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Context: Multiple sclerosis (MS) is an inflammatory, chronic, demyelinating, and neurodegenerative disorder of central nervous system, determined by an auto-immune dysfunction. Severe disability generally occurs in patients with progressive forms of MS that typically develop either after an earlier relapsing phase or less commonly from disease onset. Despite advances in research to slow the progression of MS, this condition remains a life-limiting disease with symptoms impacting negatively the lives of patients and caregivers., Objectives: To analyze the difefrent aspects of palliative cae in patients with MS., Methods: To analyse selected literature assessing several palliative care aspects in patients with MS., Results: People with MS have complex symptoms and different needs. These demands include how to deal with the burden of physical disability, how to organise daily life, restructuring social roles in the family and at work, keeping self-sufficiency in personal care, and preserving personal identity and community roles., Conclusion: An early palliative care approach aims to improve the palliative care skills and competencies of health professionals caring for the patients since the early stage of disease, including those who are actively undergoing disease-targeted therapies, rather than merely providing end-of-life care., Competing Interests: Disclosures and Acknowledgments This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest., (Copyright © 2024 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Herein, we report a photoredox nucleophilic (radio)fluorination using TEMPO-derived alkoxyamines, a class of substrates accessible in a single step from a diversity of readily available carboxylic acids, halides, alkenes, alcohols, aldehydes, boron reagents, and C-H bonds. This mild and versatile one-electron pathway affords radiolabeled aliphatic fluorides that are typically inaccessible applying conventional nucleophilic substitution technologies due to insufficient reactivity and competitive elimination. Automation of this photoredox process is also demonstrated with a user-friendly and commercially available photoredox flow reactor and radiosynthetic platform, therefore expediting access to labeled aliphatic fluorides in high molar activity ( A m ) for (pre)clinical evaluation.

Purpose: To estimate the prevalence of keratoconus in a population of subjects undergoing first eye examination in an eye clinic in Italy., Methods: A single-center, cross-sectional, study was conducted involving patients who underwent first eye examination at an eye clinic in Rome between September 2021 and June 2022. The prevalence of keratoconus was determined by Placido-disk corneal topography using the maximum keratometry (K max ) value and the Cone Magnitude and Location Index (CLMI) for keratoconus screening. Subjective analysis was performed by two experienced corneal specialists, who classified the outcome into two groups: normal and keratoconus. Risk factors, including family history of keratoconus, allergy or atopy, thyroid disease, eye rubbing habit and gender were also examined., Results: A total of 512 subjects between 7 and 81 years old were evaluated. The inter-observer agreement to classify subjects in normal or keratoconus group was excellent (k = 1.0); the estimated prevalence in the specific population was 2.1%. Presence of positive family history (9% of keratoconus vs 5% normal), concomitant allergy or atopy (27% vs 9%) and eye rubbing habit (18% vs 4%) were associated with a higher risk of disease., Conclusion: This study reported a high estimated prevalence of keratoconus in a metropolitan area of Italy, as found in recent studies in the Mediterranean and Middle East countries. Screening for keratoconus is highly recommendable and easily feasible with corneal topography under expert supervision and may be indicated primarily in young population to improve early detection and prompt therapeutic management for halting disease progression., 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.

Neuropathic pain is one of the most debilitating forms of chronic pain, resulting from an injury or disease of the somatosensory nervous system, which induces abnormal painful sensations including allodynia and hyperalgesia. Available treatments are limited by severe side-effects and reduced efficacy in the chronic phase of the disease. Sigma-1 receptor (σ1R) has been identified as a chaperone protein, which modulate opioid receptors activities and the functioning of several ion channels, exerting a role in pain transmission. As such, it represents a druggable target to treat neuropathic pain. This study aims at investigating the therapeutic potential of the novel compound (+)-2R/S-LP2, a σ1R antagonist, in reducing painful behaviour and modulating the neuroinflammatory environment. We showed that repeated administration of the compound significantly inhibited mechanical allodynia in neuropathic rats, increasing the withdrawal threshold as compared to CCI-vehicle rats. Moreover, we found that (+)-2R/S-LP2-mediated effects resolve the neuroinflammatory microenvironment by reducing central gliosis and pro-inflammatory cytokines expression levels. This effect was coupled with a significant reduction of connexin 43 (Cx43) expression levels and gap junctions/hemichannels mediated microglia-to-astrocyte communication. These results suggest that inhibition of σ1R significantly attenuates neuropathic pain chronicization, thus representing a viable effective strategy., (© 2023. The Author(s).)

Face transplant (FT) has emerged as a groundbreaking option for patients with severe facial deformities, resulting from congenital disorders, trauma, or tumor ablation. Although reconstructive surgery has made significant strides, the challenges of restoring both form and function remain, particularly in centrally located defects. This review explored the long-term outcomes of FT, addressing its challenges and potential pitfalls. A systematic review following the PRISMA guidelines was conducted, encompassing articles published in English from November 2005 to January 2023, which were searched across PubMed, MEDLINE, and EMBASE databases. Keywords included "face transplant," "face transplant outcomes," and "face transplant long-term." Data on surgical teams, patient demographics, transplant specifics, rejection episodes, additional surgeries, and patient-reported outcomes were extracted and analyzed. In total, 34 articles met the inclusion criteria. Over the 2 decades, 48 FT procedures were performed, with 23 patients followed for at least 3 years. Predominantly, patients were men (80%), averaging 31 years in age. Ballistic trauma (44.6%) and burns (25.5%) were common causes of injury. Chronic rejection emerged as a significant concern, leading to graft loss and necessitating retransplantation in 2 patients. Additional surgical procedures were often required. FT offers a remarkable solution for individuals with extensive facial disfigurement. Successful outcomes depend on factors, such as patient selection, multidisciplinary collaboration, psychiatric evaluation, and post-operative care. Nevertheless, challenges persist, including the need for lifelong immunosuppression and risk of chronic rejection. Although FT has transformed lives, continued success in this evolving field hinges on the ongoing research and vigilant patient management., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Treatment response assessment of rectal cancer patients is a critical component of personalized cancer care and it allows to identify suitable candidates for organ-preserving strategies. This pilot study employed a novel multi-omics approach combining MRI-based radiomic features and untargeted metabolomics to infer treatment response at staging. The metabolic signature highlighted how tumor cell viability is predictively down-regulated, while the response to oxidative stress was up-regulated in responder patients, showing significantly reduced oxoproline values at baseline compared to non-responder patients (p-value < 10 -4 ). Tumors with a high degree of texture homogeneity, as assessed by radiomics, were more likely to achieve a major pathological response (p-value < 10 -3 ). A machine learning classifier was implemented to summarize the multi-omics information and discriminate responders and non-responders. Combining all available radiomic and metabolomic features, the classifier delivered an AUC of 0.864 (± 0.083, p-value < 10 -3 ) with a best-point sensitivity of 90.9% and a specificity of 81.8%. Our results suggest that a multi-omics approach, integrating radiomics and metabolomic data, can enhance the predictive value of standard MRI and could help to avoid unnecessary surgical treatments and their associated long-term complications., (© 2024. The Author(s).)

Olive oil ( Olea europaea ) is one of the major components of the Mediterranean diet and is composed of a greater percentage of monounsaturated fatty acids, such as oleic acid; polyunsaturated fatty acids, such as linoleic acid; and minor compounds, such as phenolic compounds, and particularly hydroxytyrosol. The latter, in fact, are of greater interest since they have found widespread use in popular medicine. In recent years, it has been documented that phenolic acids and in particular hydroxytyrosol have anti-inflammatory, antioxidant, and antiproliferative action and therefore interest in their possible use in clinical practice and in particular in neoplasms, both solid and hematological, has arisen. This work aims to summarize and analyze the studies present in the literature, both in vitro and in vivo, on the possible use of minor components of olive oil in some hematological neoplasms. In recent years, in fact, interest in nutraceutical science has expanded as a possible adjuvant in the treatment of neoplastic pathologies. Although it is worth underlining that, regarding the object of our study, there are still few preclinical and clinical studies, it is, however, possible to document a role of possible interest in clinical practice.

Background: Cortisol levels, oxidative stress, and lower cerebral performance seem to be closely related. This study aimed to evaluate the question of whether exam stress affected oxidative stress and endothelial function parameters in the salivary samples of students., Methods: A total of 114 healthy students were recruited. All students were subjected to a 21-item DASS questionnaire to assess perceived stress. Cortisol levels, biomarkers of oxidative stress, and endothelial function were evaluated at T0, during the semester, and T1, in the morning before the exam, in saliva samples. In vitro, HUVECs were stimulated with cortisol, and oxidative stress and endothelial function parameters were evaluated., Results: At T1, cortisol levels were significantly increased compared with the levels during the semester. Moreover, exam results correlated inversely with the DASS score at T1. In addition, NOX2, H 2 O 2 and endothelin-1 significantly increased, while NO bioavailability decreased. In vitro, HUVECs treatment with human cortisol determined the increase of oxidative stress and the decrease of endothelial function, in association with impaired eNOS phosphorylation., Conclusion: NOX2-mediated oxidative stress is a mechanism that could mediate cortisol-induced transient endothelial dysfunction during academic examination. Therefore, strategies to monitor or modulate oxidative stress could help students to reduce the impact of examination-related stress.

Herein, we describe the design, synthesis, and in vitro biological evaluation of HO-1 inducers endowed with cytotoxic effects mediated by ferroptosis activation. Using the natural HO-1 inducer caffeic acid phenethyl ester (CAPE) as a chemical scaffold, new derivatives were synthesized by performing modifications in the cathecol moiety and in the phenethyl ester aromatic ring. Biological assays aimed at evaluating an imbalanced activity of ferroptosis key players identified that 2-(1 H -indol-3-yl)ethyl cinnamate (compound 24 ) possesses improved anticancer activity toward the MDA-MB 231 triple negative breast cancer cell line when compared to CAPE. Increased ROS and LOOH levels, reduced GSH levels, imbalanced mitochondrial activity, and restored cell viability after ferrostatin-1 treatment suggested a ferroptotic mechanism of action, which did not involve GPX4 inhibition. Compound 24 represents an intriguing hit compound useful for the identification of novel ferroptosis inducers., Competing Interests: The authors declare no competing financial interest., (© 2024 American Chemical Society.)

Purpose: Glioblastoma is the most common type of primary brain malignancy and has a poor prognosis. The standard treatment strategy is based on maximal safe surgical resection followed by radiotherapy and chemotherapy. Surgical resection can be optimized by using 5-delta-aminolevulinic acid (5-ALA)-induced fluorescence, which is the current mainstay. Although 5-ALA-induced fluorescence has gained general acceptance, it is also limited by inter-observer variability and non-standardized fluorescence parameters. We present a new software for processing images analysis to better recognize the tumor infiltration margins using an intraoperative immediate safety map of 5-ALA-induced fluorescence. We tested this in a brain model using a commercial surgical exoscope., Methods: A dedicated software GLIOVIS (ACQuF-II, Advanced Colorimetry-based Quantification of Fluorescence) was designed for processing analysis of images taken on the Intraoperative Orbital Camera Olympus Orbeye (IOC) to determine the relative quantification of Protoporphyrin IX (5-ALA metabolite) fluorescence. The software allows to superpose the new fluorescence intensity map and the safety margins over the original images. The software was tested on gel-based brain models., Results: Two surrogate models were developed: PpIX agarose gel-integrated in gelatin-based brain model at different scales (1:25 and 1:1). The images taken with the IOC were then processed using GLIOVIS. The intensity map and safety margins could be obtained for all available models., Conclusions: GLIOVIS for 5-ALA-guided surgery image processing was validated on various gelatin-based brain models. Different levels of fluorescence could be qualitatively digitalized using this technique. These results need to be further confirmed and corroborated in vivo and validated clinically in order to define a new standard of care for glioblastoma resection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Mazevet, Oberli, Marinelli, Zaed, Bauer, Kaelin-Lang, Marchi, Gardenghi, Reinert and Cardia.)

Background: Spontaneous orbital cephaloceles are a rare condition. The purpose of this study is to provide a description of a clinical case and to carry out a systematic literature review., Methods: A systematic review of the English literature published on the Pubmed, Scopus, and Web of Science databases was conducted, according to the PRISMA recommendations., Results: A 6-year-old patient was admitted for right otomastoiditis and thrombosis of the sigmoid and transverse sinuses, as well as the proximal portion of the internal jugular vein. Radiological examinations revealed a left orbital mass (22 × 14 mm) compatible with asymptomatic orbital meningocele (MC) herniated from the superior orbital fissure (SOF). The child underwent a right mastoidectomy. After the development of symptoms and signs of intracranial hypertension (ICH), endovascular thrombectomy and transverse sinus stenting were performed, with improvement of the clinical conditions and reduction of the orbital MC. The systematic literature review encompassed 29 publications on 43 patients with spontaneous orbital MC. In the majority of cases, surgery was the preferred treatment., Conclusions: The present case report and systematic review highlight the importance of ICH investigation and a pathophysiological-oriented treatment approach. The experiences described in the literature are limited, making the collection of additional data paramount.

We aimed to analyze the association between CYP7B1 and prostate cancer, along with its association with proteins involved in cancer and metabolic processes. A retrospective analysis was performed on 390 patients with prostate cancer (PC) or benign prostatic hyperplasia (BPH). We investigated the interactions between CYP7B1 expression and proteins associated with PC and metabolic processes, followed by an analysis of the risk of biochemical recurrence based on CYP7B1 expression. Of the 139 patients with elevated CYP7B1 expression, 92.8% had prostate cancer. Overall, no increased risk of biochemical recurrence was associated with CYP7B1 expression. However, in a non-diabetic subgroup analysis, higher CYP7B1 expression indicated a higher risk of biochemical recurrence, with an HR of 1.78 (CI: 1.0-3.2, p = 0.05). PC is associated with elevated CYP7B1 expression. In a subgroup analysis of non-diabetic patients, elevated CYP7B1 expression was associated with an increased risk of biochemical recurrence, suggesting increased cancer aggressiveness.

Despite the spread of novel-generation cochlear-implant (CI) magnetic systems, access to magnetic resonance imaging (MRI) for CI recipients is still limited due to safety concerns. The aim of this study is to assess and record the experiences of Hires Ultra 3D (Advanced Bionics) recipients who underwent an MRI examination. A multicentric European survey about this topic was conducted focusing on safety issues, and the results were compared with the current literature. We collected a total of 65 MRI scans performed in 9 otologic referral centers for a total of 47 Hires Ultra 3D recipients, including, for the first time, 2 children and 3 teenagers. Preventive measures were represented by scanning time and sedation for children. Head wrapping was used in eight cases, and six of the eight cases received local anesthesia, even if both measures were not needed. Only three patients complained of pain (3/65 examinations, 4.6%) due to the tight head bandage, and one of the three cases required MRI scan interruption. No other adverse events were reported. We believe that these results should encourage MRI execution in accordance with manufacturer recommendations for Ultra 3D recipients.

Background: In 2020, 38% of adults were affected by obesity, while infertility globally affected 1 in 6 people at some stage of their lives.Body mass index (BMI) provides an easy but occasionally inaccurate estimation of body composition. To achieve a more precise assessment, bioelectric impedance analysis serves as a validated tool that administers electrical energy through surface electrodes. Phase angle as a function of the relationship between tissues resistance and reactance, is a trustworthy predictor of body composition and cell membrane integrity., Objectives: We aim to assess whether there is an association between phase angle and seminal parameters, as well as sperm DNA fragmentation percentage., Design: Semen samples of 520 idiopathic infertile patients were analyzed according to 2021 World Health Organization guidelines and evaluated for sperm DNA fragmentation rate. Each participants underwent bioelectric impedance analysis., Results: Median age was 40 years old, median BMI was 26.3 kg/m2, median phase angle was 6.2°. In the logistic regression analysis adjusted for age and total intracorporeal water, phase angle (continuous) was significantly associated with oligozoospermia (odds ratio [OR]:0.4; p<0.01) and sperm morphology (OR: 0.65; p=0.05) and slightly with sperm DNA fragmentation (OR: 0.98; p=0.07). In subgroup analysis, the logistic regression analysis adjusted for the mentioned parameters showed that a phase angle between 6.2 and 7 (°) (OR: 0.63; p=0.02) and >7 (°) (OR: 0.12; p<0.01) were associated with a reduced risk of oligozoospermia compared to values <6.2 (°). Similarly, a phase angle between 6.2 and 7 (°) (OR: 0.57; p< 0.01 and OR: 0.58; p= 0.01) and PA > 7 (°) (OR: 0.12; p= 0.03 and OR: 0.21; p< 0.01) were associated with a reduced risk of lower sperm concentration and lower total sperm count, respectively, compared to a phase angle < 6.2 (°)., Conclusion: Our study suggests a negative association between phase angle and detrimental sperm parameters in male idiopathic infertility., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Liprino, Giacone, Lombardo, Asmundo, Russo, Abdelhameed, Cimino, Guglielmino and Chamayou.)

Data on the use of radiofrequency (RT) to ablate a tumor mass-causing pain have not been reported. A male in his 50s, diagnosed with a pelvic relapse of rectal cancer, was admitted for pain from the left groin to the perineum. The principal findings of contrast-enhanced computed tomography (CT) revealed the presence in the pelvic area of large solid tissue infiltrating the internal obturator muscle and eroding the vertebral column of the acetabulum. Also involving the gluteal muscles.He was poorly responsive to multiple opioids. He was treated with RT under CT guidance to ablate the pelvic mass. Pain relief was immediate as it was possible to reduce methadone doses since the afternoon of the operation day. Very selected patients who are not responsive to optimisation of opioid therapy, could be candidates to RF of the tumor mass, that may offer an efficient method to provide fast pain relief and allowing opioid dose reduction., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

To date, little is known concerning the circulating levels of biochemically relevant metabolites (antioxidants, oxidative/nitrosative stress biomarkers, purines, and pyrimidines) in patients with primary myelofibrosis (PMF), a rare form of myeloproliferative tumor causing a dramatic decrease in erythropoiesis and angiogenesis. In this study, using a targeted metabolomic approach, serum samples of 22 PMF patients and of 22 control healthy donors were analyzed to quantify the circulating concentrations of hypoxanthine, xanthine, uric acid (as representative purines), uracil, β-pseudouridine, uridine (as representative pyrimidines), reduced glutathione (GSH), ascorbic acid (as two of the main water-soluble antioxidants), malondialdehyde, nitrite, nitrate (as oxidative/nitrosative stress biomarkers) and creatinine, using well-established HPLC method for their determination. Results showed that PMF patients have dramatic depletions of both ascorbic acid and GSH (37.3- and 3.81-times lower circulating concentrations, respectively, than those recorded in healthy controls, p < 0.0001), accompanied by significant increases in malondialdehyde (MDA) and nitrite + nitrate (4.73- and 1.66-times higher circulating concentrations, respectively, than those recorded in healthy controls, p < 0.0001). Additionally, PMF patients have remarkable alterations of circulating purines, pyrimidines, and creatinine, suggesting potential mitochondrial dysfunctions causing energy metabolism imbalance and consequent increases in these cell energy-related compounds. Overall, these results, besides evidencing previously unknown serum metabolic alterations in PMF patients, suggest that the determination of serum levels of the aforementioned compounds may be useful to evaluate PMF patients on hospital admission for adjunctive therapies aimed at recovering their correct antioxidant status, as well as to monitor patients' status and potential pharmacological treatments.

Background: Immune checkpoint inhibitors have changed previous treatment paradigm of advanced urothelial carcinoma (UC). The ARON-2 study (NCT05290038) aimed to assess the real-world effectiveness of pembrolizumab in patients recurred or progressed after platinum-based chemotherapy., Patients and Methods: Medical records of patients with documented metastatic UC treated by pembrolizumab as second-line therapy were retrospectively collected from 88 institutions in 23 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS) and overall response rate (ORR). Cox proportional hazards models were adopted to explore the presence of prognostic factors., Results: In total, 836 patients were included: 544 patients (65%) received pembrolizumab after progression to first-line platinum-based chemotherapy in the metastatic setting (cohort A) and 292 (35%) after recurring within < 12 months since the completion of adjuvant or neoadjuvant chemotherapy (cohort B). The median follow-up time was 15.3 months. The median OS and the ORR were 10.5 months and 31% in the overall study population, 9.1 months and 29% in cohort A and 14.6 months and 37% in cohort B. At multivariate analysis, ECOG-PS ≥ 2, bone metastases, liver metastases and pembrolizumab setting (cohort A vs B) proved to be significantly associated with worst OS and PFS. Stratified by the presence of 0, 1-2 or 3-4 prognostic factors, the median OS was 29.4, 12.5 and 4.1 months (p < 0.001), while the median PFS was 12.2, 6.4 and 2.8 months, respectively (p < 0.001)., Conclusions: Our study confirms that pembrolizumab is effective in the advanced UC real-world context, showing outcome differences between patients recurred or progressed after platinum-based chemotherapy., (© 2024. The Author(s).)

Background: The treatment of heavily pretreated patients with metastatic renal cell carcinoma (mRCC) represents an unmet medical need and is still challenging., Objectives: The primary objective was to assess the effectiveness of the lenvatinib plus everolimus combination and the secondary objective was the toxicity profile of this combination., Design: We conducted a longitudinal retrospective study examining mRCC patients pre-treated with one or more lines of therapy among different cancer centers in Italy., Methods: The study included patients who received the combination of lenvatinib plus everolimus as either a second-line treatment or beyond. We assessed progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), response rate (RR), and toxicity profile. In addition, we explored the potential relationship between treatment effectiveness and clinical and laboratory parameters., Results: In all, 33 patients were assessed, the median age was 60 years, 57% had an Eastern Cooperative Oncology Group performance status of 1-2 and. 63% received ⩾ 3 prior lines of therapy. 62% were 'intermediate risk' according to the International Metastatic Renal Cell Carcinoma Database Consortium and 30% were 'poor risk'. The RR was 42% (no complete response), 18% stable disease. Median OS was 11.2 months (95% CI 6.8-19.9), median PFS was 6.7 months (95% CI 0.6-30.8), and median TTF was 6.7 months (95% CI 4.8-16.6). A shorter OS was significantly associated with lymph node metastases ( p  = 0.043, 95% CI), neutrophils/ lymphocytes ratio (NLR) ⩾ 3 ( p  = 0.007), hemoglobin/red cell distribution width ratio cutoff value <0.7 was significant ( p  = 0.03) while a shorter PFS was associated with lung ( p  = 0.048) and brain metastases ( p  = 0.023). The most frequent G1 toxicity was diarrhea (24%), G2 was fatigue (30%), and hypertension and skin toxicity (6%) for G3., Conclusion: Our findings suggest a clinically relevant effectiveness of lenvatinib plus everolimus combination with an acceptable toxicity profile for heavily pretreated patients with mRCC., Competing Interests: V.C. has served as a consultant/advisory board member for Janssen, Astellas, Merck, AstraZeneca, Amgen, and Bayer and has received speaker honoraria or travel support from Astellas, Janssen, Ipsen, Bayer, and Sanofi. E.R. had a role as consultant for Bristol Meyers Squibb, MSD, Novartis, Pierre Fabre, Immunocore, and Pfizer., (© The Author(s), 2024.)

Chronic lymphocytic leukemia, in spite of recent advancements, is still an incurable disease; the majority of patients eventually acquire resistance to treatment through relapses. In all subtypes of chronic lymphocytic leukemia, the disruption of normal B-cell homeostasis is thought to be mostly caused by the absence of apoptosis. Consequently, apoptosis induction is crucial to the management of this illness. Damaged biological components can accumulate as a result of the oxidation of intracellular lipids, proteins, and DNA by reactive oxygen species. It is possible that cancer cells are more susceptible to apoptosis because of their increased production of reactive oxygen species. An excess of reactive oxygen species can lead to oxidative stress, which can harm biological elements like DNA and trigger apoptotic pathways that cause planned cell death. In order to upset the balance of oxidative stress in cells, recent therapeutic treatments in chronic lymphocytic leukemia have focused on either producing reactive oxygen species or inhibiting it. Examples include targets created in the field of nanomedicine, natural extracts and nutraceuticals, tailored therapy using biomarkers, and metabolic targets. Current developments in the complex connection between apoptosis, particularly ferroptosis and its involvement in epigenomics and alterations, have created a new paradigm.

Robotic automation is proving itself indispensable in the modern Chemistry laboratory, but adoption is slowed down by the technical challenges of implementing such systems. This paper reports on a novel adaptive gripper mechanism that can easily and reliably grasp cylindrical and prismatic objects of various sizes with limited clearance required. The proposed design exploits the inherent compliance of a cable that is driven to fully envelope the target object. The cable is run through a rigid finger, allowing the loop to be placed around objects with minimal clearance required and to provide support for the object once the grip is complete. Thanks to the compliant nature of the mechanism, the gripper requires minimal control effort to complete a gasping task. A prototype of the gripper has been designed and built for chemistry automation tasks, where it showed very high grasp reliability with ≤ 1 % grasp failures., (© 2024. The Author(s).)

Immuno-correlated dermatological pathologies refer to skin disorders that are closely associated with immune system dysfunction or abnormal immune responses. Advancements in the field of artificial intelligence (AI) have shown promise in enhancing the diagnosis, management, and assessment of immuno-correlated dermatological pathologies. This intersection of dermatology and immunology plays a pivotal role in comprehending and addressing complex skin disorders with immune system involvement. The paper explores the knowledge known so far and the evolution and achievements of AI in diagnosis; discusses segmentation and the classification of medical images; and reviews existing challenges, in immunological-related skin diseases. From our review, the role of AI has emerged, especially in the analysis of images for both diagnostic and severity assessment purposes. Furthermore, the possibility of predicting patients' response to therapies is emerging, in order to create tailored therapies.

The balanced reciprocal translocation t (9; 22) (q34; q11) and the BCR-ABL fusion gene, which produce p210 bcr-abl protein production with high tyrosine kinase activity, are characteristics of chronic myeloid leukemia, a myeloproliferative neoplasm. This aberrant protein affects several signaling pathways connected to both apoptosis and cell proliferation. It has been demonstrated that tyrosine kinase inhibitor treatment in chronic myeloid leukemia acts by inducing oxidative stress and, depending on its level, can activate signaling pathways responsible for either apoptosis or survival in leukemic cells. Additionally, oxidative stress and reactive oxygen species generation also mediate apoptosis through genomic activation. Furthermore, it was shown that oxidative stress has a role in both BCR-ABL-independent and BCR-ABL-dependent resistance pathways to tyrosine kinases, while patients with chronic myeloid leukemia were found to have a significantly reduced antioxidant level. The ideal environment for tyrosine kinase inhibitor therapy is produced by a favorable oxidative status. We discuss the latest studies that aim to manipulate the redox system to alter the apoptosis of cancerous cells.

The development of biomaterials in recent years has made it possible to broaden their use in the surgical field. Although iliac crest bone graft harvesting currently remains the gold standard as an autograft, the properties of hydroxyapatite bone substitutes appear to be beneficial. The first fundamental step to consider is the safety of using these devices. The purpose of this retrospective cohort study is to consider all the adverse events observed in our population and assess their relationships with the bone substitute device. The population analyzed consisted of patients undergoing trauma osteosynthesis with at least one implanted porous hydroxyapatite device. We considered a court of 114 patients treated at "Azienda Ospedaliera Universitaria di Ferrara-U.O. di Ortopedia e Traumatologia" in the period from January 2015 to December 2022. Upon analyzing our population, no adverse events related to the device emerged. Taking into consideration different study groups from other National Hospital Centers, no critical issues were detected except for three cases of extrusion of the biomaterial. It is necessary to clarify that bone substitutes cannot replace compliance with the correct principles linked to the biomechanics of osteosynthesis. This report outlines a safety profile for the use of these devices as bone substitutes in trauma orthopedic surgery.

Working mothers must often balance work and family responsibilities which can be affected by rigid and irrational beliefs about motherhood. The present study had two aims: (a) to provide psychometric evidence for a shortened Italian version of the Rigid Maternal Beliefs Scale (RMBS) and (b) to facilitate mothers' return to work after maternity leave by reducing perceptions of anxiety and stress related to rigid maternal beliefs (i.e., perceptions and societal expectations of mothers, maternal confidence, maternal dichotomy) and by teaching specific recovery strategies (e.g., relaxation, mastery experiences) to manage anxiety and stress through an online psychological intervention. Results replicated the three-factor structure of the original RMBS and showed good psychometric properties. The online psychological intervention resulted in decrease in the rigidity of maternal beliefs, perceived anxiety and stress, and increase in recovery strategies. These initial results are promising and encourage further investigation into online psychological interventions for improving the well-being of working mothers., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Rapisarda, De Carlo, Pasqualetto, Volling and Dal Corso.)

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

Background: Congenital h-type tracheoesophageal fistula (H-TEF) without esophageal atresia (EA) represents about 4% of congenital esophageal anomalies. The diagnosis is challenging, and surgery is considered curative. The aim was to report a national survey on the diagnosis, management, and outcome of patients with congenital H-TEF., Methods: Following approval of the Italian Society of Pediatric Surgery, a survey was sent to all Pediatric Surgery Units to retrospectively collect H-TEF treated in the period 2010-2022. Descriptive analysis was performed, and results are given as prevalence, mean ± standard deviation (SD), or median and interquartile range (IQR)., Results: The survey was sent to 65 units. Seventeen responded with one or more cases; 78 patients were diagnosed with H-TEF during the study period. Associated malformations were present in 43%, mostly cardiac (31%). The most frequent symptoms were cough (36%), bronchopneumonia (24%), and dysphagia (19%). H-TEF was detected by tracheobronchoscopy (90%), and/or upper GI (58%), and/or esophagoscopy (32%). The median age at diagnosis was 23 days (1 day-18 years). The most common approach was cervicotomy (76%), followed by thoracoscopy (14%) and thoracotomy (9%). The fistula underwent ligation and section of the fistula in 90% of the patients and clip closure and section in 9%. In one patient, the fistula was cauterized endoscopically. H-TEF preoperative cannulation was performed in 68% of cases, and a drain was placed in 26%. One month after surgery, 13% of the patients had mild persisting symptoms, mainly hypophonia. Recurrence occurred in 5%, and a second recurrence occurred in 1%., Conclusions: H-TEF prevalence was six cases/year, consistent with the expected rate of five cases/year in our country. The diagnosis was challenging, sometimes delayed, and, in most patients, required multiple examinations. Fistula ligation and section through cervicotomy were the most frequent treatment. Long-term outcomes are good, and recurrence is a rare event.

Traditional treatments for head and neck squamous cell carcinoma (HNSCC) such as surgery, radiation therapy, and chemotherapy, often have severe side effects. Local delivery of chemotherapeutic agents can be a promising approach to minimise systemic toxicity and improve efficacy. Lauric acid (LA), was explored as a novel injectable thermosensitive drug reservoir as a depot for sustained release of anticancer drugs to treat HNSCC. LA was characterised in terms of melting temperature and gelation time. The efficacy of LA-based drug formulations was tested in vitro in a HNSCC cell line and in vivo in a mouse model of HNSCC. LA was modified to have a melting point of 38.5 °C and a gelation time of 40 s at 37.5 °C, rendering it suitable for injection at body temperature. LA- based doxorubicin (DOXO) formulation showed slow release with a maximum of 18% release after 3 days. The in vitro study showed that LA enhanced the cytotoxic effect of DOXO. LA combined with DOXO prevented tumour progression and LA alone significantly reduced the original tumour volume compared to the untreated control group. These findings confirmed that LA can function as practical carrier for the local delivery of chemotherapeutics and provides a safe and simple strategy for the delivery of hydrophobic anticancer drugs and warrant further testing in clinical trials.

Introduction: Self-induced dermatoses are self-inflicted skin lesions, whose occurrence patient denies responsibility for., Objectives: The aim of this study was to retrospectively investigate all the clinical records of dermatitis artefacta (DA) in order to put special focus on: a) epidemiological aspects; b) location, shape and additional features of the lesions; c) availability of psychiatric details in the records., Methods: A retrospective observational descriptive study on 46 patients affected by dermatitis artefacta was conducted from January 2015 to March 2021. The only inclusion criterion was clinical or histological diagnosis of DA in patients for which we had clinical images., Results: The most frequent type of lesions were erosions/excoriations and ulcers (14/46, 30.4% and 13/46, 28.3% respectively) followed by ecchymoses (9/46, 19.5%), vasculitis-like lesions (5/46, 10.9%), crusted plaques (3/46, 6.5%), scales (1/46, 2.2%) and erythema (1/46, 2.2%). Thirty-three percent of the medical records generically referred to the presence of psychiatric disorder, but none of them included a specific psychiatric diagnosis., Conclusions: In our study the main dermatologic lesions observed in DA were represented by excoriations and ulcers and that the shape and location of the lesions are essential for a correct diagnosis.

Immunotherapy combinations with tyrosine-kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) had significantly improved outcomes of patients with mRCC. Predictive and prognostic factors are crucial to improve patients' counseling and management. The present study aimed to externally validate the prognostic value of a previously developed red cell-based score, including hemoglobin (Hb), mean corpuscular volume (MCV) and red cell distribution width (RDW), in patients with mRCC treated with first-line immunotherapy combinations (TKI plus ICI or ICI plus ICI). We performed a sub-analysis of a multicentre retrospective observational study (ARON-1 project) involving patients with mRCC treated with first-line immunotherapy combinations. Uni- and multivariable Cox regression models were used to assess the correlation between the red cell-based score and progression-free survival (PFS), and overall survival (OS). Logistic regression were used to estimate the correlation between the score and the objective response rate (ORR). The prognostic impact of the red cell-based score on PFS and OS was confirmed in the whole population regardless of the immunotherapy combination used [median PFS (mPFS): 17.4 vs 8.2 months, HR 0.66, 95% CI 0.47-0.94; median OS (mOS): 42.0 vs 17.3 months, HR 0.60, 95% CI 0.39-0.92; p < 0.001 for both]. We validated the prognostic significance of the red cell-based score in patients with mRCC treated with first-line immunotherapy combinations. The score is easy to use in daily clinical practice and it might improve patient counselling., (© 2024. The Author(s).)

The uptake and translocation of four polybrominated diphenyl ethers (PBDEs) and four novel brominated flame retardants (NBFRs) in tomato plants (Solanum lycopersicum L.) were investigated via the RHIZOtest, a standard soil-based biotest, optimized for organic compounds. Tomato plants were exposed to soil samples spiked with 0 (i.e. control), 5.00 or 50.00 ng g -1 dw of each compound. Compared of those of the control, exposure to increasing spiking concentrations resulted in average reductions of 13% and 26% (w/w) in tomato plant biomass. Higher concentrations of NBFRs were analyzed both in roots, ranging from 0.23 to 8.01 ng g -1 dw for PBDEs and from 1.25 to 18.51 ng g -1 dw for NBFRs, and in shoots, ranging from 0.09 to 5.58 ng g -1 dw and from 0.47 to 7.78 ng g -1 dw for PBDEs and NBFRs, respectively. This corresponded to an average soil uptake of 5% for PBDEs and 9% for NBFRs at the lower soil-spiking level, and 3% for PBDEs and 6% for NBFRs at the higher soil spiking level. Consequently, among both initial spiking levels, the soil-root concentration factor (RCF) values were lower on average for PBDEs (0.13 ± 0.05 g dw soil g -1 dw roots) than for NBFRs (0.33 ± 0.16 g dw soil g -1 dw roots). Conversely, nondifferent values of the root-shoot transfer factor (TF) were calculated for both PBDEs (0.54 ± 0.13 g dw roots g -1 dw shoots) and NBFRs (0.49 ± 0.24 g dw roots g -1 dw shoots). The differences and similarities reported in the RCF and TF between and within the two groups of compounds can be explained by their properties. The calculated RCF and TF values of the PBDEs exhibited a decreasing trend as the number of bromine atoms increased. Additionally, a robust negative linear correlation was observed between RCF values and the respective logK ow values for the PBDEs, at both soil-spiking levels. The root uptake of NBFRs exhibited a negative correlation with their hydrophobicity; however, this was not observed in the context of root-to-shoot transfer. The presence of a second aromatic ring appears to be the key factor influencing the observed variations in NBFRs, with biphenyl NBFRs (BTBPE and DBDPE) characterized by lower uptake and reduced translocation potential than monophenyl PBEB and HBB. Understanding the transfer of these compounds to crops, especially near plastic recycling waste sites, is crucial for understanding the risks of their potential inclusion in the human food chain., 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 Ltd.. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with complex genetic basis and still no clear etiology. Multiple intertwined layers of immune system-related dysfunctions and neuroinflammatory mechanisms are emerging as substantial determinants in ALS onset and progression. In this review, we collect the increasingly arising evidence implicating four main CXC chemokines/cognate receptors signaling axes (CXCR1/2-CXCL1/2/8; CXCR3-CXCL9/10/11; CXCR4/7-CXCL12; CXCR5-CXCL13) in the pathophysiology of ALS. Findings in preclinical models implicate these signaling pathways in motor neuron toxicity and neuroprotection, while in ALS patients dysregulation of CXCLs/CXCRs has been shown at both central and peripheral levels. Immunological monitoring of CXC-ligands in ALS may allow tracking of disease progression, while pharmacological modulation of CXC-receptors provides a novel therapeutic strategy. A deeper understanding of the interplay between CXC-mediated neuroinflammation and ALS is crucial to advance research into treatments for this debilitating uncurable disorder., 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 Ltd.. All rights reserved.)

Background: Hematoma expansion (HE) is common and predicts poor outcome in patients with supratentorial intracerebral hemorrhage (ICH). We investigated the predictors and prognostic impact of HE in infratentorial ICH., Methods: We conducted a retrospective analysis of patients with brainstem and cerebellar ICH admitted at seven sites. Noncontrast computed tomography images were analyzed for the presence of hypodensities according to validated criteria, defined as any hypodense region strictly encapsulated within the hemorrhage with any shape, size, and density. Occurrence of HE (defined as > 33% and/or > 6-mL growth) and mortality at 90 days were the outcomes of interest. Their predictors were investigated using logistic regression with backward elimination at p < 0.1. Logistic regression models for HE were adjusted for baseline ICH volume, antiplatelet and anticoagulant treatment, onset to computed tomography time, and presence of hypodensities. The logistic regression model for mortality accounted for the ICH score and HE., Results: A total of 175 patients were included (median age 75 years, 40.0% male), of whom 38 (21.7%) had HE and 43 (24.6%) died within 90 days. Study participants with HE had a higher frequency of hypodensities (44.7 vs. 24.1%, p = 0.013), presentation within 3 h from onset (39.5 vs. 24.8%, p = 0.029), and 90-day mortality (44.7 vs. 19.0%, p = 0.001). Hypodensities remained independently associated with HE after adjustment for confounders (odds ratio 2.44, 95% confidence interval 1.13-5.25, p = 0.023). The association between HE and mortality remained significant in logistic regression (odds ratio 3.68, 95% confidence interval 1.65-8.23, p = 0.001)., Conclusion: Early presentation and presence of noncontrast computed tomography hypodensities were independent predictors of HE in infratentorial ICH, and the occurrence of HE had an independent prognostic impact in this population., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Contrast-enhanced mammography (CEM) is a promising technique. We evaluated the diagnostic potential of CEM performed immediately after contrast-enhanced computed tomography (CE-CT)., Methods: Fifty patients with breast cancer underwent first CE-CT and then CEM without additional contrast material injection. Two independent radiologists evaluated CEM images. The sensitivity of CEM for detecting index and additional malignant lesions was compared with that of mammography/ultrasonography by the McNemar test, using histopathology as a reference standard. Interobserver agreement for detection of malignant lesions, for classifying index tumors, and for evaluating index tumor size and extent was assessed using Cohen κ. Pearson correlation was used for correlating index tumor size/extent at CEM or mammography/ultrasonography with histopathology., Results: Of the 50 patients, 30 (60%) had unifocal disease while 20 (40%) had multicentric or multifocal disease; 5 of 20 patients with multicentric disease (25%) had bilateral involvement, for a total of 78 malignant lesions, including 72 (92%) invasive ductal and 6 (8%) invasive lobular carcinomas. Sensitivity was 63/78 (81%, 95% confidence interval 70.27-88.82) for unenhanced breast imaging and 78/78 (100%, 95.38-100) for CEM (p < 0.001). The interobserver agreement for overall detection of malignant lesions, for classifying index tumor, and for evaluating index tumor size/extent were 0.94, 0.95, and 0.86 κ, respectively. For index tumor size/extent, correlation coefficients as compared with histological specimens were 0.50 for mammography/ultrasonography and 0.75 for CEM (p ≤ 0.010)., Conclusions: CEM acquired immediately after CE-CT without injection of additional contrast material showed a good performance for local staging of breast cancer., Relevance Statement: When the CEM suite is near to the CE-CT acquisition room, CEM acquired immediately after, without injection of additional contrast material, could represent a way for local staging of breast cancer to be explored in larger prospective studies., Key Points: • CEM represents a new accurate tool in the field of breast imaging. • An intravenous injection of iodine-based contrast material is required for breast gland evaluation. • CEM after CE-CT could provide a one-stop tool for breast cancer staging., (© 2024. The Author(s).)

Context: PARP inhibitors (PARPi) are established treatments for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) deficiency after androgen receptor signalling inhibitor (ARSI) failure. New PARPi + ARSI combinations have been tested in all comers, although their clinical relevance in HRR-proficient tumours remains uncertain., Objective: To quantitatively synthesise evidence from randomised trials assessing the efficacy and safety of PARPi + ARSI combinations for first-line treatment of mCRPC., Evidence Acquisition: We searched the PubMed, EMBASE, SCOPUS, and Cochrane Library databases up to February 28, 2023. Randomised controlled trials (RCTs) comparing PARPi + ARSI versus placebo + ARSI for first-line treatment of mCRPC were eligible. Two reviewers independently performed screening and data extraction and assessed the risk of bias, while a third reviewer evaluated the eligibility criteria., Evidence Synthesis: Overall, three phase 3 RCTs were included in the systematic review: PROPEL, MAGNITUDE, and TALAPRO-2. A total of 2601 patients with mCRPC were enrolled. Two of these trials (PROPEL and TALAPRO-2) assessed the radiographic progression-free survival benefit of PARPi + ARSI for first-line treatment of mCRPC, independent of HRR status. The pooled hazard ratio was 0.62 (95% confidence interval 0.53-0.72). The pooled hazard ratio for overall survival was 0.84 (95% confidence interval 0.72-0.98), indicating a 16% reduction in the risk of death among patients who received the combination., Conclusions: Results from this meta-analysis support the use of ARSI + PARPi combinations in biomarker-unselected mCRPC. However, such combinations might be less clinically relevant in HRR-proficient cancers, especially considering the change in treatment landscape for mCRPC., Patient Summary: We looked at outcomes from trials testing combinations of two classes of drugs (PARP inhibitors and ARSI) in advanced prostate cancer. We found that these combinations seem to work regardless of gene mutations identified as biomarkers of response to PARP inhibitors when used on their own., (Copyright © 2023. Published by Elsevier B.V.)

Background: Contrast media used in mechanical therapies for stroke and myocardial infarction represent a significant cause of acute kidney injury (AKI) in acute medical scenarios. Although the continuous saline infusion line (CSIL) is a standard procedure to prevent thrombus formation within the catheter during neurovascular interventions of mechanical thrombectomy (MT), it is not utilized in percutaneous coronary interventions (PCI)., Methods: A systematic review of the incidence of AKI after MT for stroke treatment was performed. These data were compared with those reported in the literature regarding the incidence of AKI after PCI for acute myocardial infarction. A random-effect model meta-regression was performed to explore the effects of CSIL on AKI incidence, using clinical details as covariates., Results: A total of 18 and 33 studies on MT and PCI were included, respectively, with 69,464 patients (30,138 [43.4%] for MT and 39,326 [56.6%] for PCI). The mean age was 63.6 years±5.8 with male 66.6%±12.8. Chronic kidney disease ranged 2.0-50.3%. Diabetes prevalence spanned 11.1% to 53.0%. Smoking status had a prevalence of 7.5-72.0%. Incidence of AKI proved highly variable (I 2 =98%, Cochrane's Q 2985), and appeared significantly lower in the MT subgroup than in the PCI subgroups (respectively 8.3% [95% confidence interval: 4.7-11.9%] vs. 14.7 [12.6-16.8%], P<0.05). Meta-regression showed that CSIL was significantly associated with a decreased incidence of AKI (OR=0.93 [1.001-1.16]; P=0.03)., Conclusions: Implementation of CSIL during endovascular procedures in acute settings was associated with a significant decrease in the risk of AKI, and its safety should be routinely considered in such interventions.

Background: The addition of neutrophil to lymphocyte ratio (NLR) and bone metastases to the IMDC classification provided by the Meet-URO score, resulted in higher prognostic accuracy in metastatic renal cell carcinoma (mRCC) patients receiving ≥2nd line nivolumab or cabozantinib in 2 retrospective analyses and 1st line nivolumab-ipilimumab in an expanded access programme. Prognostic estimates for older mRCC patients might be key for clinical decision-making., Methods: The outcome of real-world older (≥70 years) mRCC patients treated with any line cabozantinib within the multicenter observational prospective ZEBRA (Meet-URO 9) study was analyzed according to the baseline Meet-URO score. The primary endpoint was overall survival (OS). The discriminative ability by Harrell's c-index and calibration were assessed to compare the Meet-URO and IMDC scores., Results: A total of 104 mRCC patients received cabozantinib as 1st (38%), 2nd (20%), or ≥3rd (41%) line. With a median follow-up of 11.2 months, the median OS (mOS) was of 18.4 months. According to the IMDC score, favorable (15%), intermediate (65%) and poor-risk (19%) patients had a mOS not reached, of 15.6 and 5.7 months respectively (p = .011). According to the Meet-URO score groups, mOS was not reached in both group 1 (10%) and group 2 (25%), while in group 3 (33%), group 4 (25%) and group 5 (8%) mOS was of 13.6, 12.5, and 3.7 months, respectively (p < .001). The discriminative ability of the Meet-URO score was maintained by merging groups 1 to 2 vs. 3 to 4 vs. 5 (p < .001). The Meet-URO score (with either the original 5-group stratification or the modified 3-group one) showed higher accuracy than the IMDC score (c-index of 0.686 and 0.676 vs. 0.622)., Conclusion: This analysis confirmed the prognostic accuracy of the Meet-URO score in older mRCC patients treated with cabozantinib and its role as a convenient tool for informing the patient and clinical decisions., Competing Interests: Disclosure SR received honoraria as a speaker at scientific events and travel accommodation from Amgen, GSK, BMS, and MSD. SB received honoraria as speaker at scientific events and advisory role by BMS, Pfizer, MSD, Ipsen, Roche, Eli Lilly, AstraZeneca, Pierre-Fabre, Novartis. GF services advisory boards for Astellas, Janssen, Pfizer, Bayer, MSD, Merck and received travel accomodation from Astellas, Janssen, Bayer. GP services advisory boards/consulting for Astellas, AstraZeneca, BMS, Janssen, IPSEN, Merk, MSD, Novartis, Pfizer. MS services advisory boards/consulting for Janssen, received research funding from Janssen and received travel accomodation from Ipsen, BMS, Janssen, Pfizer, Astellas Pharma. PR services advisory boards for MSD, AstraZeneca and Janssen. GLB reports personal fees from AstraZeneca and Astellas and non-financial support from Janssen. DS received honoraria for the advisory board from Amgen, Jansen, MSD, BMS, Bayer, Astra Zeneca, Ipsen, Novartis, and Merck. CN received honoraria as a speaker at scientific events from Astellas and BMS. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Surveillance is the standard management in low-risk cN0 penile squamous cell carcinoma (peSCC) patients. However, no previous analysis focused on early and long-term outcomes of these patients. We report on main oncological outcomes of a large series of low-risk cN0 peSCC patients., Patients and Methods: Between 1980 and 2017 included, 93 evaluable consecutive low-risk (ie, pT1a G1 cN0M0) peSCC patients underwent primary tumor surgery and either observation (74) or dynamic sentinel node biopsy (DSNB) (19) following a clinical diagnosis of T1 in 66 (71%), T2 in 15 (16.1%) and Tx in 12 (12.9%) patients, respectively. The statistical significance of differences in medians and proportions was tested with the Kruskal-Wallis and chi-square tests. Kaplan-Meier plots illustrated 5-year inguinal relapse (IR)-free survival rates., Results: Median age was 60 years (IQR: 50-69 years). Median follow-up was 92 months (IQR 54-133 months). Surveillance was more frequently adopted in clinical (c)T1 than in cT2 tumors (79.7% vs. 36.8%). None of 19 patients who had DSNB had nodal metastasis. Overall, 7 (7.5%) out of 93 pT1aG1cN0 peSCC patients had IR after a median interval of 9 months. Of note, 1 patient only relapsed after 12 months of surveillance. After stratification according to IR, relapses occurred more frequently in younger patients (59 vs. 64 years, P < .001). The 5-year IR-free survival rates for the entire cohort was 92% (95% Confidence interval [CI] 87-98%)., Conclusions: Observation is a safe and effective management for low-risk peSCC patients. Younger patients may be offered a mini-invasive staging as an alternative., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This paper reports the synthesis, characterization, and properties of chitosan films (CHI) grafted with a natural antifungal agent with the aim of developing active films of natural origin to prevent post-harvest losses of citrus fruit. The antifungal agent was prepared by fermentation using lemon peel (AntiFun-LM), a citrus waste, and grafted on chitosan using different coupling agents (CHI/AntiFun-LM). Bioactive films were prepared by solvent casting. FTIR-ATR and ToF-SIMS analyses provided compelling evidence of the successful grafting process. TGA-DSC demonstrated that the films are stable after grafting. SEM studies showed the continuous and compact surface of the films. WCA measurements proved that CHI/AntiFun-LM films are more hydrophilic than CHI films. Moreover, the CHI/AntiFun-LM films showed stronger UV shielding effect when compared to CHI. The biological evaluation demonstrated that CHI/AntiFun-LM films gained considerable antifungal properties against most fungi responsible for post-harvest decay. Cytotoxicity tests showed that CHI/AntiFun-LM films did not cause any toxic effect against L929 fibroblasts. This study highlights the great potential of chemical grafting of antifungal agents produced from citrus waste to chitosan and preparation of natural-based films to act as a powerful alternative in post-harvest protection of citrus fruit in a perspective of circular economy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice., Material and Methods: Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups., Results: A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis., Conclusion: In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites., (Copyright © 2024 Elsevier Inc. All rights reserved.)

SARS-CoV-2, the etiological agent of COVID-19, is devoid of any metabolic capacity; therefore, it is critical for the viral pathogen to hijack host cellular metabolic machinery for its replication and propagation. This single-stranded RNA virus with a 29.9 kb genome encodes 14 open reading frames (ORFs) and initiates a plethora of virus-host protein-protein interactions in the human body. These extensive viral protein interactions with host-specific cellular targets could trigger severe human metabolic reprogramming/dysregulation (HMRD), a rewiring of sugar-, amino acid-, lipid-, and nucleotide-metabolism(s), as well as altered or impaired bioenergetics, immune dysfunction, and redox imbalance in the body. In the infectious process, the viral pathogen hijacks two major human receptors, angiotensin-converting enzyme (ACE)-2 and/or neuropilin (NRP)-1, for initial adhesion to cell surface; then utilizes two major host proteases, TMPRSS2 and/or furin, to gain cellular entry; and finally employs an endosomal enzyme, cathepsin L (CTSL) for fusogenic release of its viral genome. The virus-induced HMRD results in 5 possible infectious outcomes: asymptomatic, mild, moderate, severe to fatal episodes; while the symptomatic acute COVID-19 condition could manifest into 3 clinical phases: (i) hypoxia and hypoxemia (Warburg effect), (ii) hyperferritinemia ('cytokine storm'), and (iii) thrombocytosis (coagulopathy). The mean incubation period for COVID-19 onset was estimated to be 5.1 days, and most cases develop symptoms after 14 days. The mean viral clearance times were 24, 30, and 39 days for acute, severe, and ICU-admitted COVID-19 patients, respectively. However, about 25-70% of virus-free COVID-19 survivors continue to sustain virus-induced HMRD and exhibit a wide range of symptoms that are persistent, exacerbated, or new 'onset' clinical incidents, collectively termed as post-acute sequelae of COVID-19 (PASC) or long COVID. PASC patients experience several debilitating clinical condition(s) with >200 different and overlapping symptoms that may last for weeks to months. Chronic PASC is a cumulative outcome of at least 10 different HMRD-related pathophysiological mechanisms involving both virus-derived virulence factors and a multitude of innate host responses. Based on HMRD and virus-free clinical impairments of different human organs/systems, PASC patients can be categorized into 4 different clusters or sub-phenotypes: sub-phenotype-1 (33.8%) with cardiac and renal manifestations; sub-phenotype-2 (32.8%) with respiratory, sleep and anxiety disorders; sub-phenotype-3 (23.4%) with skeleto-muscular and nervous disorders; and sub-phenotype-4 (10.1%) with digestive and pulmonary dysfunctions. This narrative review elucidates the effects of viral hijack on host cellular machinery during SARS-CoV-2 infection, ensuing detrimental effect(s) of virus-induced HMRD on human metabolism, consequential symptomatic clinical implications, and damage to multiple organ systems; as well as chronic pathophysiological sequelae in virus-free PASC patients. We have also provided a few evidence-based, human randomized controlled trial (RCT)-tested, precision nutrients to reset HMRD for health recovery of PASC patients., (© 2024. The Author(s).)

Behçet's disease is a systemic inflammatory disorder of unknown etiology. The disease manifests with diverse clinical symptoms, most commonly recurrent oral and genital ulcers, skin lesions, and uveitis, though it can affect multiple organ systems. Diagnosis is primarily clinical due to the lack of a definitive diagnostic test, and management involves a multidisciplinary approach to control inflammation and manage symptoms. Current treatment strategies involve corticosteroids, immunosuppressive agents, and, increasingly, biological therapies. Behçet's disease exhibits a higher prevalence along the Silk Road, suggesting a role of environmental and genetic factors. Despite significant progress in understanding its clinical characteristics and treatment approaches, gaps remain in our understanding of its pathogenesis. Future research is needed to elucidate the disease's pathophysiology and optimize treatment strategies.

Fungi are often considered a delicacy and are primarily cultivated and harvested, although numerous species are responsible for intoxication due to toxin content. Foodborne diseases are a significant public health concern, causing approximately 420 000 deaths and 600 million morbidities yearly, of which mushroom poisoning is one of the leading causes. Epidemiological data on non-cultivated mushroom poisoning in individual countries are often unrepresentative, as intoxication rarely requires emergency intervention. On the other hand, the lack of specialist knowledge among medical personnel about the toxicological manifestations of mushroom consumption may result in ineffective therapeutic interventions. This work aims to provide an easy-to-consult and wide-ranging tool useful for better understanding the variability of mushroom intoxications, the associated symptoms, and the main treatments for the most severe cases, given the absence of a complete species mapping tool toxic. Moreover, we establish an effective collection network that describes the incidence of mushroom poisonings by reporting the species and associated toxicological manifestations for each case. In conclusion, we highlight the need to establish appropriate primary prevention interventions, such as training the affected population and increasing consultancy relationships between mycological experts and specialised healthcare personnel., (© The Author(s) 2024. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.)

Background: Microphthalmia-associated transcription factor/transcription factor E (MiTF/TFE) translocation renal cell carcinoma (RCC) is a rare type of non-clear cell RCC (nccRCC), which is more common in females. Currently, there is no standardized treatment for advanced metastatic microphthalmia translocation RCC (MiT-RCC). The main treatment modalities include surgery, chemotherapy, immunotherapy, anti-vascular endothelial growth factor or vascular endothelial growth factor receptor (VEGFR) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and targeted therapy against the mesenchymal-epithelial transition (MET) factor signaling pathway., Case Description: We present the case of an 8-year-old male patient with hematuria and paroxysmal urinary pain. Based on tumor genetic testing results and targeted drug matching analysis, the patient underwent tumor biopsy, tumor radical surgery with vascular osteotomy, and cervicothoracic lymph node dissection. The patient was then treated with a combination of immunotherapy [sintilimab, a drug directed against programmed cell death receptor-1 (PD-1)] and VEGFR tyrosine kinase inhibitor (TKI) (from pazopanib to sunitinib). Throughout the 10 cycles of conventional chemotherapy (seven courses of sintilimab since the start of the third chemotherapy treatment), the patient's condition remained stable, with no tumor recurrence at the primary site. However, in the later stages, the patient developed a large amount of ascites, and the family requested discontinuation of treatment, ultimately leading to the patient's death., Conclusions: In this case report, we summarize the therapeutic strategy of a young patient with metastatic transcription factor E3 ( TFE3 ) MiT-RCC. For this disease, early immunotherapy and the use of precision-targeted drugs may have a favorable impact on the survival prognosis of the patient but may still be of less benefit in children with advanced multiple metastases. Therefore, further research on tumor driver genes, among other treatment components, is urgently needed to improve precision therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-35/coif). M.B. receives consulting fees from ROCHE, BMS, MSD, ASTRAZENECA; and participates in the advisory board of ROCHE, BMS, MSD, ASTRAZENECA. The other authors have no conflicts of interest to declare., (2024 Translational Pediatrics. All rights reserved.)

Mechanically exfoliated multilayer WS 2 flakes are used as the channel of field effect transistors for low-power photodetection in the visible and near-infrared (NIR) spectral range. The electrical characterization as a function of the temperature reveals devices with n-type conduction and slightly different Schottky barriers at the drain and source contacts. The WS 2 phototransistors can be operated in self-powered mode, yielding both a current and a voltage when exposed to light. The spectral photoresponse in the visible and the NIR ranges shows a high responsivity (4.5 μA/W) around 1250 nm, making the devices promising for telecommunication applications., (© 2024. The Author(s).)

Motor vehicle collisions are a leading cause of morbidity and mortality within the United States. Safety devices such as seatbelts and airbags have significantly reduced mortality rates for drivers. Some drivers personalize their vehicles with inexpensive items that may cause significant injury during vehicular collisions. We present a case of a face and neck penetrating injury from a metal aftermarket rhinestone emblem attached to the steering wheel during a motor vehicle collision. A 43-year-old female was involved in an accident where the airbag had deployed and projected two pieces of the metal emblem at her face and neck. The fragment in the neck was removed at the bedside, while that in the face required removal in the operating room. She recovered well postoperatively and was discharged the same day. This case highlights the potential for the dangers caused by aftermarket rhinestone emblems on steering wheels. We recommend that increased national advisories and legislative actions be considered to limit the use of these emblems., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Nguyen et al.)

The capacitance of electrode materials used in electrochemical double-layer capacitors (EDLCs) is currently limited by several factors, including inaccessible isolated micropores in high-surface area carbons, the finite density of states resulting in a quantum capacitance in series to Helmholtz double-layer capacitance, and the presence of surface impurities, such as functional groups and adsorbed species. To unlock the full potential of EDLC active materials and corresponding electrodes, several post-production treatments are commonly proposed to improve their capacitance and, thus, the energy density of the corresponding devices. In this work, we report a systematic study of the effect of a prototypical treatment, namely H 2 -assisted thermal treatment, on the chemical, structural, and thermal properties of activated carbon and corresponding electrodes. By combining multiple characterization techniques, we clarify the actual origins of the improvement of the performance (e.g., > +35% energy density for the investigated power densities in the 0.5-45 kW kg -1 range) of the EDLCs based on treated electrodes compared to the case based on the pristine electrodes. Contrary to previous works supporting a questionable graphitization of the activated carbon at temperatures <1000 °C, we found that a "surface graphitization" of the activated carbon, detected by spectroscopic analysis, is mainly associated with the desorption of surface contaminants. The elimination of surface impurities, including adsorbed species, improves the surface capacitance of the activated carbon ( C surfAC ) by +37.1 and +36.3% at specific currents of 1 and 10 A g -1 , respectively. Despite the presence of slight densification of the activated carbon upon the thermal treatment, the latter still improves the cell gravimetric capacitance normalized on the mass of the activated carbon only ( C gAC ), e.g., + 28% at 1 A g -1 . Besides, our holistic approach identifies the change in the active material and binder contents as a concomitant cause of the increase of cell gravimetric capacitance ( C g ), accounting for the mass of all of the electrode materials measured for treated electrodes compared to pristine ones. Overall, this study provides new insights into the relationship between the modifications of the electrode materials induced by H 2 -assisted thermal treatments and the performance of the resulting EDLCs.

In this work, we analyze 12 meteorological events that occurred in the Mediterranean Sea during the period November 2011-November 2021 from a seismic point of view. In particular, we consider 8 Medicanes and 4 more common storms. Each of these events, in spite of the marked differences between them, caused heavy rainfall, strong wind gusts and violent storm surge with significant wave heights usually >3 m. We deal with the relationships between these meteorological events and the features of microseism (the most continuous and widespread seismic signal on Earth) in terms of spectral content, space-time variation of the amplitude and source locations tracked employing two different methods (amplitude decay-based grid search and array techniques). By comparing the positions of the microseism sources with the areas of significant storm surges, we observe that the microseism locations align with the actual locations of the storm surges for 10 out of 12 events analyzed (two Medicanes present very low intensity in terms of meteorological parameters and the microseism amplitude does not show significant variations during these two events). We also perform two analyses that allowed us to obtain both the seismic signature of these events, by using a method that exploits the coherence of continuous seismic noise, and their strength from a seismic point of view, called Microseism Reduced Amplitude. In addition, by integrating the results obtained from these two methods, we are able to "seismically" distinguish Medicanes and common storms. Consequently, we demonstrate the possibility of creating a novel monitoring system for Mediterranean meteorological events by incorporating microseism information alongside with other commonly employed techniques for studying meteorological phenomena. The integration of microseism with the data provided by routinely used techniques in sea state monitoring (e.g., wave buoy and HF radar) has the potential to offer valuable insights into the examination of historical extreme weather events within the context of climate change., 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 B.V. All rights reserved.)