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Abstract Background Lithium is one of the most consistently effective treatment for mood disorders. However, patients may show a high level of heterogeneity in treatment response across the lifespan. In particular, the benefits of lithium use may vary in special clinical conditions. The aim of this study was to test this hypothesis by conducting an umbrella review on the efficacy and safety of lithium in childhood and adolescence, peripartum and old age. Methods We applied the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria (PRISMA) to identify systematic reviews/meta-analyses on the efficacy and/or safety of lithium in mood disorders in special clinical conditions: (i) childhood and adolescence; (ii) peripartum (pregnancy, postpartum and lactation); (iii) old age. The Risk of Bias Assessment Tool for Systematic Reviews (ROBIS) tool was used to assess the risk of bias. Overlap in primary studies across systematic reviews was calculated through the Corrected Covered Area (CCA). Results We included 20 independent studies, for a total of 8209 individuals treated with lithium. Regarding paediatric age, efficacy and safety results suggested that lithium may be superior to placebo in bipolar disorders (BD) and not associated with serious adverse events. Nevertheless, primary available data are very limited. Efficacy in paediatric major depressive disorder (MDD) is not clear. During peripartum, lithium use was superior to non-lithium in preventing mood episodes and it was associated with low risk of congenital anomalies and with normal child neurodevelopment. Regarding old age, limited evidence supported lithium as an effective treatment in BD and resistant MDD; low doses should be used in this population. Systematic reviews on paediatric age showed the lowest risk of bias (80% of the studies at low risk). The CCA range of included studies was 13–47%. Conclusions This umbrella review supports the use of lithium across the lifespan, including special clinical condition. Nevertheless, more studies with increased methodological homogeneity are needed.

A library of substituted indolo[2,3-c]quinolone-6-ones was developed as simplified Lamellarin isosters. Synthesis was achieved from indole after a four-step pathway sequence involving iodination, a Suzuki-Miyaura cross-coupling reaction, and a reduction/lactamization sequence. The inhibitory activity of the 22 novel derivatives was assessed on Haspin kinase. Two of them possessed an IC50 of 1 and 2 nM with selectivity towards a panel of 10 other kinases including the parent kinases DYRK1A and CLK1. The most selective compound exerted additionally a very interesting cell effect on the osteosarcoma U-2 OS cell line.

Introdução: No início do ano de 2020, o mundo foi exposto a pandemia de COVID-19, sendo o distanciamento social uma das medidas preventivas para controlar a disseminação da doença. A pandemia e o distanciamento social geraram diversas implicações na rotina habitual da população, dentre elas, modificações nos hábitos alimentares. Objetivo: Avaliar o consumo alimentar de estudantes universitários durante o período de distanciamento social e analisar a sua relação com percepções corporais e emocionais. Materiais e Métodos: Pesquisa transversal realizada com 445 universitários de Guarapuava-PR de ambos os sexos. A coleta de dados ocorreu através de questionário on-line, com questões sociais, emocionais, alimentares, satisfação com o corpo, sentimentos e ingestão semanal de alimentos. Resultados: Houve prevalência do sexo feminino 81,2% e idade entre 18 e 21 anos. Comparando o consumo dos alimentos antes e durante a pandemia, foi observado alterações significantes no consumo de chocolates. Com relação aos sentimentos e imagem corporal, quem consumia mais alimentos ultraprocessados apresentavam-se estressados, ansiosos, cansados e insatisfeitos com o corpo. Por outro lado, quem se apresentava tranquilo, disposto e satisfeito com o corpo, aumentou o consumo de frutas e verduras. Conclusão: O consumo alimentar teve relações significativas com as emoções e percepção corporal dos universitários analisados durante o período de distanciamento social.

Abstract Background Use of social media (SM) has exponentially grown particularly among youths in the past two years, due to COVID-19-related changing lifestyles. Based on the Italian COvid Mental hEalth Trial (COMET), we investigated the association between SM use and depressive symptoms among Italian young adults (aged 18–24). Methods The COMET is a nationwide multi-center cross-sectional study that investigated socio-demographic data, social networking addiction (BSNAS), depression, anxiety, and stress (DASS-21), as well as impulsiveness (BIS-15) and aggressiveness (AQ) in a large sample of youngsters, in order to assess the association between BSNAS and DASS-21 indices. Mediation analyses were performed to evaluate the role of impulsiveness and aggressive personality traits in the association between SM use (SMU) and depression. Results 75.8% of the sample (n = 491) had a problematic SMU. SMU was reduced by high AQ and high DASS-21 scores (F = 42.338, p

Objectives: In this study, we aimed to characterize the SARS-CoV-2-specific T cell response detected by the QuantiFERON SARS-CoV-2 research use only assay in terms of accuracy and T cell subsets involved compared with a homemade interferon (IFN)-γ release assay (IGRA).Methods: We evaluated T cell response by the standardized QuantiFERON SARS-CoV-2 tubes (antigen [Ag]1 and Ag2) and a homemade IGRA quantifying IFN-γ response to SARS-CoV-2 spike peptides (homemade-IGRA-SPIKE test). We evaluated the T cell subsets mediating the specific response using flow cytometry.Results: We prospectively enrolled 66 individuals: COVID-19 or post-COVID-19 subjects and NO-COVID-19-vaccinated subjects, including healthy donors and immunocompromised subjects. The standardized kit detected 62.1% (41/66) of T cell responders. Ag2 tube showed a higher IFN-γ quantitative and qualitative response. Ag1 tube response was mainly mediated by CD4+ T cells; Ag2 tube response was mediated by CD4+ and CD8+ T cells. The homemade-IGRA-SPIKE test detected a higher number of responders (52/66, 78.8%) than the QuantiFERON SARS-CoV-2 assay (P = 0.056). The response was found in both T cell subsets, although a higher magnitude and response rate was observed in the CD4+ T cell subset.Conclusion: The QuantiFERON SARS-CoV-2 response is mediated by CD4+ and CD8+ T cells. A lower number of responders is found compared with the homemade-IGRA-SPIKE test, likely because of the different peptide composition.

On January 30, 2020, the World Health Organization (WHO) declared the status of pandemic due to the COVID-19 infection. The initial phases of the pandemic were characterized by uncertainty and public fears. In order to cope with such unexpected conditions, people adopted different coping strategies, including search for information, accessing Internet, and using social media. The present study based on the COMET collaborative research network aims to: (1) assess use of Internet and of social media among the Italian general population; (2) explore differences in web usage between people with pre-existing mental disorders and the general population; (3) identify changes over time in social media usage along the phase 1 of the pandemic; (4) identify the clinical, socio-demographic and contextual predictors of excessive use of social media. A significant increase in time spent on Internet, with an average time of 4.8 ± 0.02 h per day, was found in the global sample of 20,720 participants. Compared with the general population, Internet use was significantly higher in people with pre-existing mental disorders (5.2 ± 0.1 h vs. 4.9 ± 0.02; p

Objective To assess the feasibility of the family paediatrician’s (FP) role in identifying the signs of postpartum depression in parents in time to guarantee child well-being.Design, setting and participants Data for this observational prospective study were collected within the NASCITA (NAscere e creSCere in ITAlia) cohort. During the first visit, paediatricians collected sociodemographic data regarding the parents and information about their health status, the pregnancy and the delivery. Whooley questions were administered during the first and second visits (scheduled 60–90 days after childbirth). Moreover, on the third visit (5–7 months after childbirth) the FP was asked to answer ‘yes’ or ‘no’ to a question on the parental postpartum depression, based on his knowledge and on the acquired information.Results In 2203 couples who completed the assessment, 529 mothers (19.9%), 141 fathers (6.3%) and 110 (5%) couples reported any depressive symptomatology. Of these, 141 mothers (5.3% of the total sample) and 18 fathers (0.8% of the total sample) were classified as ‘likely depressed’. An association was found between maternal postnatal depressive symptoms and having a diagnosed psychiatric disorder during pregnancy (OR 9.49, 95% CI: 3.20 to 28.17), not exclusively breastfeeding at hospital discharge (OR 1.76, 95% CI: 1.19 to 2.61) and the presence of child sleeping disorders at 3 (OR 2.46, 95% CI: 1.41 to 4.28) and 6 months (OR 2.18, 95% CI: 1.37 to 3.47). Another significant predictor of postpartum depression was being primiparous (OR 1.99, 95% CI: 1.31 to 3.02). Concerning the fathers, a significant association was reported only between likely depressed fathers and child sleeping disorders at 3 months (OR 7.64, 95% CI: 2.92 to 19.97). Moreover, having a likely depressed partner was strongly associated with depressive symptoms in fathers (OR 85.53, 95% CI 26.83 to 272.69).Conclusions The findings of this study support the feasibility of an active screening programme for parental postnatal depression during well-child visits as an integral part of postpartum care.Trial registration number NCT03894566; Pre-results.

Hypercholesterolemia plays a crucial role in the formation of lipid plaques, particularly with elevated low-density lipoprotein (LDL-C) levels, which are linked to increased risks of cardiovascular disease, cerebrovascular disease, and peripheral arterial disease. Controlling blood cholesterol values, specifically reducing LDL-C, is widely recognized as a key modifiable risk factor for decreasing the morbidity and mortality associated with cardiovascular diseases. Historically, statins, by inhibiting the enzyme β-hydroxy β-methylglutaryl-coenzyme A (HMG)-CoA reductase, have been among the most effective drugs. However, newer non-statin agents have since been introduced into hypercholesterolemia therapy, providing a viable alternative with a favorable cost–benefit ratio. This paper aims to delve into the latest therapies, shedding light on their mechanisms of action and therapeutic benefits.

Background: This case report outlines the presentation of an emerging complication arising from left bundle branch area pacing (LBBAP). Case summary: A 43-year-old male with no history of cardiac problems experienced recurrent episodes of syncope with no prodromal symptoms. During monitoring in the emergency department, the patient underwent an episode of asystole, leading to LBBAP implantation. The procedure encountered technical challenges, resulting in an interventricular septal hematoma and subsequent ventricular arrhythmias. Despite initial concerns, conservative management led to resolution, demonstrated through echocardiographic follow-ups. Discussion: This report underscores the significance of ventricular arrhythmias as indicators of interventricular septal hematoma, providing insights into its diagnosis, management, and implications for LBBAP procedures.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Huntington's disease manifest with the neuronal accumulation of toxic proteins. Since autophagy upregulation enhances the clearance of such proteins and ameliorates their toxicities in animal models, we and others have sought to re-position/re-profile existing compounds used in humans to identify those that may induce autophagy in the brain. A key challenge with this approach is to assess if any hits identified can induce neuronal autophagy at concentrations that would be seen in humans taking the drug for its conventional indication. Here we report that felodipine, an L-type calcium channel blocker and anti-hypertensive drug, induces autophagy and clears diverse aggregate-prone, neurodegenerative disease-associated proteins. Felodipine can clear mutant α-synuclein in mouse brains at plasma concentrations similar to those that would be seen in humans taking the drug. This is associated with neuroprotection in mice, suggesting the promise of this compound for use in neurodegeneration.

We evaluated the clinical impact, in daily clinical practice, of sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1RA) therapies in patients with type 2 diabetes. Data from 500 unselected consecutive patients were retrospectively analyzed. Only those with a full assessment at baseline (T0) and after 3 (T3), 6 (T6), and 12 (T12) months of treatment with SGLT2i or GLP1RA were included in the study (n = 167). At baseline, patients had a high mean body weight (BW), abdominal circumference (AC), body mass index (BMI), and HOMA index. Despite normal C-peptide values, 39 patients were being treated with insulin (up to 120 IU/day). During therapy, a progressive improvement in BW, BMI, and AC was observed with both the molecules. Fasting glucose and glycated Hb decrease was already significant at T3 in all patients, while the HOMA index selectively improved with SGLT2i therapy. Renal function parameters remained stable regardless of the drug used. Finally, SGLT2i reduced serum uric acid and improved the lipid profile, while GLP1RA reduced serum levels of liver enzymes. Both the therapeutic regimens allowed a significant reduction or complete suspension of unnecessary insulin therapies. Our real life data confirm the results obtained from randomized clinical trials and should be taken as a warning against inappropriate use of insulin in patients with preserved β-cell function.

Introduction The COVID-19 outbreak and the related containment measures led to the emergence of psychological distress in youth populations, possibly due to concern for their families, social isolation, increased time spent on the Internet and social media, and anxiety about the future. Objectives The study aims to evaluate differences in the access of children, adolescents, and young adults to a psychiatric emergency setting before and after the onset of the COVID-19 pandemic. Methods Data concerning the psychiatric consultations carried out at the Emergency Department of the University Hospital of Perugia was collected. Socio-demographic and clinical information, including diagnostic and treatment features, was entered into an electronic database. We considered two different time spans, one before (01.06.2017-31.12.2018) and one after (01.06.2020-31.12.2021) the COVID-19 pandemic outbreak. The characteristics of consultations carried out before and after the pandemic outbreak were compared by means of bivariate analyses (p

Introduction The use of diagnostic categories, although useful, fails in capturing the psychopathological complexity of the individual case. As for schizophrenia spectrum disorders, positive symptoms are not always included in the presentation, so further dimensions should be considered for a correct diagnosis. Objectives To describe the importance of dimensional diagnosis in schizophrenia spectrum disorder based on a clinical experience Methods We report the case of a late-onset schizophrenia spectrum disorder with an affective presentation Results I. is a 44-year-old woman who accessed the Community Mental Health Center due to subjective memory complains. After clinical evaluation, depressive symptoms and circadian rhythm disturbances emerged. The patient also reported dissociative experiences, which emerged after her brother’s death. She underwent a neurological visit that excluded the possible early manifestation of a neurodegenerative disorder. Quetiapine was at first prescribed, due to the possible action on both insomnia and mood symptoms, with insufficient response. After a few visits, a deeper mental state examination revealed the presence of delusions. The patient also reported having experienced hallucinations. Psychotic symptoms appeared to be persistent and pervasive. We changed the antipsychotic to full-dose olanzapine, with good response. After a six-month observation, the patient was diagnosed with schizophrenia. Conclusions The diagnosis of late-onset schizophrenia should take into account clinical history, drugs response, and the evaluation of different psychopathological dimensions Disclosure of Interest None Declared

Introduction Suicide is the fourth leading cause of death among adolescents and young adults (AYA) (Czyz EK, King CA. J Clin Child Adolesc Psychol.2015;44(1):181-19), and psychiatric disorders are a major contributing factor (WHO Global Health Estimates 2000-2019). Studies focusing on suicidality in Italian inpatients samples are scant. Objectives The present cross-sectional study aimed to define clinical variables associated with suicidality related phenomena in a sample of young inpatients. The main objectives were to assess the prevalence of suicidal ideation and deliberate self-harm in inpatients aged 16–24 years and to determine the relationship between suicidal behaviours and psychiatric disorders. Methods This retrospective study was conducted in a naturalistic setting, at the Psychiatric Inpatient Unit, Perugia Hospital/Local Mental Health Unit 1, from January 2018 to December 2019. Sociodemographic information, clinical history, diagnostic and treatment features were collected. Descriptive and bivariate analyses were performed (p

Introduction ADHD is a neurodevelopmental disorder that occurs in childhood and can persist in adulthood in a percentage of cases ranging from 15% to 70% (Cheung, C. H. et al. J. Psychiatr. Res. 2005; 62, 92–100). In these cases, if not treated, ADHD symptoms can cause severe dysfunction (Biederman, J., et al. Am. J. Psychiatry 2000; 157(5), 816–818) often leading to misdiagnosis. Objectives The aim of this case report is to describe the clinical picture of a 26-year-old boy with ADHD and the consequences deriving from the missed diagnosis of the disorder during childhood. Methods We report a case of undiagnosed and untreated ADHD and the ensuing consequences. Results G.V. is a boy who came to our attention complaining about a vague depressive symptomatology. After psychopathological examination we detected mood instability, with the alternance of phases characterized by deep despair and melancholy and phases of agitation with internal tension and generalized anxiety. He reported a tendency to act on an impulsive basis and an occasional abuse of cocaine together with a daily abuse of high doses of Alprazolam. During the past years the boy had been visited by several psychiatrists who made various diagnoses (borderline or avoidant personality disorder, cyclothymic disorder) and prescribed various drugs but none of these were able to stabilize the psychopathological condition. The clinical history revealed the presence of a pervasive picture of inattention and hyperactivity since childhood which had heavily conditioned the patient’s functioning over time. The inattentive pattern has persisted unchanged over the years, while the hyperactive one has improved leaving room for a stable sense of internal tension and generalized anxiety on which mood fluctuations are cyclically inscribed. A diagnosis of ADHD, combined presentation type, was made by using the DIVA-5. The patient was first prescribed lithium, which was subsequently replaced with valproic acid. After mood stabilization and the reduction of anxious symptoms prolonged-release methylphenidate was added to therapy, obtaining resolution of the clinical picture. Conclusions Almost all adults with ADHD exhibit a lifelong pattern of frequent mood swings and irritability. Given that many mental health practitioners are unfamiliar with emotional lability in adult ADHD, a bipolar, or cluster B/C personality disorder is more likely to be considered as the cause of the mood swings (Fayyad, J. et al. BJPsych 2007; 190, 402–409). An accurate collection of clinical history can guide the diagnosis and help to address adequate treatment. Disclosure of Interest None Declared

Introduction Circadian rhythms, defined as endogenous oscillations that regulate metabolism, physiology and behaviour, may be frequently disrupted in mood disorders, influencing their clinical presentation and course (Srinivasan V. et al. World J Biol Psychiatry. 2006;7(3):138-151). Objectives To characterise circadian rhythm disruptions in a population of patients with mood disorders, analysing clinical and course differences in subjects with and without clinically significant circadian rhythm alterations Methods Patients selected for this cross-sectional study were assessed with CGI-BP, HAM-D, MRS, and PANSS. Circadian rhythm disturbances were evaluated with BRIAN. Patients with clinically relevant circadian rhythm disturbances were defined as BRIAN > 36 (Mondin TC et al. J Psychiatr Res. 2017;84:98-104). Bivariate analyses were subsequently performed to compare subgroups of patients. Results In our study, 61 subjects with DD or DB were enrolled. The overall mean BRIAN test score was 40.08 ± 10.26. When comparing the BRIAN test scores, both total and subscales, between subjects with DB and DD, social rhythms were significantly more altered in subjects with DB (8.63 ± 2.90 VS 6.80 ± 2.11, p=0.034). Subjects with disruption of circadian rhythms displayed greater severity of depressive symptoms (mean total HAM-D test score 16.06±8.61 VS 8.94±5.85; p

The currently available nebulization devices have a slow aerosol flow and produce vapor with large microdrops. Improved devices that achieve higher airflow and produce smaller microdrops are needed to improve the clinical care of patients. To address this critical need, we developed a novel system for the molecular vaporization of liquids. This device vaporizes an active pharmacological substance dissolved in water, alcohol, or a mixture of water and alcohol using two energy sources at the same time: high-frequency ultrasound and thermal induction. Application of energy to a solution contained in the device’s tank allows, within tens of seconds, for the vaporization of the solution itself, with the generation of a vapor consisting of microdrops of very small diameter (0.2–0.3 μm). In this article, we illustrate the technology used, the main verification tests performed, and the primary fields of application for this device. In particular, the advantages of both the aerosol delivery system and the administration system are highlighted.

A panel of neutralizing human monoclonal antibodies targeting human cytomegalovirus offers a combination approach geared toward virus entry and replication to prevent viral dissemination.

Quality assurance through visual inspection plays a pivotal role in agriculture. In recent years, deep learning techniques (DL) have demonstrated promising results in object recognition. Despite this progress, few studies have focused on assessing human visual inspection and DL for defect identification. This study aims to evaluate visual human inspection and the suitability of using DL for defect identification in products of the floriculture industry. We used a sample of defective and correct decorative wreaths to conduct an attribute agreement analysis between inspectors and quality standards. Additionally, we computed the precision, accuracy, and Kappa statistics. For the DL approach, a dataset of wreath images was curated for training and testing the performance of YOLOv4-tiny, YOLOv5, YOLOv8, and ResNet50 models for defect identification. When assessing five classes, inspectors showed an overall precision of 92.4% and an accuracy of 97%, just below the precision of 93.8% obtained using YOLOv8 and YOLOv5 with accuracies of 99.9% and 99.8%, respectively. With a Kappa value of 0.941, our findings reveal an adequate agreement between inspectors and the standard. The results evidence that the models presented a similar performance to humans in terms of precision and accuracy, highlighting the suitability of DL in assisting humans with defect identification in artisanal-made products from floriculture. Therefore, by assisting humans with digital technologies, organizations can embrace the full potential of Industry 4.0, making the inspection process more intelligent and reliable.

Dopamine neurotransmission plays critical roles in regulating complex cognitive and behavioral processes including reward, motivation, reinforcement learning, and movement. Dopamine receptors are classified into five subtypes, widely distributed across the brain, including regions responsible for motor functions and specific areas related to cognitive and emotional functions. Dopamine also acts on astrocytes, which express dopamine receptors as well. The discovery of direct receptor–receptor interactions, leading to the formation of multimeric receptor complexes at the cell membrane and providing the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction, has expanded the knowledge of the G-protein-coupled receptor-mediated signaling processes. The purpose of this review article is to provide an overview of currently identified receptor complexes containing dopamine receptors and of their modulatory action on dopamine-mediated signaling between neurons and between neurons and astrocytes. Pharmacological possibilities offered by targeting receptor complexes in terms of addressing neuropsychiatric disorders associated with altered dopamine signaling will also be briefly discussed.

Purpose: This article identifies the association between two methods for teaching lean manufacturing (LM): problem-based learning (PBL) and classroom lectures, and students' learning styles of a postgraduate course. Design/methodology/approach: Data were collected from graduate students LM courses that present different teaching approaches. Thus, students' learning preferences were gathered through the application of the Index of Learning Style questionnaire, and their performance assessed after each course. Findings: Results indicate that learning styles are indeed associated with LM teaching approaches, and comprehending interaction effects between learning style dimensions is essential for properly adapting the teaching method. However, these interactions have different extensions. Originality/value: Although teaching LM has significantly evolved over the past decades, the single application of traditional teaching methods jeopardizes learning effectiveness of graduate students because of the practical nature of LM. This study provides evidence to better understand the effect of complementary teaching methods and their relationship with students' preferences, empirically examining that there is not one best approach for understanding LM.

On-chip deep neural network (DNN) inference and training at the Extreme-Edge (TinyML) impose strict latency, throughput, accuracy, and flexibility requirements. Heterogeneous clusters are promising solutions to meet the challenge, combining the flexibility of DSP-enhanced cores with the performance and energy boost of dedicated accelerators. We present DARKSIDE, a System-on-Chip with a heterogeneous cluster of eight RISC-V cores enhanced with 2-b to 32-b mixed-precision integer arithmetic. To boost the performance and efficiency on key compute-intensive DNN kernels, the cluster is enriched with three digital accelerators: 1) a specialized engine for low-data-reuse depthwise convolution kernels (up to 30 MAC/cycle); 2) a minimal overhead datamover to marshal 1–32-b data on-the-fly; and 3) a 16-b floating-point tensor product engine (TPE) for tiled matrix-multiplication acceleration. DARKSIDE is implemented in 65-nm CMOS technology. The cluster achieves a peak integer performance of 65 GOPS and a peak efficiency of 835 GOPS/W when working on 2-b integer DNN kernels. When targeting floating-point tensor operations, the TPE provides up to 18.2 GFLOPS of performance or 300 GFLOPS/W of efficiency—enough to enable on-chip floating-point training at competitive speed coupled with ultralow power quantized inference.

Cartilage organoids have emerged as powerful modelling technology for recapitulation of joint embryonic events, and cartilage regeneration, as well as pathophysiology of cartilage-associated diseases. Recent breakthroughs have uncovered “mini-joint” models comprising of multicellular components and extracellular matrices of joint cartilage for development of novel disease-modifying strategies for personalized therapeutics of cartilage-associated diseases. Here, we hypothesized that LGR5-expressing embryonic joint chondroprogenitor cells are ideal stem cells for the generation of cartilage organoids as “mini-joints” ex vivo “in a dish” for embryonic joint development, cartilage repair, and cartilage-associated disease modelling as essential research models of drug screening for further personalized regenerative therapy. The pilot research data suggested that LGR5-GFP-expressing embryonic joint progenitor cells are promising for generation of cartilage organoids through gel embedding method, which may exert various preclinical and clinical applications for realization of personalized regenerative therapy in the future.

Abstract The high mortality rate of patients with diabetic foot ulcers is urging the appearance of an effective biomedical drug. Senescence is one of the major reasons of aging‐induced decline in the diabetic wound. Our previous studies have demonstrated the anti‐senescence effect of secretomes derived from human fetal mesenchymal stem cells (hfMSC). The present study tends to explore the potential role of hfMSC secretome (HFS) in wound healing through anti‐aging. Meanwhile, we try to overcome several obstacles in the clinical application of stem cell secretome. A verticle bioreactor and microcarriers are employed to expand hfMSC and produce the HFS on a large scale. The HFS was then subjected to lyophilization (L‐HFS). The PLGA (poly lactic‐co‐glycolic acid) particles were used to encapsulate and protect L‐HFS from degradation in the streptozotocin (STZ)‐induced diabetic rat model. Results showed that HFS‐PLGA significantly enhanced wound healing by promoting vascularization and inhibiting inflammation in the skin wound bed. We further analyzed the contents of HFS. Isobaric tag for relative and absolute quantitation (ITRAQ) and label‐free methods were used to identify peptides in the secretome. Bioinformatics analysis indicated that exosome production‐related singling pathways and heat‐shock protein family could be used as bio‐functional markers and quality control for stem cell secretome production.

Bipolar disorder (BD) is a common, highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. Lithium is the best-established long-term treatment for BD, even though individual response is highly variable. Evidence suggests that some of this variability has a genetic basis. This is supported by the largest genome-wide association study (GWAS) of lithium response to date conducted by the International Consortium on Lithium Genetics (ConLiGen). Recently, we performed the first genome-wide analysis of the involvement of miRNAs in BD and identified nine BD-associated miRNAs. However, it is unknown whether these miRNAs are also associated with lithium response in BD. In the present study, we therefore tested whether common variants at these nine candidate miRNAs contribute to the variance in lithium response in BD. Furthermore, we systematically analyzed whether any other miRNA in the genome is implicated in the response to lithium. For this purpose, we performed gene-based tests for all known miRNA coding genes in the ConLiGen GWAS dataset (n = 2,563 patients) using a set-based testing approach adapted from the versatile gene-based test for GWAS (VEGAS2). In the candidate approach, miR-499a showed a nominally significant association with lithium response, providing some evidence for involvement in both development and treatment of BD. In the genome-wide miRNA analysis, 71 miRNAs showed nominally significant associations with the dichotomous phenotype and 106 with the continuous trait for treatment response. A total of 15 miRNAs revealed nominal significance in both phenotypes with miR-633 showing the strongest association with the continuous trait (p = 9.80E-04) and miR-607 with the dichotomous phenotype (p = 5.79E-04). No association between miRNAs and treatment response to lithium in BD in either of the tested conditions withstood multiple testing correction. Given the limited power of our study, the investigation of miRNAs in larger GWAS samples of BD and lithium response is warranted.

Antibody-mediated central nervous system (CNS) disorders including those associated with aquaporin-4 or myelin oligodendrocyte glycoprotein IgG and autoimmune encephalitis often affect women of childbearing age. Pathogenic antibodies of these diseases can potentially alter reproductive functions and influence fetal development. Hormonal changes occurring during pregnancy may modify the course of autoimmune diseases by influencing relapse risk, attack severity, and affect the delivery and postpartum period. Moreover, balancing treatment related safety issues with the risk of potentially disabling relapses during pregnancy and breastfeeding are major challenges. Intentional prenatal, gestational, and post-partum counseling is paramount to address these issues and mitigate these risks. Fortunately, new insights on risk factors for adverse pregnancy outcomes and possible preventive strategies are emerging. This review aims to summarize the interplay between antibody-mediated CNS disorders and pregnancy during the prenatal, gestational, and postpartum periods, highlight current treatment recommendations, and discuss future areas of research.

Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS).We found that the integrin α5β1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide (Iso4). The GNRs@Chit-Iso4 was stable in urine and selectively recognized α5β1 positive neoplastic urothelium, while low frequency ultrasound-assisted shaking of intravesically instilled GNRs@Chit-Iso4 allowed the distribution of nanoparticles across the entire volume of the bladder. Photoacoustic imaging of GNRs@Chit-Iso4 bound to tumor cells allowed for the detection of neoplastic lesions smaller than 0.5 mm that were undetectable by ultrasound imaging and bioluminescence.

Abstract Lithium is the gold standard therapy for Bipolar Disorder (BD) but its effectiveness differs widely between individuals. The molecular mechanisms underlying treatment response heterogeneity are not well understood, and personalized treatment in BD remains elusive. Genetic analyses of the lithium treatment response phenotype may generate novel molecular insights into lithium’s therapeutic mechanisms and lead to testable hypotheses to improve BD management and outcomes. We used fixed effect meta-analysis techniques to develop meta-analytic polygenic risk scores (MET-PRS) from combinations of highly correlated psychiatric traits, namely schizophrenia (SCZ), major depression (MD) and bipolar disorder (BD). We compared the effects of cross-disorder MET-PRS and single genetic trait PRS on lithium response. For the PRS analyses, we included clinical data on lithium treatment response and genetic information for n = 2283 BD cases from the International Consortium on Lithium Genetics (ConLi+Gen; www.ConLiGen.org ). Higher SCZ and MD PRSs were associated with poorer lithium treatment response whereas BD-PRS had no association with treatment outcome. The combined MET2-PRS comprising of SCZ and MD variants (MET2-PRS) and a model using SCZ and MD-PRS sequentially improved response prediction, compared to single-disorder PRS or to a combined score using all three traits (MET3-PRS). Patients in the highest decile for MET2-PRS loading had 2.5 times higher odds of being classified as poor responders than patients with the lowest decile MET2-PRS scores. An exploratory functional pathway analysis of top MET2-PRS variants was conducted. Findings may inform the development of future testing strategies for personalized lithium prescribing in BD.

Abstract Background Healthcare management faces complex challenges in allocating hospital resources, and predicting patients’ length-of-stay (LOS) is critical in effectively managing those resources. This work aims to map approaches used to forecast the LOS of Pediatric Patients in Hospitals (LOS–P) and patients’ populations and environments used to develop the models. Methods Using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) methodology, we performed a scoping review that identified 28 studies and analyzed them. The search was conducted on four databases (Science Direct, Scopus, Web of Science, and Medline). The identification of relevant studies was structured around three axes related to the research questions: (i) forecast models, (ii) hospital length-of-stay, and (iii) pediatric patients. Two authors carried out all stages to ensure the reliability of the review process. Articles that passed the initial screening had their data charted on a spreadsheet. Methods reported in the literature were classified according to the stage in which they are used in the modeling process: (i) pre-processing of data, (ii) variable selection, and (iii) cross-validation. Results Forecasting models are most often applied to newborn patients and, consequently, in neonatal intensive care units. Regression analysis is the most widely used modeling approach; techniques associated with Machine Learning are still incipient and primarily used in emergency departments to model patients in specific situations. Conclusions The studies’ main benefits include informing family members about the patient’s expected discharge date and enabling hospital resources’ allocation and planning. Main research gaps are associated with the lack of generalization of forecasting models and limited reported applicability in hospital management. This study also provides a practical guide to LOS–P forecasting methods and a future research agenda.

Abstract Bipolar affective disorder (BD) is a severe psychiatric illness, for which lithium (Li) is the gold standard for acute and maintenance therapies. The therapeutic response to Li in BD is heterogeneous and reliable biomarkers allowing patients stratification are still needed. A GWAS performed by the International Consortium on Lithium Genetics (ConLiGen) has recently identified genetic markers associated with treatment responses to Li in the human leukocyte antigens (HLA) region. To better understand the molecular mechanisms underlying this association, we have genetically imputed the classical alleles of the HLA region in the European patients of the ConLiGen cohort. We found our best signal for amino-acid variants belonging to the HLA-DRB1*11:01 classical allele, associated with a better response to Li (p

Abstract Keratinocytes, the main cell type of the skin, are one of the most exposed cells to environmental factors, providing a first defence barrier for the host and actively participating in immune response. In fact, keratinocytes express pattern recognition receptors that interact with pathogen associated molecular patterns and damage associated molecular patterns, leading to the production of cytokines and chemokines, including interleukin (IL)-6. Herein, we investigated whether mechanical energy transported by low intensity ultrasound (US) could generate a mechanical stress able to induce the release of inflammatory cytokine such IL-6 in the human keratinocyte cell line, HaCaT. The extensive clinical application of US in both diagnosis and therapy suggests the need to better understand the related biological effects. Our results point out that US promotes the overexpression and secretion of IL-6, associated with the activation of nuclear factor-κB (NF-κB). Furthermore, we observed a reduced cell viability dependent on exposure parameters together with alterations in membrane permeability, paving the way for further investigating the molecular mechanisms related to US exposure.

Purpose The NASCITA Study, a national-level, population-based, prospective cohort study, was set up to better understand the early health status of Italian children, comprising their physical, cognitive and psychological development, and how it is affected by social and health determinants, including nurturing care. NASCITA will also assess geographical differences and disparities in healthcare.Participants Participating family paediatricians from throughout Italy enrolled infants born during the enrolment period (April 2019–July 2020). The 5054 newborns seen by the 139 paediatricians for at least two visits, including the first well-child visit, and for whom parental consent was given, make up the baseline population.Findings to date Mothers had a mean age at delivery of 33.0 years and tended to have a high or medium level of education (42.5% university and 41.7% high school degrees) and to be employed (69.7%). One-third (36.1%) took folic acid supplementation appropriately, and 6.5% smoked or consumed alcohol (10.0%) during pregnancy. One-third (31.7%) of deliveries were caesarean deliveries. Concerning the newborns, 5.8% had a low birth weight and 6.2% were born prematurely. The majority (87.7%) slept in the supine position, and 63.6% were exclusively breast fed at 1 month, with a decreasing north to south prevalence (χ2t 52; p