The validation procedure was conducted with respect to the TLS point cloud manually segmented. The results show that using MMS with SLAM technology is suitable for precision forestry purposes in challenging environments and that FSCT performs well on MMS data.

Objective Report a case of localized necrotizing meningoencephalitis as the cause of functional hearing loss after cochlear implant (CI) surgery. Case report A 12-year-old with bilateral CI presented to our quaternary center due to severe functional hearing loss after 11 years since left ear CI surgery. CT with contrast was conducted showing a CPA tumor-like mass. Pre-operative computed tomography (CT) scans and magnetic resonance imaging (MRI) performed at the age of 1 year showed no inner ear abnormalities and in particular no evidence of a tumor in the cerebellopontine angle (CPA). Conclusion Following removal of the CI and the mass, histopathological, immunohistochemical and cultural examinations revealed a necrotizing meningoencephalitis, with the CI electrode as the focus.

The N-fluorenyl-9-methyloxycarbonyl (Fmoc)-protected amino acids have shown high antimicrobial application potential, among which the phenylalanine derivative (Fmoc-F) is the most well-known representative. However, the activity spectrum of Fmoc-F is restricted to Gram-positive bacteria only. The demand for efficient antimicrobial materials expanded research into graphene and its derivatives, although the reported results are somewhat controversial. Herein, we combined graphene oxide (GO) flakes with Fmoc-F amino acid to form Fmoc-F/GO hybrid hydrogel for the first time. We studied the synergistic effect of each component on gelation and assessed the material’s bactericidal activity on Gram-negative Escherichia coli (E. coli). GO flakes do not affect Fmoc-F self-assembly per se but modulate the elasticity of the gel and speed up its formation. The hybrid hydrogel affects E. coli survival, initially causing abrupt bacterial death followed by the recovery of the surviving ones due to the inoculum effect (IE). The combination of graphene with amino acids is a step forward in developing antimicrobial gels due to their easy preparation, chemical modification, graphene functionalization, cost-effectiveness, and physicochemical/biological synergy of each component. peerReviewed

Background and ObjectivesPrimary progressive aphasia (PPA) is a neurodegenerative syndrome of progressive language decline. PPA has 3 main subtypes: logopenic, semantic, and agrammatic. Observational studies suggested an association between language-related neurodevelopmental phenotypes and an increased risk of PPA. We sought to assess such relationships through Mendelian randomization (MR) approach, which can suggest potentially causal associations.MethodsGenome-wide significant single-nucleotide polymorphisms (SNPs) associated with dyslexia (42 SNPs), developmental speech disorders (29 SNPs), and left-handedness (41 SNPs) were used as genetic proxies for the exposures. Eighteen of 41 SNPs of left-handedness were associated with structural asymmetry of the cerebral cortex. Genome-wide association study summary statistics were obtained from publicly available databases for semantic (308 cases/616 controls) and agrammatic PPA (269 cases/538 controls). The logopenic PPA (324 cases/3,444 controls) was approximated by proxy through the rubric of clinically diagnosed Alzheimer disease with salient language impairment. Inverse-weighted variance MR was performed as the main analysis for testing the relationship between the exposures and outcomes. Sensitivity analyses were completed to test the robustness of the results.ResultsDyslexia, developmental speech disorders, and left-handedness were not associated with any PPA subtype (p> 0.05). The genetic proxy of cortical asymmetry in left-handedness was significantly associated with agrammatic PPA (β = 4.3,p= 0.007), but not with other PPA subtypes. This association was driven by microtubule-related genes, primarily by a variant that is in complete linkage disequilibrium withMAPTgene. Sensitivity analyses were overall consistent with the primary analyses.DiscussionOur results do not support a causal association between dyslexia, developmental speech disorders, and handedness with any of the PPA subtypes. Our data suggest a complex association between cortical asymmetry genes and agrammatic PPA. Whether the additional association with left-handedness is necessary remains to be determined but is unlikely, given the absence of association between left-handedness and PPA. Genetic proxy of brain asymmetry (regardless of handedness) was not tested as an exposure due to lack of suitable genetic proxy. Furthermore, the genes related to cortical asymmetry associated with agrammatic PPA are implicated in microtubule-related proteins (TUBA1B,TUBB, andMAPT), which is keeping with the association of tau-related neurodegeneration in this PPA variant.

Distortions in time processing may be regarded as an endophenotypic marker of neuropsychiatric diseases; however, investigations addressing Bipolar Disorder (BD) are still scarce.The present study compared timing abilities in 30 BD patients and 30 healthy controls (HC), and explored the relationship between time processing and affective-cognitive symptoms in BD, with the aim to determine whether timing difficulties are primary in bipolar patients or due to comorbid cognitive impairment. Four tasks measuring external timing were administered: a temporal and spatial orienting of attention task and a temporal and colour discrimination task, for assessing the ability to evaluate temporal properties of external events; two other tasks assessed the speed of the internal clock (i.e. temporal bisection and temporal production tasks). Attentional, executive and working memory (WM) demands were equated for controlling additional cognitive processes.BD patients did not show differences in external timing accuracy compared to HC; conversely, we found increased variability of the internal clock in BD and this performance was related to Major Depressive Episodes recurrence and WM functioning. Hence, variability of the internal clock is influenced by the progressive course of BD and impacted by variations in WM.Future studies including BD patients stratified by mood episode will further specify timing alterations conditional to the current affective state.Our results shed new light on the clinical phenotypes of BD, suggesting that timing might be used as a model system of the ongoing pathophysiological process.

Il modello didattico pensato dai docenti del Corso di Laurea Magistrale Interclasse per “Coordinatori di Servizi Educativi e Servizi Sociali”, del Dipartimento di Scienze della Formazione dell’Università Roma Tre, chiede agli studenti iscritti di condividere le ragioni di un approccio formativo specifico: la conoscenza di saperi e l’acquisizione di competenze sono indispensabili per qualsiasi profilo professionale, ma non sono sufficienti per garantire la qualità dell’agire professionale quotidiano e periodico; altrettanto indispensabile è acquisire l’abitudine a riflettere, pensare, commentare, spiegare, analizzare, sintetizzare, comparare, approfondire. In altre parole: la conoscenza di saperi e l’acquisizione di competenze permette di crescere, di perfezionarsi, di essere veri esperti, veri tecnici di una professione; l’abitudine a riflettere restituisce senso dell’umano ad azioni e a scelte professionali, quotidiane e periodiche. Nell’editoriale del secondo numero del 2021 di questa rivista (FOR, 2/2021) Maurizio Milan ha rilevato problemi formativi interessanti, ha letto il loro contesto in modo chiaro e attento, ha proposto idee progettuali che hanno una coerenza culturale profonda con l’approccio del Corso di Laurea Magistrale Interclasse per “Coordinatori di Servizi Educativi e Servizi Sociali”. Credo che alle sue osservazioni debbano esserne aggiunte altre. Anche le scienze umane ci hanno insegnato e ci insegnano che le ragioni delle nostre azioni, delle nostre risposte ai cambiamenti, dei nostri progetti individuali, collettivi, comunitari, globali, glocali, economici, tecnologici, sociali, formativi hanno radici nel senso di civiltà che le collettività vivono e rendono esplicito, visibile, tangibile, credibile; hanno radici nelle prospettive che i loro obiettivi rendono condivise e condivisibili, nella qualità dell’impatto possibile nelle nostre vite. Anche le scienze umane ci hanno insegnato e ci insegnano che la sostenibilità è plausibile solo se non presta esclusiva attenzione alla sfera dell’economia e delle economie, all’obiettivo dell’efficienza e della produttività, solo se non si presta ad ascoltare le voci degli stereotipi e, soprattutto, delle semplificazioni. In sostanza: le scienze dell’umano e le scienze economiche devono tornare alle interazioni che ne arricchiscono l’esistenza, gli obiettivi, il significato, il ruolo; la metafora della rete e delle reti devono tornare a caratterizzarne l’identità interdisciplinare. Perché la sostenibilità caratterizzi la qualità del futuro individuale e della vita sociale delle nuove generazioni, è necessario che attrici protagoniste di cambiamento come le università e le scuole tornino ad avere il ruolo che è stato loro assegnato di dare centralità alla persona che apprende, di superare l’idea della trasmissione dei saperi, di promuovere l’esplorazione profonda e reticolare di conoscenze e idee, di valorizzare un pensiero che spieghi, leghi, commenti, interpreti, approfondisca contenuti, significati, idee, fenomeni, eventi, fatti, impegnando pensiero deduttivo, induttivo, analitico, sintetico, simbolico, astratto, creativo, rappresentativo, partecipativo, ecc.. Perché la sostenibilità caratterizzi la qualità del futuro individuale e della vita sociale delle nuove generazioni, in altre parole, la grande attenzione che viene dedicata, per esempio, alle importantissime ragioni di una sostenibilità economica o di una sostenibilità ambientale deve crescere e dedicarsi, forse anche in modo preliminare, alle attuali ragioni di una sostenibilità educativa, formativa, sociale. Le idee proposte qui di seguito hanno l’obiettivo di rendere esplicito e concreto questo insieme di osservazioni; le loro voci riescono a coglierne le connessioni tematiche, metodologiche, strategiche.

Background Diabetic retinopathy is a principal cause of visual damage and blindness, in which laser treatment offers proven therapy. The progressive degeneration of the retina, secondary to diabetes, is believed to cause postural instability although this is not well documented. The aim of this research was to assess how optic flow stimuli contribute to the control of stance in people with impaired retinal functions. Research question Does the different retinal functionality correspond to different specific patterns of movements and muscles recruitment? Methods Postural mechanisms and motor strategies were measured by testing subjects in quiet stance on a force platform with surface electromyography under different optic flow stimulations. Root mean square values of the center of pressure time-varying signals and normalized EMG values were used to evaluate the postural sway. Results People with diabetic retinopathy, and to a greater extent laser group, were more unstable than healthy subjects. The greater amplitude of the body sway observed in the retinopathy group, and especially in the laser group, could be an expression of the difficulty for this population in processing this kind of visual information. Significance The increase in muscle activity indicates that there are musculoskeletal and postural changes in the lower limb musculature with increasing severity of diabetic retinopathy. An impaired retinal function might negatively affect postural control in a way that is dependent on the severity of retinal damage.

In many daily and sport situations, people have to simultaneously perceive and process multiple objects and scenes in a short amount of time. A wrong decision may lead to a disadvantage for a team or for a single athlete, and during daily life (i.e., driving, surgery), it could have more dangerous consequences. Considering the results of different studies, the ability to distribute visual attention depends on different levels of expertise and environment-related constraints. This article is a narrative review of the current scientific evidence in the field of eye movements in sports, focusing on the role of microsaccades in sporting task situations. Over the past 10 years, microsaccades have become one of the most increasing areas of research in visual and oculomotor studies and even in the area of sport science. Here, we review the latest findings and discuss the relationships between microsaccades and attention, perception, and action in sports.

To assay the presence of the SARS-CoV-2 genome in vaginal, rectal, and placental swabs among pregnant women and in newborn nasopharyngeal swabs and to investigate the immunological response and maternal antibody transfer through the umbilical cord blood and milk of unvaccinated mothers.Vaginal, rectal, and placental specimens, maternal and neonatal serum, and milk were collected from a wide cohort of pregnant Italian women with confirmed SARS-CoV-2 infection admitted to the hospital between February 25, 2020 and June 30, 2021. Samples were tested in selected reference laboratories according to a shared interlaboratory protocol.Among 1086 enrolled women, the SARS-CoV-2 positive rate detected in all specimens ranged from 0.7% to 8.4%. Respectively, 45.2% of maternal sera collected during pregnancy and 39.7% of those collected at birth tested positive for immunoglobulin G, whereas 50.5% tested positive among neonates. Nasopharyngeal swabs were positive in 0.8% of the newborns, and immunoglobulin G was detected in 3.0% of the milk samples. The highest immunological response was recorded within 30 days during pregnancy and within 60 days of birth and in the neonatal population.Vertical transmission should be considered a rare event; although, a good maternal immunological response and antibodies transfer throughout the umbilical cord blood was detected.

Poorly soluble drugs must be appropriately formulated for clinical use to increase the solubility, dissolution rate, and permeation across the intestinal epithelium. Polymeric and lipid nanocarriers have been successfully investigated for this aim, and their physicochemical properties, and in particular, the surface chemistry, significantly affect the pharmacokinetics of the drugs after oral administration. In the present study, PLGA nanoparticles (SS13NP) and solid lipid nanoparticles (SS13SLN) loaded with SS13, a BCS IV model drug, were prepared. SS13 bioavailability following the oral administration of SS13 (free drug), SS13NP, or SS13SLN was compared. SS13NP had a suitable size for oral administration (less than 300 nm), a spherical shape and negative zeta potential, similarly to SS13SLN. On the contrary, SS13NP showed higher physical stability but lower encapsulation efficiency (54.31 ± 6.66%) than SS13SLN (100.00 ± 3.11%). When orally administered (0.6 mg of drug), SS13NP showed higher drug AUC values with respect to SS13SLN (227 ± 14 versus 147 ± 8 µg/mL min), with higher C

In this paper we provide a framework for studying the ways in which food endures the passage of time. Central to our inquiry is the following Duration Question: when is it that the predicate-schema “Is an X-Food,” where “X-Food” stands for a certain type of food (e.g., Champagne, yoghurt) ceases to apply to an entity? We show that the answer depends on two independent theoretical aspects: the underlying conception of food and the kinds of change that a specific food can undergo. We then argue that specific answers to the duration question should take the form of conceptual rethinking among different stakeholders (e.g., producers, consumers, institutions), where philosophers would feature among the experts guiding the negotiation.

Background and ObjectiveThis was a multicenter study aimed at investigating the characteristics of cognitive decline, neuropsychiatric symptoms, and brain imaging in individuals with subjective cognitive decline (SCD) and subtle cognitive decline (pre–mild cognitive impairment [pre–MCI]).MethodsData were obtained from the Network-AD project (NET-2011-02346784). The included participants underwent baseline cognitive and neurobehavioral evaluation, FDG-PET, and amyloid PET. We used principal component analysis (PCA) to identify independent neuropsychological and neuropsychiatric dimensions and their association with brain metabolism.ResultsA total of 105 participants (SCD = 49, pre–MCI = 56) were included. FDG-PET was normal in 45% of participants and revealed brain hypometabolism in 55%, with a frontal-like pattern as the most frequent finding (28%). Neuropsychiatric symptoms emerging from the Neuropsychiatric Inventory and the Starkstein Apathy Scale were highly prevalent in the whole sample (78%). An abnormal amyloid load was detected in the 18% of the participants who underwent amyloid PET (n = 60). PCA resulted in 3 neuropsychological factors: (1) executive/visuomotor, correlating with hypometabolism in frontal and occipital cortices and basal ganglia; (2) memory, correlating with hypometabolism in temporoparietal regions; and (3) visuospatial/constructional, correlating with hypometabolism in frontoparietal cortices. Two factors emerged from the neuropsychiatric PCA: (1) affective, correlating with hypometabolism in orbitofrontal and cingulate cortex and insula; (2) hyperactive/psychotic, correlating with hypometabolism in frontal, temporal, and parietal regions.DiscussionFDG-PET evidence suggests either normal brain function or different patterns of brain hypometabolism in SCD and pre–MCI. These results indicate that SCD and pre–MCI represent heterogeneous populations. Different neuropsychological and neuropsychiatric profiles emerged, which correlated with neuronal dysfunction in specific brain regions. Long-term follow-up studies are needed to assess the risk of progression to dementia in these conditions.

The final appearance of gunshot wounds is influenced by both the projectile’s behavior from the muzzle to the terminal target and by the intrinsic characteristics of the anatomical compartments where the lesion(s) occur. The D-shaped morphology is an uncommon yet well-known finding in the forensic literature and has been described when the surface of impact with the skin is represented by the bullet’s lateral projection. Two cases where D-shaped gunshot wounds were observed are hereby presented: in both cases, interaction with multiple intermediate targets (case 1) and a human intermediate target (case 2) had been documented and confirmed by the forensic examination. Despite the different dynamics of production, this peculiar morphology was described throughout most of the intrasomatic bullet path in both the victims. The discovery of D-shaped gunshot wounds can guide the forensic pathologist in the ballistic reconstruction of the event by supporting the hypothesis of an interaction with an intermediate target that has led to deviation from the initial trajectory and destabilization of the bullet associated with loss of kinetic energy.

Bayesian inference applied to microseismic activity monitoring allows the accurate location of microseismic events from recorded seismograms and the estimation of the associated uncertainties. However, the forward modelling of these microseismic events, which is necessary to perform Bayesian source inversion, can be prohibitively expensive in terms of computational resources. A viable solution is to train a surrogate model based on machine learning techniques, to emulate the forward model and thus accelerate Bayesian inference. In this paper, we substantially enhance previous work, which considered only sources with isotropic moment tensors. We train a machine learning algorithm on the power spectrum of the recorded pressure wave and show that the trained emulator allows complete and fast event locations for $\textit{any}$ source mechanism. Moreover, we show that our approach is computationally inexpensive, as it can be run in less than 1 hour on a commercial laptop, while yielding accurate results using less than $10^4$ training seismograms. We additionally demonstrate how the trained emulators can be used to identify the source mechanism through the estimation of the Bayesian evidence. Finally, we demonstrate that our approach is robust to real noise as measured in field data. This work lays the foundations for efficient, accurate future joint determinations of event location and moment tensor, and associated uncertainties, which are ultimately key for accurately characterising human-induced and natural earthquakes, and for enhanced quantitative seismic hazard assessments., Comment: 17+4 pages, 13+3 figures, 2 tables. Matches version published in GJI, including extra tests with realistic noise and network configuration. Code available at https://github.com/alessiospuriomancini/seismoML/tree/main/Piras_2022

One of the most powerful weapons against COVID-19 is vaccines. After the worldwide spread of the disease, m-RNA vaccines were authorized not only in adult patients, but also in children and adolescents aged 12–18. Since then, alarming reports of cases of myocarditis and/or pericarditis have been noted, primarily involving males after the second vaccine shot. A typical example of myopericarditis occurring in an adolescent a few days after the second shot of an m-RNA vaccine is described here. An in-depth review of all 110 single case reports published up to July 2022 with related features and outcomes is also presented. This is the first extensive analysis focused solely on a significant number of single case reports, which have usually been excluded from systematic reviews and meta-analyses carried out in the field. The analysis presented here confirms that most cases occurred in males after the second injection of an m-RNA vaccine. Cases were mild and responsive to the usual medical treatment. What is newly reported is that not only adolescents, but also older people, especially females, were affected by this adverse event.

Innovative models for medical research are strongly required nowadays. Convincing evidence supports dog as the most suitable spontaneous model for several human genetic diseases. Decades of studies on dog genome allowed the identification of hundreds of mutations causing genetic disorders, many of which are proposed as counterparts responsible for human diseases. Traditionally, the murine model is the most extensively used in human translational research. However, this species shows large physiological differences from humans, and it is kept under a controlled artificial environment. Conversely, canine genetic disorders often show pathophysiological and clinical features highly resembling the human counterpart. In addition, dogs share the same environment with humans; therefore, they are naturally exposed to many risk factors. Thus, different branches of translational medicine aim to study spontaneously occurring diseases in dogs to provide a more reliable model for human disorders. This review offers a comprehensive overview of the knowledge and resources available today for all the researchers involved in the field of dog-human translational medicine. Some of the main successful examples from dog-human translational genomics are reported, such as the canine association studies which helped to identify the causal mutation in the human counterpart. We also illustrated the ongoing projects aiming to create public canine big datasets. Finally, specific online databases are discussed along with several information resources that can speed up clinical translational research.

The mechanism producing psychosis appears to include hippocampal inflammation, which could be associated with the microbiome-gut-brain-axis (MGBS). To test this hypothesis we are conducting a multidisciplinary study, herein described. The procedures are illustrated with testing of a single subject and group level information on the impact of C-section birth are presented. Method Study subjects undergo research diagnostic interviews and symptom assessments to be categorized into one of 3 study groups: psychosis, nonpsychotic affective disorder or healthy control. Hippocampal volume and metabolite concentrations are assessed using 3-dimensional, multi-voxel H1 Magnetic Resonance Imaging (MRSI) encompassing all gray matter in the entire hippocampal volume. Rich self-report information is obtained with the PROMIS interview, which was developed by the NIH Commons for research in chronic conditions. Early trauma is assessed and cognition is quantitated using the MATRICS. The method also includes the most comprehensive autonomic nervous system (ANS) battery used to date in psychiatric research. Stool and oral samples are obtained for microbiome assessments and cytokines and other substances are measured in blood samples. Results Group level preliminary data shows that C-section birth is associated with higher concentrations of GLX, a glutamate related hippocampal neurotransmitter in psychotic cases, worse symptoms in affective disorder cases and smaller hippocampal volume in controls. Conclusion Mode of birth appears to have persistent influences through adulthood. The methodology described for this study will define pathways through which the MGBA may influence the risk for psychiatric disorders.

The goal of this Research Topic was to examine the emerging approaches to understanding the role of visual search in human movement. The varying aspects covered in this Research Topic highlights the continued growing interest in understanding visual search behavior in human movement and the articles within the topic provide insightful ideas for continuing to develop future research.

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individual’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences.TeaserWe present a global effort to devise harmonization procedures necessary to meaningfully leverage big data.

We investigated gaze behavior of expert goalkeepers during the prediction of penalty kicks in different spatiotemporal constraints: penalties taken from 11 and 6 m. From 11 m, goalkeepers were more successful in predicting ball direction, with longer movement time initiation and a visual strategy with more fixations and greater saccade rates than penalties from 6 m, where they exhibited fewer fixations with higher microsaccade rates. As long as the opponent’s distance is large and time pressure low, gaze can be frequently shifted between the kicker’s body and the ball, due to the low cost of saccades. Conversely, when the objects are close, there is increased reliance on foveal and parafoveal information. In conclusion, when the spatiotemporal constraint is less severe, goalkeepers adopt a visual strategy with more fixations and small saccades. When the spatiotemporal constraint is more severe, they rely on peripheral vision to monitor kickers’ movements through the use of microsaccades.

This paper presents an exploratory activity with a drone inspection service for environmental control. The aim of the service is to provide technical support to decision-makers in environmental risk management. The proposed service uses IoT for the interaction between a mobile application, a Smart City platform, and an Unmanned Aircraft System (UAS). The mobile application allows the users to report risky situations, such as fire ignition, spills of pollutants in water, or illegal dumping; the user has only to specify the class of the event, while the geographical coordinates are automatically taken from device-integrated GPS. The message sent from the mobile application arrives to a Smart City platform, which shows all the received alerts on a 3D satellite map, to support decision-makers in choosing where a drone inspection is required. From the Smart City platform, the message is sent to the drone service operator; a CSV file defining the itinerary of the drone is automatically built and shown through the platform; the drone starts the mission providing a video, which is used by the decision-makers to understand whether the situation calls for immediate action. An experimental activity in an open field was carried out to validate the whole chain, from the alert to the drone mission, enriched by a Smart City platform to enable a decision-maker to better manage the situation.

Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents. Results: A novel series of 4′-fluoro-substituted ligands (5–13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability. Discussion: The 4′-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration.

The Byzantine historian Theophylact Simocatta (fl. 620s) records an exchange of letters with the Sasanian Empire. The correspondence of March 590, from the Iranian shah Khosrow II Parviz (r. 591–628) and addressed to the Byzantine emperor Maurice (r. 582–602), exhibits a particular style, focused on the ideological oppositions of order and disorder and legitimacy and usurpation. This paper suggests that Khosrow’s claims to his kingdom made use of a discourse of catastrophic motifs that reflected common Sasanian apocalyptic beliefs. Thus, the chaotic situation provoked by the inversion of the rightful order elicited, from a Zoroastrian perspective, a response that stressed the dualistic nuance of demonic anarchy in order to stigmatize the risk of deposition. For these reasons, apocalyptic doctrines and royal propaganda share a common language: a political discourse based on the justification of kingship and the demonization of the enemy.

In this paper, we bring together two unrelated strains of recent literature on eating local, which have respectively evidenced its socio-political and artistic values. Our argument contends that eating local can, in some instances, be regarded as a form of public art. Our study improves our understanding and appreciation of the complex web of culinary values linked to eating local, in particular the entanglement between its aesthetic, political, and cultural significance. We first review three extant definitions of eating local (§ 2), which we then employ to discuss the three specific forms of public art that eating local can occasion (§ 3), namely: memorial art, social protest art, and art that enhances. Finally, we present the links between the three approaches to local food and the three forms of public art (§ 4), providing a heuristic framework for both scholars and stakeholders.

Background Although outdoor water sport activities are gaining increasing attention for their therapeutic potential in the social and care management of populations with chronic diseases, these practices are currently underutilised. Moreover, the available body of literature on the topic has not been critically and comprehensively assessed yet. Aims (1) To appraise the health effects of outdoor water sport activities for chronic disease populations; (2) to preliminarily assess the potential size and scope of the available research literature for this emerging field and identify potential gaps and avenues of development. Methods A literature search was performed scanning PubMed (including MEDLINE), Physiotherapy Evidence Database (PEDro) and Scopus from inception to December 2021. A scoping review was carried out by appraising all the available evidence on outdoor water sport interventions specifically designed for therapeutic purposes for individuals with chronic disease. The quality score of each study was calculated with the Tool for the assEssment of Study qualiTy and reporting in Exercise (TESTEX) tool. Results Fifteen studies (five RCTs, seven non-RCTs and three CTs with healthy subjects as controls) met the inclusion criteria and were assessed. Among the studies selected, two focused on canoa kayak, one on stand-up paddle, two on surfing, two on sailing activity, and eight on dragon boat padding. The median TESTEX score for study quality and reporting was 6/15, i.e., “very low” (range 5–8). Based on the qualitative analysis, the few individual studies that could be included reported generally positive results, ranging from improvements in antioxidant action and cardiovascular function for dragon boating, to beneficial effects on balance, postural control, and flexibility for on-water paddle board activities. Overall, outdoor water sport interventions were associated to higher rates of adherence than conventional trainings. Conclusions Very low to low quality evidence from a limited set of pilot studies seems to suggest beneficial effects of outdoor water sports for chronic disease populations. However, such preliminary findings need to be replicated through large, high-quality RCTs to be conducted in target populations. Avenues of development, scoping directions and translational perspectives for this specific research field are proposed and discussed.

Magnus Nilsson,1 Magdalena Rhedin,2 Ramon Hendrickx,3 Susanne Berglund,1 Antonio Piras,2 Parmis Blomgran,2 Anders Cavallin,2 Mia Collins,2 Göran Dahl,4 Bilel Dekkak,5 Therese Ericsson,3 Niklas Hagberg,6 Ann Aurell Holmberg,3 Agnes Leffler,2 Anders J Lundqvist,3 Thomais Markou,5,7 James Pinkerton,5,7 Lars Rönnblom,6 Stacey Siu,8 Vanessa Taylor,8 Tiiu Wennberg,2 Dimitrios Zervas,5,7 Arian D J Laurence,9 Suman Mitra,2 Maria G Belvisi,5,7 Mark Birrell,5,7 Annika Borde2 1Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 2Bioscience, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 3DMPK, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 4Discovery Science, R&D, AstraZeneca, Gothenburg, Sweden; 5Respiratory Pharmacology Group, Division of Airway Disease, National Heart and Lung Institute, Imperial College London, London, UK; 6Rheumatology and Science for Life Laboratories, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; 7Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 8Rigel Pharmaceuticals, South San Francisco, CA, USA; 9Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UKCorrespondence: Magnus Nilsson, Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, SE-431 83, Sweden, Tel +46722237222, Email Magnus.Nilsson@astrazeneca.comPurpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats. Pharmacokinetic studies performed on rats evaluated AZD0449 at a lung deposited dose of 52 μg/kg and AZD4604 at 30 μg/kg. The efficacy of AZD0449 and AZD4604 was assessed by evaluating lung inflammation (cell count and cytokine levels) and the late asthmatic response (average enhanced pause [Penh]).Results: Both compounds inhibited JAK1-dependent cytokine signaling pathways in a dose-dependent manner in human and rat leukocytes. After intratracheal administration in rats, both compounds exhibited low systemic exposures and medium-to-long terminal lung half-lives (AZD0449, 34 hours; AZD4604, 5 hours). Both compounds inhibited STAT3 and STAT5 phosphorylation in lung tissue from ovalbumin (OVA)-challenged rats. AZD0449 and AZD4604 also inhibited eosinophilia in the lung and reduced the late asthmatic response, measured as Penh in the OVA rat model.Conclusion: AZD0449 and AZD4604 show potential as inhibitors of signaling pathways involved in asthmatic immune responses, with target engagement demonstrated locally in the lung. These findings support the clinical development of AZD0449 and AZD4604 for the treatment of patients with asthma.Keywords: AZD0449, AZD4604, JAK, STAT

The mechanisms underlying the dichotomic cortical/basal ganglia dopaminergic abnormalities in schizophrenia are unclear. Astrocytes are important non-neuronal modulators of brain circuits, but their role in dopaminergic system remains poorly explored. Microarray analyses, immunohistochemistry, and two-photon laser scanning microscopy revealed that Dys1 hypofunction increases the reactivity of astrocytes, which express only the Dys1A isoform. Notably, behavioral and electrochemical assessments in mice selectively lacking the Dys1A isoform unraveled a more prominent impact of Dys1A in behavioral and dopaminergic/D2 alterations related to basal ganglia, but not cortical functioning. Ex vivo electron microscopy and protein expression analyses indicated that selective Dys1A disruption might alter intracellular trafficking in astrocytes, but not in neurons. In agreement, Dys1A disruption only in astrocytes resulted in decreased motivation and sensorimotor gating deficits, increased astrocytic dopamine D2 receptors and decreased dopaminergic tone within basal ganglia. These processes might have clinical relevance because the caudate, but not the cortex, of patients with schizophrenia shows a reduction of the Dys1A isoform. Therefore, we started to show a hitherto unknown role for the Dys1A isoform in astrocytic-related modulation of basal ganglia behavioral and dopaminergic phenotypes, with relevance to schizophrenia.

Radiotherapy is essential in the treatment of locally advanced rectal cancer. Side effects of radiotherapy in the treatment of rectal cancer have a great effect on quality of life. The aim of this retrospective study is to evaluate the correlation between dosimetric parameters and acute toxicity in rectal cancer patients.We analyzed the Dose Volume Histogram parameters for both the target structures and the Organs at risk of 89 patients. A dedicated statistical analysis was performed for all the acute toxicities showing a frequency rate higher than 20%. A linear logistic regression model was elaborated using the variable showing the highest level of significance at the univariate analysis.The occurrence of proctitis was significantly correlated with three dosimetric parameters: D98% of low ano-rectum, DTwo dose constraints were elaborated: D98%33.5 Gy for low ano rectum to prevent grade 2 acute toxicity and D98%25 Gy for low ano-rectum wall to prevent proctitis (grade 1 or superior).

Rapid-acting insulins (RAIs) have been instrumental in the management of diabetes because of their improved postprandial glucose (PPG) control compared with regular human insulin. However, their absorption rate and time action following subcutaneous administration still falls short of the normal physiological response to meal consumption, increasing the risk of early postmeal hyperglycaemia and late postmeal hypoglycaemia. Increased demand for faster acting insulins, which can quickly control PPG excursions without increasing the risk of late hypoglycaemia, led to the development of ultra-rapid-acting insulins, including ultra-rapid lispro (URLi). URLi is a novel formulation of insulin lispro with accelerated absorption driven by two excipients: treprostinil, which increases local vasodilation, and citrate, which increases local vascular permeability. Clinical pharmacology studies consistently showed an earlier onset and shorter duration of action with URLi compared with Lispro. In a head-to-head study with Faster aspart, Aspart and Lispro, URLi was absorbed faster, provided earlier insulin action, and more closely matched physiological glucose response than the other insulins tested. URLi's unique pharmacokinetic properties increase its potential for improved PPG control beyond that achieved with RAIs. Indeed, in pivotal phase 3 trials, URLi was superior to Lispro for PPG control both at 1 and 2 hours after a meal in type 1 and type 2 diabetes with multiple daily injections, and in type 1 diabetes with continuous subcutaneous insulin infusion. This was achieved without increasing the risk of hypoglycaemia. In this review, we focus on the clinical and pharmacological evidence for URLi in the treatment of diabetes and discuss the potential benefits and considerations with URLi compared with RAIs.

Objective: To assess all different patterns of associated abnormalities on audiometry, bithermal caloric test (BCT) and cervical/ocular vestibular-evoked myogenic potentials (VEMPs) to air/bone-conduction in patients with selective posterior semicircular canal (PSC) hypofunction and to correlate them with underlying disorders. Study Design: Retrospective review. Setting: Tertiary referral center. Patients: 51 patients (23 men, 28 women, mean age 57.5 yr) with isolated PSC deficit (one bilateral). Interventions: Correlation with instrumental data and underlying diagnoses. Main Outcome Measures: Video-oculographic findings, objective measurements on audiometry, BCT, VEMPs and video-head impulse test (vHIT). Results: Ongoing or previous acute vestibular loss (AVL) was diagnosed in 13 patients (25.5%, 3 inferior vestibular neuritis, 10 AVL with sudden sensorineural hearing loss [SSNHL]), Meniere's disease (MD) in 12 (23.5%), cerebellopontine angle (CPA) lesion in 9 (17.6%), various causes in 7 (13.7%), benign paroxysmal positional vertigo (BPPV) involving the non-ampullary arm of PSC in 5 cases (9.8%) whereas unknown pathology in 5 (9.8%). Involvement of at least one additional receptor besides PSC was seen in 89.8% of cases. Cochlear involvement was diagnosed in 74.5% with pure-tone average significantly greater in patients with AVL+SSNHL (p < 0.05). Overall involvement of labyrinthine receptors or afferents was highest in patients with AVL+SSNHL (p < 0.01), MD and CPA lesions (p < 0.05). Conclusions: Isolated loss of PSC function on vHIT is mostly accompanied by additional labyrinthine deficits that could only be identified through an accurate instrumental evaluation. Assessment of all receptors and afferents should be always pursued to identify the lesion site and better understand the underlying pathophysiological mechanisms.

In recent years automobile manufacturers focused on an increasing degree of electrification of the powertrains with the aim to reduce pollutants and CO2 emissions. Despite more complex design processes and control strategies, these powertrains offer improved fuel exploitation compared to conventional vehicles thanks to intelligent energy management. A simulation study is here presented aiming at developing a new control strategy for a P3 parallel plug-in hybrid electric vehicle. The simulation model is implemented using vehicle modeling and simulation toolboxes in MATLAB/Simulink. The proposed control strategy is based on an alternative utilization of the electric motor and thermal engine to satisfy the vehicle power demand at the wheels (Efficient Thermal/Electric Skipping Strategy - ETESS). The choice between the two units is realized through a comparison between two equivalent fuel rates, one related to the thermal engine and the other related to the electric consumption. An adaptive function is introduced to develop a charge-blended control strategy. The novel adaptive control strategy (A-ETESS) is applied to estimate fuel consumption along different driving cycles. The control algorithm is implemented on a dedicated microcontroller unit performing a Processor-In-the-Loop (PIL) simulation. To demonstrate the reliability and effectiveness of the A-ETESS, the same adaptive function is built on the Equivalent Consumption Minimization Strategy (ECMS). The PIL results showed that the proposed strategy ensures a fuel economy similar to ECMS (worse of about 2% on average) and a computational effort reduced by 99% on average. This last feature reveals the potential for real-time on-vehicle applications.

The preliminary protocol for running the participatory experimental and behavioural economic activities foreseen in RADIANT is detailed within this Milestone.

Bayesian inference provides a pathway toward accurate predictions of source parameters (e.g., location and moment tensor), along with principled, well-calibrated uncertainty estimates. Unfortunately, standard Bayesian inference techniques can often require O(105) simulations per full waveform inversion, making the method infeasible when studying large numbers of events due to the high computational cost of seismological forward modelling. Machine Learning (ML) has emerged as a promising solution to this issue, with recent work demonstrating that ML-based emulators of the physics simulation can be used as rapid-executing surrogates of the forward model in the Bayesian inference workflow. It has been demonstrated that such models, in conjunction with an assumed likelihood model (e.g. Gaussian), can be used to efficiently perform Bayesian posterior inference over seismological source parameters. This work explores an extension to the above method, often referred to as “likelihood-free” or “simulation-based” inference, which removes any assumptions about the likelihood model. This approach leverages a class of neural networks known as Neural Density Estimators (NDEs) to estimate the likelihood density directly given some representation of the observables. To simplify training of these NDEs, a compression technique that can reduce the observables (i.e., full seismograms) into a small set of parameters is required. This work investigates “classical” and ML-based compression techniques for creating a reduced dimension representation. It then demonstrates simulation-based inference on the problem of source location inversion applied to synthetic examples based on a recent seismic swarm on the São Jorge island in the Azores. Comparisons between the proposed approach and other inversion techniques are also presented.

Patients suffering from mental disorders are at high risk of developing cardiovascular diseases, leading to a reduction in life expectancy. Genetic variants can display greater influence on cardiometabolic features in psychiatric cohorts compared to the general population. The difference is possibly due to an intricate interaction between the mental disorder or the medications used to treat it and metabolic regulations. Previous genome wide association studies (GWAS) on antipsychotic-induced weight gain included a low number of participants and/or were restricted to patients taking one specific antipsychotic. We conducted a GWAS of the evolution of body mass index (BMI) during early (i.e., ≤ 6) months of treatment with psychotropic medications inducing metabolic disturbances (i.e., antipsychotics, mood stabilizers and some antidepressants) in 1135 patients from the PsyMetab cohort. Six highly correlated BMI phenotypes (i.e., BMI change and BMI slope after distinct durations of psychotropic treatment) were considered in the analyses. Our results showed that four novel loci were associated with altered BMI upon treatment at genome-wide significance (p −8): rs7736552 (near MAN2A1), rs11074029 (in SLCO3A1), rs117496040 (near DEFB1) and rs7647863 (in IQSEC1). Associations between the four loci and alternative BMI-change phenotypes showed consistent effects. Replication analyses in 1622 UK Biobank participants under psychotropic treatment showed a consistent association between rs7736552 and BMI slope (p = 0.017). These findings provide new insights into metabolic side effects induced by psychotropic drugs and underline the need for future studies to replicate these associations in larger cohorts.

Objective The main aim of this study was to determine the effective magnitude of proximal tibial segment medialization achievable during tibial plateau levelling and medialization osteotomy (TPLO-M) with Fixin 1.9-2.5 mm pre-contoured T plates with three different offsets. Methods In this in vitro study, 36 tibia bone models reconstructed using stereolithography from hindlimb CT scans of a 5 kg dog and a 10 kg dog without orthopaedic disease were used. TPLO-M was performed using plates with three different offsets (2, 4 and 6 mm). Post-osteotomy radiographic and bone models measurements were performed. Results Regardless of patient weight, the +4 mm offset plates provided a translation of 2.93mm (± 0.51) while the +6 mm offset plates provided a translation of 5.03mm (± 0.47). In the 5kg dog bone model group limited bone contact at the osteotomy site was documented when using the +6mm offset plate. Conclusion The +4mm and +6mm offset Fixin plates may be considered for TPLO-M in dogs weighing between 5 and 10 kg. The +6mm offset plate should be used cautiously in dogs weighing less than 10 kg since this plate may result in insufficient postoperative bone apposition at the osteotomy site.

This study tests four "light touch" interventions in the language used in job posts of male- dominated occupations to attract female workers using a discrete choice experiment. This experiment had more than 5000 participants from five Latin American countries. We test two possible mechanisms: the gender-stereotypes related to job skills and the use of inclusive language. We find that language matters, and men and women value information and inclusive language in job advertisements. However, women are more sensitive in this regard. We test the effect of simply aggregating irrelevant, but additional words to the job ad, and find that when the inclusive language in the ad is subtle, the effect of having more words is very important. But it decreases when the language signals a strong preference for an inclusive work environment. These findings highlight the importance of language and the type of information presented in job advertisements in attracting a gender-balanced workforce.