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High-grade gliomas (HGGs) and glioblastoma multiforme (GBM) are characterized by a heterogeneous and aggressive population of tissue-infiltrating cells that promote both destructive tissue remodeling and aberrant vascularization of the brain. The formation of defective and permeable blood vessels and microchannels and destructive tissue remodeling prevent efficient vascular delivery of pharmacological agents to tumor cells and are the significant reason why therapeutic chemotherapy and immunotherapy intervention are primarily ineffective. Vessel-forming endothelial cells and microchannel-forming glial cells that recapitulate vascular mimicry have both infiltration and destructive remodeling tissue capacities. The transmembrane protein TMEM230 (C20orf30) is a master regulator of infiltration, sprouting of endothelial cells, and microchannel formation of glial and phagocytic cells. A high level of TMEM230 expression was identified in patients with HGG, GBM, and U87-MG cells. In this study, we identified candidate genes and molecular pathways that support that aberrantly elevated levels of TMEM230 play an important role in regulating genes associated with the initial stages of cell infiltration and blood vessel and microchannel (also referred to as tumor microtubule) formation in the progression from low-grade to high-grade gliomas. As TMEM230 regulates infiltration, vascularization, and tissue destruction capacities of diverse cell types in the brain, TMEM230 is a promising cancer target for heterogeneous HGG tumors.

By adolescence, two-thirds of youth report exposure to at least one traumatic event, yet the impact of trauma history is not routinely considered when evaluating the effect of psychotherapeutic interventions. Trauma may be a particularly important moderator of the effects of transdiagnostic therapies for emotional disorders, as trauma exposure is associated with risk for the development of comorbid depression and anxiety. The current study examined the history of trauma exposure and the presence of clinically significant depression as moderators of treatment outcomes in the Brief Behavioral Therapy (BBT) trial, the largest study of transdiagnostic psychotherapy for youth. Youths (age 8-16 years) were randomized to BBT (n = 89) based in pediatric primary care or assisted referral to outpatient community care (ARC; n = 86). Clinical response, functioning, anxiety symptoms, and depression symptoms were assessed at post-treatment (Week 16) and at follow-up (Week 32). A significant three-way interaction emerged between the treatment group, comorbid depression, and trauma exposure. BBT was broadly effective for 3/4 of the sample, but, for anxious-depressed youth with trauma exposure, BBT never significantly separated from ARC. Differences in outcome were not accounted for by other participant characteristics or by therapist-rated measures of alliance, youth engagement, or homework completion. Implications for models of learning and for intervention theory and development are discussed., (© 2024. The Author(s).)

Background: SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC., Methods: At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo., Results: We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes., Conclusions: These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC., (© 2024. The Author(s).)

Background: Endovascular management of portal vein thrombosis (PVT) is challenging. Transsplenic access (TSA) is growing as an access option to the portal system but with higher rates of bleeding complications. The aim of this article is to evaluate the efficacy and safety of transsplenic portal vein recanalization (PVR) using a metallic stent after pediatric liver transplantation., Materials and Methods: This is a retrospective review of 15 patients with chronic PVT who underwent PVR via TSA between February 2016 and December 2020. Two children who had undergone catheterization of a mesenteric vein tributary by minilaparotomy were excluded from the patency analysis but included in the splenic access analysis. The technical and clinical success of PVR and complications related to the procedure via TSA were evaluated., Results: Thirteen children with PVT were treated primarily using the TSA. The mean age was 4.1 years (range, 1.5-13.7 years), and the most common clinical presentation was hypersplenism (60%). Technically successful PVR was performed in 11/13 (84.6%) children, and clinical success was achieved in 9/11 (81.8%) children. No major complications were observed, and one child presented moderate pain in the TSA (from a total of 17 TSA). The median follow-up was 48.2 months. The median primary patency was 9.9 months. Primary patency in the first 4 years was 75%, and primary assisted patency was 100% in the follow-up period., Conclusions: Transsplenic PVR is a safe and effective method for the treatment of PVT after pediatric liver transplantation., (© 2023 Wiley Periodicals LLC.)

Background: Telemedicine, a term that encompasses several applications and tasks, generally involves the remote management and treatment of patients by physicians. It is known as transversal telemedicine when practiced among health care professionals (HCPs)., Objective: We describe the experience of implementing our telemedicine Eumeda platform for HCPs over the last 10 years., Methods: A web-based informatics platform was developed that had continuously updated hypertext created using advanced technology and the following features: security, data insertion, dedicated software for image analysis, and the ability to export data for statistical surveys. Customizable files called "modules" were designed and built for different fields of medicine, mainly in the ophthalmology subspecialty. Each module was used by HCPs with different authorization profiles., Implementation (results): Twelve representative modules for different projects are presented in this manuscript. These modules evolved over time, with varying degrees of interconnectivity, including the participation of a number of centers in 19 cities across Italy. The number of HCP operators involved in each single module ranged from 6 to 114 (average 21.8, SD 28.5). Data related to 2574 participants were inserted across all the modules. The average percentage of completed text/image fields in the 12 modules was 65.7%. All modules were evaluated in terms of access, acceptability, and medical efficacy. In their final evaluation, the participants judged the modules to be useful and efficient for clinical use., Conclusions: Our results demonstrate the usefulness of the telemedicine platform for HCPs in terms of improved knowledge in medicine, patient care, scientific research, teaching, and the choice of therapies. It would be useful to start similar projects across various health care fields, considering that in the near future medicine as we know it will completely change., (©Claudio Azzolini, Elias Premi, Simone Donati, Andrea Falco, Aldo Torreggiani, Francesco Sicurello, Andreina Baj, Lorenzo Azzi, Alessandro Orro, Giovanni Porta, Giovanna Azzolini, Marco Sorrentino, Paolo Melillo, Francesco Testa, Francesca Simonelli, Gianfranco Giardina, Umberto Paolucci. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 26.01.2024.)

TMEM230 promotes antigen processing, trafficking, and presentation by regulating the endomembrane system of membrane bound organelles (lysosomes, proteosomes and mitochondria) and phagosomes. Activation of the immune system requires trafficking of various cargos between the endomembrane system and cell plasma membrane. The Golgi apparatus is the hub of the endomembrane system and essential for the generation, maintenance, recycling, and trafficking of the components of the endomembrane system itself and immune system. Intracellular trafficking and secretion of immune system components depend on mitochondrial metalloproteins for ATP synthesis that powers motor protein transport of endomembrane cargo. Glycan modifying enzyme genes and motor proteins are essential for the activation of the immune system and trafficking of antigens between the endomembrane system and the plasma membrane. Recently, TMEM230 was identified as co-regulated with RNASET2 in lysosomes and with metalloproteins in various cell types and organelles, including mitochondria in autoimmune diseases. Aberrant metalloproteinase secretion by motor proteins is a major contributor to tissue remodeling of synovial membrane and joint tissue destruction in rheumatoid arthritis (RA) by promoting infiltration of blood vessels, bone erosion, and loss of cartilage by phagocytes. In this study, we identified that specific glycan processing enzymes are upregulated in certain cell types (fibroblast or endothelial cells) that function in destructive tissue remodeling in rheumatoid arthritis compared to osteoarthritis (OA). TMEM230 was identified as a regulator in the secretion of metaloproteinases and heparanase necessary tissue remodeling in OA and RA. In dendritic (DC), natural killer and T cells, TMEM230 was expressed at low or no levels in RA compared to OA. TMEM230 expression in DC likely is necessary for regulatory or helper T cells to maintain tolerance to self-antigens and prevent susceptibility to autoimmune disease. To identify how TMEM230 and the endomembrane system contribute to autoimmunity we investigated, glycan modifying enzymes, metalloproteinases and motor protein genes co-regulated with or regulated by TMEM230 in synovial tissue by analyzing published single cell transcriptomic datasets from RA patient derived synovial tissue., (Copyright © 2024. Published by Elsevier Inc.)

Glial cells provide physical and chemical support and protection for neurons and for the extracellular compartments of neural tissue through secretion of soluble factors, insoluble scaffolds, and vesicles. Additionally, glial cells have regenerative capacity by remodeling their physical microenvironment and changing physiological properties of diverse cell types in their proximity. Various types of aberrant glial and macrophage cells are associated with human diseases, disorders, and malignancy. We previously demonstrated that transmembrane protein, TMEM230 has tissue revascularization and regenerating capacity by its ability to secrete pro-angiogenic factors and metalloproteinases, inducing endothelial cell sprouting and channel formation. In healthy normal neural tissue, TMEM230 is predominantly expressed in glial and marcophate cells, suggesting a prominent role in neural tissue homeostasis. TMEM230 regulation of the endomembrane system was supported by co-expression with RNASET2 (lysosome, mitochondria, and vesicles) and STEAP family members (Golgi complex). Intracellular trafficking and extracellular secretion of glial cellular components are associated with endocytosis, exocytosis and phagocytosis mediated by motor proteins. Trafficked components include metalloproteins, metalloproteinases, glycans, and glycoconjugate processing and digesting enzymes that function in phagosomes and vesicles to regulate normal neural tissue microenvironment, homeostasis, stress response, and repair following neural tissue injury or degeneration. Aberrantly high sustained levels TMEM230 promotes metalloprotein expression, trafficking and secretion which contribute to tumor associated infiltration and hypervascularization of high tumor grade gliomas. Following injury of the central nervous or peripheral systems, transcient regulated upregulation of TMEM230 promotes tissue wound healing, remodeling and revascularization by activating glial and macrophage generated microchannels/microtubules (referred to as vascular mimicry) and blood vessel sprouting and branching. Our results support that TMEM230 may act as a master regulator of motor protein mediated trafficking and compartmentalization of a large class of metalloproteins in gliomas and gliosis., (Copyright © 2024. Published by Elsevier Inc.)

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Pediatric anxiety and depression are prevalent, impairing, and highly comorbid. Available evidence-based treatments have an average response rate of 60%. One path to increasing response may be to identify likely non-responders midway through treatment to adjust course prior to completing an episode of care. The aims of this study, thus, were to identify predictors of post-intervention response assessing (a) mid-treatment symptom severity, (b) session-by-session treatment process factors, and (c) a model optimizing the combination of these., Method: Data were drawn from the treatment arm (N = 95, ages 8-16) of a randomized transdiagnostic intervention trial (M sessions  = 11.2). Mid-point measures of youth- and parent-reported anxiety and depression were collected, and therapists rated homework completion, youth and parent engagement, and youth therapeutic alliance at each session. Logistic regression was used to predict response on the Clinical Global Impression Improvement Scale (CGI-I ≤2) rated by independent evaluators masked to treatment condition., Results: Mid-point symptom measures were significant predictors of treatment response, as were therapist-ratings of youth and parent engagement, therapeutic alliance, and homework completion. Therapist ratings were significant when tested as mean ratings summing across the first eight sessions of treatment (all ps < .004) and at individual session points (all ps <0.05). A combined prediction model included youth-reported anxiety, parent-reported depression, youth engagement at Session 2, and parent engagement at Session 8. This model correctly classified 76.5% of youth as non-responders and 91.3% as responders at post-treatment (Nagelkerke R 2  = .59, χ 2 (4, 80) = 46.54, p < .001)., Conclusion: This study provides initial evidence that response to transdiagnostic intervention for pediatric anxiety and depression may be reliably predicted by mid-point. These data may serve as foundational evidence to develop adaptive treatment strategies to personalize intervention, correct treatment course, and optimize outcomes for youth with anxiety and depression., (© 2023 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

OTX homeobox genes have been extensively studied for their role in development, especially in neuroectoderm formation. Recently, their expression has also been reported in adult physiological and pathological tissues, including retina, mammary and pituitary glands, sinonasal mucosa, in several types of cancer, and in response to inflammatory, ischemic, and hypoxic stimuli. Reactivation of OTX genes in adult tissues supports the notion of the evolutionary amplification of functions of genes by varying their temporal expression, with the selection of homeobox genes from the "toolbox" to drive or contribute to different processes at different stages of life. OTX involvement in pathologies points toward these genes as potential diagnostic and/or prognostic markers as well as possible therapeutic targets.

The patient reported here underwent hematopoietic stem cell transplantation (HSCT) due to chronic granulomatous disease (CGD) caused by biallelic mutations of the NCF1 gene. Two years later, he developed AML, which was unexpected and was recognized via sex-mismatched chromosomes as deriving from the donor cells; the patient was male, and the donor was his sister. Donor cell leukemia (DCL) is very rare, and it had never been reported in patients with CGD after HSCT. In the subsequent ten years, the AML relapsed three times and the patient underwent chemotherapy and three further HSCTs; donors were the same sister from the first HSCT, an unrelated donor, and his mother. The patient died during the third relapse. The DCL was characterized since onset by an acquired translocation between chromosomes 9 and 11, with a molecular rearrangement between the MLL and MLLT3 genes-a quite frequent cause of AML. In all of the relapses, the malignant clone had XX sex chromosomes and this rearrangement, thus indicating that it was always the original clone derived from the transplanted sister's cells. It exhibited the ability to remain quiescent in the BM during repeated chemotherapy courses, remission periods and HSCT. The leukemic clone then acquired different additional anomalies during the ten years of follow-up, with cytogenetic results characterized both by anomalies frequent in AML and by different, non-recurrent changes. This type of cytogenetic course is uncommon in AML.

Background: Lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ+) youth are at higher risk of isolation and depression than their heterosexual peers. Having access to tailored mental health resources is a documented concern for rural living LGBTQ+ youth. Social media provides access to connections to a broader and like-minded community of peers, but it also is a vehicle for negative interactions. We developed REALbot, an automated, social media-based educational intervention to improve social media efficacy, reduce perceived isolation, and bolster connections for rural living LGBTQ+ youth. This report presents data on the acceptability, feasibility, and utility of REALbot among its target audience of rural living LGBTQ+ youth., Methods: We conducted a week-long exploratory study with a single non-comparison group of 20 rural-living LGBTQ+ youth aged 14-19 recruited from social media to test our Facebook- and Instagram-delivered chatbot. We assessed pre- and post-test scores of social media self-efficacy, social isolation (4-item Patient-Reported Outcomes Measurement System - PROMIS), and depressive symptoms (Patient Health Questionnaire, Adolescent Version - PHQ-A). At post-test, we assessed acceptability (User Experience Questionnaire - UEQ-S), usability (Chatbot Usability Questionnaire -CUQ and Post-Study Satisfaction and Usability Questionnaire -PSSUQ), and satisfaction with the chatbot (Client Satisfaction Questionnaire - CSQ), along with two open-ended questions on 'likes' and 'dislikes' about the intervention. We compared pre- and post-test scores with standard univariate statistics. Means and standard deviations were calculated for usability, acceptability, and satisfaction. To analyze the responses to post-test open-end questions, we used a content analysis approach., Results: Acceptability of REALbot was high with UEQ-S 5.3 out of 7 (SD = 1.1) and received high usability scores with CUQ and PSSUQ (mean score (M) = 78.0, SD = 14.5 and M = 86.9, SD = 25.2, respectively), as well as high user satisfaction with CSQ (M = 24.9, SD = 5.4). Themes related to user 'likes' and 'dislikes' were organized in two main categories: usability and content provided. Participants were engaged with the chatbot, sending an average of 49.3 messages (SD = 43.6, median = 30). Pre-/post- changes in scores of perceived isolation, depressive symptoms and social media self-efficacy were not significant (p's > 0.08)., Conclusion: REALbot deployment was found to be feasible and acceptable, with good usability and user satisfaction scores. Participants reported changes from pre- to post-test in most outcomes of interest and effect sizes were small to medium. Additional development and a formal evaluation of feasibility and engagement with behavioral targets is warranted., Competing Interests: 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., (© 2023 The Authors.)

Objective: Suicide is a leading cause of death among adolescents. However, there are no clinical tools to detect proximal risk for suicide., Method: Participants included 13- to 18-year-old adolescents (N = 103) reporting a current depressive, anxiety, and/or substance use disorder who owned a smartphone; 62% reported current suicidal ideation, with 25% indicating a past-year attempt. At baseline, participants were administered clinical interviews to assess lifetime disorders and suicidal thoughts and behaviors (STBs). Self-reports assessing symptoms and suicide risk factors also were obtained. In addition, the Effortless Assessment of Risk States (EARS) app was installed on adolescent smartphones to acquire daily mood and weekly suicidal ideation severity during the 6-month follow-up period. Adolescents completed STB and psychiatric service use interviews at the 1-, 3-, and 6-month follow-up assessments., Results: K-means clustering based on aggregates of weekly suicidal ideation scores resulted in a 3-group solution reflecting high-risk (n = 26), medium-risk (n = 47), and low-risk (n = 30) groups. Of the high-risk group, 58% reported suicidal events (ie, suicide attempts, psychiatric hospitalizations, emergency department visits, ideation severity requiring an intervention) during the 6-month follow-up period. For participants in the high-risk and medium-risk groups (n = 73), mood disturbances in the preceding 7 days predicted clinically significant ideation, with a 1-SD decrease in mood doubling participants' likelihood of reporting clinically significant ideation on a given week., Conclusion: Intensive longitudinal assessment through use of personal smartphones offers a feasible method to assess variability in adolescents' emotional experiences and suicide risk. Translating these tools into clinical practice may help to reduce the needless loss of life among adolescents., (Copyright © 2023 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Left lateral segment grafts have become a suitable option in pediatric liver transplantation (PLT). The correlation between hepatic vein (HV) reconstruction and outcome is relevant when assessing the safe use of these grafts. We retrospectively reviewed the medical records prospectively collected from a pediatric living donor liver transplantation database and conducted a comparative analysis of the different left lateral segment graft types according to HV reconstruction. Donor, recipient, and intraoperative variables were analyzed. Post-transplant outcomes included vascular complications such as hepatic vein outflow obstruction, early (≤30 d) and late (>30 d) PVT, hepatic artery thrombosis, and graft survival. From February 2017 to August 2021, 303 PLTs were performed. According to venous anatomy, the distribution of the left lateral segment was as follows: single HV (type I) in 174 (57.4%), close HVs, simple venoplasty for reconstruction (type II) in 97 (32.01%), anomalous hepatic vein (AHV) with a distance between the HVs orifices that allowed simple venoplasty (type IIIA) in 25 (8.26%) and AHV with a distance between the HVs orifices requiring homologous venous graft interposition (type IIIB) in 07 (2.31%) grafts. Type IIIB grafts came from male donors ( p =0.04) and had a higher mean donor height ( p =0.008), a higher mean graft weight, and a higher graft-to-recipient weight ratio, both p =0.002. The median follow-up time was 41.4 months. The overall cumulative graft survival was 96.3%, and comparative graft survival showed no difference (log-rank p =0.61). No hepatic vein outflow obstructions were observed in this cohort study. There was no statistically significant difference in the post-transplant outcomes between the graft types. The venous reconstruction of the AHV with homologous venous graft interposition had similar outcomes in the short and long term., (Copyright © 2023 American Association for the Study of Liver Diseases.)

In recent years, there has been a growing interest in developing innovative anticancer therapies targeting the tumor microenvironment (TME). The TME is a complex and dynamic milieu surrounding the tumor mass, consisting of various cellular and molecular components, including those from the host organism, endowed with the ability to significantly influence cancer development and progression. Processes such as angiogenesis, immune evasion, and metastasis are crucial targets in the search for novel anticancer drugs. Thus, identifying molecules with "multi-tasking" properties that can counteract cancer cell growth at multiple levels represents a relevant but still unmet clinical need. Extensive research over the past two decades has revealed a consistent anticancer activity for several members of the T2 ribonuclease family, found in evolutionarily distant species. Initially, it was believed that T2 ribonucleases mainly acted as anticancer agents in a cell-autonomous manner. However, further investigation uncovered a complex and independent mechanism of action that operates at a non-cell-autonomous level, affecting crucial processes in TME-induced tumor growth, such as angiogenesis, evasion of immune surveillance, and immune cell polarization. Here, we review and discuss the remarkable properties of ribonucleases from the T2 family in the context of "multilevel" oncosuppression acting on the TME.

Introduction: Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO., Methods and Analysis: The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged <18 years) with a diagnosed PVO between 1 January 2001 and 1 January 2021 after liver transplantation will be eligible for inclusion. The primary endpoints are the prevalence of PVO, primary and secondary patency after PVO intervention and current management practices. Secondary endpoints are patient and graft survival, severe complications of PVO and technical success of revascularisation techniques., Ethics and Dissemination: Medical Ethics Review Board of the University Medical Center Groningen has approved the study (METc 2021/072). The results of this study will be disseminated via peer-reviewed publications and scientific presentations at national and international conferences., Trial Registration Number: Netherlands Trial Register (NL9261)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: An increasing number of COVID-19 patients were treated with continuous positive airways pressure (CPAP). To evaluate the clinical effects of personalized positive end-expiratory pressure (PEEP) compared to standard fixed PEEP in COVID-19 patients requiring CPAP., Methods: This is a single center, prospective, randomized clinical study. Sixty-three COVID-19 patients with hypoxemic respiratory failure and bilateral pneumonia were randomized in two Groups: Group A received CPAP with fixed PEEP of 10 cm H 2 O, Group B performed the "PEEP trial", that consists in the evaluation of best PEEP defined as the PEEP value that precedes the echographic appearance of "lung pulse" determining a PaO 2 /FiO 2 increase. Primary outcome was composite in-hospital mortality + intubation, secondary outcome was the percentage increase of PaO 2 /FiO 2 . As safety indicator, the incidence of pneumothorax was collected., Results: Thirty-two patients were enrolled in Group A and 31 in Group B . The two groups were comparable for clinical characteristics and laboratory parameters. The primary outcome occurred in 36 (57.1 %) patients: 23 (71.8 %) in Group A and 13 (41.9 %) in Group B (p<0.01). Mortality was higher in Group A (53.1 vs. 19.3 %, p<0.01), while intubation rate was comparable between groups. Group B showed a higher PaO 2 /FiO 2 increase than Group A (34.9 vs. 13.1 %, p<0.01). Five cases of pneumothorax were reported in Group A , none in Group B ., Conclusions: Lung ultrasound-guided PEEP trial is associated with lower mortality in COVID-19 patients treated with CPAP. Identifying the best PEEP is useful to increase oxygenation and reduce the incidence of complications., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Chronic myeloid leukemia (CML) is a rare myeloproliferative disorder caused by the reciprocal translocation t(9;22)(q34;q11) in hematopoietic stem cells (HSCs). This chromosomal translocation results in the formation of an extra-short chromosome 22, called a Philadelphia chromosome (Ph), containing the BCR-ABL1 fusion gene responsible for the expression of a constitutively active tyrosine kinase that causes uncontrolled growth and replication of leukemic cells. Mechanisms behind the formation of this chromosomal rearrangement are not well known, even if, as observed in tumors, repetitive DNA may be involved as core elements in chromosomal rearrangements. We have participated in the explorative investigations of the PhilosoPhi34 study to evaluate residual Ph+ cells in patients with negative FISH analysis on CD34+/lin- cells with gDNA qPCR. Using targeted next-generation deep sequencing strategies, we analyzed the genomic region around the t(9;22) translocations of 82 CML patients and one CML cell line and assessed the relevance of interspersed repeat elements at breakpoints (BP). We found a statistically higher presence of LINE elements, in particular belonging to the subfamily L1M, in BP cluster regions of both chromosome 22 and 9 compared to the whole human genome. These data suggest that L1M elements could be potential drivers of t(9;22) translocation leading to the generation of the BCR-ABL1 chimeric gene and the expression of the active BCR-ABL1 -controlled tyrosine kinase chimeric protein responsible for CML.

Objective: To identify oral characteristics found in children with liver disease in programming for liver transplantation., Data Source: The methodology was written according to PRISMA-ScR. We adopted the methodological framework and recommendations for this type of review by Arksey and O'Malley and the Joanna Briggs Institute. The protocol was registered in the Open Science Framework (https://doi.org/10.17605/OSF.IO/QCU4W). A systematic search (Medline/PubMed, Scopus, Web of Science, and ProQuest) was conducted to identify studies that met the inclusion criteria: systematic reviews; prospective clinical trials (parallel or crossover group designs); observational studies (cohort, case-control, and cross-sectional studies); clinical case series; and case reports evaluating children with liver disease in preparation for transplantation. The last search was conducted in July 2021, and no restrictions were imposed as to language or year of publication. Studies presenting mixed data with post-transplant evaluation, and studies evaluating not only liver transplantation but also other solid organs were excluded. Screening, inclusion, and data extraction were performed by two reviewers independently. A narrative synthesis was conducted to describe the findings of the study., Data Synthesis: The bibliographic search identified 830 references. A total of 21 articles were read in their entirety after the inclusion criteria assessment. Finally, after evaluating the exclusion criteria, only 3 studies were considered for the qualitative analysis., Conclusions: Children with liver disease in preparation for transplantation may present enamel defects, tooth pigmentation, caries, gingivitis, and opportunistic infections such as candidiasis.

Brief behavioral therapy (BBT) is an efficacious transdiagnostic intervention for pediatric anxiety and depression that targets behavioral avoidance as a key mechanism. It is unknown if change in avoidance mediates treatment effects, as theorized. Data on avoidance at baseline and Week 16 were available on 52 youth (ages 8-16 years) from a randomized controlled trial (Weersing, Jeffreys, et al., 2017) comparing BBT and assisted referral to community care (ARC). BBT had significant effects on youth-reported behavioral avoidance, and significant indirect effects on functioning and anxiety, statistically mediated through changes in youth-reported behavioral avoidance. Change in youth-reported avoidance was not a significant mediator of depression. Parent-report of avoidance was not impacted by treatment and was not a significant mediator. Overall, BBT appears to be an effective treatment for targeting behavioral avoidance, which in turn, may improve functioning and lessen anxiety. CLINICAL TRIAL REGISTRATION INFORMATION: https://clinicaltrials.gov; NCT01147614., Competing Interests: Declaration of competing interest Drs. Weersing, Rozenman, and Gonzalez may receive royalties from Oxford University Press related to the Brief Behavioral Therapy treatment manual. No additional competing interests are reported by the authors., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease., (© 2023. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.)

Measurement-based care has demonstrable benefits, but significant implementation barriers slow dissemination in real-world clinical settings, especially youth behavioral health care. Here, we describe use of measurement-based care in a specialty clinic offering a continuum of outpatient care for suicidal youth. We characterize strategies used to facilitate measurement-based care in this population and ways in which challenges to implementation have been addressed. We examined adherence to measurement-based care procedures relative to treatment engagement data from electronic medical records, as well as data from clinicians regarding acceptability and utility of measurement-based care. Results suggest that measurement-based care is both feasible and acceptable for use with suicidal youth. Here we provide future directions in measurement-based care in this, and other, behavioral health settings., Competing Interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: Dr. Brent receives research support from the National Institutes of Health, American Foundation for Suicide Prevention, the Once Upon a Time Foundation, and The Beckwith Foundation; receives royalties from Guilford Press, from the electronic self-rated version of the C-SSRS from eRT, Inc., and from performing duties as an UptoDate Psychiatry Section Editor; receives consulting fees from Healthwise; receives Honoraria from the Klingenstein Third Generation Foundation for scientific board membership and grant reviews; and is a scientific board member for the American Foundation for Suicide Prevention. With respect to intellectual property (without financial interests), funding from the National Institute of Mental Health supported the development of intellectual property for BRITE, the As Safe As Possible intervention, the Computerized Adaptive Screen for Suicidal Youth (CASSY) measure, a suicide risk machine learning algorithm, and the Screening Wizard screening tool. Dr. Goldstein has received research support from the National Institutes of Health, American Foundation for Suicide Prevention, University of Pittsburgh Clinical and Translational Science Institute, and Brain and Behavior Foundation, as well as royalties from Guilford Press. Dr. Victor has received research support from the National Institutes of Health. Ms. Poling has received royalties from Guilford Press. Dr. Salk, Ms. Porta, Mr. Hamilton, and Ms. Bero report no financial or other relationships relevant to the subject of this article. None of the above listed agencies or organizations had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Interests related to the above listed agencies, organizations, and commercial funders do not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Victor 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.)

In biliary atresia (BA), efforts to prevent premature liver transplantation (LT) are aimed at early diagnosis, timing of Kasai-portoenterostomy (KPE), and centralization of care. This report presents the clinical picture, treatment strategies, and outcomes of BA patients with no previous treatment. A retrospective cohort study (Jan/2001 to Jan/2021) was conducted to evaluate the outcome of patients with BA referred to a single team. Study groups were: 1) Kasai-only group (K-only) n=9), 2) LT-only group (n=7), and 3) Kasai+LT group (K+LT) (n=23). Survival with native liver and overall survival were 22.9 and 94.8%, respectively, at 120 months of follow-up. There was no difference in age at KPE in the K-only group (46.8±21.8 days) vs K+LT (52.1±22 days), P=0.4. Ten (25.6%) patients were babies conceived through in vitro fertilization (IVF). Four IVF patients (40%) presented associated congenital heart disease vs 5 patients (17%) in the remaining group (P=0.14). Two of the IVF patients were premature (<37 weeks). Median maternal age at birth was 35 years (33 to 41 years). Excellent patient survival is expected for patients with BA with the available treatment strategies. IVF+BA was an unexpected prevalent association in this cohort, and further studies are required to better understand these findings.

Objective: To report on broad-based outcomes of the Brief Behavioral Therapy (BBT) trial for pediatric anxiety and depression. Secondary data analyses expand on previous reports by assessing diagnostic remission and independent functioning, impact on targeted psychopathology, and spillover effects on non-targeted outcomes., Method: Youth (N = 185; 8-16.9 years; 58% female; 78% White; 21% Hispanic) with anxiety and/or depression were eligible for this multi-site trial. Enrolled youth were randomly assigned to receive 8 to 12 sessions of BBT in primary care or assisted referral to outpatient care (ARC). Assessments were conducted 16 and 32 weeks post randomization., Results: BBT was superior to ARC on remission of all targeted diagnoses (week 16: 56.8% vs 28.2%, p < .001; week 32: 62.5% vs 38.9%, p = .004), clinician-rated independent functioning (week 16: 75.0% vs 45.7%, p < .001; week 32: 81.2% vs 55.7%, p < .001), and on measures of anxiety, depression, suicide items, total comorbid behavioral and emotional problems, and hyperactivity (d = 0.21-0.49). Moderation analyses revealed superior outcomes for Hispanic youth in BBT vs ARC for diagnostic remission, anxiety, emotional problems, and parent-child conflict. Youth depression at baseline moderated effects on peer problems and parent-child conflict, with effects favoring BBT. Significant main and moderated effects of BBT on change in non-targeted outcomes were largely mediated by change in anxiety (24.2%-49.3% of total effects mediated)., Conclusion: BBT has positive effects on youth, mediated by the strong impact of the intervention on anxiety. Analyses continue to support positive outcomes for Hispanic youth, suggesting that BBT is a broadly effective transdiagnostic treatment option for diverse populations., Clinical Trial Registration Information: Brief Cognitive Behavioral Therapy (CBT) for Pediatric Anxiety and Depression in Primary Care; https://clinicaltrials.gov; NCT01147614., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: The survival rate of pediatric patients undergoing liver transplantation has increased considerably. Despite this, the period after transplantation is still complex and poses several challenges to the recipient's family, which is responsible for care management. Recently, more attention has been paid to the impact of this complex procedure on the quality of life of caregivers. Hence, this study is aimed at assessing the quality of life of caregivers of patients who have undergone liver transplantation and the aspects that influence it., Methods: This was an observational and cross-sectional study. From November 2020 to January 2021, short-form-36 questionnaires and additional questions were given to the main caregivers of children and adolescents who underwent pediatric liver transplantation., Results: Thirty-eight questionnaires were completed and the results revealed a lower quality of life in comparison to Brazilian standards, primarily in the mental domains (41.8±14.1 vs. 51.1±2.8; p <0.001). It did not show a significant association with socioeconomic or transplant-related factors, but it did show a negative impact on parents' perception of the child's health. Parents who reported worse health status for their children had a lower mental quality of life (44.1±13.8 vs. 33.3±12.6; p <0.05)., Conclusion: The caregivers of transplanted children have a lower quality of life than those of the local population. Psychological assistance should be routinely provided to parents for long-term follow-up to mitigate potential negative effects on the transplanted child's care., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2022 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)

Ovarian cancer represents one of the most malignant gynecological cancers worldwide, with an overall 5-year survival rate, being locked in the 25-30% range in the last decade. Cancer immunotherapy is currently one of the most intensively investigated and promising therapeutic strategy and as such, is expected to provide in the incoming years significant benefits for ovarian cancer treatment as well. Here, we provide a detailed survey on the highly pleiotropic oncosuppressive roles played by the human RNASET2 gene, whose protein product has been consistently reported to establish a functional crosstalk between ovarian cancer cells and key cellular effectors of the innate immune system (the monocyte/macrophages lineage), which is in turn able to promote the recruitment to the cancer tissue of M1-polarized, antitumoral macrophages. This feature, coupled with the ability of T2 ribonucleases to negatively affect several cancer-related parameters in a cell-autonomous manner on a wide range of ovarian cancer experimental models, makes human RNASET2 a very promising candidate to develop a "multitasking" therapeutic approach for innovative future applications for ovarian cancer treatment.

Background: Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive ribosomopathy mainly characterized by exocrine pancreatic insufficiency, skeletal alterations, neutropenia, and a relevant risk of hematological transformation. At least 90% of SDS patients have pathogenic variants in SBDS, the first gene associated with the disease with very low allelic heterogeneity; three variants, derived from events of genetic conversion between SBDS and its pseudogene, SBDSP1 , provided the alleles observed in about 62% of SDS patients. Methods: We performed a reanalysis of the available WES files of a group of SDS patients with biallelic SBDS pathogenic variants, studying the results by next bioinformatic and protein structural analysis. Parallelly, careful clinical attention was given to the patient focused in this study. Results: We found and confirmed in one SDS patient a germline heterozygous missense variant (c.100T>C; p.Phe34Leu) in the EIF6 gene. This variant, inherited from his mother, has a very low frequency, and it is predicted as pathogenic, according to several in silico prediction tools. The protein structural analysis also envisages the variant could reduce the binding to the nascent 60S ribosomal. Conclusion: This study focused on the hypothesis that the EIF6 germline variant mimics the effect of somatic deletions of chromosome 20, always including the locus of this gene, and similarly may rescue the ribosomal stress and ribosomal dysfunction due to SBDS mutations. It is likely that this rescue may contribute to the stable and not severe hematological status of the proband, but a definite answer on the role of this EIF6 variant can be obtained only by adding a functional layer of evidence. In the future, these results are likely to be useful for selected cases in personalized medicine and therapy., 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 © 2022 Taha, Foroni, Valli, Frattini, Roccia, Porta, Zecca, Bergami, Cipolli, Pasquali, Danesino, Scotti and Minelli.)

Cirrhosis is usually a late-onset and life-threatening disease characterized by fibrotic scarring and inflammation that disrupts liver architecture and function. While it is typically the result of alcoholism or hepatitis viral infection in adults, its etiology in infants is much less understood. In this study, we report 14 children from ten unrelated families presenting with a syndromic form of pediatric liver cirrhosis. By genome/exome sequencing, we found recessive variants in FOCAD segregating with the disease. Zebrafish lacking focad phenocopied the human disease, revealing a signature of altered messenger RNA (mRNA) degradation processes in the liver. Using patient's primary cells and CRISPR-Cas9-mediated inactivation in human hepatic cell lines, we found that FOCAD deficiency compromises the SKI mRNA surveillance pathway by reducing the levels of the RNA helicase SKIC2 and its cofactor SKIC3. FOCAD knockout hepatocytes exhibited lowered albumin expression and signs of persistent injury accompanied by CCL2 overproduction. Our results reveal the importance of FOCAD in maintaining liver homeostasis and disclose a possible therapeutic intervention point via inhibition of the CCL2/CCR2 signaling axis., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Foods are known to be modulators of inflammation and skeletal development. The intestine plays an essential role in the regulation of bone health mainly through the regulation of the absorption of vitamin D and calcium; in fact, inflammatory bowel diseases are often related to bone health issues such as low bone mineral density, high fracture risk, osteoporosis and osteopenia. Considering the complexity of the pathways involved, the use of a simple animal model can be highly useful to better elucidate the pathogenic mechanisms. Soybean flour with a high saponin content has been used in many studies to induce intestinal inflammation in zebrafish larvae. Using a 50% soybean meal (SBM), we analyzed the effects of this soy-induced inflammatory bowel disease on zebrafish larval osteogenesis. Soybean meal induces intestinal functional alterations and an inflammatory state, highlighted by neutral red staining, without altering the general development of the larvae. Our data show that the chondrogenesis as well as endochondral ossification of the head of zebrafish larvae are not affected by an SBM-diet, whereas intramembranous ossification was delayed both in the head, where the length of the ethmoid plate reduced by 17%, and in the trunk with a delayed vertebral mineralization of 47% of SBM larvae. These data highlight that diet-dependent bowel inflammation can differently modulate the different mechanisms of bone development in different zones of the skeleton of zebrafish larvae.

Background: Suicide and cardiovascular disease rank among the leading causes of disability and premature mortality worldwide. Young adult suicide attempters are at increased risk of mortality from cardiovascular disease even compared to those with major depressive disorder suggesting an increased burden of cardiovascular risk factors. We compared the cardiovascular risk burden between youth attempters and other high-risk individuals., Methods: Participants were from the Collaborative Psychiatric Epidemiology Surveys (CPES), a U.S. population-based study, aged 18-30 years [suicide attempt (SA): n = 303; suicidal ideation (SI): n = 451; controls: n = 3671]; and psychiatric inpatients admitted for a SA ( n = 38) or SI ( n = 40) and healthy controls ( n = 37) aged 15-30 years. We computed a cardiovascular risk score and high- and low-risk latent classes based on risk factors of high blood pressure, obesity, and smoking., Results: Suicide attempters showed an increased cardiovascular risk score (CPES: B = 0.43, 95% confidence interval (CI) 0.31-0.54, p < 0.001; inpatient sample: B = 1.61, 95% CI 0.53-2.68, p = 0.004) compared to controls. They were also more likely to be classified in the high cardiovascular risk group (CPES: odds ratio (OR) 3.36, 95% CI 1.67-6.78, p = 0.001; inpatient sample: OR 9.89, 95% CI 1.38-85.39, p = 0.03) compared to those with SI (CPES: OR 1.15, 95% CI 0.55-2.39, p = 0.71; inpatient sample: OR 1.91, 95% CI 0.25-15.00, p = 0.53)., Conclusions: Youth attempters show an increased burden for cardiovascular risk compared to other high-risk individuals in inpatient and population-based samples. Clinicians should pay particular attention to cardiovascular risk factors among suicide attempters in order to reduce their risk for cardiovascular events.

Background: The COVID-19 infection has received the attention of the scientific community due to its respiratory manifestations and association with evolution to severe acute respiratory syndrome (SARS-CoV-2). There are few studies characterizing SARS-CoV-2 in pediatric immunocompromised patients, such as liver transplanted patients. The aim of this study was to analyze the outcomes of the largest cohort of pediatric liver transplant recipients (PLTR) from a single center in Brazil who were infected with COVID-19 during the pandemic. Methods: Cross-sectional study. Primary outcomes: COVID-19 severity. The Cox regression method was used to determine independent predictors associated with the outcomes. Patients were divided into two groups according to the severity of COVID-19 disease: moderate−severe COVID and asymptomatic−mild COVID. Results: Patients categorized as having moderate−severe COVID-19 were younger (12.6 months vs. 82.1 months, p = 0.03), had a higher prevalence of transplantation from a deceased donor (50% vs. 4.3%, p = 0.02), and had a higher prevalence of COVID infection within 6 months after liver transplantation (LT) (75% vs. 5.7%, p = 0.002). The independent predictor of COVID-19 severity identified in the multivariate analysis was COVID-19 infection <6 months after LT (HR = 0.001, 95% CI = 0.001−0.67, p = 0.03). Conclusion: The time interval of less than 6 months between COVID-19 infection and LT was the only predictor of disease severity in pediatric patients who underwent liver transplantation.

Macular holes are a spectrum of retinal diseases that comprehends full-thickness macular holes (FTMHs), refractory/recurrent macular holes, lamellar macular holes (LMHs), myopic macular holes (MMHs), traumatic macular holes, and macular holes secondary to other retinal pathologies or injuries. There are various classifications of the subtypes of macular hole, and only in recent times researchers defined a common nomenclature, especially thanks to the evolution in retinal imaging, offered by new instruments like the swept-source OCT. The proposed therapies for macular holes are different and range from a "wait-and-see" approach to the vitrectomy, with different results in each subtype of macular hole. This narrative review has the purpose to investigate the available evidence in literature to give a summary of the knowledge about these retinal pathologies., Competing Interests: All authors declare that there are no conflicts of interest., (Copyright © 2022 Elias Premi et al.)

Inflammatory bowel diseases (IBDs) are a group of inflammatory conditions of the colon and small intestine, including Crohn's disease and ulcerative colitis. Since Danio rerio is a promising animal model to study gut function, we developed a soy-dependent model of intestinal inflammation in adult zebrafish. The soya bean meal diet was given for 4 weeks and induced an inflammatory process, as demonstrated by morphological changes together with an increased percentage of neutrophils infiltrating the intestinal wall, which developed between the second and fourth week of treatment. Pro-inflammatory genes such as interleukin-1beta, interleukin-8 and tumour necrosis factor alpha were upregulated in the second week and anti-inflammatory genes such as transforming growth factor beta and interleukin-10. Interestingly, an additional expression peak was found for interleukin-8 at the fourth week. Neuronal genes, OTX1 and OTX2, were significantly upregulated in the first two  weeks, compatible with the development of the changes in the gut wall. As for the genes of the p53 family such as p53, DNp63 and p73, a statistically significant increase was observed after two weeks of treatment compared with controls. Interestingly, DNp63 and p73 were shown an additional peak after four weeks. Our data demonstrate that soya bean meal diet negatively influences intestinal morphology and immunological function in adult zebrafish showing the features of acute inflammation. Data observed at the fourth week of treatment may suggest initiation of chronic inflammation. Adult zebrafish may represent a promising model to better understand the mechanisms of food-dependent intestinal inflammation., (© 2021 The Authors. International Journal of Experimental Pathology published by John Wiley & Sons Ltd on behalf of Company of the International Journal of Experimental Pathology (CIJEP).)

Introduction: Müller glial cells typically activate to react to hypoxic tissue damage in several retinal diseases. We evaluated the in vitro response to a hypoxia-mimicking stimulus on the expression of a set of genes, known to contribute to eye morphogenesis and cell differentiation., Materials and Methods: A MIO-M1 Müller cell line was cultured in a hypoxia-mimicking environment by the addition of cobalt chloride to the culture medium, followed by a recovery time in which we mimic restoration from the hypoxic insult. The HIF-1 α protein and VEGF-A gene expression were quantified to verify the induction of a hypoxia-like state., Results: Among the genes under study, we did not observe any difference in the expression levels of Otx1 and Otx2 during treatment; conversely, Otx1 was overexpressed during recovery steps. The VEGF-A gene was strongly upregulated at both the CoCl 2 and recovery time points. The transactivated isoform (TA) of the TP73 gene showed an overexpression in long-term exposure to the hypoxic stimulus with a further increase after recovery. Discussion . Our molecular analysis is able to describe the activation of a set of genes, never before described, that can drive the response to a hypoxia-like status. The improved comprehension of these cellular events will be useful for designing new therapeutical approaches for retinal pathologies., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Claudio Azzolini et al.)

Shwachman-Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by bone marrow failure, exocrine pancreatic insufficiency, and skeletal abnormalities, caused by loss-of-function mutations in the SBDS gene, a factor involved in ribosome biogenesis. By analyzing osteoblasts from SDS patients (SDS-OBs), we show that SDS-OBs displayed reduced SBDS gene expression and reduced/undetectable SBDS protein compared to osteoblasts from healthy subjects (H-OBs). SDS-OBs cultured in an osteogenic medium displayed a lower mineralization capacity compared to H-OBs. Whole transcriptome analysis showed significant differences in the gene expression of SDS-OBs vs. H-OBs, particularly in the ossification pathway. SDS-OBs expressed lower levels of the main genes responsible for osteoblastogenesis. Of all downregulated genes, Western blot analyses confirmed lower levels of alkaline phosphatase and collagen type I in SDS-OBs than in H-OBs. Interestingly, SDS-OBs showed higher protein levels of p53, an inhibitor of osteogenesis, compared to H-OBs. Silencing of Tp53 was associated with higher collagen type I and alkaline phosphatase protein levels and an increase in SDS-OB mineralization capacity. In conclusion, our results show that the reduced capacity of SDS-OBs to mineralize is mediated, at least in part, by the high levels of p53 and highlight an important role of SBDS in osteoblast functions.

Objective: To examine the relationship between social media use and suicidal thoughts and behaviors among adolescents in the first 30 days of an intensive outpatient program (IOP) for depression and suicidality., Method: Participants included 100 adolescents who enrolled in an IOP for depression and suicidality and completed baseline measures of social media and weekly measures of depression and suicidal thoughts and behaviors at clinical visits over the next month., Results: Lower levels of social media use (overall and messaging) were associated with a greater likelihood of having suicidal ideation with plan over the next 30 days. There was no effect on suicidal behavior. Multilevel modeling indicated no main effects of social media use on depression or average days of suicidal thoughts. However, individuals with lower levels of social media use maintained more depression symptoms and days with passive death wish across the first month of treatment., Conclusions: Among adolescents at high risk for suicide, less engagement in social media may reflect social anhedonia or withdrawal, which may heighten risk for more severe suicidal ideation or impede initial treatment. Findings highlight the importance of considering social media as an additional context when assessing social dysfunction in treatment for depression and suicidality., (© 2021 The American Association of Suicidology.)

Background: The impact of the COVID pandemic on liver transplant (LT) programs varied among countries. Few data are available about that impact in pediatric liver transplant (PLT) programs. This study aimed at comparing the data of our program in Brazil (2019 vs. 2020)., Methods: Retrospective cohort study., Results: One hundred and seventy-four PLT were performed in the period (93% living donors). Patients were divided into two groups according to the LT date: pre-COVID-19 period (march/2019-February/2020) and COVID-19 period (March/2020-February 2021). In the pre-COVID-19 period, 97 LTs were performed, and 77 LTs were performed in the COVID-19 period. Patients in the COVID-19 period were younger (10.9 months vs. 16 months, p 0.009), had higher PELD scores (15 vs. 14, p 0.04), more ascites (66.2 vs. 51.5%, p 0.03), and more frequently hospitalized before LT (27.3 vs. 17.5%). However, there was no difference in post-LT complications, retransplantation nor survival rates. Six (6.2%) patients from pre-COVID-19 period were COVID positive at a median of 15.5 months (14-17.5), and 6 (7.8%) patients from COVID-19 period were COVID positive at a median of 3 months (20 days-6 months) from LT. There was neither mortality nor complications in those patients. Four (33%) were hospitalized, and one had prolonged intubation. Four (33%) were asymptomatic, 4 (33%) had upper airways symptoms, and the remaining had gastrointestinal symptoms., Conclusion: Overall, PLT was not affected during COVID-19 period. Even though patients from COVID-19 period were sicker, there was no significant impact in LT outcomes. All the recipients who tested positive for COVID had a favorable outcome., (© 2021 Wiley Periodicals LLC.)

Background: An isochromosome of the long arm of chromosome 7, i(7)(q10), and an interstitial deletion of the long arm of chromosome 20, del(20)(q), are the most frequent anomalies in the bone marrow of patients with Shwachman-Diamond syndrome, which is caused in most cases by mutations of the SBDS gene. These clonal changes imply milder haematological symptoms and lower risk of myelodysplastic syndromes and acute myeloid leukaemia, thanks to already postulated rescue mechanisms., Results: Bone marrow from fourteen patients exhibiting either the i(7)(q10) or the del(20)(q) and coming from two large cohorts of patients, were subjected to chromosome analyses, Fluorescent In Situ Hybridization with informative probes and array-Comparative Genomic Hybridization. One patient with the i(7)(q10) showed a subsequent clonal rearrangement of the normal chromosome 7 across years. Four patients carrying the del(20)(q) evolved further different del(20)(q) independent clones, within a single bone marrow sample, or across sequential samples. One patient with the del(20)(q), developed a parallel different clone with a duplication of chromosome 3 long arm. Eight patients bore the del(20)(q) as the sole chromosomal abnormality. An overall overview of patients with the del(20)(q), also including cases already reported, confirmed that all the deletions were interstitial. The loss of material varied from 1.7 to 26.9 Mb and resulted in the loss of the EIF6 gene in all patients., Conclusions: Although the i(7)(q) and the del(20)(q) clones are frequent and clinically benign in Shwachman Diamond-syndrome, in the present work we show that they may rearrange, may be lost and then reconstructed de novo, or may evolve with independent clones across years. These findings unravel a striking selective pressure exerted by SBDS deficiency driving to karyotype instability and to specific clonal abnormalities., (© 2021. The Author(s).)

Traditionally, Cornelia de Lange Syndrome (CdLS) is considered a cohesinopathy caused by constitutive mutations in cohesin complex genes. Cohesin is a major regulator of chromatin architecture, including the formation of chromatin loops at the imprinted IGF2 / H19 domain. We used 3C analysis on lymphoblastoid cells from CdLS patients carrying mutations in NIPBL and SMC1A genes to explore 3D chromatin structure of the IGF2 / H19 &nbsp; locus and evaluate the influence of cohesin alterations in chromatin architecture. We also assessed quantitative expression of imprinted loci and WNT pathway genes, together with DMR methylation status of the imprinted genes. A general impairment of chromatin architecture and the emergence of new interactions were found. Moreover, imprinting alterations also involved the expression and methylation levels of imprinted genes, suggesting an association among cohesin genetic defects, chromatin architecture impairment, and imprinting network alteration. The WNT pathway resulted dysregulated: canonical WNT, cell cycle, and WNT signal negative regulation were the most significantly affected subpathways. Among the deregulated pathway nodes, the key node of the frizzled receptors was repressed. Our study provides new evidence that mutations in genes of the cohesin complex have effects on the chromatin architecture and epigenetic stability of genes commonly regulated by high order chromatin structure.

The term non-alcoholic fatty liver disease (NAFLD), and its definition, have limitations for both adults and children. The definition is most problematic for children, for whom alcohol consumption is usually not a concern. This problematic definition has prompted a consensus to rename and redefine adult NAFLD associated with metabolic dysregulation to metabolic (dysfunction)-associated fatty liver disease (MAFLD). Similarities, distinctions, and differences exist in the causes, natural history, and prognosis of fatty liver diseases in children compared with adults. In this Viewpoint we, an international panel, propose an overarching framework for paediatric fatty liver diseases and an age-appropriate MAFLD definition based on sex and age percentiles. The framework recognises the possibility of other coexisting systemic fatty liver diseases in children. The new MAFLD diagnostic criteria provide paediatricians with a conceptual scaffold for disease diagnosis, risk stratification, and improved clinical and multidisciplinary care, and they align with a definition that is valid across the lifespan., Competing Interests: Declaration of interests JG reports personal fees from Gilead, Pfizer, AstraZeneca, Pharmaxis, Cincera, Novartis, Roche, Intercept, Novo, and MSD during the writing of the report. LAB reports personal fees from Novo Nordisk. CM reports personal fees from Evira and Itrim, and grants and personal fees from Novo Nordisk. ME reports personal fees from Pfizer. The other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The treatment of choice for patients with cirrhosis and HPS is LT. The clinical manifestations associated with hypoxemia result in limitations and a poor health-related quality of life of affected patients. The present report aims to study the differences in outcomes between patients with PaO 2  < 50 mm Hg and those with PaO 2  ≥ 50 mm Hg., Methods: This was a retrospective study of 21 patients under 18 years of age conducted from 2001 to 2018; the patients were divided into 2 groups: G1-PaO 2  ≥ 50 mm Hg, 11 patients, and G2-PaO 2  < 50 mm Hg, 10 patients. Demographic, clinical, laboratory, and perioperative data; outcome variables; and post-transplant survival were compared between the groups., Results: In total, 2/11 (18.2%) patients in G1 and 8/10 (80%) patients in G2 required supplemental oxygen therapy at home (P = .005). Patients in G2 required prolonged MV (median 8.5 days in G2 vs 1 day in G1, P = .015) and prolonged ICU and hospital stays (P = .002 and P = .001, respectively). Oxygen weaning time was longer in G2 (median 127.5 days) than in G1 (median 3 days; P = .004). One (9.1%) patient in G1 and three (30%) patients in G2 died (P = .22). The survival at 90 months was 90.9% in G1 and 70% in G2 (P = .22)., Conclusion: The survival between groups was similar. Patients with very severe HPS required a longer MV time, longer ICU and hospital stays, and a longer O 2 weaning time than those with mild, moderate, or severe HPS., (© 2021 Wiley Periodicals LLC.)

Objective: To identify risk factors for preadolescent onset suicidal behavior compared with adolescent/young adult onset suicidal behavior in a longitudinal sample of youth with parental history of mood disorders., Methods: The sample includes 545 youth who were age 21 years or less at the time of their baseline assessment. Participants underwent baseline and yearly study assessments. Observations were censored at the time point closest to the first episode of suicidal behavior for youth with suicidal behavior and at the time of last observation for youth without suicidal behavior. Youth were categorized into 3 groups: first onset of suicidal behavior before the age of 13 (n = 32), first onset of suicidal behavior between the ages of 13-21 (n = 51) and those without suicide related behaviors (n = 462). ANOVA, Chi-square, Fisher's exact test and multinomial regression were used to test the hypotheses., Results: Significant predictors of preadolescent onset suicidal behavior were diagnosis of depressive disorder (RRR = 11.41, p<.001) and diagnosis of ADHD (RRR = 2.86, p = .02). Adolescent onset was predicted by diagnosis of depressive disorder (RRR = 4.12, p = .008), female sex (RRR = 2.68, p = .02) and self-reported suicidal ideation (RRR = 1.48, p = .004)., Limitations: These results are most applicable to offspring of parents with significant mood disorders., Conclusions: The strongest predictor of suicidal behavior in both groups was a diagnosis of depressive disorder, and the risk was nearly 3 times higher in preadolescents. ADHD was a significant predictor only for preadolescents, while female sex and self-reported suicidal ideation predicted suicidal behavior in adolescents., (Copyright © 2021. Published by Elsevier B.V.)

Introduction and Objectives: Little is known about the etiology of acute liver failure (ALF) in Latin America. The objective of this paper is to investigate the main etiologies of ALF in Brazil, including Drug Induced Liver Injury (DILI) using stringent causality criteria., Patients or Material and Methods: All the cases of individuals who underwent liver transplantation (LT) in 12 centers in Brazil for ALF were reviewed. When DILI was stated as the cause of ALF, causality criteria were applied on site by the main investigator in order to rule out other etiologies., Results: 325 individuals had ALF mainly for unknown reasons (34%), DILI (27%) and AIH (18%). Reassessment of the 89 cases of DILI, using stringent causality criteria, revealed that in only 42 subjects could DILI be confirmed as the cause of ALF. Acetaminophen (APAP) toxicity (n = 3) or DILI due to herbal and dietary supplements (HDS) (n = 2) were not commonly observed., Conclusions: Undetermined etiology and DILI are the main causes of ALF in Brazil. However, APAP toxicity and DILI due to HDS are mostly uncommon., (Copyright © 2021. Published by Elsevier España, S.L.U.)

Background: The aim of the study was to compare coronavirus disease 2019 (COVID-19) severity presentation between oncologic and non-oncologic patients and to evaluate the impact of cancer type and stage on COVID-19 course., Methods: We performed a multicentre, retrospective study involving 13 COVID-19 Units in Campania region from February to May 2020. We defined as severe COVID-19 presentation the cases that required mechanical ventilation and/or admission to Intensive Care Units (ICU) and/or in case of death., Results: We enrolled 371 COVID-19 patients, of whom 34 (9.2%) had a history or a diagnosis of cancer (24 solid, 6 onco-hematological). Oncologic patients were older (p<0.001), had more comorbidities (p<0.001) and showed a higher rate of severe COVID-19 presentation (p=0.001) and of death (p<0.001). Compared to 12 patients with non-active cancer and to 337 without cancer, the 17 patients with active cancer had more comorbidities and showed a higher rate of severe COVID-19 and of mortality (all p values <0.001). Compared to the 281 non-severe patients, the 90 subjects with a severe presentation of COVID-19 were older (p<0.01), with more comorbidities (p<0.001) and with a higher rate of cancer (p=0.001). At multivariate analysis, age (OR 1.08, 95% CI: 1.04-1.11) and suffering from cancer in an active stage (OR 5.33, 95% CI: 1.77-16.53) were independently associated with severe COVID-19., Conclusions: Since the higher risk of severe evolution of COVID-19, cancer patients, especially those with an active malignancy, should be candidates for early evaluation of symptoms and early treatment for COVID-19., 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 © 2021 Monari, Sagnelli, Maggi, Sangiovanni, Numis, Gentile, Masullo, Rescigno, Calabria, Megna, Gambardella, Manzillo, Russo, Esposito, Camaioni, Messina, Pisaturo, Allegorico, Pinchera, Pisapia, Catalano, Salzillo, Porta, Signoriello and Coppola.)

Abstract: A case of low-γ-glutamyltranspetidase cholestasis associated with ubiquitin-specific peptidase 53 (USP53) gene mutation in a Brazilian child is described. Transient jaundice and hypocholia started at the age of 10 days. Liver enzymes, total bilirubin, and total bile acids were elevated at presentation. During follow-up, he developed cholelithiasis treated with cholecystectomy, and an intracranial hemorrhage resolved with full recovery. At last, evaluation at the age of 18 months, he was not jaundiced and had normal liver tests, but experienced from moderate pruritus despite treatment with rifampicin and ursodeoxycholic acid. A genetic study revealed novel homozygous mutations c.1687&#95;1688delinsC p.Ser563Profs∗25 in the USP53 gene. His parents carried the same heterozygous mutation in the USP53 gene., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Inflammatory bowel disease have been linked to several health issues, including high risk of low bone mineral density. Danio rerio (zebrafish) is a good model to verify the effects of intestinal inflammation, since its gastrointestinal and immune systems are closely related to that of mammalians. Zebrafish is also a powerful model to study bone metabolism using the scale as the read-out model. Food strongly impacts zebrafish gut physiology, and it is well known that soybean meal induces intestinal inflammation. Adult zebrafish fed with defatted soybean meal (SBM) exhibited an intestinal inflammation evidenced by morphological alterations, inflammatory infiltrate, and increased mRNA expression of inflammatory cytokines (IL-1β, IL-6, IL-8, IL-10, TGFβ, TNF-α). The peak of acute intestinal inflammation, spanning between week 2 and 3, correlates with a transitory osteoporosis-like phenotype in the scale border. Later, a chronic inflammatory condition, associated with persistent IL-8 expression, correlates with the progression of resorption lacunae in the scale center. Both types of resorption lacunae were associated with intense osteoclastic tartrate-resistant acid phosphatase (TRAP) activity. After 3 weeks of SBM treatment, osteoclast activity decreased in the scale border but not in the center. At the same time, alkaline phosphatase (ALP) is activated in the border to repair the bone matrix. This model can contribute to elucidate in vivo the molecular mechanisms that links intestinal inflammation and bone metabolism in IBD.

Background: We examine the performance of the Diagnostic and Statistical Manual of Mental Disorders-fifth edition (DSM-5) persistent complex bereavement-related disorder (PCBD) criteria in bereaved adults to identify prolonged grief cases determined prospectively., Methods: Bereaved adults (n = 138) were assessed at 8, 21, 32, 67, and 90 months after the sudden death of a spouse or close relative. We used latent class growth analysis to identify the longitudinal trajectories of grief assessed using the Inventory for Complicated Grief. To validate the trajectory that corresponded to prolonged grief, we examined the baseline predictors of these trajectories and their relationship with functional impairment., Results: We found three distinct trajectories of grief reactions. One of these trajectories (13.8%) showed high and sustained grief reactions that persisted for almost 7.5 years after the death. Participants with prolonged grief showed greater functional impairment [relative risk ratio (RRR) = 0.82, 95% confidence interval (CI): 0.70 to -0.97; p = 0.02] and higher self-reported depression (RRR = 1.21, 95% CI 1.09 to 1.96; p = 0.001) than participants whose grief reactions subsided over time. The original PCBD (requiring 6 criterion C symptoms) criteria correctly identified cases (57.9-94.7%) with perfect specificity (100%) but low to high sensitivity (5.6-81.3%); however, its sensitivity increased when revising criterion C to require ⩾3 (45.5-94.1%). The dimensional approach showed high sensitivity (0.50-1) and specificity (0.787-0.97)., Conclusions: We recommend revisions to the PCBD criteria, which are overly restrictive and may exclude cases with clinically significant grief-related distress and impairment. In the meantime, clinicians need to monitor grief symptoms over time using available dimensional approaches to reduce the burden of grief.

Importance: Youth anxiety and depression are common and undertreated. Pediatric transdiagnostic interventions for anxiety and/or depression may be associated with improved access to treatment among youths., Objective: To evaluate the cost-effectiveness of a pediatric transdiagnostic brief behavioral therapy (BBT) program for anxiety and/or depression compared with assisted referral to community outpatient mental health care (ARC)., Design, Setting, and Participants: In this economic evaluation, an incremental cost-effectiveness analysis was performed from the societal perspective using data from a randomized clinical trial of youths with full or probable diagnoses of anxiety or depression who were recruited from pediatric clinics in San Diego, California, and Pittsburgh, Pennsylvania. The trial was conducted from October 6, 2010, through December 5, 2014, and this analysis was performed from January 1, 2019, through October 20, 2020., Interventions: In the randomized clinical trial, youths were randomized to BBT (n = 95) or ARC (n = 90). The BBT program consisted of 8 to 12 weekly 45-minute sessions of behavioral therapy delivered in pediatric clinics by master's-level therapists. Families randomized to ARC received personalized referrals to mental health care and telephone calls to support access to care., Main Outcomes and Measures: Anxiety-free days, depression-free days, quality-adjusted life-years (QALYs), and costs based on incremental cost-effectiveness ratios from intake through 32-week follow-up. A cost-effectiveness acceptability curve for QALYs was used to assess the probability that BBT was cost-effective compared with ARC over a range of amounts that a decision-maker might be willing to pay for an additional outcome., Results: Enrolled patients included 185 youths (mean [SD] age, 11.3 [2.6] years; 107 [57.8%] female; 144 [77.8%] White; and 38 [20.7%] Hispanic). Youths who received BBT experienced significantly more anxiety-free days (difference, 28.63 days; 95% CI, 5.86-50.71 days; P = .01) and QALYs (difference, 0.026; 95% CI, 0.009-0.046; P = .007) compared with youths who received ARC. Youths who received BBT experienced more depression-free days than did youths who received ARC (difference, 10.52 days; 95% CI, -4.50 to 25.76 days; P = .18), but the difference was not statistically significant. The mean incremental cost-effectiveness ratio was -$41 414 per QALY (95% CI, -$220 601 to $11 468). The cost-effectiveness acceptability curve analysis indicated that, at a recommended willingness-to-pay threshold of $50 000 per QALY, the probability that BBT would be cost-effective compared with ARC at 32 weeks was 95.6%., Conclusions and Relevance: In this economic evaluation, BBT in primary care was significantly associated with better outcomes and a greater probability of cost-effectiveness at 32 weeks compared with ARC. The findings suggest that transdiagnostic BBT may be associated with improved youth anxiety and functioning at a reasonable cost.

The aim of this study was to explore the role of lung ultrasound (LUS) in the diagnosis of SARS-CoV-2 infection and to verify its utility in the prediction of lung disease's severity and outcome. Fifty-three consecutive patients presenting to the Emergency Department of Santa Maria delle Grazie Hospital with high suspicion of SARS-CoV-2 infection underwent diagnostic test for SARS-CoV-2 on samples obtained from nasopharyngeal swab as well as complete proper diagnostic work-up that included clinical evaluation, laboratory tests, blood gas analyses, chest CT and LUS. A semiquantitative analysis of B-lines distribution was performed to calculate the LUS score. Patients were divided into two groups according to the results of both SARS-CoV-2 diagnostic test and other exams (Group A = pneumonia due to SARS-CoV2 infection vs Group B = no SARS-CoV2 infection and another definite diagnosis). LUS showed an excellent accuracy in predicting the diagnosis of SARS-CoV-2 infection (area under the ROC curve of 0.92 with a sensibility of 73% and a specificity of 89% a the cut-off of 12.5). LUS score was more impaired in SARS-CoV-2 patients (18.1 ± 6.0 vs 7.6 ± 5.9, p < 0.00001) and it is significantly negatively correlated with PF ratio values (r = - 0.719, p < 0.0001). An intrahospital mortality rate of 46% was found; patients with adverse outcome had significant higher value of LUS, PF, LDH, and APACHE II score. None of these parameters was predictive of mortality. LUS is a useful tool for the early detection of SARS-CoV-2 infection and for the evaluation of the disease severity, but does not predict mortality. Further studies with repeated evaluations of LUS score are needed to further explore the role of LUS in the assessment of severity in SARS-CoV-2 disease and in the monitoring of the response to treatments.