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Loris Cacciatore,1 Angelo Territo,2 Antonio Minore,1 Antonio Testa,1 Guglielmo Mantica,3 Francesco Esperto1 1Department of Urology, Fondazione Policlinico Universitario Campus Bio-Medico Di Roma, Rome, Italy; 2Department of Urology, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain; 3Department of Surgical and Diagnostic Integrated Sciences (DISC), University of Genova, Genoa, ItalyCorrespondence: Loris Cacciatore, Department of Urology, Fondazione Policlinico Universitario Campus Bio-Medico di Roma, Rome, Italy, Email loris.cacciatore@unicampus.itAbstract: Bladder pain Syndrome presents a multifaceted challenge in contemporary urological practice, marked by LUTS, negative behavioural, sexual, or emotional experiences, and the potential for sexual dysfunction. We meticulously explored the existing literature of conservative, non-invasive and invasive interventions, aiming to provide clinicians with a nuanced understanding of available options for comprehensive BPS management. We delve into the effectiveness and safety profiles from behavioural approaches through lifestyle changes and physical therapy, to oral or intravesical medications, until the definitive surgical treatment. The best option evaluated is the involvement of a multidisciplinary team, including urologists, urotherapists, gynaecologists, pain specialists, primary care physicians and psychologists, educating those patients regarding the condition and its chronic course and tailoring the perfect treatment for each person. Despite this, BPS remains a challenge for urologists. Indeed, our objective is to contribute to the evolving landscape of BPS management, fostering informed decision-making and personalized care for individuals grappling with this challenging condition.Keywords: bladder pain syndrome, interstitial cystitis, lower urinary tract symptoms, females, continence, therapy, conservative treatment

Abstract The abnormal biological activity of cytokines and their imbalance are implicated in developing rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Cytokine levels were measured in RA and SLE patients and compared to healthy controls using the Wilcoxon rank sum test and Kruskal–Wallis test. The relationship between cytokine levels and blood and clinical parameters was assessed using Spearman's correlation test. Compared to healthy controls, both RA and SLE patients exhibited elevated levels of GM-CSF, CX3CL1, IFN-α2, IL-12p70, IL-17A, TNF-α, IL-1β, and IFN-γ, which is evidence of their shared inflammatory signature. IL-2 levels were elevated exclusively in RA patients, while MCP-1 and IL-10 were uniquely increased in SLE patients. Notably, TNF-α showed the most significant increase in SLE patients. IL-4 was elevated in SLE patients with nephritis, correlating with IL-6, IL-10, sCD40L, and IL-8, suggesting B cell involvement in lupus nephritis. The negative correlation between CX3CL1 and TNF-α with HDL in RA and SLE respectively, highlights the potential association of these inflammatory markers with cardiovascular risk. These findings underscore the complex cytokine interplay in RA and SLE. CX3CL1 emerges as a potential therapeutic target for RA, while TNF-α and IL-4 show promise as therapeutic targets for SLE.

Only a very few studies to date have comprehensively assessed children's knowledge of sexuality. In this study, we examined the level of sexual knowledge among children aged 3-6 years in Finland. We analysed children's explanations of what they saw in drawings related to genital naming, conception and childbirth, safety skills, and adult sexual activity. Levels of knowledge were generally low. The largest number of correct answers were given for genital naming and safety skills. Knowledge increased with age. Children's gender was not related to their total level of knowledge. There was a correlation between children's ability to name their genitals and their knowledge of safety skills. The results suggest that only what is known about can be protected. Building on the findings of this study, age-appropriate sexuality education should be provided to all children.

To date, robotic surgery has gained much popularity, impacting deeply on surgical fields such as genitourinary system branches, general surgery, and cardiac surgery. We aim to outline the landscape of robotic surgery, focusing on design improvements, which have improved both the technical skills of surgeons and the outcomes of minimally invasive technique for patients. A thorough narrative literature review was conducted on PubMed/MEDLINE, employing keywords such as “robotic surgical system”, “robotic surgical device”, and “robotics AND urology”. Furthermore, the reference lists of the retrieved articles were scrutinized. The analysis focused on urological surgical systems from the 2000s to the present day. Beginning with the daVinci® Era in the 2000s, new robotic competitors, including Senhance®, Revo-I®, Versius®, Avatera®, Hi-notori®, and HugoTM RAS, have entered the medical market. While daVinci® has maintained a high competitiveness, even more new platforms are now emerging in the medical market with new intriguing features. The growing competition, driven by unique features and novel designs in emerging robotic technologies, has the potential to improve application fields, enhance diffusion, and ameliorate the cost effectiveness of procedures. Since the impact of these new surgical technologies on different specialties and healthcare systems remains unclear, more experience and research are required to define their evolving role.

Abstract Castration-resistant prostate cancer (CRPC) is a frequently occurring disease with adverse clinical outcomes and limited therapeutic options. Here, we identify methionine adenosyltransferase 2a (MAT2A) as a critical driver of the androgen-indifferent state in ERG fusion-positive CRPC. MAT2A is upregulated in CRPC and cooperates with ERG in promoting cell plasticity, stemness and tumorigenesis. RNA, ATAC and ChIP-sequencing coupled with histone post-translational modification analysis by mass spectrometry show that MAT2A broadly impacts the transcriptional and epigenetic landscape. MAT2A enhances H3K4me2 at multiple genomic sites, promoting the expression of pro-tumorigenic non-canonical AR target genes. Genetic and pharmacological inhibition of MAT2A reverses the transcriptional and epigenetic remodeling in CRPC models and improves the response to AR and EZH2 inhibitors. These data reveal a role of MAT2A in epigenetic reprogramming and provide a proof of concept for testing MAT2A inhibitors in CRPC patients to improve clinical responses and prevent treatment resistance.

Abstract Background Pancreatic Ductal Adenocarcinoma (PDAC) is an aggressive cancer characterized by an immunosuppressive microenvironment. Patients from specific ethnicities and population groups have poorer prognoses than others. Therefore, a better understanding of the immune landscape in such groups is necessary for disease elucidation, predicting patient outcomes and therapeutic targeting. This study investigated the expression of circulating key immune cell markers in South African PDAC patients of African ancestry. Methods Blood samples were obtained from a total of 6 healthy volunteers (HC), 6 Chronic Pancreatitis (CP) and 34 PDAC patients consisting of 22 resectable (RPC), 8 locally advanced (LAPC) and 4 metastatic (MPC). Real-time Quantitative Polymerase Chain reactions (RT-qPCR), Metabolomics, Enzyme-Linked Immunosorbent Assay (ELISA), Reactive Oxygen Species (ROS), and Immunophenotyping assays were conducted. Statistical analysis was conducted in R (v 4.3.2). Additional analysis of single-cell RNA data from 20 patients (16 PDAC and 4 controls) was conducted to interrogate the distribution of T-cell and Natural Killer cell populations. Results Granulocyte and neutrophil levels were significantly elevated while lymphocytes decreased with PDAC severity. The total percentages of CD3 T-cell subpopulations (helper and double negative T-cells) decreased when compared to HC. Although both NK (p = 0.014) and NKT (p

Cyclin-dependent kinase 9 (CDK9) and cytochrome P450 3A4 (CYP3A4) have emerged as promising targets in the development of anticancer drugs, presenting a consistent challenge in the quest for potent inhibitors. CDK9 inhibitors can selectively target fast-growing cancer cells by disrupting transcription elongation, which in turn hinders the production of proteins essential for cell cycle progression and survivaŚ. Understanding how CYP3A4 metabolizes specific chemotherapy drugs allows for personalized treatment plans, optimizing drug dosages according to a patient’s metabolic profile. Since many cancer patients undergo combination therapies, and CYP3A4 is vital in drug metabolism, its inhibition or induction by one drug can alter the plasma levels of others, potentially leading to treatment failure or increased toxicity. Therefore, managing CYP3A4 activity is critical for effective cancer treatment. Employing a range of computational methodologies, this study systematically investigated the binding mechanisms of pyrimidine derivatives against CDK9 and CYP3A4. The field-based model demonstrated high R2 values (0.99), with Q2 (0.66), demonstrating its ability to predict in silico inhibitory activity against the target of this study. The screening process followed in this work led to the discovery of powerful new inhibitor compounds. Of the 15 new compounds designed, three have a high affinity with the target (ranging from −8 to −9 kcal/mol kcal/mol) and were singled out through docking filtration for more detailed investigation. As well as, a reference compound with a substantial pIC50 value of 8.4, serving as the foundation for the development of the new compounds, was included for comparative analysis. To elucidate the essential features of CDK9 and CYP3A4 inhibitor design, a comparative analysis was conducted between 3D-QSAR-generated contours and molecular docking conformations of ligands. Molecular dynamics simulations were carried out for a duration of 100 ns on selected docked complexes, specifically those involving novel compounds with CDK9 and CYP3A4 enzymes. Additionally, the binding free energy for these complexes was assessed using the MM/PBSA method, which evaluates the free energy landscape of protein-ligand interactions. The results of MM/PBSA highlighted the strength of the new compounds in enhancing interactions with the target protein, which favors the results of molecular docking and MD simulation. These insights contribute to a deeper understanding of the mechanisms underlying CDK9 and CYP3A4 inhibition, offering potential avenues for the development of innovative and effective CDK9 inhibitors.

Abstract Background The aim of this study is to compare two groups of celiac patients: the first one, in which diagnosis was based on a “biopsy sparing” approach according to the 2012 ESPGHAN criteria, and the second one, based on the biopsy approach like the one of the 1991 Revised Criteria, in order to find relevant difference for sex, M/F ratio, age at diagnosis, clinical features at the onset, presence and prevalence of concomitant autoimmune disorders. Methods Our study involves 61 patients having the Celiac Disease (CD) onset from February 2013 to February 2020. The 32 patients who received diagnosis according “biopsy sparing” criteria were enrolled in group (1) The 29 patients who received diagnosis by duodenal biopsy were enrolled in group (2) Prevalence of comorbidities was analysed through chi-square test. Results In group 1 the prevalence of comorbidities such as Insulin-Dependent Diabetes Mellitus (IDDM) and thyroiditis was of 53%, while in group 2 it was only of 24%. Analysing the IDDM prevalence between the two groups we found a relevant difference. At the same time, the prevalence of thyroiditis was also significantly different. In group 1, male patients, in particular, would seem to have a higher incidence of CD related autoimmune disorders. Conclusions An increased prevalence of IDDM, thyroiditis and juvenile idiopathic arthritis (JIA) in the first group would show that the “biopsy sparing” approach could expose patients to a greater length of disease activity that might be responsible for the onset of such comorbidities. Further studies should be carried out on more numerous samples of patients in order to confirm or not these data.

Abstract Background CLAD (Chronic Lung Allograft Dysfunction) remains a serious complication following lung transplantation. Some evidence shows that portions of Extracorporeal Photopheresis (ECP)-treated patients improve/stabilize their graft function. In spite of that, data concerning molecular mechanisms are still lacking. Aims of our study were to assess whether ECP effects are mediated by Mononuclear Cells (MNCs) modulation in term of microRNAs (miRNAs) expression and growth factors release. Methods Cells from leukapheresis of 16 CLAD patients, at time 0 and 6-months (10 cycles), were cultured for 48h ± PHA (10 ug/ml) or LPS (2 ug/ml). Expression levels of miR-146a-5p, miR-155-5p, miR-31-5p, miR181a-5p, miR-142-3p, miR-16-5p and miR-23b-5p in MNCs-exosomes were evaluated by qRT-PCR, while ELISA assessed different growth factors levels on culture supernatants. Results Our result showed miR-142-3p down-regulation (p = 0.02) in MNCs of ECP-patients after the 10 cycles and after LPS stimulation (p = 0.005). We also find miR-146a-5p up-regulation in cells after the 10 cycles stimulated with LPS (p = 0.03). Connective tissue growth factor (CTGF) levels significantly decreased in MNCs supernatant (p = 0.04). The effect of ECP is translated into frequency changes of Dendritic Cell (DC) subpopulations and a slight increase in T regulatory cells (Treg) number and a significant decrease in CTGF release. Conclusions ECP might affect regulatory T cell functions, since both miR-142 and miR-146a have been shown to be involved in the regulation of suppressor regulatory T cell functions and DCs. On the other side ECP, possibly by regulating macrophage activation, is able to significantly down modulate CTGF release.

AbstractPurpose Orthostatic hypotension (OH) may predispose older adults to health complications leading to functional impairment. Despite the central role of the kidney in blood pressure control, the contribution of renal function in orthostatic hypotension is poorly investigated. To verify the association between Chronic Kidney Disease (CKD) and OH a population of hospitalised elderly patients with comorbidities was studied.Materials and methods 174 patients were consecutively admitted to Acute Geriatric Wards. On admission, patients underwent postural systolic (SBP) and diastolic (DBP) blood pressure evaluation by automatic oscillometric device after 10 min rest in lying position, and in standing position at time 0, 1, 3 and 5 min. CKD was assumed for estimated glomerular filtration rate (e-GFR) less than 60 mL/min/1.73 m2.Results The mean age of the population enrolled was 74.4 ± 7.0. OH was found in 46.0% and CKD in 56.3% of patients, respectively. A lower e-GFR was observed in patients with (56.1 ± 16.7 mL/min/1.73 m2) than in those without OH (61.1 ± 15.9 mL/min/1.73 m2) (p

The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition.

IntroductionThe relationship between neural social cognition patterns and performance on social cognition tasks in daily life is a topic of debate, with key consideration given to the extent to which theory of mind (ToM) brain circuits share properties reflecting everyday social functioning. To test the efficacy of ecological stimuli in eliciting brain activation within the ToM brain circuits, we adapted the Edinburgh Social Cognition test social scenarios, consisting of dynamic ecological contextually embedded social stimuli, to a fMRI paradigm.MethodsForty-two adults (21 men, mean age ± SD = 34.19 years ±12.57) were enrolled and underwent an fMRI assessment which consisted of a ToM task using the Edinburgh Social Cognition test scenarios. We used the same stimuli to prompt implicit (movie viewing) and explicit (silent and two-choice answers) reasoning on cognitive and affective mental states. The fMRI analysis was based on the classical random effect analysis. Group inferences were complemented with supplemental analyses using overlap maps to assess inter-subject variability.ResultsWe found that explicit mentalizing reasoning yielded wide neural activations when two-choice answers were used. We also observed that the nature of ToM reasoning, that is, affective or cognitive, played a significant role in activating different neural circuits.DiscussionThe ESCoT stimuli were particularly effective in evoking ToM core neural underpinnings and elicited executive frontal loops. Future work may employ the task in a clinical setting to investigate ToM network reorganization and plasticity.

IntroductionThe Theory of Mind (ToM) assessment is becoming essential to evaluate the response to a social cognition intervention and to monitor the progression of social abilities impairment in atypical conditions. In the Italian setting, the Yoni task has been recently validated in its short version (the Yoni-48 task) to evaluate ToM in the clinical setting. The present study aimed to verify the test-retest reliability and the Minimal Detectable Change (MDC) of the Yoni-48 task.MethodsThe Yoni-48 task was administered to 229 healthy adults at two evaluation sessions 3 weeks apart (mean days between sessions = 20.35 ± 1.75) by a psychologist. The test-retest reliability of the Yoni-48 task accuracy and response time was tested by the Intraclass Correlation Coefficient (ICC2,1, two-way random model, absolute agreement type). Then, the MDC95 and MDC90 were computed based on the standard error of measurement. Finally, the 95% limits of agreement were plotted (LOA plot) to visualize the difference and mean score of each pair of measurements.ResultsThe total Yoni-48 task accuracy, but not the response time score, showed a high ICC (>0.80), with an MDC of 0.10. By plotting the LOA plot for the accuracy score no systematic trends were observed.DiscussionThis evidence will support the adoption of the Yoni task in longitudinal designs.

Cardiogenic shock occurring in older adults is associated with higher short-term mortality rates and poorer outcomes. However, current evidence and dedicated approaches in clinical practice to assess and manage this condition in older adults are limited. The American Heart Association (AHA) has issued a scientific statement to tackle the primary issues related to the risk of cardiogenic shock in older persons, as well as to provide potential solutions for its optimal management. This editorial delves into the primary principles examined by the AHA concerning decision-making process, clinical management practices, and forthcoming strategies for the treatment of older patients with cardiogenic shock.

Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients’ physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.

Objective: Li-Fraumeni Syndrome (LFS) is a rare autosomal-dominant syndrome caused by a heterozygous germline mutation of the TP53 gene. It is characterized by early-onset malignancies and high penetrance. Non-bacterial thrombotic endocarditis (NBTE) is an uncommon condition for which cancer is a significant risk factor. Here we present a complex case of LFS unveiled by a NBTE-related ischemic stroke. Case presentation: A 41-year-old woman was admitted following a syncopal episode, preceded by a history of ischemic stroke. She had a notable family history of cancers. Imaging studies revealed ischemic damage and hemorrhagic infarcts, indicating a possible embolic origin or neoplastic involvement. Subsequent examinations revealed a NBTE on the aortic valve as well as multiple primary malignancies including high-grade invasive ductal carcinoma in the breast and primary lung adenocarcinoma. Genetic testing confirmed the presence of a pathogenic variant in TP53. Conclusion: This case underscores the intricate interplay between LFS, oncological manifestations, and thrombotic complications leading to ischemic stroke through NBTE embolization.

Background: Sarcopenia is characterized by the progressive loss of skeletal muscle mass, strength, and function, significantly impacting overall health and quality of life in older adults. This narrative review explores emerging targets and potential treatments for sarcopenia, aiming to provide a comprehensive overview of current and prospective interventions. Methods: The review synthesizes current literature on sarcopenia treatment, focusing on recent advancements in muscle regeneration, mitochondrial function, nutritional strategies, and the muscle–microbiome axis. Additionally, pharmacological and lifestyle interventions targeting anabolic resistance and neuromuscular junction integrity are discussed. Results: Resistance training and adequate protein intake remain the cornerstone of sarcopenia management. Emerging strategies include targeting muscle regeneration through myosatellite cell activation, signaling pathways, and chronic inflammation control. Gene editing, stem cell therapy, and microRNA modulation show promise in enhancing muscle repair. Addressing mitochondrial dysfunction through interventions aimed at improving biogenesis, ATP production, and reducing oxidative stress is also highlighted. Nutritional strategies such as leucine supplementation and anti-inflammatory nutrients, along with dietary modifications and probiotics targeting the muscle–microbiome interplay, are discussed as potential treatment options. Hydration and muscle–water balance are emphasized as critical in maintaining muscle health in older adults. Conclusions: A combination of resistance training, nutrition, and emerging therapeutic interventions holds potential to significantly improve muscle function and overall health in the aging population. This review provides a detailed exploration of both established and novel approaches for the prevention and management of sarcopenia, highlighting the need for further research to optimize these strategies.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disorder with two main subtypes: ulcerative colitis (UC) and Crohn’s disease (CD). The pathogenesis involves genetic predisposition, dysbiosis, and immune dysregulation. Complications include perianal lesions, strictures, fistulas, perforations, and an increased risk of colon cancer. Clinical classification ranges from mild to fulminant and recurrent disease, with common symptoms such as abdominal discomfort, rectal bleeding, diarrhea, and weight loss. Extraintestinal manifestations include arthritis, erythema nodosum, pyoderma gangrenosum, and uveitis. Conventional treatments using aminosalicylates, corticosteroids, and immunomodulators have limitations. Biologics, introduced in the 1990s, offer improved efficacy and specificity, targeting factors like TNF-α, integrins, and cytokines. Monoclonal antibodies play a crucial role in IBD management, aiming to reduce relapses, hospitalizations, and surgeries. In conclusion, this review is aimed at summarizing the latest knowledge, advantages, and drawbacks of IBD therapies, such as small molecules, biologics, and monoclonal antibodies, to provide a basis for further research in the IBD field.

Humor is widespread in communication and its use in the context of science is no exception. Although science jokes are pervasive on social media, we are only beginning to understand the mechanisms through which humor affects people's attitudes, opinions, and perceptions of scientific topics. Here, we add to our understanding of how funny science content influences attitude formation and behavioral intentions; these results can help communicators make strategic decisions related to humor's use in real-world practice. Extending recent work in science communication, this study aims to understand the conditional nature of the mechanism by which funny images about three different scientific topics, combined with verbal humor, affects people's social media engagement intentions by eliciting mirth. Our results offer evidence that choices about which humor types to employ matter when it comes to communicating scientific topics. For two of the three topics, artificial intelligence and microbiomes, exposure to different humor types resulted in different levels of mirth and humor's effect on engagement intentions was moderated by respondents' need for humor. However, humor did not have the same effect on global warming engagement intentions. Our findings have implications for the practice of, training, and scholarship in science communication.

Background: Ignorance, misconceptions and fear hinder the implementation of young children's age-appropriate sexuality education (SE) globally. Methods to promote the SE of young children are needed. Aim: We aimed to evaluate why parents and professionals resist the concept of childhood SE and to test whether a child-centred term could reduce this resistance. Setting: We conducted nationwide studies in Finland plus focused studies in three groups. Methods: In open online situation analysis and needs assessment studies among early childhood education professionals (n = 507) and parents (n = 614) of 1--6-year-olds, negative, adulthood-associated connotations for the term 'sexuality education' were detected. We then evaluated whether a less sex-connected term than SE would be feasible to promote SE of young children. We combined 'body' and 'emotion', after our earlier study on children's most common sexuality-related expressions, to form the new Finnish term "Kehotunnekasvatus" [body-- emotion education] and tested it among professionals of sexual health (n = 17) and early education (n = 63) and primary health nurses (n = 29). Results: Acceptance of the new term was excellent in all three groups; the new term was reported as 'more positive, more neutral, downplaying thoughts of sex'. Most respondents deemed it appropriate, necessary and usable in their work. Furthermore, the majority of those working daily with the parents of young children preferred the new term to 'sexuality education'. Conclusion: After testing the functionality of a new Finnish term among Finnish professionals, the authors suggest considering replacing the term 'sexuality education' with a more child-centred and less sex-connected synonym when referring to SE for young children.

Background Systemic sclerosis (SSc) is a chronic autoimmune disease, with impaired immune response, increased fibrosis and endothelial dysfunction. Regulatory T cells (Tregs), which are essential to control inflammation, tissue repair and autoimmunity, have a decreased frequency and impaired function in SSc patients. Low-dose interleukin-2 (IL-2LD) can expand and activate Tregs and has, therefore, a therapeutic potential in SSc.Objective We aimed to assess the safety and biological efficacy of IL-2LD in patients with SSc.Methods As part of the TRANSREG open-label phase IIa basket trial in multiple autoimmune diseases, we studied nine patients with SSc without severe organ involvement. Patients received 1 million international units (MIU)/day of IL-2 for 5 days, followed by fortnightly injections for 6 months. Laboratory and clinical evaluations were performed between baseline and month 6.Results At day 8, the primary endpoint (Treg frequency) was reached with a 1.8±0.5-fold increase of Treg levels among CD4+ T lymphocytes (p=0.0015). There were no significant changes in effector T cells nor in B cells. IL-2LD was well tolerated, and no serious adverse events related to treatment occurred. There was a globally stable measurement in the modified Rodnan skin score and Valentini score at month 6. Disease activity and severity measures, the quality of life evaluated by EuroQL-5D-5L and pulmonary function test parameters remained stable during the study period.Conclusion IL-2LD at a dosage of 1 MIU/day safely and selectively activates and expands Tregs. Clinical signs remain stable during the study period. This opens the door to properly powered phase II efficacy trials investigating IL-2LD therapeutic efficacy in SSc.

BackgroundOccupational e–mental health (OeMH) interventions significantly reduce the burden of mental health conditions. The successful implementation of OeMH interventions is influenced by many implementation strategies, barriers, and facilitators across contexts, which, however, are not systematically tracked. One of the reasons is that international consensus on documenting and reporting the implementation of OeMH interventions is lacking. There is a need for practical guidance on the key factors influencing the implementation of interventions that organizations should consider. Stakeholder consultations secure a valuable source of information about these key strategies, barriers, and facilitators that are relevant to successful implementation of OeMH interventions. ObjectiveThe objective of this study was to develop a brief checklist to guide the implementation of OeMH interventions. MethodsBased on the results of a recently published systematic review, we drafted a comprehensive checklist with a wide set of strategies, barriers, and facilitators that were identified as relevant for the implementation of OeMH interventions. We then used a 2-stage stakeholder consultation process to refine the draft checklist to a brief and practical checklist comprising key implementation factors. In the first stage, stakeholders evaluated the relevance and feasibility of items on the draft checklist using a web-based survey. The list of items comprised 12 facilitators presented as statements addressing “elements that positively affect implementation” and 17 barriers presented as statements addressing “concerns toward implementation.” If a strategy was deemed relevant, respondents were asked to rate it using a 4-point Likert scale ranging from “very difficult to implement” to “very easy to implement.” In the second stage, stakeholders were interviewed to elaborate on the most relevant barriers and facilitators shortlisted from the first stage. The interview mostly focused on the relevance and priority of strategies and factors affecting OeMH intervention implementation. In the interview, the stakeholders’ responses to the open survey’s questions were further explored. The final checklist included strategies ranked as relevant and feasible and the most relevant facilitators and barriers, which were endorsed during either the survey or the interviews. ResultsIn total, 26 stakeholders completed the web-based survey (response rate=24.8%) and 4 stakeholders participated in individual interviews. The OeMH intervention implementation checklist comprised 28 items, including 9 (32.1%) strategies, 8 (28.6%) barriers, and 11 (39.3%) facilitators. There was widespread agreement between findings from the survey and interviews, the most outstanding exception being the idea of proposing OeMH interventions as benefits for employees. ConclusionsThrough our 2-stage stakeholder consultation, we developed a brief checklist that provides organizations with a guide for the implementation of OeMH interventions. Future research should empirically validate the effectiveness and usefulness of the checklist.

The heterocycle compounds, with their diverse functionalities, are particularly effective in inhibiting Janus kinases (JAKs). Therefore, it is crucial to identify the correlation between their complex structures and biological activities for the development of new drugs for the treatment of rheumatoid arthritis (RA) and cancer. In this study, a diverse set of 28 heterocyclic compounds selective for JAK1 and JAK3 was employed to construct quantitative structure-activity relationship (QSAR) models using multiple linear regression (MLR). Artificial neural network (ANN) models were employed in the development of QSAR models. The robustness and stability of the models were assessed through internal and external methodologies, including the domain of applicability (DoA). The molecular descriptors incorporated into the model exhibited a satisfactory correlation with the receptor-ligand complex structures of JAKs observed in X-ray crystallography, making the model interpretable and predictive. Furthermore, pharmacophore models ADRRR and ADHRR were designed for each JAK1 and JAK3, proving effective in discriminating between active compounds and decoys. Both models demonstrated good performance in identifying new compounds, with an ROC of 0.83 for the ADRRR model and an ROC of 0.75 for the ADHRR model. Using a pharmacophore model, the most promising compounds were selected based on their strong affinity compared to the most active compounds in the studied series each JAK1 and JAK3. Notably, the pharmacokinetic, physicochemical properties, and biological activities of the selected compounds (As compounds ZINC79189223 and ZINC66252348) were found to be consistent with their therapeutic effects in RA, owing to their non-toxic, cholinergic nature, absence of P-glycoprotein, high gastrointestinal absorption, and ability to penetrate the blood-brain barrier. Furthermore, ADMET properties were assessed, and molecular dynamics and MM/GBSA analysis revealed stability in these molecules.

Tetanus is an infectious disease caused by Clostridium tetani toxin. Although easily preventable through vaccination, over 73,000 new infections and 35,000 deaths due to tetanus occurred worldwide in 2019, with higher rates in countries with healthcare barriers. Here, we present a clinical case of C. tetani infection in an 85-year-old patient. Patient robustness and high functional reserve before infection are favorable predictors of survival for an otherwise fatal disease. However, the patient did not experience any severe complications. Therefore, this report is a strong call for tetanus vaccination.

Abstract Dominantly inherited GAA repeat expansions in FGF14 are a common cause of spinocerebellar ataxia (GAA-FGF14 ataxia; spinocerebellar ataxia 27B). Molecular confirmation of FGF14 GAA repeat expansions has thus far mostly relied on long-read sequencing, a technology that is not yet widely available in clinical laboratories. We developed and validated a strategy to detect FGF14 GAA repeat expansions using long-range PCR, bidirectional repeat-primed PCRs, and Sanger sequencing. We compared this strategy to targeted nanopore sequencing in a cohort of 22 French Canadian patients and next validated it in a cohort of 53 French index patients with unsolved ataxia. Method comparison showed that capillary electrophoresis of long-range PCR amplification products significantly underestimated expansion sizes compared to nanopore sequencing (slope, 0.87 [95% CI, 0.81 to 0.93]; intercept, 14.58 [95% CI, − 2.48 to 31.12]) and gel electrophoresis (slope, 0.84 [95% CI, 0.78 to 0.97]; intercept, 21.34 [95% CI, − 27.66 to 40.22]). The latter techniques yielded similar size estimates. Following calibration with internal controls, expansion size estimates were similar between capillary electrophoresis and nanopore sequencing (slope: 0.98 [95% CI, 0.92 to 1.04]; intercept: 10.62 [95% CI, − 7.49 to 27.71]), and gel electrophoresis (slope: 0.94 [95% CI, 0.88 to 1.09]; intercept: 18.81 [95% CI, − 41.93 to 39.15]). Diagnosis was accurately confirmed for all 22 French Canadian patients using this strategy. We also identified 9 French patients (9/53; 17%) and 2 of their relatives who carried an FGF14 (GAA)≥250 expansion. This novel strategy reliably detected and sized FGF14 GAA expansions, and compared favorably to long-read sequencing.

s Kyrgyzstan undergoes significant demographic transitions, with an increasing aging population, the intersection of healthy aging and cardiovascular health emerges as a critical aspect of public health. We explore the relationship of healthy aging and cardiovascular health, underlining both the opportunities and challenges inherent in this demographic shift. Applying the World Health Organization's concept of "intrinsic capacity" and the "Integrated Care for Older People" (ICOPE) approach, we suggest strategies for addressing these crucial public health issues.

Objective The objectives were to (1) compare satisfaction with social roles and activities in a large multinational systemic sclerosis (SSc) cohort to general population normative data and (2) identify sociodemographic, lifestyle and SSc disease factors associated with satisfaction with social roles and activities.Methods Participants in the Scleroderma Patient-centered Intervention Network Cohort completed the Patient Reported Outcomes Information System Version 2 satisfaction with social roles and activities domain questionnaire. Multivariable regression was used to assess associations with sociodemographic, lifestyle and disease factors.Results Among 2385 participants, mean satisfaction with social roles and activities T-score (48.1, SD=9.9) was slightly lower than the US general population (mean=50, SD=10). Factors independently associated with satisfaction were years of education (0.54 per SD, 95% CI 0.14 to 0.93); non-White race or ethnicity (−1.13, 95% CI −2.18 to –0.08); living in Canada (−1.33, 95% CI −2.40 to –0.26 (reference USA)) or the UK (−2.49, 95% CI −3.92 to –1.06); body mass index (−1.08 per SD, 95% CI −1.47 to –0.69); gastrointestinal involvement (−3.16, 95% CI −4.27 to –2.05); digital ulcers (−1.90, 95% CI −3.05 to –0.76); moderate (−1.62, 95% CI −2.78 to –0.45) or severe (−2.26, 95% CI −3.99 to –0.52) small joint contractures; interstitial lung disease (−1.11, 95% CI −1.97 to –0.25); pulmonary arterial hypertension (−2.69, 95% CI −4.08 to –1.30); rheumatoid arthritis (−2.51, 95% CI −4.28 to –0.73); and Sjogren’s syndrome (−2.42, 95% CI −3.96 to –0.88).Conclusion Mean satisfaction with social roles and activities is slightly lower in SSc than the general population and associated with multiple sociodemographic and disease factors.