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Background: Receiving communication of positivity for metabolic diseases at Expanded Newborn Screening can be extremely stressful for parents, both in case of false positive and true positive cases. However, little is known about the predictors of distress and differential impact on mothers and fathers., Methods: In this longitudinal study, 169 fathers and 171 mothers referred to one of the Italian metabolic centres for communication of positivity completed a survey including General Health Questionnaire-12, Emotion Thermometers (measuring stress, anxiety, depression, anger and need for help), Impact of Event Scale-Revised, Multidimensional Scale of Perceived Social Support and Emotion Regulation Questionnaire. Perceived severity and control of the children's health were also assessed. The survey was completed in person after the first session at metabolic centres and online after 1, 3 and 6 months., Results: Nearly 80% of parents reported a clinical level of distress and anxiety after the communication of positivity, one-third of them reported post-traumatic symptoms and more than half of parents reported a need for help. After 6 months, there are still more than 30% of parents with a clinical level of distress and anxiety, 6% with post-traumatic symptoms and more than 20% who continue to express a need for help. No gender difference was reported and no differences emerged between pre-COVID-19 and post-COVID-19 periods for parental distress and post-traumatic symptoms.Social support, perceived severity and control of the child's health-but not gender or previous parental experience-predicted the post-traumatic symptoms at baseline while at 6 months the only significant predictor was perceived severity., Conclusion: Adequate psychological support should be provided from the initial communication for both parents and for true positive, false positive and variants of uncertain significance/heterozygous carrier cases., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ Group.)

During the COVID-19 pandemic, mask-wearing became prominent or required worldwide as a predominant preventative strategy up until and even after vaccines became widely available. Because masks make emotion recognition more challenging for both the face and voice, medical and behavioral/mental health providers became aware of the disruptions this generated in practitioner-patient relationships. The current set of studies utilized two adult samples, first from United States college students (N = 516) and second from the U.S. American general public (N = 115), to document the severity and types of errors in facial expression recognition that were exacerbated by medical mask occlusion. Using a within-subjects experimental design and a well-validated test of emotion recognition that incorporated multi-ethnic adult facial stimuli, both studies found that happy, sad, and angry faces were significantly more difficult to interpret with masks than without, with lesser effects for fear. Both high- and low-intensity emotions were more difficult to interpret with masks, with a greater relative change for high-intensity emotions. The implications of these findings for medical and behavioral/mental health practitioners are briefly described, with emphasis on strategies that can be taken to mitigate the impact in healthcare settings.

Purpose: Obstructive sleep apnoea (OSA) is a prevalent sleep disorder characterized by pharyngeal airway collapse during sleep, leading to intermittent hypoxia, intrathoracic pressure swings, and sleep fragmentation. OSA is associated with various comorbidities and risk factors, contributing to its substantial economic and social burden. Machine learning (ML) techniques offer promise in predicting OSA severity and understanding its complex pathogenesis. This study aims to compare the accuracy of different ML techniques in predicting OSA severity and identify key associated factors contributing to OSA., Methods: Adult patients suspected of OSA underwent clinical assessments and polysomnography. Demographic, anthropometric and clinical data were collected. Five supervised ML models (logistic regression, decision tree, random forest, extreme gradient boosting, support vector machine) were employed, optimized through grid search and cross-validation., Results: ML models exhibited varied performance across OSA severity levels. SVM demonstrated the highest accuracy for mild OSA, XGBoost for moderate OSA, and random forest for severe OSA. Logistic regression showed the highest AUC for moderate and severe OSA. Anthropometric measures, gender, and hypertension were significant predictors of OSA severity., Conclusion: ML models offer valuable insights into predicting OSA severity and identifying associated factors. Our findings support the relevant potential clinical utility of ML in OSA management, although further validation and refinement are warranted., Competing Interests: Declarations. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the Ethics Committee of the Policlinico ‘Umberto I’ (No. 6131, 18 November 2020) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study. Conflict of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The Hippo signaling pathway is commonly dysregulated in human cancer, which leads to a powerful tumor dependency on the YAP/TAZ transcriptional coactivators. In this study, we used paralog cotargeting CRISPR screens to identify kinases MARK2/3 as absolute catalytic requirements for YAP/TAZ function in diverse carcinoma and sarcoma contexts. Underlying this observation is the direct MARK2/3-dependent phosphorylation of NF2 and YAP/TAZ, which effectively reverses the tumor suppressive activity of the Hippo module kinases LATS1/2. To simulate targeting of MARK2/3, we adapted the CagA protein from Helicobacter pylori as a catalytic inhibitor of MARK2/3, which we show can regress established tumors in vivo. Together, these findings reveal MARK2/3 as powerful codependencies of YAP/TAZ in human cancer, targets that may allow for pharmacology that restores Hippo pathway-mediated tumor suppression. Significance: We show how genetic redundancy conceals tight functional relationships between signaling and transcriptional activation in cancer. Blocking the function of MARK2/3 kinases leads to the reactivation of the Hippo tumor suppressive pathway and may have therapeutic potential in YAP/TAZ-dysregulated carcinomas and sarcomas. See related commentary by Gauthier-Coles and Sheltzer, p. 2312., (©2024 The Authors; Published by the American Association for Cancer Research.)

Aim: The present study aimed to evaluate the contribution of personality, empathy, and the perception of instructor's caring in predicting burnout in nursing students., Background: Burnout is alarmingly prevalent and rising among nursing students. Furthering our understanding of individual and clinical environmental antecedents of burnout is crucial to shield nursing students' well-being during their training., Methods: In a cross-sectional study design, the Ten Item Personality Inventory (TIPI), the Brief version of the Interpersonal Reactivity Index (BIRI), the Nursing Students' Perception of Instructor Caring (NSPIC), and the Copenhagen Burnout Inventory (CBI) were administered to 361 (83.9 % females) Italian nursing students between July and December 2021. t-Tests, analyses of variance, Pearson's correlations, and hierarchical regressions were performed to examine the association of CBI with socio-demographics, TIPI, BIRI, and NSPIC., Results: Being female and having a low household income were predictors of Personal Burnout and Work-related Burnout. Personal Burnout was positively associated with TIPI-Neuroticism and BIRI-Personal Distress. Work-related Burnout was positively associated with BIRI-Personal Distress and NSPIC-Control, and negatively associated TIPI-Openness to Experience, NSPIC-Support, NSPIC-Confidence. Client-related Burnout was negatively associated with TIPI-Agreeableness, NSPIC-Support, NSPIC-Confidence. Beyond the effect of socio-demographics, TIPI, and BIRI, NSPIC subscales significantly contributed to the explained variance in CBI scores., Conclusions: Sex, household income, personality, and empathy should be considered when designing interventions to decrease burnout in nursing students. Promoting caring relationships between clinical instructors and their pupils may contribute to reduce nursing students' burnout., 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: Donation-related fears are prevalent even among regular donors and can hinder both recruitment and retention. This cross-sectional study aimed to estimate the prevalence of these fears in Italian whole-blood and plasma donors, across different levels of donation experience., Study Design and Methods: A sample of 615 voluntary, unpaid donors from Italy (64.1% male, mean age 45.42 ± 11.80 years) completed an online survey assessing their fear of common donation-related stimuli (fear of blood, needles, pain, and fainting), experience of vasovagal symptoms at the last donation, and their intention to donate again. Donors were grouped based on donation history and their most recent donation type (whole-blood or plasma)., Results: A significant negative relationship was found between donation history and most types of donation-related fears, suggesting that greater experience corresponds to reduced fear. Plasma donors reported lower levels of fear across all stimuli compared to whole-blood donors. Despite this, nearly one-third of the most experienced whole-blood donors and 20% of plasma donors still reported some level of fear. Greater fear was associated with increased reports of pain and vasovagal symptoms during donation, regardless of donation type. However, no significant association emerged between donation-related fears and the intention to donate again., Discussion: Donation-related fear persists even among experienced donors, for both whole-blood and plasma donors. Given its potential to impact donor comfort and retention, the assessment and management of donation-related fears should be integrated into donor care, with appropriate strategies to help donors regulate their fear throughout their donation careers., (© 2024 The Author(s). Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Purpose: The aim of this study was to evaluate the effectiveness of CDK 4/6 inhibitors (CDK 4-6i) according to HER2 status (low/zero), and endocrine resistance/sensitivity, as well as the efficacy of second-line treatments, in a large real-world cohort., Methods: The GIM14/BIOMETA study (NCT02284581) is a retrospective/prospective study of the Gruppo Italiano Mammella evaluating treatment patterns and survival outcomes in patients with metastatic breast cancer (MBC). We retrieved data on patients with hormone receptor-positive/HER2-negative MBC receiving first-line CDK 4/6i., Results: Among 3832 patients enrolled in the GIM14-BIOMETA study, 701 were eligible. At a median follow-up of 24.80 months, no significant differences were found between HER2-zero and HER2-low subgroups in terms of first-line time to treatment discontinuation (TTD) (26.16 months [IQR 12.84-NR] vs. 27.60 months [IQR 12.12-64.44], p = 0.972) or overall survival (OS) (mOS>60 months for both groups, p = 0.398). Median TTD was 33.24 months (IQR 16.32-NR) for the endocrine sensitive subgroup, 19.92 months (IQR 8.88-51.24) for the secondary endocrine resistant subgroup and 17.40 months (IQR 7.44-24.72) for the primary endocrine resistant subset, respectively (p < 0.001). Among 239 patients receiving second-line treatment, no significant difference (p = 0.188) was found in terms of second-line TTD between those treated with capecitabine (6.11 months, IQR 2.96-11.47), taxane-based chemotherapy (5.06 months, IQR 2.99-9.99), everolimus plus exemestane (5.39 months, IQR 2.53-9.03) or fulvestrant (6.44 months, IQR 3.38-NR)., Conclusions: Endocrine therapy plus CDK 4/6i represents an effective treatment, regardless of HER2 status (low/zero). Second-line agents did not differ significantly in terms of TTD. Endocrine resistant cancers exhibit poor response to CDK 4/6i., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chiara Molinelli reports honoraria for consultancy and consulting fees from Daiichi Sankyo, travel support to attend conferences from Gilead, Menarini and fees for medical writing from Lilly and Seagen. Eva Blondeaux reports honoraria from Eli Lilly and research funding (to institution) from Gilead. Michelino De Laurentiis reports honoraria or consultation fees for speaker, consultancy or advisory roles from Eli Lilly, Seagen, Therapeutics, GSK, Roche, Novartis, Genetic, Pfizer, Pierre Fabre, MSD, Menarini Stemline, Sophos Biotech, Max Farma, Celltrion Healthcare, Gilead, Daiichi Sankyo; institutional financial interests, financial support for clinical trials or contracted research, from: Novartis, Pierre Fabre, Pfizer, Roche, Stemline Therapeutics. Alessandra Fabi reports consulting fees and honoraria from Roche, Novartis, Lilly, Pfizer, MSD, Gilead, Seagen, Astra Zeneca, Daiichi Sankyo. Support for attending meetings and/or travel from Novartis, Lilly, Pfizer, MSD. Grazia Arpino reports research and medical writing from AstraZeneca; advisory boards, travel grants, activities as a speaker, consultancy from AstraZeneca, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Exact Science, Novartis, Roche, Seagen, Viatris. Andrea Fontana reports advisory boards from Roche, Novartis, Eli Lilly, Pfizer, MSD, Pierre Fabre, Eisai, Gilead, Seagen, Astra Zeneca, Exact Sciences; consulting fees from Dompé Farmaceutici S.p.A. D.G. Research funding from Menarini, Seagen, Novartis, AstraZeneca; advisory boards, activities as a speaker, consultancy from Seagen, Novartis, Eli Lilly, Roche, Gilead, Pfizer, Eisai, Exact Sciences. Fabio Puglisi reports advisory role for and receiving speaker honoraria from Amgen, AstraZeneca, Daichii Sankyo, Celgene, Eisai, Eli Lilly, Exact Sciences, Gilead, Ipsen, Menarini, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Seagen, Takeda, and Viatris. Travel grants from AstraZeneca, Daichii Sankyo, Novartis, Roche. Research grants (to his institution) from Astrazeneca, Eisai, Roche. Claudia Bighin reports personal fees from Roche, Novartis, Lilly, Gilead, and Daiichi. Matteo Lambertini reports advisory role for Roche, Lilly, Novartis, Astrazeneca, Pfizer, Seagen, Gilead, MSD, Exact Sciences, Pierre Fabre, Menarini; speaker honoraria from Roche, Lilly, Novartis, Pfizer, Sandoz, Libbs, Daiichi Sankyo, Takeda, Menarini, AstraZeneca; travel Grants from Gilead, Daiichi Sankyo, Roche; research funding (to the Institution) from Gilead all outside the submitted work. Lucia Del Mastro reports grants from Eli Lilly, Novartis, Roche, Daiichi Sankyo, Seagen, AstraZeneca, Gilead, and Pierre Fabre; receiving consulting fees from Eli Lilly, Gilead, and Daiichi Sankyo; receiving speaker honoraria from Roche, Novartis, Pfizer, Eli Lilly, AstraZeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact Sciences, Ipsen, GSK, and Agendia-Stemline; receiving travel grants from Roche, Pfizer, Eisai, Daiichi Sankyo, and AstraZeneca; and having an advisory role for Novartis, Roche, Eli Lilly, Pfizer, Daiichi Sakyo, Exact Sciences, Gilead, Pierre Fabre, Eisai, AstraZeneca, Agendia, GSK, and Seagen. All the other authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: This study, derived from the phase 3 SAFE trial (ClinicalTrials.gov identifier: NCT2236806), explores subclinical cardiac damage in breast cancer patients receiving anthracycline-based chemotherapy and left-sided breast radiation therapy (RT)., Materials and Methods: Eligible patients were randomized to a cardioprotective pharmacological therapy (bisoprolol, ramipril, or both) or placebo, with cardiac surveillance at multiple time-point using standard and 3-dimensional echocardiography. Dosimetric parameters were analysed, including mean heart dose (MHD) and various metrics for heart substructures, employing advanced contouring techniques and auto-contouring software., Results: In the analysis of left-sided breast RT patients, the study encompassed 39 out of 46 irradiated individuals, focusing on GLS and 3D-LVEF outcomes with ≥ 10% worsening, defined as subclinical heart damage. Distinct RT schedules were used, with placebo exhibiting the highest ≥ 10% worsening (36.4%). In terms of treatment arms, bisoprolol exhibited 11.1% worsening, while ramipril 16.7% and bisoprolol + ramipril 25%. For patients with no subclinical damage, the mean MHD was 1.5 Gy; for patients with subclinical heart damage, the mean MHD was 1.6 Gy (p = 0.94). Dosimetric parameters related to heart and heart substructures (left anterior descending artery, right and left atrium, right and left ventricle) showed no statistically significant differences between patients with and without subclinical damage., Conclusion: Our results emphasize the crucial role of cardioprotective measures in mitigating adverse effects, highlighting RT as having negligible influence on cardiac performance. An extended follow-up assessment of the whole series is warranted to determine whether a subclinical effect could significantly influence clinical outcomes and cardiac events., Competing Interests: Declarations. Conflict of interest: Icro Meattini declares occasional small fees received for advisory boards supported by Eli Lilly, Novartis, Astra Zeneca, Daiichi Sankyo, Gilead, SeaGen, Pfizer, and Menarini StemLine. Roberto Pellegrini is an employee of Elekta AB (Stockholm, Sweden). Isacco Desideri, Jacopo Nori, and Lorenzo Livi are editors in this journal. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of University of Florence. Consent to participate: Informed consent was obtained from all individual participants included in the study. Consent to publish: The authors affirm that human research participants provided informed consent for publication., (© 2024. Italian Society of Medical Radiology.)

A multimodal spectroscopic approach is proposed to correlate the mechanical and chemical properties of plastic materials in art and design objects, at both surface and subsurface levels, to obtain information about their conservation state and to monitor their degradation. The approach was used to investigate the photo-oxidation of acrylonitrile butadiene styrene (ABS), a plastic commonly found in many artistic and design applications, using ABS-based LEGO bricks as model samples. The modifications of the chemical and viscoelastic properties of ABS during photoaging were monitored by correlative Brillouin and Raman microspectroscopy (BRaMS), combined with portable and noninvasive broad-range external reflection infrared (IR) spectroscopy and nuclear magnetic resonance (NMR) relaxometry, directly applicable in museums. BRaMS enabled combined measurements of Brillouin light scattering and Raman spectroscopy in a microspectroscopic setup, providing for the coincident probe of the chemical and mechanical changes of ABS at the sample surface. NMR relaxometry allowed for noninvasive measurements of relaxation times and depth profiles which are directly related to the molecular mobility of the material. Complementary chemical information was acquired by external reflection IR spectroscopy. The simultaneous probe of the chemical and mechanical properties by this multimodal spectroscopic approach enabled us to define a decay model of ABS in terms of compositional changes and variation of stiffness and rigidity occurring with photodegradation. The knowledge acquired on LEGO samples has been used to rate the conservation state of ABS design objects noninvasively investigated by external reflection Fourier transform IR spectroscopy and NMR relaxometry offered by the MObile LABoratory (MOLAB) platform of the European Research Infrastructure of Heritage Science., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Video slot machines (VSM) are considered a particularly harmful gambling format; however, scant data is available on their use among underage Italian individuals. Two surveys were conducted in 2018 and 2022 involving 7,959 underage high school students (57.8% female) in Pavia, Northern Italy. We estimated adjusted odds ratios (aOR) and corresponding 95% confidence intervals (CI) for lifetime experience and current regular (at least monthly) use of VSM, according to family, educational and behavioral factors. Overall, participants reporting lifetime VSM experience were 13.2% (95% CI: 12.5 - 13.9), 15.2% (95% CI: 14.0-16.4%) in 2018, and 12.0% (95% CI: 11.1-13.0%) in 2022. Current regular VSM users were 1.4% (95% CI: 1.1-1.7) in total, 1.2% (95% CI: 0.8-1.6%) in 2018 and 1.5% (95% CI: 1.1-1.8%) in 2022. VSM lifetime experience and current regular use were significantly more frequent in males (aORs: 1.55 and 4.81, respectively), students who failed a year (aORs: 2.07 and 3.44), or with daily gambling parents/siblings (aORs: 2.83 and 4.86). Lifetime use of alcohol, tobacco, or illicit substances was significantly directly associated with lifetime VSM use (aORs between 2.64 and 4.75); monthly alcohol, tobacco, or illicit substances use was significantly directly associated with current regular VSM use (aORs between 4.47 and 18.21). Sexting and voluntary self-injury were significantly more frequent among VSM lifetime/current regular users. VSM use, which is directly associated with other risky behaviors, may be pervasive among Italian minors. Such public health concern calls for legislative enforcements and integrated multidisciplinary health promotion and prevention strategies., Competing Interests: Declarations Ethical Approval All subjects received a comprehensive explanation about the purpose of the research and provided informed consent to participate in the study. Participation in the study was on a voluntary basis, and all collected data were kept fully anonymous. All included school boards formally approved participation in the “Selfie Project” and the Declaration of Helsinki was adequately addressed. Competing Interests The authors have no relevant financial or non-financial interests to disclose., (© 2024. The Author(s).)

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

Dodecanedioic acid (DC12) is a dicarboxylic acid present in protective polymers of fruit and leaves. We explored the effects of DC12 on metabolic dysfunction-associated steatohepatitis (MASH) and obesity. DC12 supplementation (100 mg/kg/day) was added to a high-fat diet (HFD) for 8 weeks in rodents to assess its impact on obesity and MASH prevention. Rats given DC12 experienced significant reductions of weight gain, liver and visceral fat weight, and improved glucose tolerance and insulin sensitivity. Liver histology showed protection against diet-induced MASH, with reduced steatosis, hepatocyte ballooning, and fibrosis. For weight-loss and MASH reversion, rats were fed HFD for 14 weeks, followed by 6 weeks with or without DC12. DC12 supplementation (100 mg/kg/day) led to a significant reduction of weight gain and liver weight. DC12 induced white adipose tissue beiging and reduced adiposity with a decrease of visceral fat. It also improved glucose tolerance, insulin sensitivity, and reduced hepatic gluconeogenic gene expression. Liver histology revealed a significant reduction in steatosis, hepatocyte ballooning, and inflammation as well as fibrosis, indicating MASH reversal. DC12 reduced hepatic lipogenesis enzymes as well as de novo lipogenesis measured by deuterated water and increased fatty acid β-oxidation. Plasma lipid profile showed lower triglycerides and phosphatidylcholines in the DC12 group. Notably, DC12 decreased mINDY expression, the cell membrane Na+-coupled citrate transporter, reducing citrate uptake and de-novo lipogenesis, linking its effects to improved lipid metabolism and reduced steatosis. We found that during the hepatic first pass, half of the DC12 ingested with water was taken up by the liver. The concentration of DC12 in the portal vein falls within the range identified in vitro as sufficient to inhibit citrate transport in hepatocytes., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Microneedles (MNs) are a prospective system in cancer immunotherapy to overcome barriers regarding proper antigen delivery and presentation. This study aims at identifying the potential of MNs for the delivery of Peptide-coated Conditionally Replicating Adenoviruses (PeptiCRAd), whereby peptides enhance the immunogenic properties of adenoviruses presenting tumor associated antigens. The combination of PeptiCRAd with MNs containing polyvinylpyrrolidone and sucrose was tested for the preservation of structure, induction of immune response, and tumor eradication. The findings indicated that MN-delivered PeptiCRAd was effective in peptide presentation in vivo, leading to complete tumor rejection when mice were pre-vaccinated. A rise in the cDC1 population in the lymph nodes of the MN treated mice led to an increase in the effector memory T cells in the body. Thus, the results of this study demonstrate that the combination of MN technology with PeptiCRAd may provide a safer, more tolerable, and efficient approach to cancer immunotherapy, potentially translatable to other therapeutic applications., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Hélder A. Santos reports a relationship with Research Council Finland and UMCG that includes: funding grants. Carmine D'Amico reports a relationship with 10.13039/501100003125Finnish Cultural Foundation that includes: funding grants. Vincenzo Cerullo reports a relationship with 10.13039/501100000781European Research Council (ERC), 10.13039/501100004155Magnus Ehrnrooth Foundation, 10.13039/501100004012Jane and Aatos Erkko Foundation, Finnish Cancer Foundation that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

For patients with rectal cancer, the standard approach of chemotherapy, radiation therapy, and surgery (trimodality therapy) is associated with significant long-term toxicity and/or colostomy for most patients. Patient options focused on quality of life (QOL) have dramatically improved, but there remains limited guidance regarding comparative effectiveness. This systematic review and associated guidelines evaluate how various treatment strategies compare to each other in terms of oncologic outcomes and QOL. Cochrane and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology were used to search for prospective and retrospective trials and meta-analyses of adequate quality within the Ovid Medline database between January 1, 2012, and June 15, 2023. These studies informed the expert panel, which rated the appropriateness of various treatments in 6 clinical scenarios through a well-established consensus methodology (modified Delphi). The search process yielded 197 articles that advised voting. Increasing data have shown that nonoperative management (NOM) and primary surgery result in QOL benefits noted over trimodality therapy without detriment to oncologic outcomes. For patients with rectal cancer for whom total mesorectal excision would result in permanent colostomy or inadequate bowel continence, NOM was strongly recommended as usually appropriate. Restaging with tumor response assessment approximately 8 to 12 weeks after completion of radiation therapy/chemoradiation therapy was deemed a necessary component of NOM. The panel recommended active surveillance in the setting of a near-complete or complete response. In the setting of NOM, 54 to 56 Gy in 27 to 31 fractions concurrent with chemotherapy and followed by consolidation chemotherapy was recommended. The panel strongly recommends primary surgery as usually appropriate for a T3N0 high rectal tumor for which low anterior resection and adequate bowel function is possible, with adjuvant chemotherapy considered if N+. Recent data support NOM and primary surgery as important options that should be offered to eligible patients. Considering the complexity of multidisciplinary management, patients should be discussed in a multidisciplinary setting, and therapy should be tailored to individual patient goals/values., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cell death frequently occurs in the pathogenesis of obesity and metabolic dysfunction-associated fatty liver disease (MAFLD). However, the exact contribution of core cell death machinery to disease manifestations remains ill-defined. Here, we show via the direct comparison of mice genetically deficient in the essential necroptotic regulators, receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like (MLKL), as well as mice lacking apoptotic caspase-8 in myeloid cells combined with RIPK3 loss, that RIPK3/caspase-8 signaling regulates macrophage inflammatory responses and drives adipose tissue inflammation and MAFLD upon high-fat diet feeding. In contrast, MLKL, divergent to RIPK3, contributes to both obesity and MAFLD in a manner largely independent of inflammation. We also uncover that MLKL regulates the expression of molecules involved in lipid uptake, transport, and metabolism, and congruent with this, we discover a shift in the hepatic lipidome upon MLKL deletion. Collectively, these findings highlight MLKL as an attractive therapeutic target to combat the growing obesity pandemic and metabolic disease., (© 2024 Tye et al.)

The manipulation and control of free-standing liquid film drainage dynamics is of paramount importance in many technological fields and related products, ranging from liquid lenses to liquid foams and 2D structures. In this context, we theoretically design and introduce a device where we can reversibly drive flow regime switch between viscous-capillary and viscous-gravity in a thin free-standing liquid film by altering its shape, allowing us to manipulate and stabilize the film thickness over time. The device, which mainly consists of a syringe pump, a pressure transducer, and a 3D-printed cylinder, is coupled with a digital holography setup to measure, in real time, the evolution of the local film thickness map, revealing characteristic features of viscous-capillary and viscous-gravity driven drainage regimes. By using polyvinyl alcohol/water concentrated solutions, we are also able to produce viscoelastic membranes after manipulation and water evaporation, which presents manipulation history-dependent geometrical properties. Furthermore, using a system composed of carboxymethyl cellulose, water, and rod-like zinc oxide nanoparticles, we show a clear effect of film manipulation on particle rearrangement. We believe this device could represent a starting point for the development of a useful and practical tool to study thin liquid film dynamics and to produce novel (patterned) 2D structures for the numerous scientific and technical fields where they are of use.

The marked increase in incidence and mortality in endometrial cancer over the last two decades is driven in part by rising rates of higher grade, more aggressive endometrial cancers with mutations in TP53, uterine serous cancers and their dedifferentiated component, uterine carcinosarcomas (collectively USC). USC rates have been increasing among all racial and ethnic groups, with higher rates of this aggressive uterine cancer in Black women. The National Cancer Institute (NCI) hosted a workshop in June 2023 to examine the diverse aspects of USC across epidemiology, biology, and molecular genetics, and to advance knowledge from basic to preclinical and translational efforts. Key stakeholders came together including basic scientists, clinical investigators, and patient advocates to identify critical research gaps that, when addressed, would facilitate more comprehensive and rapid progress in understanding and ultimately treating USC across all patients. NCI released a supplemental funding opportunity (NOT-CA-24-044) in Spring 2024 to facilitate rapid translation of these recommendations., (Published by Oxford University Press 2024.)

This comprehensive review provides insights and suggested strategies for the analysis of germline variants using second- and third-generation sequencing technologies (SGS and TGS). It addresses the critical stages of data processing, starting from alignment and preprocessing to quality control, variant calling, and the removal of artifacts. The document emphasized the importance of meticulous data handling, highlighting advanced methodologies for annotating variants and identifying structural variations and methylated DNA sites. Special attention is given to the inspection of problematic variants, a step that is crucial for ensuring the accuracy of the analysis, particularly in clinical settings where genetic diagnostics can inform patient care. Additionally, the document covers the use of various bioinformatics tools and software that enhance the precision and reliability of these analyses. It outlines best practices for the annotation of variants, including considerations for problematic genetic alterations such as those in the human leukocyte antigen region, runs of homozygosity, and mitochondrial DNA alterations. The document also explores the complexities associated with identifying structural variants and copy number variations, underscoring the challenges posed by these large-scale genomic alterations. The objective is to offer a comprehensive framework for researchers and clinicians, ensuring that genetic analyses conducted with SGS and TGS are both accurate and reproducible. By following these best practices, the document aims to increase the diagnostic accuracy for hereditary diseases, facilitating early diagnosis, prevention, and personalized treatment strategies. This review serves as a valuable resource for both novices and experts in the field, providing insights into the latest advancements and methodologies in genetic analysis. It also aims to encourage the adoption of these practices in diverse research and clinical contexts, promoting consistency and reliability across studies., (© 2024. The Author(s).)

Purpose: We assessed the 27-gene RT-qPCR-based DetermaIO assay and the same score calculated from RNA sequencing (RNA-seq) data as predictors of sensitivity to immune checkpoint therapy in the neoTRIPaPDL1 randomized trial that compared neoadjuvant carboplatin/nab-paclitaxel chemotherapy (CT) plus atezolizumab with CT alone in stage II/III triple-negative breast cancer. We also assessed the predictive function of the immuno-oncology (IO) score in expression data of patients treated with pembrolizumab plus paclitaxel (N = 29) or CT alone (N = 56) in the I-SPY2 trial., Experimental Design: RNA-seq data were obtained from pretreatment core biopsies from 242 (93.8%) of the 258 patients in the per-protocol-population. The DetermaIO RT-qPCR test, performed in the CAP/CLIA-accredited laboratory of Oncocyte Corp., was available for 220 patients (85.3%). A previously established threshold was used to assign DetermaIO-positive versus DetermaIO-negative status. Publicly available microarray data were used from I-SPY2., Results: IO scores calculated from RNA-seq and RT-qPCR data were highly concordant. In neoTRIPaPDL1, DetermaIO-positive cancers (N = 92, 41.8%) had pathologic complete response (pCR) rates of 69.8% and 46.9% in the CT + atezolizumab and CT arms, respectively. In DetermaIO-negative cases, pCR rates were similar in both arms (44.6% vs. 49.2%; interaction test P = 0.04). PDL1 protein expression and stromal tumor-infiltrating lymphocyte count were not predictive of differential benefit from atezolizumab. In I-SPY2, IO-positive cancers (45.9%) had pCR rates of 85.7% and 16%, with and without immunotherapy, respectively. In IO-negative cancers, pCR rates were 46.7% versus 16.1%., Conclusions: DetermaIO identified patients who benefited from neoadjuvant immunotherapy resulting in improved pCR rate, independently of PDL1., (©2024 The Authors; Published by the American Association for Cancer Research.)

The immunoregulatory cation channel TMEM176B plays a dual role in tumor immunity. On the one hand, TMEM176B promotes antigen cross-presentation to CD8 + T cells by regulating phagosomal pH in dendritic cells (DCs). On the other hand, it inhibits NLRP3 inflammasome activation through ionic mechanisms in DCs, monocytes and macrophages. We speculated that formulating BayK8644 in PEGylated chitosan nanoparticles (NP-PEG-BayK8644) should slowly release the compound and by that mean avoid cross-presentation inhibition (which happens with a fast 30 min kinetics) while still triggering inflammasome activation. Chitosan nanocarriers were successfully obtained, exhibiting a particle size within the range of 200 nm; they had a high positive surface charge and a 99 % encapsulation efficiency. In in vitro studies, NP-PEG-BayK8644 did not inhibit antigen cross-presentation by DCs, unlike the free compound. The NP-PEG-BayK8644 activated the inflammasome in a Tmem176b-dependent manner in DCs. We administered either empty (eNP-PEG) or NP-PEG-BayK8644 to mice with established tumors. NP-PEG-BayK8644 significantly controlled tumor growth and improved mice survival compared to both eNP-PEG and free BayK8644 in melanoma and lymphoma models. This effect was associated with enhanced inflammasome activation by DCs in the tumor-draining lymph node and infiltration of the tumor by CD8 + T cells. Thus, encapsulation of BayK8644 in chitosan NPs improves the anti-tumoral properties of the compound by avoiding inhibition of antigen cross-presentation., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MH is founder and CSO of ARDAN Pharma. One patent application related to this work has been filed at the USA Patent and Trademark Office., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Early identification of sepsis in the emergency department (ED) triage is both valuable and challenging. Numerous studies have endeavored to pinpoint clinical and biochemical criteria to assist clinicians in the prompt diagnosis of sepsis, but few studies have assessed the efficacy of these criteria in the ED triage setting. The aim of the study was to explore the accuracy of clinical and laboratory markers evaluated at the triage level in identifying patients with sepsis., Methods: A prospective study was conducted in a large academic urban hospital, implementing a triage protocol aimed at early identification of septic patients based on clinical and laboratory markers. A multidisciplinary panel of experts reviewed cases to ensure accurate identification of septic patients. Variables analyzed included: Charlson comorbidity index, mean arterial pressure (MAP), partial pressure of carbon dioxide (PetCO 2 ), white cell count, eosinophil count, C-reactive protein to albumin ratio, procalcitonin, and lactate., Results: A total of 235 patients were included. Multivariable analysis identified procalcitonin ≥1 ng/mL (OR 5.2; p < 0.001); CRP-to-albumin ratio ≥32 (OR 6.6; p < 0.001); PetCO 2  ≤ 28 mmHg (OR 2.7; p = 0.031), and MAP <85 mmHg (OR 7.5; p < 0.001) as independent predictors for sepsis. MAP ≥85 mmHg, CRP/albumin ratio <32, and procalcitonin <1 ng/mL demonstrated negative predictive values for sepsis of 90%, 89%, and 88%, respectively., Conclusions: Our study underscores the significance of procalcitonin and mean arterial pressure, while introducing CRP/albumin ratio and PetCO 2 as important variables to consider in the very initial assessment of patients with suspected sepsis in the ED., Clinical Relevance: Early identification of sepsis since the emergency department (ED) triage is challenging Implementing the ED triage protocol with simple clinical and laboratory markers allows to recognize patients with sepsis with a very good discriminatory power (AUC 0.88)., (© 2024 Sigma Theta Tau International.)

Background and Objectives: Facemasks represent an essential measure of prevention against the spread of infectious diseases; however, they lessen the ability to convey and understand emotions through facial expressions. In blood donation settings, facemask wearing could interfere with professionals' tasks, reduce the satisfaction of blood donors and affect their future blood donation behaviour. This preliminary cross-sectional study explored the association of mandatory facemask wearing with the quality of the blood donation process at the end of the coronavirus 2019 (COVID-19) pandemic., Materials and Methods: A sample of 615 voluntary unpaid Italian blood and plasma donors completed an online survey assessing their attitude towards facemask wearing, the perceived distress due to facemasks in the different steps of the donation process, self-reported vasovagal reactions after donation and the intention to donate again., Results: Nearly 24% of donors reported a worsened quality of the donation process due to facemask wearing, and 36% reported moderate to severe distress during the donation itself. Donors with a more negative attitude towards facemasks reported a worse donation experience, mainly related to the interactions and the communication with physicians and nurses, and a higher probability of experiencing vasovagal reactions at their last donation. No significant correlations were observed between negative facemask attitudes towards facemask wearing, distress or future intention to donate blood/plasma., Conclusion: Facemasks have worsened the quality of blood and plasma donations for one fourth of donors, confirming the interference with the quality of communications and relationships with healthcare professionals., (© 2024 The Author(s). Vox Sanguinis published by John Wiley & Sons Ltd on behalf of International Society of Blood Transfusion.)

Background and Study Aims: Balanced propofol sedation (BPS) administered by adequately trained non-anaesthesiologist personnel has gained popularity in GI endoscopy because of its shorter procedure and recovery time, high patient satisfaction, and low rate of adverse events (AEs), despite being considered controversial. We report data from an audit of endoscopist-directed (ED) nurse-administered sedation in an Italian referral hospital., Patients and Methods: Consecutive endoscopic procedures performed between 2020 and 2022 were considered. Under the guidance of the endoscopist, the nurse administered midazolam/fentanyl, followed by a progressive top-up dosage of a 10-20 mg bolus of propofol to achieve moderate to deep sedation. The endoscopists and nurses were all certified in our hospital with a continuous and scheduled training from 2006., Results: During the study period, a total of 19,407 examinations (7,803 EGDS, 10,439 colonoscopies, 77 PEG, 697 EUS, and 365 ERCP) and 14,415 patients were included. Of these, 29.4 % of patients were classified as ASA I, 66.5 % as ASA II, and 5.1 % as ASA III. Hypotension was recorded in 1,293 (6 %) examinations and bradycardia in 176 (0.9 %) patients. Eleven patients (0.06 %) had minor respiratory adverse events. Two patients (0.01 %) had major AEs requiring orotracheal intubation., Conclusions: ED-BPS is safe in low-risk patients. Major AEs occurred in 0.01 % of procedures., Competing Interests: Conflicts of interest No conflict of interest, (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Context: Silver-Russell Syndrome (SRS) is a growth retardation disorder characterized by pre- and post-natal growth failure, relative macrocephaly at birth, prominent forehead, body asymmetry, and feeding difficulties. The main molecular mechanisms are imprinting alterations at multiple loci, though a small number of pathogenic variants have been reported in the SRS genes IGF2-PLAG1-HMGA2 and CDKN1C. However, around 40% of clinically suspected SRS cases do not achieve a molecular diagnosis, highlighting the necessity to uncover the underlying mechanism in unsolved cases., Objective: evaluate the frequency of genetic variants in undiagnosed SRS patients (NH-CSS≥4), and investigate whether (epi)genetic patients may be distinguished from genetic patients., Methods: 132 clinically SRS patients without (epi)genetic deregulations were investigated by Whole Exome (n=15) and Targeted (n=117) Sequencing. Clinical data from our cohort and from an extensive revision of literature were compared., Results: pathogenic variants were identified in 9.1% of this cohort: 3% in IGF2, PLAG1, and HMGA2 genes, while 3% in the IGF1R gene, associated with IGF-1 resistance (IGF1RES), an SRS differential diagnosis. Overall, IGF2-PLAG1-HMGA2 and IGF1R account for 3.6% of SRS with NH-CSS score ≥ 4. A clinical cross-comparison of (epi)genetic versus genetic SRS underlined (epi)genotype-phenotype correlation, highlighted the prevalence of body asymmetry and relative macrocephaly in mosaic (epi)genetic SRS and recurrence of genetic familial cases. Furthermore, overlapping features were evidenced in (epi)genetic SRS and IGF1RES patients., Conclusion: Our study explores the frequency of genetic SRS, underscores body asymmetry as distinctive phenotype in (epi)genetic SRS and suggests IGF1R sequencing in SRS diagnostic flow-chart., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.)

Carnosine is an endogenous dipeptide characterized by a multimodal mechanism of action. However, its clinical potential is limited by serum and cytosolic carnosinases, which significantly reduce its bioavailability. Based on that, different research groups have worked on the development of new strategies able not only to prevent its rapid metabolization but also to improve its distribution and specific targeting. In the present study, the development and in vitro characterization of new liposomal formulations loaded with carnosine are described. Nanoliposomes, produced through Thin-Layer Hydration followed by Extrusion method, were first investigated for their physicochemical stability. Photon correlation spectroscopy and electrophoretic light scattering, assessing the stability of the formulations, showed a strong homogeneity-oriented tendency for up to two months. Particle size, polydispersity index, and zeta potential were determined through dynamic light scattering and electrophoretic light scattering, demonstrating an almost neutral charge of the formulation and an effective encapsulation of carnosine. The morphology assessment performed via scanning electron microscopy showed good conformity and polydispersity. Differential scanning calorimetry measurements suggest the ability of carnosine to stabilize the large unilamellar vesicles. Lastly, the newly developed carnosine-loaded liposomal formulations also showed a good safety profile in human microglia.

Background: Considering the growing population of older adults, addressing the influence of loneliness among this demographic group has become imperative, especially due to the link between social isolation and deterioration of mental and physical well-being. Technology has the potential to be used to create innovative solutions to increase socialization and potentially promote healthy aging., Objective: This 6-month study examined the usability and acceptability of a technology-based socialization service and explored how stress and living situation affect older adults' and their ecosystem's perceptions of technology, investigating cross-sectional and longitudinal differences among and across user groups., Methods: Participants were recruited in Tuscany and Apulia (Italy) through a network of social cooperatives and a research hospital, respectively. A total of 20 older adults were provided with the same technology installed on a tablet and on a smart television. The technology has three functionalities: video calling, playing games, and sharing news. Additionally, 20 informal caregivers (IC) and 13 formal caregivers (FC) connected to the older adults were included in the study. After both initial training in the use of the system (T0) and 6 months of using the system (T6), questionnaires on usability, acceptability, and technostress were filled in by older adults, IC, and FC. Nonparametric or parametric tests were conducted to investigate group differences at both time points and changes over time. Additional analyses on older adults were done to assess whether differences in usability and acceptability were related to living situation (ie, alone or with someone). Furthermore, correlation analyses were performed between usability, acceptability, and stress toward technology at T0 and T6., Results: At both T0 and T6, older adults had lower usability scores than IC and FC and higher anxiety than IC. Over time, there was a significant decrease in older adults' attitudes toward technology score, depicting a negative attitude over time (T0 median 4.2, IQR 0.5; T6 median 3.7, IQR 0.8; Cohen d=0.7), while there was no change for IC and FC. At T0, those living alone had lower acceptability than those living with someone but this difference disappeared at T6. People or participants living with someone had a decline in anxiety, attitudes toward technology, enjoyment, and perceived usefulness. Stress toward technology affected usability and acceptability in the older adult group entering the study (ρ=-.85) but this was not observed after 6 months. In the IC group, stress affected trust at T0 (ρ=-.23) but not at T6., Conclusions: At the start of the study, older adults judged the system to be less usable and more stressful than did the caregivers. Indeed, at first, technostress was correlated with usability and acceptability; however, with repeated use, technostress did not influence the perception of technology. Overall, getting accustomed to technology decreased anxiety and stress toward technology., (© Jasmine Pani, Letizia Lorusso, Lara Toccafondi, Grazia D'Onofrio, Filomena Ciccone, Sergio Russo, Francesco Giuliani, Daniele Sancarlo, Novella Calamida, Gianna Vignani, Tarmo Pihl, Erika Rovini, Filippo Cavallo, Laura Fiorini. Originally published in JMIR Aging (https://aging.jmir.org).)

Here we demonstrate for the first time that an antibody-gold nanoparticles (AuNPs)-polymer conjugate thin-film biosensor can easily be fabricated to selectively capture Tau protein. Gold nanoparticles (AuNPs) are employed as sensing elements, thus capitalizing on their propensity to undergo assembly or disassembly in response to the adsorption or conjugation of various biomolecules on their surface, thereby forming robust interactions with the target analyte. We show that the Tau protein in its different aggregation phases can be detected, by restricting the reaction area on the solid thin polymer film and thus reducing the diffusion effects usually encountered in immunosensors. A limit of detection (LOD) of 460 pg/mL was reached, demonstrating a great potential for detecting Tau in aggregation states. This sensor based on thin polymer film could open new routes for sensing and monitoring Tau protein in biological assays and biomedical diagnosis., 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.)

In a recent study, Reinforcement Learning (RL) used in combination with many-objective search, has been shown to outperform alternative techniques (random search and many-objective search) for online testing of Deep Neural Network-enabled systems. The empirical evaluation of these techniques was conducted on a state-of-the-art Autonomous Driving System (ADS). This work is a replication and extension of that empirical study. Our replication shows that RL does not outperform pure random test generation in a comparison conducted under the same settings of the original study, but with no confounding factor coming from the way collisions are measured. Our extension aims at eliminating some of the possible reasons for the poor performance of RL observed in our replication: (1) the presence of reward components providing contrasting feedback to the RL agent; (2) the usage of an RL algorithm (Q-learning) which requires discretization of an intrinsically continuous state space. Results show that our new RL agent is able to converge to an effective policy that outperforms random search. Results also highlight other possible improvements, which open to further investigations on how to best leverage RL for online ADS testing., (© The Author(s) 2024.)

Objectives: The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP-CML patients., Methods: A retrospective analysis was conducted on 332 CP-CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the "Campus CML" project., Results: Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second-generation TKIs (2G-TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G-TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra-hematologic toxicity (9.5%), with no significant difference between IM and 2G-TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G-TKIs., Conclusions: IM was in our Centers the preferred frontline therapy for older CP-CML patients, with increasing utilization after the introduction of generic formulations. However, 2G-TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population., (© 2024 The Author(s). European Journal of Haematology published by John Wiley & Sons Ltd.)

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5' UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5' UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity., (© 2024 Wiley Periodicals LLC.)

Soft robots typically involve manual assembly of core hardware components like actuators, sensors, and controllers. This increases fabrication time and reduces consistency, especially in small-scale soft robots. We present a scalable monolithic fabrication method for millimeter-scale soft-rigid hybrid robots, simplifying the integration of core hardware components. Actuation is provided by soft-foldable polytetrafluoroethylene film-based actuators powered by ionic fluid injection. The desired motion is encoded by integrating a mechanical controller, comprised of rigid-flexible materials. The robot's motion can be self-sensed using an ionic resistive sensor by detecting electrical resistance changes across its body. Our approach is demonstrated by fabricating three distinct soft-rigid hybrid robotic modules, each with unique degrees of freedom: translational, bending, and roto-translational motions. These modules connect to form a soft-rigid hybrid continuum robot with real-time shape-sensing capabilities. We showcase the robot's capabilities by performing object pick-and-place, needle steering and tissue puncturing, and optical fiber steering tasks., (© 2024. The Author(s).)

Background: Silver-Russell Syndrome (SRS, MIM #180860) is a clinically and genetically heterogeneous disorder characterized by intrauterine and postnatal growth retardation; SRS is also accompanied by dysmorphic features such as triangular facial appearance, broad forehead, body asymmetry and significant feeding difficulties. The incidence is unknown but estimated at 1:30,000-100,000 live births. The diagnosis of SRS is guided by specific criteria described in the Netchine-Harbison clinical scoring system (NH-CSS)., Case Presentation: Hereby we describe four patients with syndromic short stature in whom, despite fitting the criteria for SRS genetic analysis (and one on them even meeting the clinical criteria for SRS), molecular analysis actually diagnosed a different syndrome. Some additional features such as hypotonia, microcephaly, developmental delay and/or intellectual disability, and family history of growth failure, were actually discordant with SRS in our cohort., Conclusions: The clinical resemblance of other short stature syndromes with SRS poses a risk of diagnostic failure, in particular when clinical SRS only criteria are met, allowing SRS diagnosis in the absence of a positive result of a genetic test. The presence of additional features atypical for SRS diagnosis becomes a red flag for a more extensive and thorough analysis. The signs relevant to the differential diagnosis should be valued as much as possible since a correct diagnosis of these patients is the only way to provide the appropriate care pathway, a thorough genetic counselling, prognosis definition, follow up setting, appropriate monitoring and care of possible medical problems., (© 2024. The Author(s).)

Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC., Competing Interests: Oncolytic viruses encoding for cytokines CXCL9, CXCL10 and IL-15 have been licensed to Ximbio/CancerTools.org for commercialization to other academic or commercial researchers. V.S. is currently employed by AstraZeneca. V.C is a co-founder and shareholder at VALO Therapeutics. Other authors report there are no competing interests to declare., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Colonoscopies are vital procedures allowing diagnosis of colorectal cancer and other gastrointestinal diseases. However, excessive forces may be applied to the colon during navigation. This can cause bleeding, especially in patients presenting inflammatory bowel diseases. The endoscopist is often unable to detect bleeding as visualization is limited to the distal tip camera of the endoscope. Thus, there is a need to have bleeding detection capabilities behind the device tip. This work presents a soft optical blood sensor that can be mounted onto a colonoscope. The presence of blood in the sensor's microchannel causes a reduction in optical transmission, and the endoscopist is alerted. We evaluate the sensor safety and performance ex vivo with a cohort of 10 endoscopists (novices and experts). We demonstrate the ability of the sensor to rapidly identify bleeding and easily integrate into the clinical workflow, without significantly affecting navigation time and the users' learning curve., Competing Interests: Declaration of Interests Max McCandless is currently a post-doctoral researcher at Boston Children’s Hospital, Harvard University. His contributions in this paper were from his tenure as a PhD student at the Material Robotics Laboratory, Boston University (affiliation as declared on the manuscript).

The field emission properties of rhenium diselenide (ReSe 2 ) nanosheets on Si/SiO 2 substrates, obtained through mechanical exfoliation, have been investigated. The n-type conduction was confirmed by using nano-manipulated tungsten probes inside a scanning electrode microscope to directly contact the ReSe 2 flake in back-gated field effect transistor configuration, avoiding any lithographic process. By performing a finite element electrostatic simulation of the electric field, it is demonstrated that the use of a tungsten probe as anode, at a controlled distance from the ReSe 2 emitter surface, allows the collection of emitted electrons from a reduced area that furtherly decreases by reducing the tip-sample distance, i.e. allowing a local characterization of the field emission properties. Experimentally, it is shown that the turn-on voltage can be linearly reduced by reducing the cathode-anode separation distance. By comparing the measured current-voltage characteristics with the numerical simulations, it is also shown that the effective field enhancement on the emitter surface is larger than expected because of surface defects. Finally, it is confirmed that ReSe 2 nanosheets are suitable field emitters with high time stability and low current fluctuations.

Purpose: To investigate the outcome and toxicity of patients affected by malignant peripheral nerve sheath tumors (MPNSTs) treated with high-dose carbon ion radiation therapy (CIRT)., Methods and Materials: We retrospectively analyzed the outcome of 23 patients with MPNSTs treated between July 2013 and December 2020. Out of these, 13 patients (56.5%) had incompletely resected tumors, 8 patients (34.7%) experienced recurrence after surgery, and 2 patients (8.7%) had unresectable tumors. Before CIRT treatment, 4 patients underwent a second surgery after the first local recurrence (LR), and 1 patient underwent a third surgery for the second local relapse of the disease. Six (26%) patients received neoadjuvant chemotherapy. The most frequent tumor site was the brachial plexus (n = 9; 39.1%). In 5 patients (21.7%), neurofibromatosis type 1 disorder was found, while 4 patients (17, 4%) had radiation-induced MPNSTs. The median CIRT prescribed total dose was 69.8 Gy (relative biological effectiveness; range, 54-76.8) delivered in a median of 16 fractions (range, 15-22). Eleven patients (47.82%) were treated according to a sequential boost protocol with a median prescribed dose to clinical target volume LR of 45 Gy (relative biological effectiveness; range, 41.4-54)., Results: After a median follow-up time of 23 months (range, 3-100 months), the overall survival rates at 1 and 2 years were 82.38% and 61.51%, respectively. The 1-year and 2-year local relapse-free survival rates were 65.07% and 48.80%, respectively, and the 1-year and 2-year progression-free survival rates were 56.37% and 40.99%, respectively. No patients showed acute or late grade 4 toxicity or any treatment-related deaths. Ten patients (43.48%) reported acute toxicities of grade ≥ 2, which included dermatitis in 6 patients, mucositis in 2 patients, and peripheral neuropathy in 4 patients. Eight patients (34.78%) reported late toxicities of grade ≥ 2, mainly due to loco-regional neuropathy., Conclusions: High-dose CIRT shows favorable local effects with acceptable toxicities in patients with gross residual and LR after surgery or unresectable malignant peripheral nerve sheath tumors. Advanced treatment modalities such as particle therapy should be considered for MPNSTs., Competing Interests: Maria Rosaria Fiore, Agnieszka Chalaszczyk, Amelia Barcellini, Viviana Vitolo, Giulia Fontana, Stefania Russo, Marco Rotondi, Silvia Molinelli, Alfredo Mirandola, Alessia Bazani, and Ester Orlandi declare no conflict of interest., (© 2024 The Authors.)

Post-transcriptional tRNA modifications contribute to the decoding efficiency of tRNAs by supporting codon recognition and tRNA stability. Recent work shows that the molecular and cellular functions of tRNA modifications and tRNA-modifying-enzymes are linked to brain development and neurological disorders. Lack of these modifications affects codon recognition and decoding rate, promoting protein aggregation and translational stress response pathways with toxic consequences to the cell. In this review, we discuss the peculiarity of local translation in neurons, suggesting a role for fine-tuning of translation performed by tRNA modifications. We provide several examples of tRNA modifications involved in physiology and pathology of the nervous system, highlighting their effects on protein translation and discussing underlying mechanisms, like the unfolded protein response (UPR), ribosome quality control (RQC), and no-go mRNA decay (NGD), which could affect neuronal functions. We aim to deepen the understanding of the roles of tRNA modifications and the coordination of these modifications with the protein translation machinery in the nervous system., (© 2024 The Author(s). BioEssays published by Wiley Periodicals LLC.)

Background: Scalp EEG is one of the main tools in the clinical evaluation of epilepsy. In some cases intracranial Interictal Epileptiform Discharges (IEDs) are not visible from the scalp. Recent studies have shown the feasibility of revealing them in the EEG if their timings are extracted from simultaneous intracranial recordings, but their potential for the localization of the epileptogenic zone is not yet well defined., New Method: We recorded simultaneous high-density EEG (HD-EEG) and stereo-electroencephalography (SEEG) during interictal periods in 8 patients affected by drug-resistant focal epilepsy. We identified IEDs in the SEEG and systematically analyzed the time-locked signals on the EEG by means of evoked potentials, topographical analysis and Electrical Source Imaging (ESI). The dataset has been standardized and is being publicly shared., Results: Our results showed that IEDs that were not clearly visible at single-trials could be uncovered by averaging, in line with previous reports. They also showed that their topographical voltage distributions matched the position of the SEEG electrode where IEDs had been identified, and that ESI techniques can reconstruct it with an accuracy of ∼2 cm. Finally, the present dataset provides a reference to test the accuracy of different methods and parameters., Comparison With Existing Methods: Our study is the first to systematically compare ESI methods on simultaneously recorded IEDs, and to share a public resource with in-vivo data for their evaluation., Conclusions: Simultaneous HD-EEG and SEEG recordings can unveil hidden IEDs whose origins can be reconstructed using topographical and ESI analyses, but results depend on the selected methods and parameters., Competing Interests: Declaration of Competing Interest Marcello Massimini is co-founder and shareholder of Intrinsic Powers. Simone Russo is the Chief Medical Officer of Manava Plus. All other authors report no competing interests., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Nitroreductases (NRs) are NAD(P)H-dependent flavoenzymes that reduce nitro aromatic compounds to their corresponding arylamines via the nitroso and hydroxylamine intermediates. Because of their broad substrate scope and versatility, NRs have found application in multiple fields such as biocatalysis, bioremediation, cell-imaging and prodrug activation. However, only a limited number of members of the broad NR superfamily (> 24 000 sequences) have been experimentally characterized. Within this group of enzymes, only few are capable of amine synthesis, which is a fundamental chemical transformation for the pharmaceutical, agricultural, and textile industries. Herein, we provide a comprehensive description of a recently discovered NR from Bacillus tequilensis, named BtNR. This enzyme has previously been demonstrated to have the capability to fully convert nitro aromatic and heterocyclic compounds to their respective primary amines. In this study, we determined its biochemical, kinetic and structural properties, including its apparent melting temperature (T m ) of 59 °C, broad pH activity range (from pH 3 to 10) and a notably low redox potential (-236 ± 1 mV) in comparison to other well-known NRs. We also determined its steady-state and pre-steady-state kinetic parameters, which are consistent with other NRs. Additionally, we elucidated the crystal structure of BtNR, which resembles the well-characterized Escherichia coli oxygen-insensitive NAD(P)H nitroreductase (NfsB), and investigated the substrate binding in its active site through docking and molecular dynamics studies with four nitro aromatic substrates. Guided by these structural analyses, we probed the functional roles of active site residues by site-directed mutagenesis. Our findings provide valuable insights into the biochemical and structural properties of BtNR, as well as its potential applications in biotechnology., (© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug-controlled generalized tonic-clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith-Magenis syndrome (SMS). Analysis of brothers' DNAs by next-generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents' peripheral blood and from buccal swab raised the suspicion of low-grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk., (© 2024 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)

Background: Endoscopic surgery is a minimally invasive procedure that has been shown to relieve intradiscal pressure, irrigation of inflammatory factors, and visual debridement, which are crucial for the successful treatment of spondylodiscitis. This study proposes a systematic review and meta-analysis to evaluate the effectiveness and safety of endoscopic treatment of thoracolumbar spondylodiscitis., Methods: Multiple databases were searched for studies involving thoracolumbar spondylodiscitis treated by endoscopic disc drainage with or without additional posterior fixation over the last 20 years. Studies that met the inclusion criteria, which included outcomes related to the percentage of cured infections, patient satisfaction, regression of inflammatory markers, and/or the percentage of adverse event rates, were included in the analysis. For each study, the percentage of patients who showed improvement or experienced an adverse event was abstracted and pooled in a meta-analysis., Results: Based on the search strategy and inclusion criteria, our systematic review and meta-analysis included 20 studies with 546 participants. The success rate was 89.4% (95% CI 83.1%-94.5%). The rate of major adverse events was 0.3%, while that of postoperative transient paresthesia was 2.6% (95% CI 0.8%-5.1%). The recurrence rate was 1.7% (95% CI 0.3%-4.0%), and revision surgery was 8.5% (95% CI 3.8%-14.6%). The causative pathogen diagnosis rate was 73.9% (95% CI 67.7%-79.8%), while progression of deformity was 3.7% (95% CI 0.2%-9.8%), and spontaneous fusion was 40.1% (95% CI 11.0%-73.3%)., Conclusions: Endoscopic discectomy for thoracolumbar spondylodiscitis has been shown to be a safe technique with satisfactory clinical outcomes and a high causative pathogen identification rate., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Among hydrocolloids used in the food industry, gelatin (an animal protein) is remarkably known for its unique gel forming ability. Creating a perfect, green substitute for animal gelatin is extremely difficult if not impossible, because this versatile hydrocolloid offers many special properties that are not easily imitated by other vegetable-based systems. The combination of more than one type of hydrocolloid is commonly used in food either to bridge the above-mentioned gap or to impart novel organoleptic characteristics (such as mouthfeel) to food products, to modify rheological characteristics, and to satisfy processing requirements in the industry. In this work, we study the rheology and the texture of water mixtures of κ-Carrageenan (κ-C) and Locust Bean Gum (LBG). By fixing different κ-C concentrations and varying the LBG/κ-C ratio, we explore a wide range of potentially useful textures. The results obtained for the green systems are also compared to those exhibited by animal gelatin formulations.

The rabies virus (RABV) is the exclusive lyssavirus affecting both wild and domestic mammalian hosts in the Americas, including humans. Additionally, the Americas stand out as the sole region where bat rabies occurs. While carnivore rabies is being increasingly managed across the region, bats are emerging as significant reservoirs of RABV infection for humans and domestic animals. Knowledge of the bat species maintaining rabies and comprehending cross-species transmission (CST) and host shift processes are pivotal for directing surveillance as well as ecological research involving wildlife reservoir hosts. Prior research indicates that bat RABV CST is influenced by host genetic similarity and geographic overlap, reflecting host adaptation. In this study, we compiled and analyzed a comprehensive nucleoprotein gene dataset representing bat-borne RABV diversity in Argentina and the broader Americas using Bayesian phylogenetics. We examined the association between host genus and geography, finding both factors shaping the global phylogenetic structure. Utilizing a phylogeographic approach, we inferred CST and identified key bat hosts driving transmission. Consistent with CST determinants, we observed monophyletic/paraphyletic clustering of most bat genera in the RABV phylogeny, with stronger CST evidence between host genera of the same family. We further discuss Myotis as a potential ancestral spreader of much of RABV diversity.

Background: Psychopathological disorders are often comorbid diagnosis in eating disorders (EDs). We aimed to assess the presence of psychopathological traits and symptoms associated with EDs in an Italian high school adolescent population., Methods: A sample of high school adolescents was enrolled, and demographic and clinical data were collected. Two self-report questionnaires, the Eating Disorder Inventory-3 (EDI-3) and the Questionnaire for the Assessment of Psychopathology in Adolescence (Q-PAD), were administered., Results: 548 adolescents (333 F/215 M; 16.89 ± 0.85 years) were included. Symptoms associated with EDs of clinical or high clinical concern were prevalent in a range of individuals, with percentages varying from 26.82% for body dissatisfaction to 51.83% for Interoceptive Deficits. The findings from the Q-PAD assessment indicated the presence of psychological distress, leading to discomfort or challenging situations requiring potential intervention in a percentage of adolescents ranging from 2.93% for psychosocial risks to 23.77% for anxiety. These percentages showed differences between genders (F > M, p < 0.001). Our study also highlighted an association between symptoms of EDs and lifestyle factors within families. We observed correlations between Q-PAD measures and EDI-3 scores, including a positive correlation between Q-PAD and EDI-3 body dissatisfaction (r = 0.7), Q-PAD interpersonal conflicts and EDI-3 interpersonal problems (r = 0.6) and a negative correlation between Q-PAD self-esteem and well-being and EDI-3 ineffectiveness Composite (r=-0.7)., Conclusions: a substantial prevalence of ED symptoms and psychological distress among high school adolescents were recorded. These conditions are interrelated, suggesting the importance of addressing them comprehensively. Early detection is essential to improve treatment outcomes and to implement preventive strategies., (© 2024. The Author(s).)

Over the past 40 years, the prevalence of obesity has risen dramatically, reaching epidemic proportions. By 2030 the number of people affected by obesity will reach 1.12 billion worldwide. Gastrointestinal hormones, namely incretins, play a vital role in the pathogenesis of obesity and its comorbidities. GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 (glucagon-like peptide-1), which are secreted from the intestine after nutrient intake and stimulate insulin secretion from pancreatic β cells, influence lipid metabolism, gastric empting, appetite and body weight. The gut microbiota plays an important role in various metabolic conditions, including obesity and type 2 diabetes and influences host metabolism through the interaction with enteroendocrine cells that modulate incretins secretion. Gut microbiota metabolites, such as short-chain fatty acids (SCFAs) and indole, directly stimulate the release of incretins from colonic enteroendocrine cells influencing host satiety and food intake. Moreover, bariatric surgery and incretin-based therapies are associated with increase gut bacterial richness and diversity. Understanding the role of incretins, gut microbiota, and their metabolites in regulating metabolic processes is crucial to develop effective strategies for the management of obesity and its associated comorbidities., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: This umbrella review aimed to consolidate the evidence base on the impact of high-fidelity simulation on knowledge and performance among undergraduate nursing students., Design: Umbrella review with meta-analyses of pooled effect sizes, followed by an additional meta-analysis of primary studies from the included systematic reviews, excluding overlapping results., Data Sources: Systematic searches were performed up to August 2023 in PubMed, Embase, and Cochrane Library. We included reviews that compared high-fidelity simulation against other learning strategies., Review Methods: The risk of bias was assessed for each included systematic review (ROBIS tool) and primary study (RoB 2 or ROBINS-I as appropriate). Random-effect meta-analyses of meta-analyses were performed to estimate the pooled effects of high-fidelity simulation on knowledge and performance. Further random-effect meta-analyses of primary studies were conducted, with overlapping studies excluded (12 %). Subgroup analyses were performed to provide a more comprehensive analysis of the findings. Trim-and-fill analyses were conducted to adjust for potential publication bias., Results: Six systematic reviews were included and encompassed 133 primary studies (2767 and 3231 participants concerning performance and knowledge, respectively). The adjusted pooled effects for knowledge (SMD = 0.877, 95 % CI: 0.182 to 1.572) and performance (SMD = 0.738, 95 % CI: 0.466 to 1.010) closely aligned with those obtained from meta-analyzing the primary studies for knowledge (SMD = 0.980) and performance (SMD = 0.540), both showing high statistical heterogeneity. Traditional lectures represented the more common comparison. The subgroup analysis revealed significant differences in effect sizes across geographic locations, topics, types of control, and how interventions were reported., Conclusions: The results provide robust evidence supporting the integration of high-fidelity simulation into undergraduate nursing programs to enhance students' knowledge and performance. The high reported heterogeneity may be attributed to variations in study contexts or methodologies. Future research should explore the optimal use of high-fidelity simulation in different educational and cultural contexts., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis by glutaminase (GLS). However, this metabolic addiction can be lost in the tumour microenvironment, rendering GLS inhibitors ineffective in the clinic. Here we show that glutamine-addicted breast cancer cells adapt to chronic glutamine starvation, or GLS inhibition, via AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine, but α-ketoglutarate (α-KG). Mechanistically, we find that phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained α-KG production when glutamate is depleted. Breast cancer cells with resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied α-KG. Accordingly, inhibition of the SSP prevents adaptation to glutamine blockade, resulting in a potent drug synergism that suppresses breast tumour growth. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumour growth in a particular nutrient environment. This, in turn, has practical consequences for therapies targeting cancer metabolism., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Imprinting disorders are rare diseases resulting from altered expression of imprinted genes, which exhibit parent-of-origin-specific expression patterns regulated through differential DNA methylation. A subgroup of patients with imprinting disorders have DNA methylation changes at multiple imprinted loci, a condition referred to as multi-locus imprinting disturbance (MLID). MLID is recognised in most but not all imprinting disorders and is also found in individuals with atypical clinical features; the presence of MLID often alters the management or prognosis of the affected person. Some cases of MLID are caused by trans-acting genetic variants, frequently not in the patients but their mothers, which have counselling implications. There is currently no consensus on the definition of MLID, clinical indications prompting testing, molecular procedures and methods for epigenetic and genetic diagnosis, recommendations for laboratory reporting, considerations for counselling, and implications for prognosis and management. The purpose of this study is thus to cover this unmet need., Methods: A comprehensive literature search was conducted resulting in identification of more than 100 articles which formed the basis of discussions by two working groups focusing on clinical diagnosis (n = 12 members) and molecular testing (n = 19 members). Following eight months of preparations and regular online discussions, the experts from 11 countries compiled the preliminary documentation and determined the questions to be addressed during a face-to-face meeting which was held with the attendance of the experts together with four representatives of patient advocacy organisations., Results: In light of available evidence and expert consensus, we formulated 16 propositions and 8 recommendations as interim guidance for the clinical and molecular diagnosis of MLID., Conclusions: MLID is a molecular designation, and for patients with MLID and atypical phenotypes, we propose the alternative term multi-locus imprinting syndrome. Due to the intrinsic variability of MLID, the guidelines underscore the importance of involving experts from various fields to ensure a confident approach to diagnosis, counselling, and care. The authors advocate for global, collaborative efforts in both basic and translational research to tackle numerous crucial questions that currently lack answers, and suggest reconvening within the next 3-5 years to evaluate the research advancements and update this guidance as needed., (© 2024. The Author(s).)

Purpose/objective: To perform a dosimetric and a normal tissue complication probability (NTCP) comparison between intensity modulated proton therapy and photon volumetric modulated arc therapy in a cohort of patients with parotid gland cancers in a post-operative or radical setting., Materials and Methods: From May 2011 to September 2021, 37 parotid gland cancers patients treated at two institutions were eligible. Inclusion criteria were as follows: patients aged ⩾ 18 years, diagnosis of parotid gland cancers candidate for postoperative radiotherapy or definitive radiotherapy, presence of written informed consent for the use of anonymous data for research purposes. Organs at risk (OARs) were retrospectively contoured. Target coverage goal was defined as D95 > 98%. Six NTCP models were selected. NTCP profiles were calculated for each patient using an internally-developed Python script in RayStation TPS. Average differences in NTCP between photon and proton plans were tested for significance with a two-sided Wilcoxon signed-rank test., Results: Seventy-four plans were generated. A lower Dmean to the majority of organs at risk (inner ear, cochlea, oral cavity, pharyngeal constrictor muscles, contralateral parotid and submandibular gland) was obtained with intensity modulated proton therapy vs volumetric modulated arc therapy with statistical significance (p < .05). Ten (27%) patients had a difference in NTCP (photon vs proton plans) greater than 10% for hearing loss and tinnitus: among them, seven qualified for both endpoints, two patients for hearing loss only, and one for tinnitus., Conclusions: In the current study, nearly one-third of patients resulted eligible for proton therapy and they were the most likely to benefit in terms of prevention of hearing loss and tinnitus., Competing Interests: Declaration of conflicting interestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The Division of Radiation Oncology of IEO received Institutional grants from Accuray InC. and Ion Beam Applications (IBA). BAJF received speakers’ fees from Roche, Bayer, Janssen, Carl Zeiss, Ipsen, Accuray, Astellas, Elekta, IBA and Astra Zeneca (all outside the current project). The remaining authors declare no conflicts of interest.

Psoriasis, a systemic autoimmune disorder primarily affecting the skin, manifests through erythematous plaques and scales, impacting approximately 2-3% of the global population. Chronic periodontitis, a prevalent oral disease characterized by the destruction of tooth-supporting tissues, affects roughly 10-15% of adults worldwide. Emerging evidence suggests a bidirectional relationship between psoriasis and chronic periodontitis, supported by epidemiological studies indicating a higher prevalence of periodontitis among individuals with psoriasis and vice versa. Both conditions are chronic inflammatory diseases marked by dysregulated immune responses and altered cytokine profiles, notably involving proinflammatory cytokines such as TNF-α and IL-17. Clinical studies highlight a reciprocal impact of treating one condition on the other, underscoring the necessity of interdisciplinary collaboration between dermatologists and periodontists in managing patients with both conditions. This narrative review provides a comprehensive overview of the relationship between psoriasis and chronic periodontitis, examining epidemiological associations, shared inflammatory pathways, genetic insights, microbial dysbiosis, environmental factors, and clinical implications. The review emphasizes the importance of integrated care approaches and the potential for targeted therapeutic interventions to improve both psoriatic and periodontal patient outcomes, advocating for further research into the molecular and cellular mechanisms underpinning the comorbidity of these diseases.