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Fibrillary aggregation of α-synuclein in Lewy body inclusions and nigrostriatal dopaminergic neuron degeneration define Parkinson's disease neuropathology. Mutations in GBA1, encoding glucocerebrosidase, are the most frequent genetic risk factor for Parkinson's disease. However, the lack of reliable experimental models able to reproduce key neuropathological signatures has hampered the clarification of the link between mutant glucocerebrosidase and Parkinson's disease pathology. Here, we describe an innovative protocol for the generation of human induced pluripotent stem cell-derived midbrain organoids containing dopaminergic neurons with nigral identity that reproduce characteristics of advanced maturation. When applied to patients with GBA1-related Parkinson's disease, this method enabled the differentiation of midbrain organoids recapitulating dopaminergic neuron loss and fundamental features of Lewy body pathology observed in human brains, including the generation of α-synuclein fibrillary aggregates with seeding activity that also propagate pathology in healthy control organoids. Still, we observed that the retention of mutant glucocerebrosidase in the endoplasmic reticulum and increased levels of its substrate glucosylceramide are determinants of α-synuclein aggregation into Lewy body-like inclusions. Consistently, the reduction of glucocerebrosidase activity accelerated α-synuclein pathology by promoting fibrillary α-synuclein deposition. Finally, we demonstrated the efficacy of ambroxol and GZ667161 - two modulators of the glucocerebrosidase pathway in clinical development for the treatment of GBA1-related Parkinson's disease - in reducing α-synuclein pathology in this model, supporting the use of midbrain organoids as a relevant pre-clinical platform for investigational drug screening., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: The Italic Iron Age is characterized by the presence of various ethnic groups partially examined from a genomic perspective. To explore the evolution of Iron Age Italic populations and the genetic impact of Romanization, we focus on the Picenes, one of the most fascinating pre-Roman civilizations, who flourished on the Middle Adriatic side of Central Italy between the 9 th and the 3 rd  century BCE, until the Roman colonization., Results: More than 50 samples are reported, spanning more than 1000 years of history from the Iron Age to Late Antiquity. Despite cultural diversity, our analysis reveals no major differences between the Picenes and other coeval populations, suggesting a shared genetic history of the Central Italian Iron Age ethnic groups. Nevertheless, a slight genetic differentiation between populations along the Adriatic and Tyrrhenian coasts can be observed, possibly due to different population dynamics in the two sides of Italy and/or genetic contacts across the Adriatic Sea. Additionally, we identify several individuals with ancestries deviating from their general population. Lastly, in our Late Antiquity site, we observe a drastic change in the genetic landscape of the Middle Adriatic region, indicating a relevant influx from the Near East, possibly as a consequence of Romanization., Conclusions: Our findings, consistently with archeological hypotheses, suggest genetic interactions across the Adriatic Sea during the Bronze/Iron Age and a high level of individual mobility typical of cosmopolitan societies. Finally, we highlight the role of the Roman Empire in shaping genetic and phenotypic changes that greatly impact the Italian peninsula., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: The advent of artificial intelligence (AI) in microsurgery has tremendous potential in plastic and reconstructive surgery, with possibilities to elevate surgical precision, planning, and patient outcomes. This systematic review seeks to summarize available studies on the implementation of AI in microsurgery and classify these into subdomains where AI can revolutionize our field., Methods: Adhering to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a meticulous search strategy was used across multiple databases. The inclusion criteria encompassed articles that explicitly discussed AI's integration in microsurgical practices. Our aim was to analyze and classify these studies across subdomains for future development., Results: The search yielded 2377 articles, with 571 abstracts eligible for screening. After shortlisting and reviewing 86 full-text articles, 29 studies met inclusion criteria. Detailed analysis led to the classification of 6 subdomains within AI applications in microsurgery, including information and knowledge delivery, microsurgical skills training, preoperative planning, intraoperative navigational aids and automated surgical tool control, flap monitoring, and postoperative predictive analytics for patient outcomes. Each subtheme showcased the multifaceted impact of AI on enhancing microsurgical procedures, from preoperative planning to postoperative recovery., Conclusions: The integration of AI into microsurgery signals a new dawn of surgical innovation, albeit with the caution warranted by its nascent stage and application diversity. The authors present a systematic review and 6 clear subdomains across which AI will likely play a role within microsurgery. Continuous research, ethical diligence, and cross-disciplinary cooperation is necessary for its successful integration within our specialty., Competing Interests: The authors have no financial interest to declare in relation to the content of this article., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: People with HIV (PWH) are at increased risk of atherosclerotic cardiovascular disease (ASCVD). Lowering low-density lipoprotein cholesterol (LDL-C) is central of cardiovascular disease prevention. The aim of this study was to assess the prevalence, treatment, and control of high LDL-C levels as assessed on the basis of the ASCVD risk profiles indicated by European Society of Cardiology (ESC) guidelines of a cohort of PWH in order to evaluate the state of LDL-C management in current clinical practice., Methods: We retrospectively assessed the prevalence, treatment, and control of high LDL-C levels in a cohort of PWH aged ≥40 years who accessed our HIV outpatient clinic between 1 March 2022 and 31 March 2023. Their 10-year ASCVD risk was calculated on the basis of their age and co-morbidities as recommended by guidelines. High LDL-C levels were defined as those above the "step two" target of their specific ASCVD risk category., Results: Among the 1404 assessed PWH, who were prevalently male (74.5 %) and Caucasian (85.6 %), and had a median age of 56 years (interquartile range [IQR] 49-61), 295 (21 %) were at very high risk (VHR), 634 (45.2 %) at high-risk (HR), and 348 (24.8 %) not at HR. The overall median LDL-C level was 116 mg/dL (IQR 96-141). Five hundred and sixteen (37 %) were undergoing lipid lowering treatment (LLT), and 650 (46.3 %) failed to achieve any step of their target LDL-C levels., Conclusions: Despite the high prevalence of PWH at VHR/HR for ASCVD, LDL-C levels were poorly controlled and LLT was greatly under used., Competing Interests: Declaration of competing interest AG has received consultancy fees and speakers' honoraria from ViiV, Gilead, Janssen, MSD and Mylan, outside the present work. CG has received personal fees from MSD, ViiV, Gilead, and Janssen Cilag, outside the present work. SA has received support for research activities from Pfizer, ViiV, Gilead and Merck Sharp & Dome, outside the present work. APM has received personal fees for participating in committees of studies supported by Bayer, Novartis, Sanofi, and Astra Zeneca, outside the present work. GC, BC, LO, SC, SL, AP, SP, MLC, MB, GC, and ALR have nothing to declare., (Copyright © 2024. Published by Elsevier B.V.)

Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson's disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4-5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration., Competing Interests: Competing interests The authors declare no competing interests related to this article. B.A.G. provides consulting services for Natera, Inc. D.J.S. has received consultancy honoraria in the past 3 years from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda, and Vistagen. P.S. reports personal fees from Bial, AbbVie, and Boston Scientific. G.G. owns stocks in Koios Care (https://www.koios.care/) and has received consultancy fees from Abbvie Belgium, Zambon Belgium, and EG Belgium (Stada group). He also received an Honorarium from Abbvie Belgium, Zambon Belgium, and EG Belgium. J.W. has received Honoraria from the Movement Disorders Society. K.P. owns stocks in Amprion and Curasen. She has also received honoraria from invited scientific presentations to universities and professional societies not exceeding $5000/yr and provides consulting services to Curasen. J.K. has received Honoraria from Ipsen and Merz. Y.D.v.d.W. has received a speaker’s fee for postdoctoral training organized by Medilex and AbbVie., (© 2024. The Author(s).)

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a multisystemic, immune-mediated disease that occurs in patients with asthma and eosinophilia. It is characterized by inflammation of small- and medium-caliber blood vessels., Case Report: This report presents an unusual clinical case of EGPA with positive anti-neutrophil cytoplasmic antibodies who manifested bilateral pleural effusion. The diagnosis was confirmed through laboratory assessments and bronchial biopsies. The patient was treated with methylprednisolone showing improvement in symptoms., Conclusions: Our case appear interesting considering the limited evidence of pleural effusion in patients with EGPA documented in the literature.

Antidepressants are known for their neurotrophic effects, particularly through the regulation of brain-derived neurotrophic factor (BDNF) expression. Mirtazapine, a tetracyclic noradrenergic and specific serotonergic antidepressant (NaSSA) has been observed to upregulate BDNF, though its underlying mechanism remains unclear. In this study, we used the human neuroblastoma SH-SY5Y cell line to investigate whether mirtazapine could enhance BDNF translation by modulating serotonin and/or norepinephrine and their receptors. A 1-h stimulation with 1 or 10 µM mirtazapine led to downregulation of serotonergic receptors 5HT1A, while increasing ADRA2A and ADRB2 receptors. Mirtazapine at 10 µM upregulated endogenous BDNF after 3h, but not 1h stimulation. To investigate the translation of major BDNF transcripts, we used chimeric BDNF-luciferase constructs with the untranslated 5'UTR exons I, IIc, IV, or VI, and the long version of the 3'UTR. Luciferase assays and Western blotting revealed that mirtazapine selectively enhanced exon-IIc-BDNF-long3'UTR-Luciferase translation. This increase was associated with norepinephrine release and was inhibited by blocking ADRA2A or ADRB2 adrenoceptors for the exon-IIc-BDNF-long3'UTR-Luciferase, and ADR2B for endogenous BDNF. These findings provide a new perspective on the critical role of the noradrenergic system in mediating mirtazapine's effects on BDNF translation. We propose a novel mechanism of action in which mirtazapine promotes norepinephrine release and noradrenergic responses by upregulating ADRA2A and ADRB2 while downregulating serotonergic receptors., Competing Interests: Declarations Ethical Approval and Consent to Participate Not applicable. Consent for Publication Not applicable. Conflicts of Interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: To prevent the transfer of embryos affected by monogenic conditions and/or chromosomal defects, preimplantation genetic testing (PGT) requires trophectoderm biopsy and cryopreservation. In 2-6% of biopsies, the diagnosis may be inconclusive due to DNA amplification failure or low-quality results. In these cases, a round of re-warming, re-biopsy, and re-cryopreservation is required to obtain a genetic diagnosis. In other cases, when the IVF centre starts providing PGT and/or when the patients develop an indication because of multiple failures, miscarriages or the birth of an affected child after IVF, cryopreserved untested embryos may be warmed, biopsied, and then re-vitrified. However, it is still unclear whether multiple manipulations may reduce reproductive outcomes after PGT., Objective and Rationale: This study aimed at conducting a systematic review to investigate the available evidence on the safety of double biopsy and/or double cryopreservation-warming and provide recommendations in this regard. We performed meta-analyses of the differences in the reproductive outcomes (live birth per embryo transfer [LBR per ET], clinical pregnancy rate per ET [CPR per ET], and miscarriage rate per clinical pregnancy [MR per CP]) in double cryopreservation and single biopsy (CBC) or double biopsy and double cryopreservation (BCBC) flows vs the control single biopsy and single cryopreservation (BC) flow. Cryo-survival rates before ET and gestational and perinatal outcomes were also reported., Search Methods: PRISMA guidelines were followed to gather all available information from the literature (PubMed, Scopus, and Embase). We used Medical Subject Headings (MeSH) terms and a list of specific keywords relevant for the study question. We searched for original studies in humans, published in peer-reviewed journals in English up to April 2024. Four independent authors assessed the articles for inclusion. One included paper was retrieved from another source., Outcomes: A total of 4219 records were identified, and 10 studies were included in the meta-analysis. Certainty of evidence level ranged from low to moderate. Both the CBC and BCBC groups showed reduced reproductive outcomes compared to the control (BC). Specifically, live birth rates per embryo transfer were lower in the CBC group (OR: 0.56, 95% CI: 0.38-0.81, I2 = 58%; six studies) and the BCBC group (OR: 0.51, 95% CI: 0.34-0.77, I2 = 24%; six studies). CPR per ET were also lower in the CBC group (OR: 0.68, 95% CI: 0.51-0.92, I2 = 57%; seven studies) and the BCBC group (OR: 0.60, 95% CI: 0.46-0.78, I2 = 0%; seven studies). Additionally, MR per CPs were higher in both the CBC group (OR: 1.68, 95% CI: 1.02-2.77, I2 = 50%; seven studies) and the BCBC group (OR: 2.08, 95% CI: 1.13-3.83, I2 = 28%; seven studies). Cryo-survival as well as gestational and perinatal outcomes were within the expected norms in the studies reporting them., Wider Implications: Improved genetic technologies, standardization of laboratory protocols, operators' proficiency with biopsy and cryopreservation, and continuous monitoring of the performance are essential to minimize inconclusive diagnoses and the putative impact of additional embryo manipulations. Although poorer reproductive outcomes might result from double biopsy and/or double cryopreservations, these practices may still be worthwhile to avoid transferring affected/aneuploid blastocysts. Therefore, the risks must be weighed against the potential benefits for each specific couple., Registration Number: PROSPERO (ID: CRD42024503678)., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Recurrent pericarditis (RP) is defined by the European Society of Cardiology (ESC) as an instance of acute pericarditis (AP) that occurs at least 4-6 weeks after the resolution of a previous episode of the same ailment. To mitigate the risk of RP, it is advised to administer accurate and prolonged pharmacological treatment for both the initial AP and subsequent RP. ESC guidelines recommend commencing treatment for any single episode of AP, including those that contribute to RP, with non-steroidal anti-inflammatory drugs (NSAIDs) in conjunction with colchicine for several months, often followed by gradual tapering. If there is an inadequate response, corticosteroids (CS) may be introduced cautiously. However, in a minority of cases, even when NSAIDs, colchicine, and CS are administered together at the highest recommended dosages, they may prove ineffective. In such instances, treatment with immunosuppressive drugs or biologics is advised. Among biologics, interleukin (IL)-1 inhibitors have been extensively studied, although certain gaps remain. This narrative review delves into the rationale for employing IL-1 inhibitors and presents findings from existing studies regarding their efficacy, tolerability, and safety. Analysis of the literature indicates that there is currently insufficient data to ascertain the true therapeutic role of IL-1 inhibitors in managing and preventing RP. However, theoretically, drugs targeting both IL-1α and IL-1β may offer superior efficacy compared to those solely targeting IL-1β due to the significant involvement of both cytokines in inflammation. Further research is warranted to determine the comparative effectiveness of IL-1α and IL-1β inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT., Competing Interests: Declaration of interests B.J.T. holds patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72., (Published by Elsevier Inc.)

The pH effect on the photophysics of three push-pull compounds bearing dimethoxytriphenylamine (TPA-OMe) as electron donor and pyridine as electron acceptor, with different ortho-functionalization (-H, -Br, -TPA-OMe), is assessed through steady-state and time-resolved spectroscopic techniques in DMSO/water mixed solutions and in water dispersions over a wide pH range. The enhanced intramolecular charge transfer upon protonation of the pyridine leads to the acidochromic (from colorless to yellow) and acido(fluoro)chromic (from cyan to pink) behaviours of the investigated compounds. In dilute DMSO/buffer mixtures these molecules exhibited low pKa values (≤ 3.5) and short singlet lifetimes. Nevertheless, it is by exploiting the aggregation phenomenon in aqueous environment that the practical use of these compounds largely expands: i) the basicity increases (pKa ≈ 4.5) approaching the optimum values for pH-sensing in cancer cell recognition; ii) the fluorescence efficiencies are boosted due to Aggregation-Induced Emission (AIE), making these compounds appealing as fluorescent probes; iii) longer singlet lifetimes enable Excited-State Proton Transfer, paving the way for the application of these molecules as photobases (pKa* = 9.1). The synergy of charge and proton transfers combined to the AIE behaviour in these pyridines allows tunable multi-responsive optical properties providing valuable information for the design of new light-emitting photobases., (© 2024 Wiley‐VCH GmbH.)

Living systems rely on coordinated molecular interactions, especially those related to gene expression and protein activity. The Unfolded Protein Response is a crucial mechanism in eukaryotic cells, activated when unfolded proteins exceed a critical threshold. It maintains cell homeostasis by enhancing protein folding, initiating quality control, and activating degradation pathways when damage is irreversible. This response functions as a dynamic signaling network, with proteins as nodes and their interactions as edges. We analyze these protein-protein networks across different organisms to understand their intricate intra-cellular interactions and behaviors. In this work, analyzing twelve organisms, we assess how fundamental measures in network theory can individuate seed proteins and specific pathways across organisms. We employ network robustness to evaluate and compare the strength of the investigated protein-protein interaction networks, and the structural controllability of complex networks to find and compare the sets of driver nodes necessary to control the overall networks. We find that network measures are related to phylogenetics, and advanced network methods can identify main pathways of significance in the complete Unfolded Protein Response mechanism., Competing Interests: Declaration Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

19 F nuclei serve as versatile sensors for detecting protein interactions and dynamics in biomolecular NMR spectroscopy. Although various methods have been developed to incorporate fluorine-containing aromatic residues into proteins using E. coli or cell-free expression techniques, similar approaches for protein production in mammalian cell lines remain limited. Here, we present a cost-effective synthetic route to obtain selectively deuterated, carbon-13 labeled fluorotryptophan and demonstrate its use in introducing 19 F- 13 C spin pairs into carbonic anhydrase 2 and superoxide dismutase, following an expression protocol utilizing HEK cells.

Background: Antibody-mediated rejection is a significant cause of kidney transplant failure. Recent studies have shown that the MHC class I MICA gene influences the transplantation outcome. However, the role of the primary MICA receptor, NKG2D, has yet to be explored., Aim: We aimed to investigate the correlation between recipient/donor MICA allele matching and NKG2D genotype with the risk of antibody-mediated rejection and their potential clinical effects and implications for organ maintenance therapy., Methods: Of the 524 patients who underwent transplantation, 387 were eligible for the study. Complete MICA allele and two functional polymorphisms of NKG2D ( rs1049174C>G and rs2255336G>A ) were analyzed in 148 transplanted patients and 146 controls., Results: Increased recipient/donor MICA allele mismatches correlate with an elevated risk of antibody-mediated rejection (X 2 = 6.95; Log-rank=0.031). Notably, the rs1049174[GG] genotype contributes to a significantly increased risk of antibody-mediated rejection (X 2 = 13.44; Log-rank=0.001 and X 2 = 0.34; Log-rank=0.84). The combined effect of two MICA allele mismatches and rs1049174[GG] genotype shows the highest risk (X 2 = 23.21; Log-rank<0.001). Most importantly, patients with rs1049174[GG] and rs2255336[ AA ] genotypes may respond less to mTOR inhibitor immunosuppressive therapy than Calcineurin inhibitors ( rs1049174[GG]; P=0.035; and rs2255336[AA] ; P=0.002)., Conclusion: Recipient/donor MICA allele mismatches and specific NKG2D variants, as well as their combinations, influence kidney transplant outcomes, providing insights for personalized treatment and enhancing graft survival., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Littera, Mocci, Argiolas, Littarru, Lai, Melis, Sanna, Mereu, Lorrai, Mascia, Angioi, Mascia, Matta, Lepori, Floris, Manieli, Bianco, Onnis, Rassu, Deidda, Carta, Giuressi, Perra, Chessa, Giglio and Pani.)

Background and Importance: Climate change is widely recognised as a critical public health challenge., Objective: The objective of this study was to assess the awareness, preparedness and mitigation plans for climate change threats., Design, Settings and Participants: A cross-sectional observational study targeting emergency medical societies in different countries was conducted between 15 February and 15 March 2024., Intervention or Exposure: The survey featured 16 closed questions on climate change awareness, preparedness and risks. Focus groups of 4-6 members were organised by country. Results were correlated to income levels, United Nations (UN) regional classification and the World Risk Index., Outcome Measure and Analysis: The questions were ranked using a Likert-like scale from 0 to 9 (9 being the highest). Descriptive statistics used central tendency estimators, and inferential analysis used chi-square and Kruskal-Wallis tests, with the significance level set at P < 0.05., Results: Forty-two focus groups responded, representing 36 countries: 21 (50%) high-income, seven (16.7%) low-income, five (11.9%) lower middle-income and nine (21.4%) upper middle-income countries, representing 31 of the 22 UN regions. According to the World Risk Index, the respondent countries belonged to the different categories as follows: very low risk, 6 (14%); low risk, 8 (19%); medium risk, 5 (12%); high risk, 8 (19%) and very high risk, 14 (34%). The estimated impact of climate change on national health systems had a mean score of 6.75 (SD = 2.16), while on Emergency Medical Systems was 6.96 (SD = 2.05). Overall, assessment and preparedness measures were reported by just 21.4 and 37.6% of respondents, respectively. Analysis by income did not show significant differences, with the exception of food supply. The main differences in the analysis by region were the risks of extreme weather events, vector-borne diseases and wildfires, whereas the World Risk Index was food and chain of supplies. Education and integration of health services were indicated by all as the main mitigation actions., Conclusion: Geographical position and country risk index influence risk perception among focus groups more than income economy, with vector-borne diseases, extreme weather events and food shortages being the threats with the most variability. The most important actions identified to mitigate Climate Change effects are educational and strategic plans., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The purpose of this narrative review is to analyze the most recent studies about the role of C-reactive protein (CRP) and procalcitonin (PCT), two of the main biomarkers of infection, in distinguishing viral from bacterial etiology, in predicting the severity of infection and in guiding antibiotic stewardship in children with community-acquired pneumonia (CAP). The studies examined reveal that both CRP and PCT play a valuable role in diagnosing pediatric CAP, though each has limitations. CRP has moderate accuracy in distinguishing bacterial from viral infections, but its elevated levels are not exclusive to bacterial infections; PCT, however, shows higher specificity for bacterial CAP, with studies confirming its ability to differentiate bacterial causes, especially in severe cases. When integrated with clinical findings, CRP and PCT improve the sensitivity of pneumonia diagnoses and help in predicting severe outcomes such as sepsis and empyema; furthermore, both biomarkers prove useful in guiding antibiotic therapy, with PCT showing a more dynamic response to treatment. However, even though CRP and PCT offer valuable insights into the diagnosis and management of pediatric CAP, their application should be always integrated with clinical assessment rather than used in isolation. More studies are needed to define standardized thresholds and decision algorithms that incorporate these biomarkers.

Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2-576.7); P = 4.02 ×10-7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The striped venus clam (Chamelea gallina) is a relevant economic resource in the Adriatic Sea. This study explored the physiological status of C. gallina at four sites selected along a gradient from high to low incidence of recorded historical mortality events and low to high productivity in the Northwestern Adriatic Sea. Investigations were performed during the marine heatwave in 2022 (from July to November). The optimal temperature range for C. gallina was exceeded in July and September, exacerbating stress conditions and a poor nutritional status, particularly at the low productivity sites. Transcriptional profiles assessed in digestive glands showed that clams from the low productivity sites up-regulated transcripts related to feeding/digestive functions as a possible compensatory mechanism to withstand adverse environmental conditions. Clams from the high productivity sites, that in a previous study showed enrichment of health-promoting microbiome components, displayed a healthier metabolic makeup (IDH up-regulation) and induction of protective antioxidant and immune responses. These features are hallmarks of putative enhanced resilience of the species towards environmental stress. Despite the well-known high sensitivity of C. gallina to environmental variations and its narrow window of acclimatory potential, results highlight that local conditions may influence physiological plasticity of this clam species and shape either positively or negatively its response capabilities to environmental changes. The identification of health-promoting endogenous mechanisms both from the animal (this study) and from its associated microbiome may provide the foundation for developing novel tools and strategies to improve clam health and production in low productivity areas or under adverse environmental conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Intraperitoneal cellular immunotherapy with CAR-redirected lymphocytes is an intriguing approach to target peritoneal carcinomatosis (PC) from ovarian cancer (OC), which is currently evaluated in clinical trials. PC displays a composite structure with floating tumor cells within ascites and solid-like masses invading the peritoneum. Therefore, a comprehensive experimental model is crucial to optimize CAR-cell therapies in such a peculiar environment. Here, we explored the activity of cytokine-induced killer lymphocytes (CIK), redirected by CAR against mesothelin (MSLN-CAR.CIK), within reductionistic 3D models resembling the structural complexity of both liquid and solid components of PC. MSLN-CAR.CIK effectively killed and were functionally efficient against OC targets. In a "floating-like" 3D context with floating OC spheroids, both tumor localization and killing by MSLN-CAR.CIK were significantly boosted by fluid flow. In a "solid-like" context, MSLN-CAR.CIK were recruited through the extracellular matrix on embedded tumor aggregates, with variable kinetics depending on the effector-target distance. Furthermore, MSLN-CAR.CIK penetrated the inner levels of OC spheroids exerting effective tumor killing. Our findings provide currently unknown therapeutically relevant information on intraperitoneal approaches with CAR.CIK, supporting further developments and improvements for clinical studies in the context of locoregional cell therapy approaches for patients with PC from OC., (© 2024. The Author(s).)

Introduction: Microwave imaging presents several potential advantages including its non-ionising and harmless nature. This open, multicentric, interventional, prospective, non-randomised trial aims to validate MammoWave's artificial intelligence (AI)-based classification algorithm, leveraging microwave imaging, to achieve a sensitivity exceeding 75% and a specificity exceeding 90% in breast screening., Methods and Analysis: 10 000 volunteers undergoing regular mammographic breast cancer screening will be recruited across 9 European centres and invited to participate in the clinical study, involving MammoWave testing on both breasts. MammoWave results will be checked against the reference standard, to be intended as the output of conventional breast examination path (with histological confirmation of cancer cases) with 2 years follow-up. Anonymised clinical and MammoWave's results, including microwave images, associated features and a label provided by the AI-based classification algorithm, will be collected and stored in a dedicated electronic case report form. The prospective study will involve a comparative analysis between the output of the conventional breast examination path (control intervention) and the labels provided by MammoWave's AI system (experimental intervention). These labels will categorise breasts into two groups: breast With Suspicious Finding, indicating the presence of a suspicious lesion or No Suspicious Finding, indicating the absence of a lesion or the presence of a low-suspicion lesion. This trial aims to provide evidence regarding the novel MammoWave's AI system for detecting breast cancer in asymptomatic populations during screening., Ethics and Dissemination: This study was approved by the Research Ethics Committee of the Liguria Region (CET), Italy (CET-Liguria: 524/2023-DB id 13399), the Research Ethics Committee of Complejo Hospitalario de Toledo (CEIC), Spain (CEIC-1094), the National Ethics Committee for Clinical Research (CEIC), Portugal (CEIC-2311KC814), the Bioethical Committee of Pomeranian Medical University in Szczecin, Poland (KB-006/23/2024) and the Zurich Cantonal Ethics Commission, Switzerland (BASEC 2023-D0101). The findings of this study will be disseminated through academic and scientific conferences as well as peer-reviewed journals., Trial Registration Number: NCT06291896., Competing Interests: Competing interests: NG, GT, BK and Alessandra Bigotti are employed by UBT—Umbria Bioengineering Technologies Srl. NG and GT are shareholders of UBT—Umbria Bioengineering Technologies. UBT—Umbria Bioengineering Technologies Srl manufactured the microwave imaging device known as MammoWave. This does not alter our adherence to BMJ Open policies., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Between August and 28 October 2024, 199 autochthonous cases of dengue virus serotype 2 were notified in the city of Fano, central Italy. We describe the ongoing epidemiological and microbiological investigation and public health measures implemented to contain the outbreak. The high transmissibility and the extension of the outbreak suggest that dengue should be expected in temperate regions during favourable seasons, highlighting the need for heightened awareness among healthcare providers and the public to ensure timely detection and response.

The River Sacco Basin (Rsb) is a site of National interest, characterized by several environmental pressures such as industrial facilities. This study investigates the association between long-term exposure to industrial-PM10 and -NOx and cause-specific mortality (non-accidental, cardiovascular, respiratory, and cancer) in the Rsb in the 2006-2018 period. We enrolled 301,681 residents near 14 major industrial plants (grouped into 5 30-km2 spatial domains). Residential exposure to annual PM10 and NOx was considered as categorical exposure (high (>80th percentile), medium (50th-80th), and low (<50th)). We applied adjusted domain specific Cox regression models (covariates: age, sex, and deprivation index) and performed a relative meta-analysis. We obtain a pooled 34% increase in respiratory mortality for high PM10 levels. Elevated risks were also observed for non-accidental and cancer mortality, highlighting the need for continuous monitoring and preventive interventions.

Background: Students' professional identity is essential to build nursing competence. Cognitive flexibility plays a crucial role in developing professional identity, as well as clinical supervisors and academic teachers through role modeling. This study analyzed the role of internship and theoretical modeling in the link between cognitive flexibility and professional identity., Method: Participants were first-, second-, and third-year nursing students ( n = 284) at a university in northern Italy. Participants completed an online survey, and multigroup analysis was performed., Results: Internship modeling was positively associated with professional identity but not for second-year students. Theoretical modeling was not significantly associated with professional identity and cognitive flexibility. Theoretical modeling did not mediate the relationship between cognitive flexibility and professional identity. Clinical internship modeling mediated the relationship between cognitive flexibility and professional identity but not for second-year students., Conclusion: Internship modeling helps students give sense and coherence to learning, which contributes to their professional identity. [ J Nurs Educ . 2024;63(11):764-772.] ., Competing Interests: Disclosure: The authors have disclosed no potential conflicts of interest, financial or otherwise.

Background: The prospective, single-arm, observational, phase 4 ETNA-AF Europe study collected real-world data about safety, effectiveness and therapeutic adherence in European patients with non-valvular atrial fibrillation newly prescribed with edoxaban and followed up for 4 years., Methods: Overall, 13 164 patients were included in the full-analysis set, which means that they had at least one documentation after baseline at 4 years. The current paper reports about the 3329 Italian patients out of the whole European population., Results: In the Italian cohort, median age was 76.0 (69.0-82.0) years, with 57.4% of the patients being ≥75 years old. The CHA2DS2-VASc score was >4 in 586 (18.1%) patients. At baseline, 670 (20.8%) patients were classified as frail by the investigators. Edoxaban 30 mg/day was prescribed to 1013 (31.8%) patients: these were older, with more comorbidities and a lower estimated creatinine clearance compared with those receiving 60 mg/day. All-cause mortality was 4.1%/year and there were very low yearly rates of bleeding and thromboembolic events: major bleeding, 0.9%; intracranial hemorrhage, 0.2%; ischemic stroke, 0.3%; systemic embolism, <0.1%. These events were more frequent in patients ≥75 years or in patients with renal impairment or treated with edoxaban 30 mg/day. Advancing age was not associated with an increased incidence of intracranial bleeding., Conclusions: These findings confirm the favorable long-term safety and effectiveness profile of edoxaban in non-valvular atrial fibrillation patients treated in routine clinical care in Italy.

Background: Expected and unexpected donor-derived infections (DDI) are a rare event in solid organ transplant (SOT) recipients but are potentially associated with significant morbidity and mortality. To assure the microbial safety of transplantation, both national guidelines and the current, regional, and local epidemiology of infectious diseases must be considered., Methods: In the present paper the strategies adopted by the Italian National Center for Transplantation (CNT) since 2003 and their evolution to guarantee the safety of organ transplantation are reported. Starting in 2012 mandatory reporting to the CNT of all adverse reactions was started. The number and type of DDI reported to the CNT are currently being analyzed., Results: The infectious diseases second opinion has written and updated the guidelines on the safety of organs for transplantation and supported the Italian transplant network for the use of organs from donors with suspected or documented potentially transmissible infections., Conclusion: A transplant safety network was developed in Italy in 2003 and has been updated according to the evolving knowledge and the changing epidemiology. This is an evolving field, and a continuous update of the recommendation is needed., (© 2024 The Author(s). Transplant Infectious Disease published by Wiley Periodicals LLC.)

The first international consensus guideline on physiological interpretation of cardiotocograph (CTG) produced by 44 CTG experts from 14 countries was published in 2018. This guideline ensured a paradigm shift from classifying CTG by arbitrarily grouping certain features of the fetal heart rate into different "categories", and then, randomly combining them to arrive at an overall classification of CTG traces into "Normal, Suspicious and Pathological" (or Category I, II and III) to a classification which is based on the understanding of fetal pathophysiology. The guideline recommended the recognition of different types of fetal hypoxia, and the determination of features of fetal compensatory responses as well as decompensation to ongoing hypoxic stress on the CTG trace. Since its first publication in 2018, there have been several scientific publications relating physiological interpretation of CTG, especially relating to features indicative of autonomic instability due to hypoxic stress (i.e., the ZigZag pattern), and of fetal inflammation. Moreover, emerging evidence has suggested improvement in maternal and perinatal outcomes in maternity units which had implemented physiological interpretation of CTG. Therefore, the guideline on Physiological Interpretation of CTG has been revised to incorporate new scientific evidence, and the interpretation table has been expanded to include features of chorioamnionitis and relative utero-placental insufficiency of labour (RUPI-L)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

This systematic review aims to examine evidence on telemedicine-delivered interventions for autistic children and adolescents, considering diverse approaches, settings, and modalities used to address core symptoms and co-occurring conditions. A comprehensive search strategy consulted PubMed and PsycInfo databases from inception to March 2023. PROSPERO registration: CRD42023404111. Each work was screened, and two blind authors extracted data. Out of 6010 studies, 19 publications with 366 participants (305 carers and 61 autistic children/adolescents) were included. Combined findings from observational and experimental studies indicate telemedicine-delivered interventions are comparable in effectiveness to traditional "in-person" treatments and involve lower costs. Tele-intervention outcomes show promise in facilitating interventions, actively engaging parents, and generalizing the socio-communicative behaviors of children. While the enforced adoption of telemedicine during the COVID-19 pandemic has prompted clinicians to assess its role in the field of autism, a comprehensive understanding of its efficacy, benefits, and associated costs has yet to be fully established. Future studies should prioritize rigorous experimental methodologies, including subgroup analyses based on child/adolescent and family characteristics, aiding intervention implementation., Competing Interests: Declaration of Competing Interest None, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Multisystem inflammatory disease in children (MIS-C) is a post-infectious condition following coronavirus disease-19 infection. Long-term follow-up data suggests that initial clinical severity does not necessarily correlate with long-term outcomes. The long-term immunological response in children with MIS-C remains poorly understood. We analyzed cytokine profiles at diagnosis and during follow-up, in pediatric patients with MIS-C, exploring correlations among cytokine expressions and standard biochemical and hormonal test results., Methods: Twenty-five MIS-C patients (mean 9.4 ± 3.9) with complete test results at diagnosis and at 6- and 12-months follow-up were included in the study. Selected cytokines, such as IL-9, eotaxin, IP-10, MIP-1β, RANTES, MCP-1(MCAF), TNF-α, PDGF-B, IL-4, and MIP-1α, were included in the analysis., Results: IP-10, MCP-1 (MCAF), and MIP-1α levels normalized or nearly normalized at 6-12 months, the remaining cytokines, including IL-9, eotaxin, MIP-1β, RANTES, TNF-α, PDGF-B, IL-4, remained higher in MIS-C than in controls at our last follow-up time. At 6 months post-diagnosis, a mild negative correlation between triglycerides and HOMA-IR with MCP-1 (MCAF), IL-4, and Eotaxin was noted. At the 12-month follow-up we found a mild positive correlation of cortisol and ACTH levels with PDGF-B, MIP-1α, and TNF-α. Conversely, a negative correlation between these cytokines with fasting glucose and HOMA-IR was observed., Conclusions: Our study findings highlight a notable cytokine-mediated inflammatory response in pediatric patients with MIS-C, characterized by sustained elevated levels over a 12-month monitoring period compared to the control group. We have identified various interrelationships among different cytokines, as well as correlations between heightened cytokine levels and metabolic and hormonal patterns. The pronounced inflammatory response underscores its involvement in acute organ damage, while its persistence suggests potential implications for long-term metabolic disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The main genetic risk factors for Parkinson's disease (PD) are presently represented by variants in GBA1 gene encoding for the β-glucocerebrosidase (GCase). Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting GBA1-associated PD (GBA1-PD) is a current challenge. We previously demonstrated that α-synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross-sectional study investigates an unexplored cohort of GBA1-PD (n = 27) compared to 28 HC, and 36 iPD cases to (i) analyze α-synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific GBA1 mutations. PLA score discriminates GBA1-PD from HC with sensitivity = 88.9% (95% CI 70.84-97.65), specificity = 88.5% (95% CI 69.85-97.55), and PPV = 88.9% (95% CI 73.24-95.90), AUC value = 0.927 (95% CI 0.859-0.996). No difference was found between GBA1-PD patients and iPD, suggesting a common pathological pathway based on α-synuclein oligomers. GCase score did not differ in GBA1-PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in GBA1-PD compared to iPD and HC (P < 0.0001). Employing ROC curve to discriminate GBA1-PD from iPD, we found an AUC value for synaptic density = 0.855 (95% CI 0.749-0.961) with sensitivity = 85.2% (95% CI 66.27%-95.81%), specificity = 77.1% (95% CI 59.86%-89.58%), and PPV = 74.19% (60.53%-84.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing GBA1-PD from iPD and to their potential to stratify and monitor patients in the context of new pathway-specific therapeutic options., (© 2024 The Author(s). Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Cholesterol crystal embolism (CCE) implies immunothrombosis, tissue necrosis, and organ failure but no specific treatments are available. As CCE involves complement activation, we speculated that inhibitors of the C5a/C5aR axis would be sufficient to attenuate the consequences of CCE like that with systemic vasculitis. Cholesterol microcrystal injection into the kidney artery of wild-type mice initiated intra-kidney immunothrombosis within a few hours followed by a sudden drop of glomerular filtration rate and ischemic kidney necrosis after 24 hours. Genetic deficiency of either C3 or C5aR prevented immunothrombosis, glomerular filtration rate drop, and ischemic necrosis at 24 hours as did preemptive treatment with inhibitors of either C5a or C5aR. Delayed C5a blockade after crystal injection still resolved crystal clots and prevented all consequences. Thus, selective blockade of C5a or C5aR is sufficient to attenuate the consequences of established CCE and prospective inhibition in high-risk patients may be clinically feasible and safe., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: Masticatory function seems to play a role in the aetiology of obesity. However, literature on the association between oral myofunctional status and overweight and obesity in children and adolescents is scarce and contrasting., Objective: To compare masticatory performance, orofacial myofunctional status and tongue strength and endurance between children and adolescents with overweight and obesity and those with normal weight., Methods: Thirty children and adolescents with overweight and obesity and 30 subjects with normal weight matched for age and sex were recruited. All subjects were evaluated with the Test of Masticating and Swallowing Solids in Children (TOMASS-C) for masticatory performance and with the Italian Orofacial Myofunctional Evaluation with Scores (I-OMES) for the orofacial myofunctional status. Anterior and posterior maximum tongue pressures and tongue endurance were measured. Parents-reported (PRO) duration of meals was recorded. Data were compared between the groups through the paired samples t-test or the Wilcoxon signed-rank test., Results: Children and adolescents with overweight showed significantly lower number of bites (p = .033), lower I-OMES scores (p < .05), and shorter meal duration (p = .005) compared to their peers with normal weight. No significant differences were found between the two groups for the number of swallows, the number of masticatory cycles and the total time of the TOMASS-C, and none of the tongue pressure measurements., Conclusions: Eating in children and adolescents with overweight and obesity is characterised by a larger bolus sizes and shorter PRO meal duration. Additionally, overweight and obesity seem to be associated with poorer orofacial skills and structures in the paediatric population., (© 2024 The Author(s). Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)