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Background: Serum inflammation-based scores can predict clinical outcome in several cancer types, including adrenocortical carcinoma (ACC). It is unclear whether the extent of inflammation-based scores alterations in ACC reflects malignancy, steroid excess, or both. Methods: We investigated a large retrospective cohort of adrenocortical adenomas (ACA, n= 429) and ACC (n= 61) with available baseline full blood count and hormonal evaluation. We examined the relationship between different inflammation-based scores [neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and prognostic nutrition index (PNI)] and both malignancy and steroid secretion patterns. Results: All inflammation-based scores differed between ACC and ACA: patients with ACC had higher NLR, PLR, SII and lower LMR and PNI levels compared to ACA (all pvalues < 0.001). NLR showed a positive correlation with cortisol levels after overnight 1 mg-dexamethasone suppression test (1 mg-DST), both in ACC and ACA (p< 0.01). The ROC curve analysis determined NLR > 2.6 as the best cut-off to discriminate ACC from ACA [AUC = 0.846, p< 0.01]. At multivariable analysis, NLR > 2.6 was independently associated with ACC, 1 mg-DST cortisol levels and age, but not with tumour size. Considering the ACC, NLR and SII were higher and PNI was lower in patients with cortisol excess compared to those without cortisol excess (p= 0.002, p= 0.007, and p= 0.044 respectively). Finally, LMR and NLR differed between inactive-ACC (n= 10) and inactive-ACA (n= 215) (p= 0.040 and p= 0.031, respectively). Conclusion: Inflammation-based scores are related to steroid secretion both in ACC and ACA. ACCs present a higher grade of inflammation regardless of their hormonal secretion, likely as a feature of malignancy itself.

AbstractIn the latter half of the twentieth century, particularly in developed countries, a growing awareness of the environmental impact of personal choices—encompassing climate, pollution, land degradation, and biodiversity loss—resulted in an upsurge of environmental labels on goods. Environmental labels play a crucial role in assisting consumers in selecting environmentally superior products, fostering market development towards eco-friendly production systems, and serving as a foundation for product differentiation and increased product value. Despite a growing public interest in environmental quality and climate change, surveys reveal a gap between consumers’ environmental attitudes and actual purchasing behaviour. In addition, concerns about the complexity and cost of certification systems have arisen, with fears of creating market barriers for small producers. This review aims to provide an overview of environmental labelling in the context of animal food products, emphasising social and regulatory aspects, exploring technical considerations of life cycle thinking approaches in certification schemes, and discussing the pros and cons of standardising procedures for the development of multi-dimensional environmental labelling in the animal food sector.

The cultural apocalypse represents for a human community, according to the anthropologist Ernesto De Martino, the summit of the "crisis of presence" and the "loss of the world". In my speech I will distinguish two modes of cultural apocalypse: the one that compromises memory, leaving us at the mercy of an objectless memory, and the one that liquidates memory, leaving us at the mercy of mechanical memories deposited on impersonal electronic strings. The first Is an analog apocalypse, the second a digital apocalypse. The pharmacological function of the "archive" then consists in attempting to bridge this fracture, linking memory to memory and giving the statements back their horizon of meaning. [ABSTRACT FROM AUTHOR]

A laser-based technique known as Doppler-free saturation spectroscopy (DFSS) has been designed, fabricated, and installed on the DIII-D National Fusion Facility to measure the helicon wave electric field vector in the edge plasma. These experimental measurements quantify phenomena resulting in decreased current drive efficiency due to wave/edge plasma interactions. This implementation of DFSS on DIII-D is the first of its kind on a tokamak and thus presents unique engineering challenges, including integration of the system onto an existing multidiagnostic port flange without impacts to system serviceability, as well as maintaining precise laser alignment over a 2-m distance during disruptions and thermal drift of the vessel. These challenges were resolved using innovative design approaches such as a novel decoupled shutter system to facilitate serviceability of the in-vessel mirror assemblies without the need for personnel vessel entry, as well as an ex-vessel piezo-mirror-based optical system for laser beam shaping and real-time steering of the measurement location. The solutions to these engineering challenges were demonstrated during the successful installation and operation of these diagnostic components during the 2022 DIII-D vent and subsequent experimental campaign.

Recycling end-of-life (EoL) magnets is a necessary strategy to mitigate environmental impacts in magnet production and rare-earth extraction. Utilizing these waste materials as raw materials in magnet production means advancement in the economy and sustainability gains. In this work, the reduction-diffusion (RD) was adopted to recover highly oxidized and corroded EoL magnets, which are generally disposed in more traditional recycling routes. The EoL magnets with 57800 ppm of O were demagnetized, and the corroded portion was sieved (opening $\lt 500~\mu $ m) and characterized by X-ray diffraction (XRD), and the results show the presence of $\Phi $ -phase (Nd2Fe14B) and rare-earth oxides dissociated from $\Phi $ -phase in the powder, which indicate that this material is suitable to be recovered; however, the presence of $\alpha $ -Fe was observed in some process conditions. The results obtained after RD process show coercivity above 800 kA/m and $\Phi $ -phase particles with diameter under $2~\mu $ m and absence of $\alpha $ -Fe.

Compared to Si, IGZO is a competitive choice for FeFET channel material, because of the interlayer-free structure, which can lead to a higher endurance. However, the ferroelectric switching mechanism of erasure remains unclear due to the lack of holes in IGZO. In this work, we present a quasi-static charge sheet model of Metal/Ferroelectric/IGZO stack, considering the charges supplied by IGZO Density of States and interface states. The modeling results suggest that shallow donors, by emitting electrons into the conduction band and thereby partially ionized, can become positively charged and thus support the erase operation. Cryogenic Negative Bias Illumination Stress measurement indicates the presence of shallow donors.

By using high-speed electrical measurements, we evaluate the endurance and retention performance of the Si channel ferroelectric transistor (FeFET) having SiOx interfacial layer (IL) scaled using the oxygen scavenging technique. The interfacial SiOx is scaled from 1 to 0.4 nm by depositing a 2-nm Si capping (Si-cap) layer on the HfO2 ferroelectric layer (FL). Trapping and detrapping processes are monitored using read-disturb-free fast P–V and ${I}_{\text {d}}$ – ${V}_{\text {g}}$ measurements. FeFETs with a thicker (1 nm) SiO2 IL showed a ~2-V shift in threshold voltage ( ${V}_{\text {th}}\text {)}$ postprogramming pulse due to trapping in and around the IL, resulting in ~1-s write-to-read delay. The addition of Si-cap eliminated read-after-write delay in the pristine state, which is attributed to the shorter tunneling distance for the traps in the IL and near the FL-IL interface. The endurance cycling was found to degrade subthreshold swing (SS) and shift ${V}_{\text {th}}$ in the without Si-cap (w/o Si-cap) devices, suggesting the generation of both interface states and bulk defects. The addition of Si-cap was found to help reduce the generation of interface states and the bulk FL defects owing to the lower effective electric field. It was also found that fatigue cycling introduces a read-after-write delay in the Si-cap (w/Si-cap) devices, which points to the generation of defects near the FL:IL interface. Even though the endurance and read-after-write delay performance improved, the tradeoff is higher depolarization due to a partially oxidized paraelectric Si-cap layer in series with the FL in the devices w/Si-cap. Our study shows that avoiding the formation of SiOx IL and improving the quality of the FL are critical for improving both retention and endurance performance in Si channel FeFETs.

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2H)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved. Intratracheal administration of lead compound 26resulted in a promising pharmacokinetic profile, thus demonstrating that the optimization strategy of in vitroprofiles successfully translated to an in vivosetting.

Eukaryotes have evolved towards one of two extremes along a spectrum of strategies for remodelling the nuclear envelope during cell division: disassembling the nuclear envelope in an open mitosis or constructing an intranuclear spindle in a closed mitosis1,2. Both classes of mitotic remodelling involve key differences in the core division machinery but the evolutionary reasons for adopting a specific mechanism are unclear. Here we use an integrated comparative genomics and ultrastructural imaging approach to investigate mitotic strategies in Ichthyosporea, close relatives of animals and fungi. We show that species in this clade have diverged towards either a fungal-like closed mitosis or an animal-like open mitosis, probably to support distinct multinucleated or uninucleated states. Our results indicate that multinucleated life cycles favour the evolution of closed mitosis.

Questo articolo esplora il legame tra il Binge Eating Disorder (BED) e diabete mellito di tipo 2 (DM2), focalizzandosi sull’obesità come ponte clinico. Il DM2, in costante crescita a livello globale e strettamente correlato all’obesità, evidenzia la rilevanza dei disturbi dell’alimentazione come il BED nella gestione terapeutica e negli esiti a lungo termine. Il BED mostra un’associazione significativa con l’obesità estrema ed è riscontrabile in circa il 30% delle persone che cercano interventi per la perdita di peso. Con una prevalenza dell’1,8% nelle donne e dello 0,7% negli uomini, il BED si manifesta con episodi di abbuffata e perdita di controllo sul cibo. Le ipotesi eziopatogenetiche del BED sottendono un legame con l’impulsività, la compulsione e la disfunzione dei meccanismi di ricompensa, con lesioni nei circuiti cortico-striatali simili a quelli nella dipendenza da sostanze psicoattive. Gli individui con obesità e BED mostrano alterazioni nelle regioni cerebrali coinvolte nel controllo degli impulsi, alterazioni capaci di influenzare la percezione del cibo come ricompensa. Le emozioni negative, in particolare rabbia e frustrazione, svolgono un ruolo chiave nel BED, con una maggiore sensibilità allo stress e una ridotta capacità di regolazione emotiva. I modelli psicodinamici del BED evidenziano strategie disadattive come la soppressione e la ruminazione, che influenzano la percezione delle emozioni e ostacolano la regolazione emotiva. Le teorie della “fuga dalla consapevolezza di sé” e della “regolazione emotiva” chiariscono come il BED possa fungere da meccanismo di coping per evitare percezioni negative su di sé o contenere emozioni indesiderate. In conclusione, considerare gli aspetti psicodinamici del BED è cruciale nella gestione clinica di pazienti obesi con DM2. La profonda comprensione di questi aspetti può orientare verso strategie terapeutiche più efficaci, affrontando la complessità della psicopatologia associata al BED e le implicazioni per la gestione a lungo termine dell’obesità e delle sue complicanze.

Hospitals serve as critical environments for the management of diverse medical conditions, ranging from routine illnesses to life-threatening emergencies. However, alongside providing healthcare services, hospitals represent reservoirs for the transmission of microbial pathogens. Understanding the distribution and dynamics of pathogens within hospital settings is crucial for effective infection control and prevention strategies. Concurrently, the integration of cutting-edge technologies for the early detection and monitoring of target bacteria stands as a pivotal strategy in this battle against nosocomial infections. This critical review aims to provide a systematic insight into the main threatening microbes in hospitals and the detection of pathogens in different environments, ranging from intensive care units to general wards, including hospital entrances, bathrooms, high-touch surfaces, patient bed rails, medical equipment, and floors, which are often contaminated. We discuss recent scientific and technological advances in pathogen detection by exploring innovative methods that leverage nanotechnology to improve biosensing effectiveness and selectivity. This review is divided into sections focusing on various types of hospital environments, classes of mostly represented pathogens and kinds of available nanobiosensors. We include two comprehensive tables summarizing bacterial contamination in hospital wards and the materials and substrates associated with the nanobiosensors that have been developed. Eventually, we highlight the open challenges and perspectives in nanotechnology-based healthcare-environment monitoring and remediation as a promising solution to counteract pathogen emergence and spread.

The rapid advancement of artificial intelligence (AI) sparked the development of principles and guidelines for ethical AI by a broad set of actors. Given the high-level nature of these principles, stakeholders seek practical guidance for their implementation in the development, deployment and use of AI, fueling the growth of practical approaches for ethical AI. This paper reviews, synthesizes and assesses current practical approaches for AI in health, examining their scope and potential to aid organizations in adopting ethical standards. We performed a scoping review of existing reviews in accordance with the PRISMA extension for scoping reviews (PRISMA-ScR), systematically searching databases and the web between February and May 2023. A total of 4284 documents were identified, of which 17 were included in the final analysis. Content analysis was performed on the final sample. We identified a highly heterogeneous ecosystem of approaches and a diverse use of terminology, a higher prevalence of approaches for certain stages of the AI lifecycle, reflecting the dominance of specific stakeholder groups in their development, and several barriers to the adoption of approaches. These findings underscore the necessity of a nuanced understanding of the implementation context for these approaches and that no one-size-fits-all approach exists for ethical AI. While common terminology is needed, this should not come at the cost of pluralism in available approaches. As governments signal interest in and develop practical approaches, significant effort remains to guarantee their validity, reliability, and efficacy as tools for governance across the AI lifecycle.

Embedding signal processing in the front-end of radiation detectors represents an approach to cope with the growing complexity of nuclear imaging scanners with increasing field of view (i.e., higher number of channels). Machine learning (ML) offers a good compromise between intrinsic image reconstruction performance and computational power. While most hardware accelerators for ML are based on digital circuits and, thus, require the analog-to-digital conversion of all individual signals from photodetectors, an analog approach allows to streamline the pipeline. We present the study of an analog accelerator implementing a neural network (NN) with 42 neurons in a 0.35- ${\mu }$ m CMOS process node. The specific target is the reconstruction of the position of interaction of gamma-rays in the scintillator crystal of Anger cameras used for PET and SPECT. This chip can be used stand-alone or monolithically integrated within the application specific integrated circuit (ASIC) for the filtering of current signals from arrays of silicon photomultipliers (SiPMs). Computation is performed in charge domain by means of crossbar arrays of programmable capacitor. The architecture of the 64-input ASIC and the training of the NN are presented, discussing the impact of weight quantization on 5 bits. From MATLAB and circuit simulations, consistent with ASIC topology and operations, the NN capabilities were tested using two different datasets, obtained from both simulated data and experimental data, both based on PET detector composed by a monolithic scintillator crystal readout by an $8\times 8$ array of SiPMs. Simulations show an achievable spatial resolution better than 2-mm full-width-at-half-maximum with a 10-mm thick crystal, a max. count rate of 200kHz and the energy efficiency per inference is estimated to be of 93.5GOP/J, i.e., competitive with digital counterparts, with an energy consumption of 38nJ per inference and area of 23mm2.

Purpose: In the present short report, we encompass the radiobiological and dosimetric advantages of particle beam radiotherapy and we illustrate the oncological pathway for patients eligible for hadrontherapy being used at the National Center for Oncological Hadrontherapy (CNAO). Methods: With a narrative approach, we examined the clinical and practical aspects of hadrontherapy compared to traditional photon beam radiotherapy. We described the need to select patients considering the intrinsic characteristics both of the tumour and the patient. Moreover, we described the decisional oncological tree and the patient pathway by our facility. Results: Considering the dosimetric and radiobiological characteristics of particle beam radiotherapy, the selection of patients can not be done regardless of the intrinsic tumour and patient hallmarks. In particular, the tumour radioresistance, the patient radiosensitivity and the need to avoid post-actinic toxicities in long-term survivors should guide the clinical indication. The finite range of particles should be considered to avoid treatment uncertainties. Multidisciplinary national and international collaboration is crucial to better manage patients to treat with hadrontherapy and to create robust clinical evidence. Conclusion: Hadrontherapy, with its distinctive physical and biological advantages, heralds a promising era in the field of precision radiotherapy. Patients’ radiosensitivity, tumour radioresistance, and treatment uncertainties should be considered to enhance the efficacy and to ameliorate the selection of patients.

Restoration cork in the porticus post scaenam of the theatre of Terracina and a new statue dedication to Constantius II In 2020, after archaeological excavation’s resumption at the Roman theater of Terracina, in the porticus post scaenam it was identified a limestone base of statue, covered by the foundation wall of a modern building demolished during excavation activities. The inscription, a dedication to the emperor Flavius Iulius Constantius, is engraved on an older support datable to the early imperial age. The piece, once removed from its original location, was repositioned at the edge of the porticus, leaning its rear part against one of the columns. The discovery is of great interest both for monumental complex’s study and for technical and methodological approach implemented to arrive to a correct reading. Firstly the dedication helps to define a terminus ante quem for porticus usability, secondly inscription’s conservation state, determined by its history and by the fact that it has been reused, in order to achieve an integral reading, required the use, together with three-dimensional survey techniques, of MSII filtering.

A growing consensus that the brain is a mechanosensitive organ is driving the need for tools that mechanically stimulate and simultaneously record the electrophysiological response of neurons within neuronal networks. Here we introduce a synchronized combination of atomic force microscopy, high-density microelectrode array and fluorescence microscopy to monitor neuronal networks and to mechanically characterize and stimulate individual neurons at piconewton force sensitivity and nanometre precision while monitoring their electrophysiological activity at subcellular spatial and millisecond temporal resolution. No correlation is found between mechanical stiffness and electrophysiological activity of neuronal compartments. Furthermore, spontaneously active neurons show exceptional functional resilience to static mechanical compression of their soma. However, application of fast transient (∼500 ms) mechanical stimuli to the neuronal soma can evoke action potentials, which depend on the anchoring of neuronal membrane and actin cytoskeleton. Neurons show higher responsivity, including bursts of action potentials, to slower transient mechanical stimuli (∼60 s). Moreover, transient and repetitive application of the same compression modulates the neuronal firing rate. Seemingly, neuronal networks can differentiate and respond to specific characteristics of mechanical stimulation. Ultimately, the developed multiparametric tool opens the door to explore manifold nanomechanobiological responses of neuronal systems and new ways of mechanical control.

Purpose: To review experience and indications for head and neck (HN) tumors at our center in relation to the published literature. Methods: HN cancer patients treated at our center either with protons (PT) or carbon ions (CIRT) were extracted from our institutional retrospective and longitudinal Registry (NCT05203250 REGAL), including all the patients treated since the beginning of our clinical activity. A literature search was conducted with selection of most representative published studies for adenoid cystic carcinoma (ACC), mucosal melanoma (MM), sinonasal cancers (SNCs) and reirradiations. Results: Since the beginning of the clinical activity in 2011, 1311 HN tumors have been treated a tour center. Majority of treated patients were ACC (52%), non-ACC salivary gland tumors (18%), paranasal sinuses tumors (9%), MM (7%), and reirradiation of recurrent tumors after previous RT (14%). Oncological outcome in terms of safety and efficacy has been published on the series of 184 ACC and 40 MM, both treated with CIRT in the years 2013–2020. Reviewed reirradiation published series included a cohort of 52 recurrent salivary gland tumors retreated with CIRT from 2013 to 2016, and the experience of 2013–2020 of retreatment of 15 SNCs (13 with CIRT and 2 with PT). Conclusion: HN tumors are major indications for particle treatment around the world and at our center. Particle treatment might be personalized for each patient, with CIRT indicated for radioresistant tumors such as ACC and MM. Data on oncologic outcomes of CIRT at our center are consistent with published series.

Human cellular models of neurodegeneration require reproducibility and longevity, which is necessary for simulating age-dependent diseases. Such systems are particularly needed for TDP-43 proteinopathies1, which involve human-specific mechanisms2–5that cannot be directly studied in animal models. Here, to explore the emergence and consequences of TDP-43 pathologies, we generated induced pluripotent stem cell-derived, colony morphology neural stem cells (iCoMoNSCs) via manual selection of neural precursors6. Single-cell transcriptomics and comparison to independent neural stem cells7showed that iCoMoNSCs are uniquely homogenous and self-renewing. Differentiated iCoMoNSCs formed a self-organized multicellular system consisting of synaptically connected and electrophysiologically active neurons, which matured into long-lived functional networks (which we designate iNets). Neuronal and glial maturation in iNets was similar to that of cortical organoids8. Overexpression of wild-type TDP-43 in a minority of neurons within iNets led to progressive fragmentation and aggregation of the protein, resulting in a partial loss of function and neurotoxicity. Single-cell transcriptomics revealed a novel set of misregulated RNA targets in TDP-43-overexpressing neurons and in patients with TDP-43 proteinopathies exhibiting a loss of nuclear TDP-43. The strongest misregulated target encoded the synaptic protein NPTX2, the levels of which are controlled by TDP-43 binding on its 3′ untranslated region. When NPTX2 was overexpressed in iNets, it exhibited neurotoxicity, whereas correcting NPTX2 misregulation partially rescued neurons from TDP-43-induced neurodegeneration. Notably, NPTX2 was consistently misaccumulated in neurons from patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration with TDP-43 pathology. Our work directly links TDP-43 misregulation and NPTX2 accumulation, thereby revealing a TDP-43-dependent pathway of neurotoxicity.

Background:Alzheimer’s disease (AD) is characterised by abnormal protein aggregates in the brain that lead to cognitive decline. While current therapies only treat symptoms, disease-modifying treatments are urgently needed. Studies suggest that the composition of the microbiota is altered in people with AD, suggesting a link between gut bacteria and AD-related brain changes. Summary:In our narrative review, we explore various microbial interventions, such as faecal microbiota transplantation, probiotics, and diet, as powerful potential treatments. Studies suggest changes in microbiota composition following these interventions, with some beneficial effects on cognitive function. However, the mechanism of action of these microbial interventions is still unknown. Key Message:Our aim was to highlight the importance of personalised approaches, taking into account individual metabolic and microbiome profiles. We try to address gaps in current research and emphasise the need for microbiota analysis at different stages of the disease and its integration with clinical parameters and lifestyle information for a comprehensive understanding of AD progression (summarised in online suppl. Fig. 1; for all online suppl. material, see

Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a relevant response latency, with a range of adverse events, including weight gain and sexual dysfunction. Novel rapid agents were developed with the aim of overcoming at least in part these issues. Novel drugs target glutamate, gamma-aminobutyric acid, orexin, and other receptors, providing a broader range of pharmacodynamic mechanisms, that is, expected to increase the possibility of personalizing treatments on the individual clinical profile. These new drugs were developed with the aim of combining a rapid action, a tolerable profile, and higher effectiveness on specific symptoms, which were relatively poorly targeted by standard antidepressants, such as anhedonia and response to reward, suicidal ideation/behaviours, insomnia, cognitive deficits, and irritability. This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.

The design of soft and nanometer-scale photoelectrodes able to stimulate and promote the intracellular concentration of reactive oxygen species (ROS) is searched for redox medicine applications. In this work, we show semiconducting polymer porous thin films with an enhanced photoelectrochemical generation of ROS in human umbilical vein endothelial cells (HUVECs). To achieve that aim, we synthesized graft copolymers, made of poly(3-hexylthiophene) (P3HT) and degradable poly(lactic acid) (PLA) segments, P3HT-g-PLA. In a second step, the hydrolysis of sacrificial PLA leads to nanometer-scale porous P3HT thin films. The pore sizes in the nm regime (220–1200 nm) were controlled by the copolymer composition and the structural arrangement of the copolymers during the film formation, as determined by atomic force microscopy (AFM) and transmission electron microscopy (TEM). The porous P3HT thin films showed enhanced photofaradaic behavior, generating a higher concentration of ROS in comparison to non-porous P3HT films, as determined by scanning electrochemical microscopy (SECM) measurements. The exogenous ROS production was able to modulate the intracellular ROS concentration in HUVECs at non-toxic levels, thus affecting the physiological functions of cells. Results presented in this work provide an important step forward in the development of new tools for precise, on-demand, and non-invasive modulation of intracellular ROS species and may be potentially extended to many other physiological or pathological cell models.

The relationship between psychiatric symptoms and thyroid function has been well known and studied since antiquity. The common view is that clinical hypothyroidism is associated with depressive symptoms, whereas the psychiatric manifestations of hyperthyroidism are agitation, emotional lability, hyperexcitability, occasionally accompanied by angry outbursts, and euphoria. The case here reported overturns this conventional medical knowledge. A 73-year-old Italian woman experienced a severe major depressive episode with psychotic and melancholic features during laboratory thyrotoxicosis. No classical clinical signs and symptoms of thyrotoxicosis were present. Psychiatric symptoms improved together with the resolution of the hyperthyroid state. Historically, different cases of so-called ‘apathetic hyperthyroidism’ have been described. Recent neuroimaging and animal studies provided possible neurobiological explanations, showing how the excess thyroid hormones could affect brain structures involved in the regulation of mood, leading to depression. A direct link between hyperthyroidism and depression seems to be likely. This insight may be relevant in facilitating early diagnosis of thyroid disease and the planning of therapeutic strategies.

Aging accounts for increased risk and dismal outcome of ischemic stroke. Here, we investigated the impact of age-related changes in the immune system on stroke. Upon experimental stroke, compared with young mice, aged mice had increased neutrophil clogging of the ischemic brain microcirculation, leading to worse no-reflow and outcomes. Aged mice showed an enhanced granulopoietic response to stroke that led to the accumulation of CD101+CD62Llomature and CD177hiCD101loCD62Lloand CD177loCD101loCD62Lhiimmature atypical neutrophils in the blood, endowed with increased oxidative stress, phagocytosis and procoagulant features. Production of CXCL3 by CD62Lloneutrophils of the aged had a key role in the development and pathogenicity of aging-associated neutrophils. Hematopoietic stem cell rejuvenation reverted aging-associated neutropoiesis and improved stroke outcome. In elderly patients with ischemic stroke, single-cell proteome profile of blood leukocytes identified CD62Lloneutrophil subsets associated with worse reperfusion and outcome. Our results unveil how stroke in aging leads to a dysregulated emergency granulopoiesis impacting neurological outcome.

Scirtothrips dorsalisHood (Thysanoptera: Thripidae) is an invasive pest that is popularly known as chilli thrips. This insect pest has a wide range of hosts distributed across 72 plant families, causing damage to numerous crops of great economic importance. In the Americas, it is present in the USA, Mexico, Suriname, Venezuela, Colombia, and some Caribbean Islands. Knowing the regions which have environmentally suitable conditions for the survival of this pest is important for phytosanitary monitoring and inspection. Thus, our objective was to forecast the distribution potential of S. dorsaliswith a focus on the Americas. Models were produced to design this distribution, in which the environmental variables used were made available in Wordclimversion 2.1. The algorithms used for the modeling were the generalized additive model (GAM), generalized linear model (GLM), maximum entropy (MAXENT), random forest (RF), and Bioclim, in addition to the ensemble, which consisted of the grouping of the algorithms used. The metrics used to evaluate the models were area over the curve (AUC), true ability statistics (TSS), and Sorensen score. All models had satisfactory results (> 0.8) for all metrics used. In North America, the model showed favorable regions on the west coast of the USA and east coast near New York. In South America, the potential distribution of the pest is significant, encompassing regions in all countries. It is concluded that S. dorsalishas suitable areas for the occurrence in the three American subcontinents and, in particular, a large part of South America.

An equation for estimating the effective diffusivity χφeffbased on the thermal and frictional forces arising from the interactions with neutral particles is provided. These interactions are primarily attributed to charge-exchange processes between ions and neutral particles. Our analysis indicates that the proposed forces are strong candidates to act as sources or sinks of momentum at the plasma edge. Furthermore, although we only have an estimated profile of neutral particles, the results demonstrate a strong dependence of the effective diffusivity on the ion-neutral collision frequency and a comparatively weaker dependence on ion temperature. We showed that the toroidal rotation profile in the TCABR tokamak is well described by the Helander model for toroidal rotation velocity in the Pfirsch-Schlüter regime, which depends on the ion temperature gradient in the presence of the neutral particles. The toroidal rotation profile has been reconstructed by a sum of Bessel functions, derived from the solution of a second-order differential equation for the toroidal velocity. In this initial study on momentum transport in TCABR, our findings indicate that χφeff—which accounts for both the diffusivity and pinch terms in the momentum equation—increases significantly in the outer plasma region. Additionally, it achieves a reasonable maximum value of approximately χφeff≈20m2/s near the plasma edge at r/a≃0.87, in the same radial position of the maximum ion-neutral collision frequency, demonstrating that the applied method successfully captures the general behaviour of this component as reported in other works, and guiding future experimental validation.

We examine the origins of threshold voltage ( ${V}_{\text {TH}}{)}$ variability in planar ferroelectric FETs (FeFETs) considering process variations and source–drain channel percolation. Using a percolation-aware physics-based multidomain FeFET model, we are able to capture the ${V}_{\text {TH}}$ statistics measured on fabricated devices across different channel dimensions. We show that the bimodal ${V}_{\text {TH}}$ distribution observed in large devices can be explained by percolation, while the transition to monomodal distribution in scaled devices is qualitatively reproduced by the overlapping Pelgrom-type and percolative variabilities in the model. We further demonstrate that in terms of device geometry, the percolation-related FeFET ${V}_{\text {TH}}$ variability is minimized for a channel aspect ratio equal to 1.

Macrophages are involved in immune defense, organogenesis and tissue homeostasis. Macrophages contribute to the different phases of mammary gland remodeling during development, pregnancy and involution postlactation. Less is known about the dynamics of mammary gland macrophages in the lactation stage. Here, we describe a macrophage population present during lactation in mice. By multiparameter flow cytometry and single-cell RNA sequencing, we identified a lactation-induced CD11c+CX3CR1+Dectin-1+macrophage population (liMac) that was distinct from the two resident F4/80hiand F4/80lomacrophage subsets present pregestationally. LiMacs were predominantly monocyte-derived and expanded by proliferation in situ concomitant with nursing. LiMacs developed independently of IL-34, but required CSF-1 signaling and were partly microbiota-dependent. Locally, they resided adjacent to the basal cells of the alveoli and extravasated into the milk. We found several macrophage subsets in human milk that resembled liMacs. Collectively, these findings reveal the emergence of unique macrophages in the mammary gland and milk during lactation.

Pathogenic variants impacting upon assembly of mitochondrial respiratory chain Complex IV (Cytochrome c Oxidase or COX) predominantly result in early onset mitochondrial disorders often leading to CNS, skeletal and cardiac muscle manifestations. The aim of this study is to describe a molecular defect in the COX assembly factor gene COX18as the likely cause of a neonatal form of mitochondrial encephalo-cardio-myopathy and axonal sensory neuropathy. The proband is a 19-months old female displaying hypertrophic cardiomyopathy at birth and myopathy with axonal sensory neuropathy and failure to thrive developing in the first months of life. Serum lactate was consistently increased. Whole exome sequencing allowed the prioritization of the unreported homozygous substitution NM_001297732.2:c.667 G > C p.(Asp223His) in COX18. Patient’s muscle biopsy revealed severe and diffuse COX deficiency and striking mitochondrial abnormalities. Biochemical and enzymatic studies in patient’s myoblasts and in HEK293 cells after COX18silencing showed a severe impairment of both COX activity and assembly. The biochemical defect was partially rescued by delivery of wild-type COX18cDNA into patient’s myoblasts. Our study identifies a novel defect of COX assembly and expands the number of nuclear genes involved in a mitochondrial disorder due to isolated COX deficiency.

This article focuses on in- depth examination of the imprint effect in lanthanum-doped Hf $_{{0}.{5}}$ Zr0.5O2 (La:HZO) capacitors. The first part shows the imprint effect in a single positive up negative down (PUND) measurement caused by different delays between pulses. In addition, a unique wake-up reversal behavior (i.e., current peak split in the ${I}$ ,– ${V}$ curve and pinched ${P}$ ,– ${V}$ loop) induced by imprint has been investigated in devices with two different prepolarized states (positive and negative). The results have shown that this behavior is accelerated by the bake temperature. Quantitative evaluation of the observed current peak split at each bake time and bake temperature yielded activation energy, suggesting that the wake-up reversal is due to oxygen vacancy redistribution. Moreover, corresponding models explaining how these charged defects and the polarization dipoles interact at each measurement step are proposed. Lastly, analysis of temperature-dependent field cycling characteristics suggests that the degraded wake-up of La:HZO film at high temperature can be attributed to the wake-up reversal effect being concurrent with wake-up.

AbstractMountain dairy products are recognised as high-quality food but there are still few studies concerning the effects of seasonality and herd management on the profile of bioactive compounds in cheeses. This study was planned to assess the effect of season (summer versus winter) and feeding management (pasture versus integration) on fatty acids (FAs) profile, anti-hypertensive (ACE-IA) and anti-oxidant properties (ABTS-SA, FRAP), total thiol (SH) and phenolic (TP) contents of cheeses from two dairy cow farms (Farm A and Farm B) located in Piedmontese Alps (Italy). Cheese samples collected in the farms were submitted to an integrated analytical approach and the results were processed by full factorial ANOVA and PCA. The trends observed from the FAs profile confirmed the beneficial influence of supplying fresh forage to lactating cows. The ACE-IA was higher in summer than in winter cheese but depended upon the farm factor. Among the indicators of antioxidant activity, only the ABTS-SA was affected by the season, even though with significant differences between the farms. The TP content did not show any clear pattern, but it was higher than the values described in the literature. The PCA of all the data showed that several FAs and the ABTS-SA gave relevant contributions to clearly group the cheese samples according to the production season or farm. In conclusion, alpine cheese exhibited high nutritional quality under the consumers’ health standpoint, and the identification of the healthier summer cheeses for traceability or labelling purposes, can be obtained.HighlightsSeasonality and herd management practices affected the nutritional quality of cheese produced in two dairy farms in Piedemontese Alps.Lipid quality was affected by the feeding strategy, with the greater improvements obtained by pasture grazing or fresh grass consumption in the barn.ACE-inhibitory activity and anti-oxidant properties were influenced by both seasonality and farm of origin, with the best values measured in summer cheese.

The purpose of this article is to discuss the published evidence related to quality of life (QoL) and financial toxicity (FT) differences between female and male head and neck cancer patients treated with (chemo)radiotherapy. There is a need of promoting methods for assessing QoL difference between female and male patients in order to set up early rehabilitation, psychosocial care, and lifestyle interventions, as well as setting up specific interventions for minimizing financial stress.

Binge-eating (BE) symptoms are relatively common in major depressive disorder (MDD), but their prognostic role is not fully understood. This study compared two groups of patients with MDD experiencing or not BE symptoms to ascertain differences in terms of clinical manifestations, presence of bipolar features, and antidepressant treatment outcomes. The study involved 482 outpatients collected within the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, who were assessed with scales for depressive and hypomanic symptomatology, suicidality, comorbid mental disorders, and childhood traumas. BE symptoms were reported in 95 patients (20%). Patients with MDD experiencing BE symptoms were characterized by higher scores of negative self-outlook (P= 0.0018), negative outlook of future (P= 0.0014), irritability (P= 0.0043), comorbid anxiety disorders (generalized anxiety disorder: P= 0.0006; panic disorder: P< 0.0001; social phobia: P< 0.0001), obsessive-compulsive disorder (P= 0.0053), hypomanic symptoms (increased talkativeness: P= 0.0029; reduced need for sleep: P= 0.0171), and suicidality (suicidal propensity: P= 0.0013; suicidal risk: P= 0.0148; lifetime suicidal behavior: P= 0.0052). BE symptoms (OR = 2.02; 95% CI = 1.06–3.84) and depression severity (OR = 1.04; 95% CI = 1.00–1.08) were independently associated with lifetime attempted suicide. The presence of BE symptoms might indicate higher severity of depressive disorder. Suicidal risk is a major issue in these patients, whereas the association between BE and bipolar features needs further research.

Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D2receptor binding affinity. Twenty studies examining the combination aripiprazole – high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.

Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools.

ABSTRACTGut microbiota is responsible for essential functions in human health. Several communication axes between gut microbiota and other organs via neural, endocrine, and immune pathways have been described, and perturbation of gut microbiota composition has been implicated in the onset and progression of an emerging number of diseases. Here, we analyzed peripheral nerves, dorsal root ganglia (DRG), and skeletal muscles of neonatal and young adult mice with the following gut microbiota status: a) germ-free (GF), b) gnotobiotic, selectively colonized with 12 specific gut bacterial strains (Oligo-Mouse-Microbiota, OMM12), or c) natural complex gut microbiota (CGM). Stereological and morphometric analyses revealed that the absence of gut microbiota impairs the development of somatic median nerves, resulting in smaller diameter and hypermyelinated axons, as well as in smaller unmyelinated fibers. Accordingly, DRG and sciatic nerve transcriptomic analyses highlighted a panel of differentially expressed developmental and myelination genes. Interestingly, the type III isoform of Neuregulin1 (NRG1), known to be a neuronal signal essential for Schwann cell myelination, was overexpressed in young adult GF mice, with consequent overexpression of the transcription factor Early Growth Response 2 (Egr2), a fundamental gene expressed by Schwann cells at the onset of myelination. Finally, GF status resulted in histologically atrophic skeletal muscles, impaired formation of neuromuscular junctions, and deregulated expression of related genes. In conclusion, we demonstrate for the first time a gut microbiota regulatory impact on proper development of the somatic peripheral nervous system and its functional connection to skeletal muscles, thus suggesting the existence of a novel ‘Gut Microbiota-Peripheral Nervous System-axis.’

Introduction: Anorexia Nervosa (AN) is a complex psychiatric illness, characterized by a high risk of developing cardiovascular complications. Given the high risk of vascular diseases in patients with AN, we can assume that patients with severe AN have a high risk of developing ischemic stroke. However, to the best of our knowledge, no reports of patients with AN presenting with ischemic stroke have been published, other than a report of the development of IS during refeeding therapy in patients with severe AN. Case presentation: The present case report is aimed at describing the characteristics of an ischemic stroke occurring in a 19-year-old university student who had a 6-month history of AN. She was a non-smoker, had no relevant medical history and no family history of stroke. Upon hospital admission due to symptoms of stroke (aphasia and facial droop), she exhibited severe malnutrition with a BMI of 12.8 kg/m2. Computerized tomography imaging revealed occlusion of the left M2 branch and a congruous extensive area of hypoperfusion. Further investigations ruled out all common causes of stroke: she had no vascular stenosis, no heart diseases or arrhythmias, and no shunts, and gave negative results in autoimmune, toxicological and thrombophilia screenings. Conclusion: Clinicians should suspect development of severe complications, including ischemic stroke, in patients with severe AN. Further extensive group studies or group-based studies are needed to elucidate the etiology of ischemic stroke in patients with severe AN. This will enable us to develop more precise and effective interventions. Graphical Abstract:

Purpose: Treatment resistance is a significant challenge in addressing eating disorders (EDs). The Autonomous and Controlled Motivation for Treatment Questionnaire (ACMTQ) has been previously validated in ED populations to assess patients’ motivation for treatment. This study aimed to validate the ACMTQ in the Italian language (ACMTQ-ITA) and evaluate its psychometric properties. Methods: We recruited a clinical sample of adults aged 18 or older, diagnosed with EDs, proficient in the Italian language, and providing written informed consent. Participants with psychiatric comorbidities such as schizophrenia, bipolar disorder, and substance use disorder were excluded from the study. Validity of the ACMTQ-ITA was assessed using reliability analysis with Cronbach’s α and McDonald’s ω estimates, and Confirmatory Factor Analysis (CFA). Results: Results from the reliability analysis confirmed the internal consistency of the Autonomous Motivation (AM) factor (α = 0.82, ω = 0.82), the Controlled Motivation (CM) factor (α = 0.76, ω = 0.77), and the ACMTQ-ITA overall score (α = 0.79). The CFA confirmed the two-factor solution (i.e., AM and CM) identified in the original validation of the ACMTQ (Comparative Fit Index = 0.92, Akaike Information Criterion = 3427.26, Bayesian Information Criterion = 3486.82; Root Mean Square Error of Approximation = 0.08, Standardized Root Mean Square Residual = 0.09). Conclusion: The ACMTQ-ITA emerged as a valid and reliable tool for measuring motivation for treatment in individuals with EDs. Its implementation may facilitate the comprehension of treatment motivation, offering valuable clinical insights and implications for health management practices.

For nearly 20% of patients diagnosed with Anorexia Nervosa, the eating disorder is prolonged and becomes long-lasting. Those patients have worse ED symptoms, higher rates of lifetime hospitalization, and lower psychosocial well-being compared to patients with shorter disease duration. This review aims to describe the treatments proposed to date and their effectiveness on severe enduring anorexia nervosa related outcomes. The data obtained show how the intervention techniques primarily used in these patients are psychotherapy (in particular, cognitive behavioral therapy and Specialist Supportive Clinical Management), pharmacological treatments, and Brain Stimulation Therapies (such as Repetitive Transcranial Magnetic Stimulation and Deep Brain Stimulation). To our knowledge, research evidence on treatment options for SE-AN remains limited and these findings denote the need to focus future research efforts on effective treatment strategies specific to long-lasting eating disorders.

ABSTRACTIntroductionThe adenosine pathway has been suggested to play a key role in several carcinogenetic processes, with the metabolism of adenosine-5′-triphosphate (ATP) and its derivatives reported to be dysregulated in breast cancer. Preclinical evidence has supported the role of adenosine in the pathogenesis of this malignancy as well as the development of selective adenosine pathway inhibitors.Areas coveredThe paper overviews the evidence regarding the use of adenosine pathway inhibitors in breast cancer; a literature search was conducted in January 2022 of Pubmed/Medline, Cochrane library, and Scopus databases.Expert OpinionThe adenosine pathway regulates inflammation, apoptosis, metastasis, and cell proliferation in breast cancer cells, and adenosine pathway inhibitors have yielded encouraging results in early-phase clinical trials. Well-designed, multicenter studies focused on monotherapies and combination therapies (which include immune checkpoint inhibitors) are warranted in this setting.

The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing).