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Brazil is an influential and successful food-producing country, where we can highlight artisanal cheeses gaining visibility in foreign markets. Some of these cheeses are made from raw milk, making them susceptible to contamination by microorganisms, including fungi, which can produce harmful mycotoxins. Feed contaminated with aflatoxin B1, when consumed by dairy animals, is metabolized and transformed into aflatoxin M1 (AFM1), which is excreted in milk. Therefore, the aim of this research was to investigate the occurrence of AFM1 in artisanal cheeses from two Brazilian states: Minas Gerais and São Paulo. This toxin was extracted from 10 g of sample and 50 ml pepsin solution. An aliquot of the extract was passed through an immunoaffinity column, eluted, and dried under nitrogen. For the analysis of the detection and quantification of AFM1, the High-Performance Liquid Chromatography (HPLC) fluorescence detection system was used. A total of 130 samples were analyzed; 41 tested positive for AFM1, while 89 were negative. Out of 41 positive samples, only two were above the maximum tolerated limit by ANVISA of 2.5 µg/kg. These results show the importance of investigating the occurrence of AFM1 in artisanal cheeses, aiming to prevent and increase food safety.

Background: The issue of retreatment with surfactant of infants with respiratory distress syndrome (RDS) has been poorly investigated. Our aim was to identify possible clinical predictors of the need for multiple doses of surfactant in a large cohort of very preterm infants., Methods: Data were analyzed from three previous studies on infants born between 25 + 0 and 31 + 6 weeks of gestation with RDS who were treated with surfactant., Results: We studied 448 infants. Among them 306 (68%) were treated with a single dose of surfactant and 142 (32%) were treated with multiple doses. Multivariable mixed effects logistic regression analysis showed that the odd of requiring multiple doses of surfactant was significantly lower in patients with higher gestational age (27-28 vs. 25-26 wks: OR 0.46, 95% C.l. 0.26-0.79; ≥29 vs. 25-26 wks: OR 0.34, 95% C.l. 0.13-0.85; overall P = 0.013), while it increased in infants born to mothers with hypertensive disorders of pregnancy (OR 2.53, 95% C.l. 1.49-4.31; P < 0.001) and with hemodynamically significant PDA (OR 2.74, 95% C.l. 1.66-4.53, P < 0.001)., Conclusions: Gestational age, hypertension in pregnancy, and hemodynamically significant PDA can predict the need for multiple doses of surfactant. Further investigation is needed to evaluate if these sub-groups of preterm infants represent specific phenotypes of RDS who deserve a peculiar surfactant treatment., Competing Interests: Declarations. Ethics approval and consent to participate: All studies used for pooled analyses were approved by pediatric ethics committees of Tuscany (ID 29/2011, ID 234/2019, and ID 58/2019, respectively) and carried out in accordance with the 1964 Declaration of Helsinki. Infants were enrolled after informed parental consent. Only data of infants who were treated with surfactant were analyzed. Local ethics committees approved the study. Parental consent was not required because this is a retrospective study and data were anonymized. Consent for publication: Not applicable. Competing interests: Prof. Carlo Dani received honoraria from Chiesi Farmaceutici SpA and Vyaire Medical Inc. for scientific consultancies. Other authors declare that there are no conflicts of interests. Prof. Carlo Dani and Dr. Raffaele Falsaperla are members of the Editorial Board of the Italian Journal of Pediatrics., (© 2024. The Author(s).)

Borderline personality disorder (BPD) is associated with a high risk of suicide. Despite several risk factors being known, identifying vulnerable patients in clinical practice remains a challenge so far. The current study aimed at predicting suicide attempts among BPD patients during disorder-specific psychotherapeutic interventions exploiting machine learning techniques. The study took into account several potential predictors relevant to BPD psychopathology: emotion dysregulation, temperamental and character factors, attachment style, impulsivity, and aggression. The sample included 69 patients with BPD who completed the Temperament and Character Inventory, Attachment Style Questionnaire, Difficulties in Emotion Regulation Scale, Barratt Impulsiveness Scale, and Aggression Questionnaire at baseline and after 6 months of psychotherapy. To detect future suicide attempts, baseline questionnaires were entered as predictors into an elastic net penalized regression, whose predictive performance was assessed through nested fivefold cross-validation. At the same time, 5000 iterations of a non-parametric bootstrap were used to determine predictors' robustness. The elastic net model discriminating BPD suicide attempters from non-attempters reached a balanced accuracy of 64.09% and an area under the receiver operating curve of 70.44%. High preoccupation with relationships, harm avoidance, and reward dependence, along with low motor impulsiveness, verbal aggression, cooperativeness, and self-transcendence were the most contributing predictors. Our findings suggest that interpersonal vulnerability and internalizing factors are the strongest predictors of future suicide attempts in BPD. Machine learning on self-report psychological scales may be helpful to identify individuals at suicidal risk, potentially helping clinical settings to develop individualized preventive strategies., (© 2024 Wiley Periodicals LLC.)

In search of semisynthetic derivatives with increased antitumor activity, we condensed sulforaphane (SFR) with rhodol, a fluorophore platform capable of modifying the intracellular trafficking and pharmacokinetics of the linked molecules. The two tested derivatives, namely MG28 and MG46, showed a far higher, as compared to SFR, cytotoxicity toward cancer cells. Apoptotic cell death was preceded by the extensive generation of DNA lesions, which were repaired relatively slowly and caused formation of micronuclei. Unlike SFR, rhodol-SFR conjugates' DNA lesions resulted from direct interactions with nuclear DNA. Overall, MG28 and MG46 exhibit a remarkable cytotoxic effect, which is the likely consequence of their direct and intense DNA damaging activity, i.e., a novel and peculiar mechanism arising from the conjugation of the parental rhodol and SFR. Considering that a wide number of clinically used drugs kill cancer cells by inducing DNA damage, MG could represent a new and promising chance in antitumor chemotherapy., 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. Published by Elsevier Masson SAS.)

Background: Empirically-based developmental psychopathology approach identified three domains involved in the emergence of borderline personality disorder (BPD): i) underlying liabilities to develop psychopathology (i.e., early patterns of internalizing and externalizing manifestations); ii) invalidating relational experiences (e.g., childhood traumatic experiences, maladaptive parenting, problematic peer relationships); iii) regulatory mechanisms of emotions and behaviors. Nevertheless, no studies have quantitatively summarized empirical findings concerning how and to what extent these domains might be temporally associated to the emergence of BPD features from adolescence to adulthood., Methods: The current multi-level meta-analysis included 106 studies (N = 86,871 participants) assessing the role of previously mentioned antecedents and risk factors for BPD., Results: The analysis showed moderate effect sizes capturing temporal associations between early internalizing/externalizing psychopathological manifestations, different invalidating relational experiences, emotion/behavior regulation processes with later BPD features. The effect sizes of these domains were not statistically different from each other., Conclusion: This evidence supports a transactional developmental model of BPD. Consistently, the emergence of BPD could be viewed in the light of dynamic interplays between an underlying liability to psychopathology and invalidating relational experiences across different stages of development, which are progressively reinforced through increasing alterations of emotion and behavior regulation mechanisms., Competing Interests: Declaration of competing interest The authors alone are responsible for the content and writing of this paper. All authors approved the final version of the manuscript. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors report no relevant financial conflicts., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Thus far, no manufacturing process able to support industrialization has been reported for the recombinant human brain-derived neurotrophic factor (rhBDNF). Here, we described the setup of a new protocol for its production in Escherichia coli ( E. coli ) and its purification to homogeneity. A synthetic gene, codifying for the neurotrophin precursor, was inserted into an E. coli expression vector and transformed into BL21 (DE3) strain. The recombinant protein accumulates, at high yields, into inclusion bodies. With the developed strategy, more than 50% of the precursor can be refolded. The protein is successively digested by trypsin and the rhBDNF mature form is finally purified by two additional chromatographic steps If the wild-type precursor can be efficiently obtained by the proposed methodology, its pro-peptide remotion, through enzymatic digestion, is however problematic. To circumvent this difficulty, the precursor hinge region, containing the natural furin recognition site, was engineered to be more specifically cleaved by trypsin. Notwithstanding the substitution of three residues in the pro-region carboxyterminal, the precursor correctly refolds and is efficiently cleaved to generate a biologically active mature rhBDNF. This efficient high-yield process fills the current need of a scalable protocol to produce GMP-grade material and unlocks the rhBDNF employment in future clinical investigations.

A (target) quantum system is often measured through observations performed on a second (meter) system to which the target is coupled. In the presence of global conservation laws holding on the joint meter-target system, the Wigner-Araki-Yanase theorem and its generalizations predict a lower bound on the measurement's error (Ozawa's bound). While practically negligible for macroscopic meters, it becomes relevant for microscopic ones. Here, we propose a simple interferometric setup, arguably within reach of present technology, in which a flying particle (a microscopic quantum meter) is used to measure a qubit by interacting with it in one arm of the interferometer. In this scenario, the globally conserved quantity is the total energy of particle and qubit. We show how the measurement error ϵ is linked to the nonstationary nature of the measured observable and the finite duration of the target-meter interaction while Ozawa's bound ϵ&#95;{B} only depends on the momentum uncertainty of the meter's wave packet. When considering short wave packets with respect to the evolution time of the qubit, we show that ϵ/ϵ&#95;{B} is strictly tied to the position-momentum uncertainty of the meter's wave packet and ϵ/ϵ&#95;{B}→1 only when employing Gaussian wave packets. On the contrary, long wave packets of any shape lead to ϵ/ϵ&#95;{B}→sqrt[2]. In addition to their fundamental relevance, our findings have important practical consequences for optimal resource management in quantum technologies.

Sleep-disordered breathing is a highly prevalent disorder with negative impact on healthcare systems worldwide. This condition has detrimental effects on cardiovascular health and quality of life, and is frequently associated with a variety of comorbidities, including cardiovascular disease, heart failure, diabetes and atrial fibrillation. Nevertheless, it remains frequently undiagnosed and undertreated, especially in specific populations. Studies on sleep-disordered breathing have been conducted mainly on male patients, and the prevalence and severity of this disorder in women are underestimated. Recently, some clinical and laboratory evidence has highlighted the epidemiological and pathophysiological differences between men and women with sleep-disordered breathing. In this review, we discuss sex-related mechanisms of sleep-disordered breathing in frequently associated disorders, to improve clinical understanding of this condition and to simplify the practical application of targeted interventions. The aim is to improve prognosis among female patients and guarantee a better quality of life and a reduction in healthcare costs., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

An affective variant of the Stop-Signal task was used to study the interaction between emotion and response inhibition (RI) in healthy young participants. The task involved the covert presentation of emotional faces as go stimuli, as well as a manipulation of motivation and affect by inducing a negative mood through the assignment of unfair punishment. In the literature on emotion and RI, there are contrasting findings reflecting the variability in the method used to calculate the RI latency, namely the Stop-Signal Reaction Time (SSRT). In fact, previous studies found both facilitatory and detrimental effects of affective manipulations over RI. However, they did not use the most robust SSRT estimation approach, namely the integration, casting some doubts on the reliability of the inferences. For these reasons, the present research draws attention on how the effect of the emotional manipulation may be due to a biased SSRT estimation. Specifically, the focus of our study was on how the effect of emotion on the SSRT may vary according to different estimation procedures, the mean and two variants of the integration method. We predicted that the effect of the emotional manipulation in the SST would depend on the SSRT estimation method employed. Indeed, a significant effect of emotion was only found when SSRT was estimated with the mean method. We conclude that the mean method should be avoided in the study of emotion and RI because it overestimates SSRT. Rather, the integration approach should be used for future research in this field, while also factoring in information about the participants' strategy in emotional contexts that require greater effortful control and offer a challenge to self-regulation both in health and disease., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Coccaro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Competing Interests: The authors have no conflict of interest to declare.

Purpose: First-line medical therapy for acromegaly management includes first-generation somatostatin receptor ligands (fgSRLs), but resistance limits their use. Despite international guidelines, the choice of second-line therapy is debated., Methods: We aim to discuss resistance to fgSRLs, identify second-line therapy determinants and assess glycemia's impact to provide valuable insights for acromegaly management in clinical practice. A group of Italian endocrinologists expert in the pituitary field participated in a two-round Delphi panel between July and September 2023. The Delphi questionnaire encompassed a total of 75 statements categorized into three sections: resistance to fgSRLs therapy and predictors of response; determinants for the selection of second-line therapy; the role of glycemia in the therapeutic management. The statements were rated on a 6-point Likert scale., Results: Fifty-nine (79%) statements reached a consensus. IGF-1 levels resulted central for evaluating resistance to fgSRLs, that should be defined considering also symptomatic clinical response, degree of tumor shrinkage and complications, using clinician- and patient-reported outcome tools available. Factors to be evaluated for the choice of second-line medical therapy are hyperglycemia-that should be managed as in non-acromegalic patients-tumor remnant, resistant headache and compliance. Costs do not represent a main determinant in the choice of second-line medical treatment., Conclusion: The experts agreed on a holistic management approach to acromegaly. It is therefore necessary to choose currently available highly effective second-line medical treatment (pegvisomant and pasireotide) based on the characteristics of the patients., (© 2024. The Author(s).)

Introduction and Objectives: Multiparametric magnetic resonance imaging (mpMRI) has improved the detection of clinically significant prostate cancer (csPCa), and microultrasound (micro-US) shows promise in enhancing detection rates. We compared mpMRI-guided targeted biopsy (MTBx) and micro-US-guided targeted biopsy (micro-US-TBx) in biopsy-naïve patients with discordant lesions at micro-US and mpMRI to detect csPCa (grade group ≥2) and clinically insignificant PCa (ciPCa; grade group 1) and assessed the role of nontargeted systematic biopsy (SBx)., Material and Methods: We analyzed 178 biopsy-naive men with suspected PCa and discordant lesions at mpMRI and micro-US. All patients underwent mpMRI followed by micro-US, the latter being performed immediately before the biopsy. Imaging findings were interpreted blindly, followed by targeted and SBx. Median age was 63 years (IQR, 57-70), median prostate-specific antigen level was 7 ng/mL (IQR, 5-9 ng/mL), and median prostate volume was 49 cm^3 (IQR, 35-64 cm^3). Overall, 86/178 (48%) patients were diagnosed with PCa, 51/178 (29%) with csPCa., Results: Micro-USTBx detected csPCa in 36/178 men (20%; 95% CI: 26-46), and MTBx detected csPCa in 28/178 men (16%; 95% CI: 36-50), resulting in a -8% difference (95% CI: -10, 4; P = 0.022) and a relative detection rate of 0.043. Micro-USTBx detected ciPCa in 9/178 men (5%; 95% CI: 3, 15), while MTBx detected ciPCa in 12/178 men (7%; 95% CI: 5, 20), resulting in a -3% difference (95% CI: -2 to 4; P = 0.2) and a relative detection rate of 0.1. SBx detected ciPCa in 29 (16%) men. mpMRI plus micro-US detected csPCa in 51/178 men, with no additional cases with the addition of SBx. Similarly, MTBx plus micro-USTBx plus SBx detected ciPCa in 35/178 men (20%; 95% CI: 18, 37) compared to 9 (5%) in the micro-US pathway (P = 0.002) and 14/178 (8%; 95% CI: 6, 26) in the mpMRI plus micro-US pathway (P = 0.004)., Conclusions: In conclusion, a combined micro-US/mpMRI approach could characterize primary disease in biopsy-naïve patients with discordant lesions, potentially avoiding SBx. Further studies are needed to validate our findings and assess micro-US's role in reducing unnecessary biopsies., 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.)

Background: Pulmonary hypertension (PH) is a pathophysiological problem that may involve several clinical symptoms and be linked to various respiratory and cardiovascular illnesses. Its diagnosis is made invasively by Right Cardiac Catheterization (RHC), which is difficult to perform routinely. Aim of the current study was to develop a Machine Learning (ML) algorithm based on the analysis of anamnestic data to predict the presence of an invasively measured PH., Methods: 226 patients with clinical indication of RHC for suspected PH were enrolled between October 2017 and October 2020. All patients underwent a protocol of diagnostic techniques for PH according to the recommended guidelines. Machine learning (ML) approaches were considered to develop classifiers aiming to automatically detect patients affected by PH, based on the patient's characteristics, anamnestic data, and non-invasive parameters, transthoracic echocardiography (TTE) results and spirometry outcomes., Results: Out of 51 variables of patients undergoing RHC collected, 12 resulted significantly different between patients who resulted positive and those who resulted negative at RHC. Among them 8 were selected and utilized to both train and validate an Elastic-Net Regularized Generalized Linear Model, from which a risk score was developed. The AUC of the identification model is of 83 % with an overall accuracy of 74 % [95 % CI (61 %, 84 %)], indicating very good discrimination between patients with and without the pathology., Conclusions: The PH-targeted ML models could streamline routine screening for PH, facilitating earlier identification and better RHC referrals., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Authors.)

Competing Interests: The authors declare no conflicts of interest.

The aim was to investigate trait social anxiety and social evaluative stress in autistic children and adolescents and Specific Learning Disorders (SLD). This was done by evaluating behavioral, subjective, and autonomic responses to the Trier Social Stress Test (TSST). Study 1 included 280 children and adolescents: 60 autistic without intellectual disability (ID), 70 SLD, and 150 non-diagnosed (ND) peers. Study 2 involved 55 participants: 15 autistic without ID, 15 SLD, and 20 ND. The sample was predominantly male. In Study 1, behavioral (quality of public speech) and subjective (valence, arousal, perceived competence, and worries) aspects of social stress were examined. Study 2 expands upon the first study, as physiological responses to social stress were also measured. Trait social anxiety was investigated using both parents' and children's reports in the two studies. Parents of autistic participants and with SLD reported higher trait social anxiety in their children than the parents of ND. No differences emerged from the participants' self-reports, though those autistic and with SLD were assigned lower scores in the public speech quality than ND. Autistic children and adolescents reported lower arousal and higher perceived competence than ND, while those with SLD reported a lower perception of competence. Autistic participants had a decreased cardiac reactivity across the TSST when compared to SLD and ND. Our findings show unique patterns of responses within each group, confirming that the combined investigation of trait anxiety and social stress responses could be a valuable insight in research and clinical practice., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Multiple myeloma (MM) with pulmonary extramedullary disease is rare and usually associated with poor prognosis, and no data on daratumumab-based regimens have been reported yet., Case Presentation: Here, a 64-year-old man with pulmonary plasmacytoma received daratumumab-based regimens and has achieved a very good partial response with lung mass disappearance and overall survival of 16 months. He did not receive autologous stem cell transplantation because of several comorbidities, such as severe drug-induced neuropathy and JAK2-mutated myeloproliferative neoplasm with marked splenomegaly., Conclusions: We showed the efficacy of daratumumab in combination with targeted therapies for the treatment of pulmonary MM., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Objective: The SeLECT 2.0 score is a prognostic model of epilepsy after ischemic stroke. We explored whether replacing the severity of stroke at admission with the severity of stroke after treatment at 72 h from onset could improve the predictive accuracy of the score., Methods: We retrospectively identified consecutive adults with acute first-ever neuroimaging-confirmed ischemic stroke who were admitted to the Stroke Unit of the Ospedale Civile Baggiovara (Modena, Italy) and treated with intravenous thrombolysis and/or endovascular treatment. Study outcome was the occurrence of at least one unprovoked seizure presenting >7 days after stroke., Results: Participants included in the analysis numbered 1094. The median age of the subjects was 74 (interquartile range [IQR] = 64-81) years, and 595 (54.4%) were males. Sixty-five (5.9%) subjects developed unprovoked seizures a median of 10 (IQR = 6-27) months after stroke. The median values of the original and modified SeLECT2.0 scores were 3 (IQR = 2-4) and 2 (IQR = 1-3). The modified SeLECT 2.0 score showed better discrimination for the prediction of poststroke epilepsy at 36, 48, and 60 months after stroke compared to the original score according to the area under time-dependent receiver operating characteristic curves. The modified SeLECT 2.0 score had higher values of Harrell C and Somers D parameters and lower values of Akaike and Bayesian information criteria than the original score. The modified SeLECT 2.0 score produced more accurate risk predictions compared to the SeLECT 2.0 score at all evaluated time points from 12 to 60 months after stroke according to the Net Reclassification Index., Significance: Replacing baseline with posttreatment stroke severity may improve the ability of the SeLECT 2.0 score to predict poststroke epilepsy., (© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Four European Reference Networks (ERN-EYE, ERKNet, Endo-ERN, ERN-ITHACA) have teamed up to establish a consensus statement and recommendations for Bardet-Biedl syndrome (BBS). BBS is an autosomal recessive ciliopathy with at least 26 genes identified to date. The clinical manifestations are pleiotropic, can be observed in utero and will progress with age. Genetic testing has progressively improved in the last years prompting for a revision of the diagnostic criteria taking into account clinical Primary and Secondary features, as well as positive or negative molecular diagnosis. This consensus statement also emphasizes on initial diagnosis, monitoring and lifelong follow-up, and symptomatic care that can be provided to patients and family members according to the involved care professionals. For paediatricians, developmental anomalies can be at the forefront for diagnosis (such as polydactyly) but can require specific care, such as for associated neuro developmental disorders. For ophthalmology, the early onset retinal degeneration requires ad hoc functional and imaging technologies and specific care for severe visual impairment. For endocrinology, among other manifestations, early onset obesity and its complications has benefited from better evaluation of eating behaviour problems, improved lifestyle programs, and from novel pharmacological therapies. Kidney and urinary track involvements warrants lifespan attention, as chronic kidney failure can occur and early management might improve outcome. This consensus recommends revised diagnostic criteria for BBS that will ensure certainty of diagnosis, giving robust grounds for genetic counselling as well as in the perspective of future trials for innovative therapies., Competing Interests: Competing interests The development of this work was made without external financial support from industries involved in the manufacturing of therapies for BBS. Competing interests of members of the guideline development group have been recorded in writing and addressed. HD has consulted for Novartis, Rhythm Pharmaceuticals, Jansen Pharmaceutical, GenSight Biologics and Sparing Vision. JK, DL, AG, MMVH and JM have consulted for Rhythm Pharmaceuticals. EVDA’s institute was the recipient of a research grant from Rhythm Pharmaceuticals. MC is a principal investigator for the RM-IMC-901 study (a Registry of Patients with Biallelic Proopiomelanocortin (POMC), Proprotein Convertase Subtilisin/Kexin Type 1 (PCSK1), or Leptin Receptor (LEPR) Deficiency Obesity, or Bardet-Biedl Syndrome (BBS), Treated with Setmelanotide) and received payments for lectures, expert testimony and consulting fees and study support from Rhythm Pharmaceuticals; MC also received payments for lectures from Canon Medical Systems. CB is the medical and managing director of Medizinische Genetik Mainz and Limbach Genetics. BPL has consulted for Novartis, Jansen Pharmaceutical, GenSight Biologics and Sparing Vision. CP has consulted for Rhythm Pharmaceuticals and Novo Nordisk. SR has consulted for Rhythm Pharmaceuticals, Sandoz and Novo Nordisk. MRL, PM, AV, GMB, MGP, FT, MFS, FS, AG, MZ, HM, AMVE, DM, AS, DV, have no competing interests to declare., (© 2024. The Author(s).)

fMRI neurofeedback using autobiographical memory recall to upregulate the amygdala is associated with resting-state functional connectivity (rsFC) changes between the amygdala and the salience and default mode networks (SN and DMN, respectively). We hypothesize the existence of anatomical circuits underlying these rsFC changes. Using a cross-species brain parcellation, we identified in non-human primates locations homologous to the regions of interest (ROIs) from studies showing pre-to-post-neurofeedback changes in rsFC with the left amygdala. We injected bidirectional tracers in the basolateral, lateral, and central amygdala nuclei of adult macaques and used bright- and dark-field microscopy to identify cells and axon terminals in each ROI (SN: anterior cingulate, ventrolateral, and insular cortices; DMN: temporal pole, middle frontal gyrus, angular gyrus, precuneus, posterior cingulate cortex, parahippocampal gyrus, hippocampus, and thalamus). We also performed additional injections in specific ROIs to validate the results following amygdala injections and delineate potential disynaptic pathways. Finally, we used high-resolution diffusion MRI data from four post-mortem macaque brains and one in vivo human brain to translate our findings to the neuroimaging domain. Different amygdala nuclei had significant monosynaptic connections with all the SN and DMN ipsilateral ROIs. Amygdala connections with the DMN contralateral ROIs are disynaptic through the hippocampus and parahippocampal gyrus. Diffusion MRI in both species benefitted from using the ground-truth tracer data to validate its findings, as we identified false-negative ipsilateral and false-positive contralateral connectivity results. This study provides the foundation for future causal investigations of amygdala neurofeedback modulation of the SN and DMN through these anatomic connections., (© 2024. The Author(s).)

Background: In addition to its critical role in neurogenesis, brain-derived neurotrophic factor (BDNF) modulates pain and depressive behaviors., Methods: In a translational perspective, we tested the anti-migraine activity of highly purified and characterized recombinant human BDNF (rhBDNF) in an animal model of cephalic pain based on the chronic and intermittent NTG administration (five total injections over nine days), used to mimic recurrence of attacks over a given period. To achieve this, we assessed the effects of two doses of rhBDNF (40 and 80 µg/kg) administered intranasally to adult male Sprague-Dawley rats, on trigeminal hyperalgesia (by orofacial formalin test), gene expression (by rt-PCR) of neuropeptides and inflammatory cytokines in specific areas of the brain related to migraine pain. Serum levels of CGRP, PACAP, and VIP (by ELISA) were also evaluated. The effects of rhBDNF were compared with those of sumatriptan (5 mg/kg i.p), administered 1 h before the last NTG administration., Results: Both doses of rhBDNF significantly reduced NTG-induced nocifensive behavior in Phase II of the orofacial formalin test. The anti-hyperalgesic effect of intranasal high-dose rhBDNF administration in the NTG-treated animals was associated with a significant modulation of mRNA levels of neuropeptides (CGRP, PACAP, VIP) and cytokines (IL-1beta, IL-10) in the trigeminal ganglion, medulla-pons, and hypothalamic area. Of note, the effects of rhBNDF treatment were comparable to those induced by the administration of sumatriptan. rhBDNF administration at both doses significantly reduced serum levels of PACAP, while the higher dose also significantly reduced serum levels of VIP., Conclusions: The findings suggest that intranasal rhBDNF has the potential to be a safe, non-invasive and effective therapeutic approach for the treatment of primary headache, particularly migraine., (© 2024. The Author(s).)

Background: The adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine (RSVPreF3 OA) is approved in adults aged ≥60 years. We evaluated RSVPreF3 OA immunogenicity and safety in adults aged 50-59 years without or with increased risk for RSV disease due to specific chronic medical conditions., Methods: This observer-blind, phase 3, noninferiority trial included adults aged 50-59 years, stratified into 2 subcohorts: those with and those without predefined, stable, chronic medical conditions leading to an increased risk for RSV disease. Participants in both subcohorts were randomized 2:1 to receive RSVPreF3 OA or placebo. A control group of adults aged ≥60 years received RSVPreF3 OA. Primary outcomes were RSV-A and RSV-B neutralization titers (geometric mean titer ratios and sero-response rate differences) 1 month post-vaccination in 50-59-year-olds versus ≥60-year-olds. Cell-mediated immunity and safety were also assessed., Results: The exposed population included 1152 participants aged 50-59 years and 381 participants aged ≥60 years. RSVPreF3 OA was immunologically noninferior in 50-59-year-olds versus ≥60-year-olds; noninferiority criteria were met for RSV-A and RSV-B neutralization titers in those with and those without increased risk for RSV disease. Frequencies of RSVPreF3-specific polyfunctional CD4+ T cells increased substantially from pre- to 1 month post-vaccination. Most solicited adverse events had mild-to-moderate intensity and were transient. Unsolicited and serious adverse event rates were similar in all groups., Conclusions: RSVPreF3 OA was immunologically noninferior in 50-59-year-olds compared to ≥60-year-olds, in whom efficacy was previously demonstrated. The safety profile in 50-59-year-olds was consistent with that in ≥60-year-olds., Clinical Trial Registration: ClinicalTrials.gov: NCT05590403., Competing Interests: Potential conflicts of interest . H. A. H., M. d. H., B. S., S. D., M.-P. D., D. D., J. H., C. V., and V. H. are/were GSK employees at the time when the study was designed and/or conducted. H. A. H., M. d. H., B. S., S. D., M.-P. D., D. D., J. H., and V. H. hold shares in GSK as part of their employee remuneration. M.-P. D. is a co-applicant on a pending patent filed by GSK. M. F. received study-related payments for training and study conduct from GSK. T. F. S. received honoraria for lectures from AstraZeneca, Bavarian Nordic, Biogen, CSL-Seqirus, GSK, Janssen-Cilag, Merck-Serono, Moderna, Novavax, MSD, Pfizer, Roche, Sanofi-Aventis, and Takeda; he participated on advisory boards for Bavarian Nordic, CSL-Seqirus, BioNTech, GSK, Moderna, Novavax, and Takeda. S. A. N. declares study-related payments to his institution from GSK and support from GSK to attend investigators meetings. J. R.-G. declares study-related payments from GSK and honoraria and support for attending meetings and/or travel from GSK, Pfizer, and Sanofi-MSD; he also participated on data and safety monitoring boards or advisory boards from GSK and Pfizer. C. Z. received grants from GSK for the conduct of this study and support from GSK for attending meetings. J. G. declares study-related payments from GSK; grants from Novartis, Pharmalog, New Amsterdam Pharma, Syneos, Winecker Pharma, and Lilly; and consulting fees, honoraria, payment for expert testimony, and support for attending meetings and/or travel from GSK. C. V.-P. is a former employee of QPS Netherlands B.V. The other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The stress that the space environment can induce on plant physiology is of both abiotic and biotic nature. The abiotic space environment is characterized by ionizing radiation and altered gravity, geomagnetic field (GMF), pressure, and light conditions. Biotic interactions include both pathogenic and beneficial interactions. Here, we provide an overall picture of the effects of abiotic and biotic space-related factors on plant physiology. The knowledge required for the success of future space missions will lead to a better understanding of fundamental aspects of plant physiological responses, thus providing useful tools for plant breeding and agricultural practices on Earth., (© 2024. The Author(s).)

Context: Acromegaly, characterized by excessive growth hormone (GH) and insulin-like growth factor-1 (IGF-1), impacts quality of life (QoL) and mortality. Standard of care (SoC; octreotide long-acting repeatable or lanreotide autogel) treatment typically requires healthcare provider administration. CAM2029, a novel subcutaneous octreotide depot with increased bioavailability using FluidCrystal technology, enables self-administration and room-temperature storage., Objective: Assess superiority of CAM2029 versus placebo for biochemical control in patients with controlled acromegaly., Design: 24-week, multinational, randomized, double-blind, phase 3 trial (NCT04076462)., Setting: 45 sites; ten countries., Patients: 72 patients on SoC with biochemical control at screening (IGF-1 ≤upper limit of normal [ULN]; mean GH <2.5 μg/L)., Interventions: Patients were randomized 2:1 to once-monthly CAM2029 (n=48) or placebo (n=24)., Main Outcome Measures: Primary endpoint was proportion of patients with IGF-1 ≤ULN (Week 22/24 mean), with dose-reduced patients classified as non-responders; first key secondary endpoint was the same, including dose-reduced responders. Second key secondary endpoint was proportion of patients with IGF-1 ≤ULN (Week 22/24) and mean GH <2.5 μg/L (Week 24)., Results: At Week 22/24 (intention-to-treat analysis), CAM2029-treated patients demonstrated superior response rates versus placebo for IGF-1 (72.2% versus 37.5%; risk difference: 34.6, 95% confidence interval: 11.3, 57.9; p=0.0018), and combined IGF-1/GH (70.0% versus 37.5%; p=0.0035). CAM2029-treated patients had well-controlled symptoms, improved QoL and treatment satisfaction versus placebo and baseline. CAM2029 was well tolerated; safety was consistent with SoC., Conclusions: CAM2029 provides a convenient and effective treatment option for acromegaly, with superior biochemical control versus placebo. Symptom control, QoL and satisfaction were improved from baseline SoC., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms., (© 2024. The Author(s).)

Background: Early-life antibiotic exposure is disproportionately high compared to the burden of culture-proven early-onset sepsis (CP-EOS). We assessed the contribution of culture-negative cases to the overall antibiotic exposure in the first postnatal week., Methods: We conducted a retrospective analysis across eleven countries in Europe, North America, and Australia. All late-preterm and term infants born between 2014 and 2018 who received intravenous antibiotics during the first postnatal week were classified as culture-negative cases treated for ≥5 days (CN ≥ 5d), culture-negative cases treated for <5 days (CN < 5d), or CP-EOS cases., Results: Out of 757,979 infants, 21,703 (2.9%) received intravenous antibiotics. The number of infants classified as CN ≥ 5d, CN < 5d, and CP-EOS was 7996 (37%), 13,330 (61%), and 375 (1.7%). The incidence of CN ≥ 5d, CN < 5d, and CP-EOS was 10.6 (95% CI 10.3-10.8), 17.6 (95% CI 17.3-17.9), and 0.49 (95% CI 0.44-0.54) cases per 1000 livebirths. The median (IQR) number of antibiotic days administered for CN ≥ 5d, CN < 5d, and CP-EOS was 77 (77-78), 53 (52-53), and 5 (5-5) per 1000 livebirths., Conclusions: CN ≥ 5d substantially contributed to the overall antibiotic exposure, and was 21-fold more frequent than CP-EOS. Antimicrobial stewardship programs should focus on shortening antibiotic treatment for culture-negative cases., Impact: In a study of 757,979 infants born in high-income countries, we report a presumed culture-negative early-onset sepsis incidence of 10.6/1000 livebirths with an associated antibiotic exposure of 77 antibiotic days per 1000 livebirths. This study sheds light on the major contribution of presumed culture-negative early-onset sepsis to early-life antibiotic exposure. Given the diagnostic uncertainty surrounding culture-negative early-onset sepsis, the low mortality rate, and the disproportionate antibiotic exposure associated with this condition, our study emphasizes the importance of targeting culture-negative early-onset sepsis in antimicrobial stewardship programs., Competing Interests: Competing interests: Alberto Berardi reported receiving personal fees from Atheneum Partners, GmbH outside the submitted work. Joseph M. Bliss reported receiving personal fees from Mead Johnson Nutrition outside the submitted work. No other disclosures were reported., (© 2024. The Author(s).)

Background and Objective: High-resolution micro-ultrasound (microUS) is an advanced imaging tool. Our objective was to determine whether systematic microUS use for transrectal biopsy (TRBx) improves the detection rate for clinically significant prostate cancer (csPCa) in comparison to transperineal biopsy (TPBx) performed with magnetic resonance imaging (MRI)/conventional transrectal ultrasound (TRUS) fusion software., Methods: We retrospectively analyzed data for men who underwent prostate biopsies, including those on active surveillance (AS). TRBx was performed under microUS guidance, while MRI/TRUS fusion was consistently used to guide TPBx. Patients were matched according to propensity score matching (PSM). The primary endpoint was comparison of the csPCa detection rate with the two approaches. Secondary endpoints included predictors of csPCa (International Society of Urological Pathology grade group ≥2, assessed via multivariable logistic regression) and complication rates., Key Findings and Limitations: Overall, 1423 patients were enrolled. After applying PSM we identified an analytical cohort of 1094 men, 582 in the TRBx group and 512 in the TPBx group. There was no significant difference in the csPCa detection rate between the TRBx (45%) and TPBx (51%) groups ( p  = 0.07). Complications occurred in nine of 1094 patients (1%). On adjusted multivariable analysis, TPBx had a similar csPCa detection rate to TRBx (adjusted odds ratio [aOR] 1.26; p  = 0.09). Predictors of csPCa detection were a positive family history (aOR 1.68; 95% confidence interval [CI] 1.20-2.35; p  = 0.002); age (aOR 1.04, 95% CI 1.02-1.06; p  < 0.001); positive digital rectal examination (aOR 2.35, 95% CI 1.70-3.25; p  < 0.001); prostate-specific antigen density ≥0.15 ng/ml/cm 3 (aOR 3.23, 95% CI 2.47-4.23; p  < 0.001); and a Prostate Imaging-Reporting and Data System score ≥3 (aOR 2.46; 95% CI 1.83-3.32; p  < 0.001). Limitations include the retrospective nature of the study, the risk of underestimating the complication rate, and the heterogeneity of biopsy indications., Conclusions and Clinical Implications: TRBx using microUS alone showed a comparable csPCa detection rate to TPBx guided by MRI/TRUS fusion software. Given the better visualization and real-time detection of suspicious zones with microUS, the potential for improvement in the csPCa detection rate with greater integration of microUS in the TPBx setting warrants further investigation., Patient Summary: We compared the ability of two different prostate biopsy approaches to detect clinically significant prostate cancer. We found that transrectal biopsy guided by micro-ultrasound had similar detection rates to transperineal biopsy guided by a combination of magnetic resonance imaging and conventional ultrasound. More research is needed to confirm the potential of micro-ultrasound for transperineal biopsy., (© 2024 The Author(s).)

Photon counting computed tomography (PCCT) represents a paradigm shift from conventional CT imaging, propelled by a new generation of X-ray detectors capable of counting individual photons and measuring their energy. The first part of this narrative review is focused on the technical aspects of PCCT and describes its key advancements and benefits compared to conventional CT but also its limitations. By synthesizing the existing literature, the second part of the review seeks to elucidate the potential of PCCT as a valuable tool for assessing carotid artery disease. Thanks to the enhanced spatial resolution and image quality, PCCT allows for an accurate evaluation of carotid luminal stenosis. With its ability to finely discriminate between different tissue types, PCCT allows for detailed characterization of plaque morphology and composition, which is crucial for assessing plaque vulnerability and the risk of cerebrovascular events.

Importance: A multicenter randomized clinical trial (RCT) showed a lung recruitment maneuver using high-frequency oscillatory ventilation just before surfactant administration (ie, intubate-recruit-surfactant-extubate [IN-REC-SUR-E]) improved the efficacy of treatment compared with the standard intubate-surfactant-extubate (IN-SUR-E) technique without increasing the risk of adverse neonatal outcomes., Objective: To examine follow-up outcomes at corrected postnatal age (cPNA) 2 years of preterm infants previously enrolled in an RCT and treated with IN-REC-SUR-E or IN-SUR-E in 35 tertiary neonatal intensive care units., Design, Setting, and Participants: This was a follow-up study of infants recruited into the primary RCT from 2015 to 2018 at 35 tertiary neonatal intensive care units (NICUs) in Italy. Follow-up examinations included neurodevelopmental, growth, and respiratory outcomes of these children at cPNA 2 years. Participants included spontaneously breathing extremely preterm neonates (24 0/7 to 27 6/7 weeks' gestation) reaching failure criteria for continuous positive airway pressure within the first 24 hours of life. Data were analyzed from April 2023 to January 2024., Intervention: Infants were randomly assigned (1:1) to IN-REC-SUR-E or IN-SUR-E and then followed up., Main Outcomes and Measures: The primary outcome was the occurrence of death after discharge or major disability at cPNA 2 years. Secondary outcomes were neurodevelopmental outcomes (major disability, cerebral palsy, cognitive impairment, visual deficit, or auditory deficit), anthropometric measurements (weight, length, and head circumference), and recurrent respiratory infections and hospitalizations because of respiratory causes at 2y cPNA., Results: A total of 137 extremely preterm infants (median [IQR] gestational age, 26.5 [25.3-27.5] weeks and 75 [54.7%] female), initially enrolled in the original RCT, were followed up at cPNA 2 years, including 64 infants in the IN-SUR-E group and 73 infants in the IN-REC-SUR-E group. There were no significant differences in the occurrence of death after discharge or major disability at cPNA 2 years (IN-SUR-E: 13 children [20.3%] vs IN-REC-SUR-E: 10 children [13.7%]; P = .36). There were no significant differences in incidence of disability, cerebral palsy, or cognitive impairment in the IN-REC-SUR-E group compared with the IN-SUR-E group. There were no significant differences in anthropometric measurements (weight, length, and head circumference) between groups. There were no significant differences in the incidence of recurrent respiratory infections or in hospitalizations because of respiratory causes between groups., Conclusions and Relevance: In this RCT of lung recruitment before surfactant vs standard care there were no significant differences between the 2 groups in death, neurodevelopmental outcomes, anthropometric measurements, or recurrent respiratory infections at the 2-year follow-up. These findings can aid clinicians in decision-making for the best strategy to administer surfactant, considering long-term outcomes.

Lymph node (LN) fine-needle aspiration cytology (FNAC) is a common diagnostic procedure for lymphadenopathies. Despite the qualities and potentialities of LN-FNAC, the number of possible pathologies and the variety of clinical contexts represent a challenge and require a continuous upgrading of the procedure according to the emerging clinical requests and new technologies. This study presents an overview of the current and future impact of LN-FNAC on the care of patients with lymphadenopathy., Competing Interests: Disclosure The authors have not to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Glucagon-like peptide-1 (GLP-1) receptor agonists have gained widespread use in the treatment of individuals with type 2 diabetes because of their potent weight loss promoting effect, ability to augment β-cell function, and cardiovascular protective effects. However, despite causing impressive weight loss, GLP-1 receptor agonists do not normalise insulin sensitivity in people with type 2 diabetes and obesity, and the long-term effects of this class of antidiabetic medication on muscle mass, frailty, and bone density have been poorly studied. Although GLP-1 receptor agonists improve insulin sensitivity secondary to weight loss, the only true direct insulin-sensitising drugs are thiazolidinediones. Because of side-effects associated with type 2 diabetes therapy, these drugs have not gained widespread use. In lieu of the important role of insulin resistance in the cause of type 2 diabetes and in the pathogenesis of atherosclerotic cardiovascular disease in type 2 diabetes, development of potent insulin-sensitising drugs that can be used in combination with GLP-1 receptor agonists remains a large unmet need in the management of individuals with type 2 diabetes., Competing Interests: Declaration of interests RAD is on advisory boards for AstraZeneca, Novo Nordisk, Boehringer Ingelheim, Intarcia, Aardvark, Renalytix, CORCEPT, and Alnylam; has received research grants from Boehringer Ingelheim, AstraZeneca, 89Bio, Amgen, Medality, and CORCEPT; and is a member of speakers bureaus for AstraZeneca, CORCEPT, and Renalytix. All other authors declare no competing interests., (Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Pregnancy represents a stress test for every woman's cardiovascular (CV) system, and a pre-existing maternal unfavorable cardio-metabolic phenotype can uncover both adverse pregnancy outcomes and the subsequent development of cardiovascular disease (CVD) risk factors during and after pregnancy. Moreover, the maternal cardiac and extracardiac environment can affect offspring's cardiovascular health through a complex mechanism called developmental programming, in which fetal growth can be influenced by maternal conditions. This interaction continues later in life, as adverse developmental programming, along with lifestyle risk factors and genetic predisposition, can exacerbate and accelerate the development of CV risk factors and CVD in childhood and adolescence. The aim of this narrative review is to summarize the latest evidences regarding maternal-fetal dyad and its role on primordial, primary and secondary CV prevention., 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 Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) recommendations standardise the reporting of prostate magnetic resonance imaging (MRI) in patients on active surveillance (AS) for prostate cancer. An international consensus group recently updated these recommendations and identified the areas of uncertainty., Methods: A panel of 38 experts used the formal RAND/UCLA Appropriateness Method consensus methodology. Panellists scored 193 statements using a 1-9 agreement scale, where 9 means full agreement. A summary of agreement, uncertainty, or disagreement (derived from the group median score) and consensus (determined using the Interpercentile Range Adjusted for Symmetry method) was calculated for each statement and presented for discussion before individual rescoring., Key Findings and Limitations: Participants agreed that MRI scans must meet a minimum image quality standard (median 9) or be given a score of 'X' for insufficient quality. The current scan should be compared with both baseline and previous scans (median 9), with the PRECISE score being the maximum from any lesion (median 8). PRECISE 3 (stable MRI) was subdivided into 3-V (visible) and 3-NonV (nonvisible) disease (median 9). Prostate Imaging Reporting and Data System/Likert ≥3 lesions should be measured on T2-weighted imaging, using other sequences to aid in the identification (median 8), and whenever possible, reported pictorially (diagrams, screenshots, or contours; median 9). There was no consensus on how to measure tumour size. More research is needed to determine a significant size increase (median 9). PRECISE 5 was clarified as progression to stage ≥T3a (median 9)., Conclusions and Clinical Implications: The updated PRECISE recommendations reflect expert consensus opinion on minimal standards and reporting criteria for prostate MRI in AS., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Recent advancements in computer-assisted diagnosis (CAD) have catalysed significant progress in pathology, particularly in the realm of urine cytopathology. This review synthesizes the latest developments and challenges in CAD for diagnosing urothelial carcinomas, addressing the limitations of traditional urinary cytology. Through a literature review, we identify and analyse CAD models and algorithms developed for urine cytopathology, highlighting their methodologies and performance metrics. We discuss the potential of CAD to improve diagnostic accuracy, efficiency and patient outcomes, emphasizing its role in streamlining workflow and reducing errors. Furthermore, CAD tools have shown potential in exploring pathological conditions, uncovering novel biomarkers and prognostic/predictive features previously unknown or unseen. Finally, we examine the practical issues surrounding the integration of CAD into clinical practice, including regulatory approval, validation and training for pathologists. Despite the promising results, challenges remain, necessitating further research and validation efforts. Overall, CAD presents a transformative opportunity to revolutionize diagnostic practices in urine cytopathology, paving the way for enhanced patient care and outcomes., (© 2024 John Wiley & Sons Ltd.)

Background and Objective: The introduction of photon-counting computed tomography (PCCT) represents the most recent groundbreaking advancement in clinical computed tomography (CT). PCCT has the potential to overcome the limitations of traditional CT and to provide new quantitative imaging information. This narrative review aims to summarize the technical principles, benefits, and challenges of PCCT and to provide a concise yet comprehensive summary of the applications of PCCT in the domain of coronary imaging., Methods: A review of PubMed, Scopus, and Google Scholar was performed until October 2023 by using relevant keywords. Articles in English were considered., Key Content and Findings: The main advantages of PCCT over traditional CT are enhanced spatial resolution, improved signal and contrast characteristics, diminished electronic noise and image artifacts, lower radiation exposure, and multi-energy capability with enhanced material discrimination. These key characteristics have made room for improved assessment of plaque volume and severity of stenosis, more precise assessment of coronary artery calcifications, also preserved in the case of a reduced radiation dose, improved assessment of plaque composition, possibility to provide details regarding the biological processes occurring within the plaque, enhanced quality and accuracy of coronary stent imaging, and improved radiomic analyses., Conclusions: PCCT can significantly impact diagnostic and clinical pathways and improve the management of patients with coronary artery diseases (CADs)., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-52/coif). F.C. and L.S. serve as unpaid editorial board members of Cardiovascular Diagnosis and Therapy from September 2023 to August 2025. The other authors have no conflicts of interest to declare., (2024 Cardiovascular Diagnosis and Therapy. All rights reserved.)

This paper outlines the protocol for the deployment of a cloud-based universal medical image repository system. The proposal aims not only at the deployment but also at the automatic expansion of the platform, incorporating Artificial Intelligence (AI) for the analysis of medical image examinations. The methodology encompasses efficient data management through a universal database, along with the deployment of various AI models designed to assist in diagnostic decision-making. By presenting this protocol, the goal is to overcome technical challenges and issues that impact all phases of the workflow, from data management to the deployment of AI models in the healthcare sector. These challenges include ethical considerations, compliance with legal regulations, establishing user trust, and ensuring data security. The system has been deployed, with a tested and validated proof of concept, possessing the capability to receive thousands of images daily and to sustain the ongoing deployment of new AI models to expedite the analysis process in medical image exams., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pacheco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This paper presents an artificial intelligence-based classification model for the detection of pulmonary embolism in computed tomography angiography. The proposed model, developed from public data and validated on a large dataset from a tertiary hospital, uses a two-dimensional approach that integrates temporal series to classify each slice of the examination and make predictions at both slice and examination levels. The training process consists of two stages: first using a convolutional neural network InceptionResNet V2 and then a recurrent neural network long short-term memory model. This approach achieved an accuracy of 93% at the slice level and 77% at the examination level. External validation using a hospital dataset resulted in a precision of 86% for positive pulmonary embolism cases and 69% for negative pulmonary embolism cases. Notably, the model excels in excluding pulmonary embolism, achieving a precision of 73% and a recall of 82%, emphasizing its clinical value in reducing unnecessary interventions. In addition, the diverse demographic distribution in the validation dataset strengthens the model's generalizability. Overall, this model offers promising potential for accurate detection and exclusion of pulmonary embolism, potentially streamlining diagnosis and improving patient outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Vitamin K is an essential dietary cofactor required for the synthesis of active forms of vitamin K-dependent procoagulant proteins. Vitamin K deficiency, particularly late-onset deficiency occurring between 1 week and 6 months of age, can cause a life-threatening bleeding disorder. An exclusively breastfed, full-term, 6-week-old infant male presented with severe haemorrhagic shock and multi-system organ failure related to caregiver refusal of intramuscular vitamin K after birth. Coagulation studies were normalised within 8 hours of intramuscular vitamin K administration. An increasing number of caregivers are refusing intramuscular vitamin K which has led to a rise in the incidence of vitamin K deficiency bleeding. Health policy organisations around the world emphasise the benefits of intramuscular vitamin K and risks of refusal, particularly in exclusively breastfed infants who are at higher risk due to low vitamin K levels in breast milk. This case highlights the multi-system severity of this life-threatening yet preventable disorder., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The accurate measurement of three-dimensional (3D) fiber orientation in the brain is crucial for reconstructing fiber pathways and studying their involvement in neurological diseases. Comprehensive reconstruction of axonal tracts and small fascicles requires high-resolution technology beyond the ability of current in vivo imaging (e.g. diffusion magnetic resonance imaging). Optical imaging methods such as polarization-sensitive optical coherence tomography (PS-OCT) and polarization microscopy can quantify fiber orientation at micrometer resolution but have been limited to two-dimensional in-plane orientation or thin slices, preventing the comprehensive study of connectivity in 3D. In this work we present a novel method to quantify volumetric 3D orientation in full angular space with PS-OCT. We measure the polarization contrasts of the brain sample from two illumination angles of 0 and 15 degrees and apply a computational method that yields the 3D optic axis orientation and true birefringence. We further present 3D fiber orientation maps of entire coronal cerebrum sections and brainstem with 10 μm in-plane resolution, revealing unprecedented details of fiber configurations. We envision that our method will open a promising avenue towards large-scale 3D fiber axis mapping in the human brain as well as other complex fibrous tissues at microscopic level., Competing Interests: Disclosures B.F. is a medical advisor to DeepHealth, a company whose medical pursuits focus on imaging and measurement technologies. B.F.’s interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their conflict-of-interest policies. Additional Declarations: Competing interest reported. B.F. is a medical advisor to DeepHealth, a company whose medical pursuits focus on imaging and measurement technologies. B.F.’s interests were reviewed and are managed by MGH and Partners HealthCare in accordance with their conflict-of-interest policies.

COQ7 pathogenetic variants cause primary CoQ 10 deficiency and a clinical phenotype of encephalopathy, peripheral neuropathy, or multisystemic disorder. Early diagnosis is essential for promptly starting CoQ 10 supplementation. Here, we report novel compound heterozygous variants in the COQ7 gene responsible for a prenatal onset (20 weeks of gestation) of hypertrophic cardiomyopathy and intestinal dysmotility in a Bangladesh consanguineous family with two affected siblings. The main clinical findings were dysmorphisms, recurrent intestinal occlusions that required ileostomy, left ventricular non-compaction cardiomyopathy, ascending aorta dilation, arterial hypertension, renal dysfunction, diffuse skin desquamation, axial hypotonia, neurodevelopmental delay, and growth retardation. Exome sequencing revealed compound heterozygous rare variants in the COQ7 gene, c.613&#95;617delGCCGGinsCAT (p.Ala205HisfsTer48) and c.403A>G (p.Met135Val). In silico analysis and functional in vitro studies confirmed the pathogenicity of the variants responsible for abolished activities of complexes I + III and II + III in muscle homogenate, severe decrease of CoQ 10 levels, and reduced basal and maximal respiration in patients' fibroblasts. The first proband deceased at 14 months of age, whereas supplementation with a high dose of CoQ 10 (30 mg/kg/day) since the first days of life modified the clinical course in the second child, showing a recovery of milestones acquirement at the last follow-up (18 months of age). Our study expands the clinical spectrum of primary CoQ 10 deficiency due to COQ7 gene defects and highlights the essential role of multidisciplinary and combined approaches for a timely diagnosis., (© 2024. The Author(s).)

Background: In the neonatal intensive care unit (NICU), elevated noise negatively impacts the neurodevelopmental environment, interrupts sleep, and can affect brain development in neonates. The American Academy of Pediatrics recommends that noise levels in the NICU should not exceed 45 dB., Purpose: The project aims were to: (1) decrease average noise level by 10% from baseline and (2) decrease exposure to severe noise (>65 dB) to <5% of the time., Methods: This quality improvement project was conducted during 2021-2022 as a pre/post observational design in a Level IV NICU in New York City. We monitored sound levels for 20-24 h, 5 d/wk. Quality improvement interventions included: novel approaches to staff education, visual cues for when noise thresholds were exceeded, parent education, including access to personal decibel meters, technical improvements to vital sign monitors and entry doors, and defined quiet times (HUSH) for 2 h each 12-hour shift., Results: Education efforts and technical improvements successfully reduced median noise levels within the stepdown unit ( P < .001), though not in the acute care NICU. In contrast, the implementation of 2-hour periods of enforced "quiet time" every 12 h effectively reduced both median noise levels and the incidence of severe noise (>65 dB) in both locations., Implications for Practice and Research: The HUSH strategy may be a sustainable way to decrease noise in the NICU. Future projects should prioritize education and dedicated quiet times to align with recommended standards, while research should explore the long-term developmental impacts of excessive noise levels on neonatal growth., Competing Interests: The authors declare no conflict of interest and no relevant financial interest or affiliation with any commercial interests related to the subjects discussed within this article. No grant or financial support for the implementation of this project. The authors declare no conflicts of interest., (Copyright © 2024 by The National Association of Neonatal Nurses.)

Introduction: The demand for effective and safe treatments of genitourinary syndrome (GSM) in post-menopausal women (PMW) is growing. Published data on the efficacy and safety of ospemifene (OSP) prompt an updated literature review to enlighten possible improvements in the GSM treatment., Area Covered: We searched articles published in English from 2010 to 2023 through Medline (PubMed) and Embase databases with Boolean terms: OSP, PMW, GSM, endometrium, breast cancer, cardiometabolic syndrome, bone metabolism, adherence to treatment, and patient satisfaction. We selected randomized controlled trials (RCTs) and observational and cross-sectional studies and completed the search manually., Expert Opinion: Of the 157 retrieved records, 25 primary studies met the inclusion criteria (15 regarding efficacy and safety, two for additional effects, and four for adherence and satisfaction with the OSP treatment). Seven RCTs involved nearly 5,000 patients, 10 out of 18 prospective observational studies 563, and six retrospective analyses 356,439. Evidence of OSP treatment in PMW with GSM relies on RCTs and remarkable real-world data. The 25 primary studies showcased the high clinical response to symptoms, the favorable safety profile of OSP with very few adverse events, a neutral impact on the endometrium, breast, bone, and thrombosis, and the possible improvement of cardiovascular risk factors.

Melanomas originating within the urinary tract represent a rare and clinically challenging subset of malignancies. Despite extensive research on cutaneous melanomas, urinary tract melanomas remain relatively unexplored, presenting diagnostic dilemmas and limited treatment consensus. In this comprehensive review, we synthesize current knowledge on the epidemiology, risk factors, clinical presentation, histopathological characteristics, and treatment strategies specific to this disease. Enhancing clinical awareness, refining diagnostic approaches, and exploring novel therapeutic interventions hold promise for improving outcomes in this challenging malignancy subset., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Di(ethylhexyl) phthalate (DEHP) is a ubiquitous environmental contaminant to which humans are exposed via multiple routes. Human health risk assessments for this substance have recently been updated, focusing on reproductive toxicity, including DEHP, in the list of chemicals classified as carcinogenic, mutagenic, or toxic to reproduction (CMR). Moreover, DEHP has also been defined as probably and possibly carcinogenic to humans based on its carcinogenicity in rodents. However, the mechanism of action of DEHP and its relevance in humans remain unclear. Rodent data suggests that DEHP induces cancer through non-genotoxic mechanisms related to multiple molecular signals, including PPARα activation, perturbation of fatty acid metabolism, induction of cell proliferation, decreased apoptosis, production of reactive oxygen species, and oxidative stress. According to the DEHP toxicological dataset, several in vitro cell transformation assays have been performed using different protocols and cellular models to produce different results. This study aimed to evaluate the carcinogenic potential of DEHP by using the A31-1-1 BALB/c-3T3 cell line in a standard cell transformation assay. Additionally, transcriptomic analysis was performed to explore the molecular responses and identify the affected toxicological pathways. Although DEHP treatment did not induce transformation in BALB/c-3T3 cells, the transcriptomic results revealed significant modulation of several pathways associated with DEHP metabolism, tissue-specific functions related to systemic metabolism, and basal cellular signaling with pleiotropic outcomes. Among these signaling pathways, modulation of cell-regulating signaling pathways, such as Notch, Wnt, and TGF-β, can be highlighted. More specific modulation of such genes and pathways with double functions in metabolism and neurophysiology underlies the well-known crosstalk that may be crucial for the mechanism of action of DEHP. Our findings offer evidence to support the notion that these models are effective in minimizing the use of animal testing for toxicity assessment., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Pillo, Aldrovandi, Mescoli, Maffei, Mascolo, Vaccari and Colacci.)

To understand the reactivity of resonantly stabilized radicals, often found in relevant concentrations in gaseous environments, it is important to determine their main reaction pathways. Here, it is investigated whether the fulvenallenyl radical (C 7 H 5 · ) reacts preferentially with closed-shell molecules or radicals. Electronic structure calculations on the C 10 H 9 potential energy surface accessed by the reactions of C 7 H 5 · with methylacetylene (CH 3 CCH) and allene (H 2 CCCH 2 ) were combined with RRKM-ME calculations of temperature- and pressure-dependent rate constants using the automated EStokTP software suite and kinetic modeling to assess the reactivity of C 7 H 5 · with closed-shell unsaturated hydrocarbons. Experimentally, the reactions were attempted in a chemical microreactor heated to 998 ± 10 K by preparing fulvenallenyl radicals via pyrolysis of trichloromethylbenzene (C 7 H 5 Cl 3 ) and seeding the radicals in methylacetylene or allene carrier gas, with product identification by means of photoionization mass spectrometry. The measured photoionization efficiency curve of m / z = 128 was assigned to a linear combination of the reference curves of two C 10 H 8 isomers, azulene (minor) and naphthalene (major), presumably resulting from the C 7 H 5 · plus C 3 H 4 reactions. However, the calculations demonstrated that these reactions are too slow, and kinetic modeling of processes in the reactor allowed us to conclude that the observation of naphthalene and azulene is due to the C 7 H 5 · plus C 3 H 3 · reaction, where propargyl is produced by direct hydrogen atom abstraction by chlorine (Cl) atoms from allene or methylacetylene and Cl stem from the pyrolysis of C 7 H 5 Cl 3 . Modeling results under the copyrolysis conditions of toluene and methylacetylene in high-temperature shock tube experiments confirmed the prevalence of the fulvenallenyl reaction with propargyl over its reactions with C 3 H 4 even when the concentrations of allene and methylacetylene largely exceed that of propargyl. Overall, the reactions of fulvenallenyl with both allene and methylacetylene were found to be noncompetitive in the formation of naphthalene and azulene thus attesting the inefficiency of the fulvenallenyl radical reactions with the prototype closed-shell hydrocarbon species. In the meantime, the new reaction pathways revealed, including H-assisted isomerizations between C 10 H 8 isomers and decomposition reactions of various C 10 H 9 isomers, emerge as relevant and are recommended for inclusion in combustion kinetic models for naphthalene formation.

Cullin-1-RING ubiquitin ligases (CRL1) or SCF1 (SKP1-CUL1-RBX1) E3 ubiquitin ligases are the largest and most extensively investigated class of E3 ligases in mammals that regulate fundamental processes, such as the cell cycle and proliferation. These enzymes are multiprotein complexes comprising SKP1, CUL1, RBX1, and an F-box protein that acts as a specificity factor by interacting with SKP1 through its F-box domain and recruiting substrates via other domains. E3 ligases are important players in the ubiquitination process, recognizing and transferring ubiquitin to substrates destined for degradation by proteasomes or processing by deubiquitinating enzymes. The ubiquitin-proteasome system (UPS) is the main regulator of intracellular proteolysis in eukaryotes and is required for parasites to alternate hosts in their life cycles, resulting in successful parasitism. Leishmania UPS is poorly investigated, and CRL1 in L. infantum, the causative agent of visceral leishmaniasis in Latin America, is yet to be described. Here, we show that the L. infantum genes LINF&#95;110018100 (SKP1-like protein), LINF&#95;240029100 (cullin-like protein-like protein), and LINF&#95;210005300 (ring-box protein 1 -putative) form a LinfCRL1 complex structurally similar to the H. sapiens CRL1. Mass spectrometry analysis of the LinfSkp1 and LinfCul1 interactomes revealed proteins involved in several intracellular processes, including six F-box proteins known as F-box-like proteins (Flp) (data are available via ProteomeXchange with identifier PXD051961). The interaction of LinfFlp 1-6 with LinfSkp1 was confirmed, and using in vitro ubiquitination assays, we demonstrated the function of the LinfCRL1(Flp1) complex to transfer ubiquitin. We also found that LinfSKP1 and LinfRBX1 knockouts resulted in nonviable L. infantum lineages, whereas LinfCUL1 was involved in parasite growth and rosette formation. Finally, our results suggest that LinfCul1 regulates the S phase progression and possibly the transition between the late S to G2 phase in L. infantum. Thus, a new class of E3 ubiquitin ligases has been described in L. infantum with functions related to various parasitic processes that may serve as prospective targets for leishmaniasis treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Rolemberg Santana Travaglini Berti de Correia et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lessons conducted in hospitals ensure school continuity for hospitalized children unable to attend regular school. Hospital-based school (HS) provides a tailored experience that ensures normality for children through education. The objective of this study is to evaluate the effects of the proposed lessons in reducing negative emotions, distress, and pain in children, as well as fostering positive affects. The study was conducted with 32 hospitalized children, aged 8-12 years, in the Onco-Hematology and Pediatric Unit of Meyer Children's Hospital IRCCS (Florence, Italy). Positive and negative emotions were measured using the Positive and Negative Affect Scale for Children ; distress was measured using the Physiological Hyperarousal for Children ; pain was measured using the Visual Analogue Scale for children. Variables were assessed before (T0) and after (T1) lessons, for three times; for each variable, collected data were averaged at both T0 and T1. Statistical analyses showed a significant increase in positive emotions in hospitalized children and a significant decrease in negative emotions, distress, and pain; nevertheless, only for pain the significant correlation between its scores before and after the HS lessons indicated that the detected change occurred for all participants in much the same way. These preliminary results suggest that HS lessons can promote hospitalized children's well-being, at least as far as pain reduction is concerned., Competing Interests: The authors have no competing interests to declare., (Copyright: © 2024 The Author(s).)