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Marco Solmi,1,2 Andrea Murru,3 Isabella Pacchiarotti,3 Juan Undurraga,4,5 Nicola Veronese,2,6 Michele Fornaro,7,8 Brendon Stubbs,2,9–11 Francesco Monaco,2 Eduard Vieta,3 Mary V Seeman,12 Christoph U Correll,13,14 André F Carvalho2,15 1Neuroscience Department, University of Padua, 2Institute for Clinical Research and Education in Medicine, Padua, Italy; 3Bipolar Disorders Unit, Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain; 4Department of Psychiatry, Faculty of Medicine, Clínica Alemana Universidad del Desarrollo, 5Early Intervention Program, J. Horwitz Psychiatric Institute, Santiago, Chile; 6National Research Council, Ageing Section, Padua, 7Laboratory of Molecular and Translational Psychiatry, Department of Neuroscience, School of Medicine, University “Federico II”, Naples, Italy; 8New York State Psychiatric Institute, Columbia University, New York, NY, USA; 9Health Service and Population Research Department, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 10Physiotherapy Department, South London and Maudsley NHS Foundation Trust, London, 11Faculty of Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK; 12Institute of Medical Science, Toronto, ON, Canada; 13Department of Psychiatry Research, Zucker Hillside Hospital, Northwell Health, Glen Oaks, 14Department of Psychiatry and Molecular Medicine Hempstead, Hofstra Northwell School of Medicine, Hempstead, NY, USA; 15Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, Ceará, Brazil Abstract: Since the discovery of chlorpromazine (CPZ) in 1952, first-generation antipsychotics (FGAs) have revolutionized psychiatric care in terms of facilitating discharge from hospital and enabling large numbers of patients with severe mental illness (SMI) to be treated in the community. Second-generation antipsychotics (SGAs) ushered in a progressive shift from the paternalistic management of SMI symptoms to a patient-centered approach, which emphasized targets important to patients – psychosocial functioning, quality of life, and recovery. These drugs are no longer limited to specific Diagnostic and Statistical Manual of Mental Disorders (DSM) categories. Evidence indicates that SGAs show an improved safety and tolerability profile compared with FGAs. The incidence of treatment-emergent extrapyramidal side effects is lower, and there is less impairment of cognitive function and treatment-related negative symptoms. However, treatment with SGAs has been associated with a wide range of untoward effects, among which treatment-emergent weight gain and metabolic abnormalities are of notable concern. The present clinical review aims to summarize the safety and tolerability profile of selected FGAs and SGAs and to link treatment-related adverse effects to the pharmacodynamic profile of each drug. Evidence, predominantly derived from systematic reviews, meta-analyses, and clinical trials of the drugs amisulpride, aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, CPZ, haloperidol, loxapine, and perphenazine, is summarized. In addition, the safety and tolerability profiles of antipsychotics are discussed in the context of the “behavioral toxicity” conceptual framework, which considers the longitudinal course and the clinical and therapeutic consequences of treatment-emergent side effects. In SMI, SGAs with safer metabolic profiles should ideally be prescribed first. However, alongside with safety, efficacy should also be considered on a patient-tailored basis. Keywords: antipsychotics, side effects, tolerability, safety, psychosis, psychiatry

Abstract Indoor air quality is negatively affected by the emission of different combustion sources releasing airborne particles and related particle-bound toxic compounds (e.g., heavy metals and polycyclic aromatic hydrocarbons). To date, very few studies focused on the chemical characterization of the airborne particles emitted by indoor sources were carried out; moreover, no data on their size-resolved chemical compositions are available. In the present study, an experimental analysis aimed at determining the size-segregated content of heavy metals and polycyclic aromatic hydrocarbons in airborne particles (including sub-micrometric ones) emitted by widely-used indoor combustion sources (i.e., incenses, candles, mosquito-coils, and cooking activities) was carried out. To this purpose, airborne particles were collected through an electric low-pressure impactor and were post-analyzed by means of chromatography–mass spectrometry and atomic emission spectrometry techniques. Results of the analyses showed that the chemical composition of the emitted particles is not invariant to the particle size, indeed, an important contribution of sub-micrometric particle range to the total mass of chemical compounds emitted by the sources was noticed. These findings also demonstrated that significant underestimations of particle-bound compounds depositing in the lungs could occur if size-dependent compositions are not adopted.

Abstract The Alto Tiberina Fault system, located in Central Italy, is an active structure about 60 km long composed of a principal low-angle normal fault and several minor synthetic and antithetic splays. The system is monitored by a dense seismic network, giving us the opportunity to construct high-definition seismic catalogs with a low completeness magnitude. We analyze the clustering properties of the 2010-2015 seismicity by using a 3D stochastic declustering algorithm that also includes the earthquakes’ depth. We demonstrate that the earthquake size distribution is strongly correlated with the clustering of seismic events and their depth; in particular, the principal fault and secondary faults show an opposite behavior both in terms of earthquake size distribution and clustering properties.

Objective: This study aimed to assess the relationship between dietary palmitic acid (PA) intake and its association with body fat deposition and metabolic flexibility (MF) in middle-aged healthy individuals. Methods: Fifteen healthy participants (n = 15; 6 males, 9 females) with a mean age of 54 were enlisted. They were subjected to graded exercise tests using a cycle ergometer coupled with a calorimeter. Respiratory gas exchange was evaluated to determine two MF parameters. First, the MF index was derived by multiplying peak fatty acid oxidation (PFO) per kg of fat-free mass (FFM) with the percentage of VO2max at PFO. The second parameter, peak energy substrates’ oxidation (aka PESO), was computed by aggregating the kilocalories from PFO and peak carbohydrate oxidation, normalized per kg FFM. Dietary intake was gauged using a 7-day dietary record. Spearman’s regression was employed to analyze the association between dietary intake of specific fat classes, PA, MF parameters, and body fat percentage. Results: Preliminary results demonstrate that dietary saturated fatty acids (SFA) within physiological limits correlate with enhanced substrate oxidation capacity. This suggests augmented MF in middle-aged subjects. Among dietary SFA, PA was identified as the primary factor in this favorable correlation. Conclusions: Our initial observations, even though preliminary, strongly suggest a beneficial association between PA intake, MF, and body fat percentage. This underscores the potential nutritional importance of PA in promoting MF. Significance Statement Disparities in data regarding the health effects of dietary fats may arise from the distinct roles various dietary fatty acids play in MF.

BackgroundBrain magnetic resonance imaging (MRI) is mandatory or highly recommended in many pediatric endocrinological conditions to detect causative anatomic anomalies and rule out neoplastic lesions. However, MRI can also show findings associated with the underlying clinical condition, as well as unrelated “incidentalomas”. These latter findings are often abnormalities with a high incidence in the general population for which there is no clear literature regarding their management, especially in pediatric patients. The present study aimed to evaluate the number of unnecessary performed MRIs in pediatric endocrinology.MethodsRetrospective analysis on 584 MRI scans performed in 414 patients (254 growth hormone deficiency, 41 other causes of short stature, 116 central precocious puberty).ResultsThe MRI scans were completely normal in 67% of the individuals, and the prevalence of individuals who underwent more than one MRI was 18%, with no significant differences among the groups. The overall prevalence of incidentalomas was 17%. Among 170 repeated MRI scans, 147 (86%) were not required according to a dedicated protocol. Only five patients (four GHD, one Noonan) correctly repeated the MRI. All the repeated MRI scans did not reveal any progression in the findings. If we include the MRIs performed in cases of OCSS other than Noonan syndrome (n=32) and girls with CPP older than 6 years (n=89), an additional 121 MRIs could have been avoided, leading to a total number of unnecessary MRIs to 268 (46%).ConclusionsOnly a few specific neuroimaging findings in endocrinologic pediatric patients warrant further investigation, while too often repeated imaging is carried out unnecessarily. We advocate the importance of guidelines to reduce costs for both the healthcare system and patients’ families, as well as to alleviate physical and psychological distress for patients and caregivers.

Background Bipolar disorder is highly prevalent and consists of biphasic recurrent mood episodes of mania and depression, which translate into altered mood, sleep and activity alongside their physiological expressions. Aims The IdenTifying dIgital bioMarkers of illnEss activity and treatment response in BipolAr diSordEr with a novel wearable device (TIMEBASE) project aims to identify digital biomarkers of illness activity and treatment response in bipolar disorder. Method We designed a longitudinal observational study including 84 individuals. Group A comprises people with acute episode of mania (n = 12), depression (n = 12 with bipolar disorder and n = 12 with major depressive disorder (MDD)) and bipolar disorder with mixed features (n = 12). Physiological data will be recorded during 48 h with a research-grade wearable (Empatica E4) across four consecutive time points (acute, response, remission and episode recovery). Group B comprises 12 people with euthymic bipolar disorder and 12 with MDD, and group C comprises 12 healthy controls who will be recorded cross-sectionally. Psychopathological symptoms, disease severity, functioning and physical activity will be assessed with standardised psychometric scales. Physiological data will include acceleration, temperature, blood volume pulse, heart rate and electrodermal activity. Machine learning models will be developed to link physiological data to illness activity and treatment response. Generalisation performance will be tested in data from unseen patients. Results Recruitment is ongoing. Conclusions This project should contribute to understanding the pathophysiology of affective disorders. The potential digital biomarkers of illness activity and treatment response in bipolar disorder could be implemented in a real-world clinical setting for clinical monitoring and identification of prodromal symptoms. This would allow early intervention and prevention of affective relapses, as well as personalisation of treatment.

Objective: Recent studies have demonstrated that prenatal exposure to the psychoactive ingredient of cannabis that is tetrahydrocannabinol (THC) disrupts fatty acid (FA) signaling pathways in the developing brain, potentially linking to psychopathologic consequences. Our research aims to investigate whether changes in midbrain FA metabolism are linked to modifications in peripheral metabolism of FAs and shifts in microbiota composition. Methods: In order to model prenatal exposure to THC (PTE) in rats, Sprague Dawley dams were systemically administered with THC (2 mg/kg, s.c.) or vehicle once daily from gestational day 5–20. To evaluate the metabolic impact of PTE in the offspring during preadolescence (postnatal day, PND, 25–28), we analyzed FA profiles and their bioactive metabolites in liver and midbrain tissues, and microbiota alterations. Results: Our findings indicate that PTE leads to sex-specific metabolic changes. In both sexes, PTE resulted in increased liver de novo lipogenesis (DNL) and alterations in FA profiles, as well as changes in N-acylethanolamines (NAEs), ligands of peroxisome proliferator-activated receptor alpha (PPAR-α). In females only, PTE influenced gene expression of PPAR-α and fibroblast growth factor 21 (Fgf21). In male offspring only, PTE was associated with significantly reduced fasting glycaemia and with alterations in the levels of midbrain NAEs. Our analysis of the progeny gut microbiota revealed sex-dependent effects of PTE, notably an increased abundance of Ileibacterium in PTE-exposed male offspring, a change previously associated with the long-term effects of a maternal unbalanced diet. Conclusions: Our data suggest that in male PTE offspring a reduced fasting glycaemia, resulting from increased liver DNL and the absence of a compensatory effect by Ppar-α and FGF21 on glycemic homeostasis, are associated to alterations in midbrain NAEs ligands of PPAR-α. These metabolic changes within the midbrain, along with Ileibacterium abundance, may partly elucidate the heightened susceptibility to psychopathologic conditions previously observed in male offspring following PTE.

Abstract Neuromodulation by means of vagus nerve stimulation (VNS) therapy, reduces seizure frequency and improves quality of life in subjects with drug‐resistant epilepsy (DRE), yet its molecular mechanism remains unclear. This study investigates the impact of chronic VNS on lipid bioactive metabolites and fatty acids (FA) in the plasma and red blood cells of seven subjects with DRE. By measuring expression levels of peroxisome proliferator‐activated receptor α (PPARα) and sirtuin1 (SIRT1) genes—key regulators in energy and lipid metabolism—and lipid profiles before and after various stages of VNS, this study identifies potential mechanisms by which VNS may reduce seizure frequency. Blood samples collected before VNS device implantation, after acute VNS stimulus, and following gradual intensity increments up to therapeutic levels revealed that VNS increases SIRT1 and PPARα expression and erythrocyte concentrations of PPARα ligands. Additionally, we observe reduced de novo lipogenesis biomarkers in erythrocytes, indicating that VNS may influence systemic lipid and energy metabolism. Our findings suggest that VNS could enhance neuronal function by modulating energy metabolism, thus potentially reducing seizure frequency in subjects with DRE. Future research targeting SIRT1 and PPARα may provide innovative therapeutic strategies for managing DRE. Plain Language Summary: The exact mechanism of VNS is still unknown. This study investigated the effects of VNS Therapy on energetic metabolism, suggesting possible novel biomarkers for DRE subjects and neuromodulation therapies.

Abstract Introduction Biomarker testing is mandatory for the clinical management of patients with advanced non-small cell lung cancer (NSCLC). Myriads of technical platforms are now available for biomarker analysis with differences in terms of multiplexing capability, analytical sensitivity, and turnaround time (TAT). We evaluated the technical performance of the diagnostic workflows of 24 representative Italian institutions performing molecular tests on a series of artificial reference specimens built to mimic routine diagnostic samples. Methods Sample sets of eight slides from cell blocks of artificial reference specimens harboring exon 19 EGFR (epidermal growth factor receptor) p.E746_AT50del, exon 2 KRAS (Kirsten rat sarcoma viral oncogene homologue) p.G12C, ROS1 (c-ros oncogene 1)-unknown gene fusion, and MET (MET proto-oncogene, receptor tyrosine kinase) Δ exon 14 skipping were distributed to each participating institution. Two independent cell block specimens were validated by the University of Naples Federico II before shipment. Methodological and molecular data from reference specimens were annotated. Results Overall, a median DNA concentration of 3.3 ng/µL (range 0.1–10.0 ng/µL) and 13.4 ng/µL (range 2.0–45.8 ng/µL) were obtained with automated and manual technical procedures, respectively. RNA concentrations of 5.7 ng/µL (range 0.2–11.9 ng/µL) and 9.3 ng/µL (range 0.5–18.0 ng/µL) were also detected. KRAS exon 2 p.G12C, EGFR exon 19 p.E736_A750del hotspot mutations, and ROS1 aberrant transcripts were identified in all tested cases, whereas 15 out of 16 (93.7%) centers detected MET exon 14 skipping mutation. Conclusions Optimized technical workflows are crucial in the decision-making strategy of patients with NSCLC. Artificial reference specimens enable optimization of diagnostic workflows for predictive molecular analysis in routine clinical practice.

Summary: Background: Marginal zone lymphomas (MZL), comprised of three unique but related subtypes, lack a unifying prognostic score applicable to all the patients in need for systemic chemotherapy and/or immunotherapy. Methods: Patients from the prospective NF10 study (NCT02904577) with newly diagnosed MZL and receiving frontline systemic therapy at diagnosis or after observation were used to train a prognostic model. The primary endpoint was progression-free survival (PFS) from start of treatment. The model was externally validated in a pooled analysis of two independent cohorts from the University of Iowa and Mayo Clinic Molecular Epidemiology Resource and the University of Miami. Findings: We identified 501 eligible patients. After multivariable modeling, lactate dehydrogenase (LDH) above upper normal limit, hemoglobin

Schwannomas are benign, slow-growing tumors originating from the Schwann cells of nerve sheaths. Extracranial schwannomas are rare, particularly in pediatric populations. Here, we report the case of a hypoglossal schwannoma in a 15-year-old male who experienced tongue paresthesia and fasciculations and difficulty swallowing two years before hospital admission. Magnetic resonance imaging showed an oval mass with sharp and regular limits of approximately 45 × 29 × 25 mm in the cranial portion of the right carotid adipose space, caudal to the right carotid and lateral foramen. The patient underwent surgery, and a histological examination confirmed a schwannoma of the hypoglossal nerve. Six months after surgery, the patient was symptom-free. The literature on schwannomas of the hypoglossal nerve is scarce, with only a few previously reported cases in the adult population. Despite their rarity, schwannomas should be considered in the differential diagnosis of masses located in the neck that present with lingual and occasionally auditory symptoms, even in pediatric patients. Surgical resection is recommended and has a low risk of long-term recurrence.

Introduction Predicting acute affective episodes in individuals with Bipolar Disorder (BD) remains a clinical challenge. Specific environmental stressors, including air pollution, noise, and temperature variations might worsen affective symptoms or sleep in the general population, but their role in BD relapses is often overlooked. Indeed, they might exacerbate BD by perturbing circadian rhythms – fundamental aspects of BD. Objectives We thereby present the protocol of this pilot study and future preliminary data. We aim to longitudinally assess sleep alterations, mood fluctuations, and environmental exposure to several factors (air pollutants, climate, noise, artificial light-at-night, green space access) in patients with BD and to check the association of these variables with BD relapses. Methods In this pilot study, we will recruit 40 patients with BD in a 6-month prospective study. Patients were assessed during baseline, at 3 and 6 months. Data recollected will consist of a subjective (questionnaires) and objective (through meteorological stations) evaluation of physical environmental factors around the home residence; clinical assessment of mood and circadian rhythms, and continuous tracking of sleep-wake patterns, energy, and movement using actigraphy. Results Expected results will show that exposure to a worse environment (higher pollution, noise, light exposure, climate) will be associated with worse BD outcomes (i.e., relapse, mood symptoms, sleep alterations). Conclusions We will be sharing preliminary data from our ongoing study, offering insights into early patterns and findings that shed light on our objectives. Disclosure of Interest None Declared

Introduction Bipolar disorder (BD) is a multifaceted illness encompassing mood, energy, cognitive and biorhythms alterations. Sleep disturbances are common in prodromic, acute and inter-episodic phases of BD. Suicidality presents a known association with sleep disturbances. However, their interplay in BD remains intricate and not fully elucidated. Objectives The aim of the present systematic review (SR) and meta-analysis (MA) is to summarise the available evidence and to provide an estimate of the association between sleep disturbances and suicidality, defined as presence of suicide ideation, behaviour and suicide attempts, in patients with BD. Methods We conducted a comprehensive literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines across PubMed, PsycINFO, and SCOPUS databases. We included all studies reporting an association between sleep problems and suicidal behaviour in BD patients. No language restriction was imposed. Effect sizes were calculated as odds ratio (OR) for dichotomic variables, standard mean difference (SMD) for continuous outcomes, and Spearman’s coefficient (r) for correlations. Heterogeneity was assessed using the I2 statistic. Global inconsistency was evaluated using the Q statistics with the corresponding p-value. Results The initial search yielded 911 unique abstracts, of which 62 underwent full-text screening. Fourteen publications were included, comprising twelve cross-sectional and two longitudinal studies. The total sample consisted of 19,601 subjects diagnosed with BD, of which 51.76% were females and 69.52% had a diagnosis of BD type 1. We found that people with BD and sleep disturbances tend to have higher suicidality, both current (SMD=0.79, 95%CI=0.53, 1.05) and lifetime (OR=1.8; 95%CI=1.41, 2.55), when compared with people with BD and no sleep disturbances. Additionally, patients with BD and a history of suicide attempts tend to have more sleep problems (OR=1.37, 95%CI=1.21, 1.55). Moreover, a positive correlation exists between suicidality and poor sleep quality measured by the Pittsburgh Sleep Quality Index (PSQI) (r= 0.24, 95%CI=0.10, 0.36). No heterogeneity was found, except in the subanalysis of correlation (I2=66.67%, Q p-value=0.01). Conclusions Our SRMA outlines a positive relation between sleep disturbances and suicidality in patients with BD. The small number of included studies and the scarcity of longitudinal studies, preventing the inference of a causal relationship, represent the major limitations of this study. Also, studies with objective measures of sleep alterations are currently lacking. The prompt recognition, objective measurement, and treatment of sleep alterations could be crucial in averting or reducing suicidal attempts in BD. Disclosure of Interest C. Possidente: None Declared, M. Bort: None Declared, M. De Prisco: None Declared, V. Oliva: None Declared, G. Fico Grant / Research support from: Fellowship from “La Caixa” Foundation (ID 100010434 - fellowship code LCF/BQ/DR21/11880019), L. Bracco: None Declared, C. Sommerhoff: None Declared, L. Montejo: None Declared, A. Murru Grant / Research support from: Spanish Ministry of Science and Innovation (PI19/00672, PI22/00840) integrated into the Plan Nacional de I+D+I and co-financed by the ISCIII-Subdireccion General de Evaluacio ́n and the Fondo Europeo de Desarrollo Regional (FEDER), E. Vieta Grant / Research support from: Spanish Ministry of Science and Innovation (PI18/ 00805, PI21/00787) integrated into the Plan Nacional de I+D+I and cofinanced by the ISCIII-Subdireccio ́n General de Evaluacio ́n and the Fondo Europeo de Desarrollo Regional (FEDER); the Instituto de Salud Carlos III; the CIBER of Mental Health (CIBERSAM); the Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2017 SGR 1365), the CERCA Programme, and the Departament de Salut de la Generalitat de Catalunya for the PERIS grant SLT006/17/00357; the European Union Horizon 2020 research and innovation program (EU.3.1.1. Understanding health, wellbeing and disease: Grant No 754907 and EU.3.1.3. Treating and managing disease: Grant No 945151).

The majority of human diseases attributed to seafood are caused by Vibrio spp. and the most commonly reported species are Vibrio parahaemolyticus, Vibrio vulnificus, and Vibrio cholerae. The conventional methods for the detection of Vibrio species involve the use of selective media, which are inexpensive and simple but time-consuming. The present work aimed to develop a rapid method based on the use of multiplex real-time polymerase chain reaction (PCR) to detect V. parahaemolyticus, V. vulnificus, and V. cholerae in bivalve mollusks. 30 aliquots of bivalve mollusks (Mytilus galloprovincialis) were experimentally inoculated with two levels of V. parahaemolyticus, V. vulnificus, and V. cholerae. ISO 21872-1:2017 was used in parallel for qualitative analysis. The limit of detection of 50% was 7.67 CFU/g for V. cholerae, 0.024 CFU/g for V. vulnificus, and 1.36 CFU/g for V. parahaemolyticus. For V. vulnificus and V. cholerae, the real-time PCR protocol was demonstrated to amplify the pathogens in samples seeded with the lowest and highest levels. The molecular method evaluated showed a concordance rate of 100% with the reference microbiological method. V. parahaemolyticus was never detected in samples contaminated with the lowest level, and it was detected in 14 samples (93.33%) seeded with the highest concentration. In conclusion, the multiplex real-time PCR developed proved to be reliable for V. vulnificus and V. cholerae. Results for V. parahaemolyticus are promising, but further analysis is needed. The proposed method could represent a quick monitoring tool and, if used, would allow the implementation of food safety.