MAYEX is an old long noncoding RNA recruited for X chromosome dosage compensation in a reptile.

Long noncoding RNAs (lncRNAs) are essential regulatory elements of sex chromosomes that act to equalize gene expression levels between males and females. XIST, RSX, and roX2 regulate X chromosomes in placental mammals, marsupials, and Drosophila, respectively. Because the green anole (Anolis carolinensis) shows complete dosage compensation of its X chromosome, we tested whether a lncRNA was involved. We found an ancient lncRNA, MAYEX, that gained male-specific expression more than 89 million years ago. MAYEX evolved a notable association with the acetylated histone 4 lysine 16 (H4K16ac) epigenetic mark and the ability to loop its locus to the totality of the X chromosome to increase expression levels. MAYEX is the first lncRNA in reptiles linked to a dosage compensation mechanism that balances the expression of sex chromosomes.

Development of the European Laparoscopic Intermediate Urological Skills LUSs2 Curriculum: A Delphi Consensus from the European School of Urology.

Background and objective: While programmes such as the European Basic Laparoscopic Urological Skills have made strides in foundational training, a significant gap exists for intermediate and advanced laparoscopy education. Our objective is to develop and validate the European laparoscopic intermediate urological skills (LUSs2) curriculum, which will establish uniformity in the training of urological laparoscopic procedures and facilitate proficiency among practitioners. Methods: The study combines a literature review, cognitive task analysis development by a steering group, and a two-round Delphi survey involving international experts in urological laparoscopy. Consensus was defined as agreement of ≥70% among experts. The survey included statements on various laparoscopic procedures, assessed on a Likert scale from 1 (strongly disagree) to 9 (strongly agree). Key findings and limitations: The Delphi process achieved consensus on 85% (235/275) of statements, indicating a strong agreement on the curriculum's content. Areas covered include renal hilum dissection, major vessel injury management, enucleation and renorrhaphy, vesicourethral anastomosis, and pyeloplasty. Limitations include the nonsystematic nature of the literature review and potential biases inherent in expert-based consensus methods. Conclusions and clinical implications: The LUSs2 curriculum significantly advances the standardised training of laparoscopic urological skills. It offers a detailed, consensus-validated framework that addresses the need for uniformity in surgical education and aims to enhance surgical proficiency and patient care. Patient summary: This study presents the development of a new standardised training curriculum for urological laparoscopic surgery. We intend this curriculum to improve the quality of surgical training and ensure high-quality patient care.

Fossil Geyserite and Testate Amoebae in Geothermal Spring Vent Pools: Paleoecology and Variable Preservation Quality in Jurassic Sinter of Patagonia (Deseado Massif, Argentina).

Geyserite is a type of terrestrial siliceous hot spring deposit (sinter) formed subaerially in proximal vent areas, with near-neutral pH, alkali chloride discharge fluids characterized by initial high temperatures (~73°C to up to 100°C) that fluctuate rapidly in relation to dynamic hydrology, seasonality, wind, and other environmental parameters. We analyzed sinters at the Claudia paleogeothermal field from the Late Jurassic (~150 Ma) Deseado Massif geological province, Argentinean Patagonia. The geyserite samples-with spicular to columnar to nodular morphologies-contain abundant microfossils in monotypic assemblages that occur in three diagenetic states of preservation. The best-preserved microfossils consist of vesicle-like structures with radial heteropolar symmetry (~35 µm average diameter), circular apertures, smooth walls lacking ornamentation, and disk- or beret-like shapes. Comparisons with extant, morphologically similar organisms suggest an affinity with the testate amoebae of the Arcella hemisphaerica-Arcella rotundata complex and Centropyxis aculeata strain discoides. These species occur in active geothermal pools between 22°C and 45°C, inconsistent with the temperature of formation of modern geyserites. We propose that the testate amoebae may have colonized the geyserite during cooler phases in between spring-vent eruptive cycles to prey on biofilms. Silica precipitation through intermittent bathing and splashing of fluctuating thermal fluid discharge could have led to their entrapment and fossilization. Petrographic analysis supports cyclicity in paleovent water eruptions and later diagenesis that transformed the opal into quartz. Spatially patchy degradation and modification of the silicified microorganisms resulted in variable preservation quality of the microfossils. This contribution illustrates the importance of microscale analysis to locate early silicification and identify high-quality preservation of fossil remains in siliceous hot spring deposits, which are important in early life studies on Earth and potentially Mars.

Identification of insect body fragments found in fecal samples of Sapajus nigritus (Primates: Cebidae) from five Conservation Units in Rio de Janeiro state, Brazil.

Sapajus nigritus (Primates: Cebidae) is endemic of the Atlantic Forest, occurring from the Southeastern and Southern regions of Brazil to Northeastern Argentina. This species plays a role in two ecosystem services: seed dispersal through endozoochory and insect population control in agricultural plantations and forest environments. Fruits and invertebrates represent approximately 90% of their diet, and there is a large number of insects in the diet of S. nigritus in urban and conserved areas. However, it is known that insect diversity decreases in anthropized environments. Our objective was to identify the insects present in the fecal samples of S. nigritus from five Conservation Units in Rio de Janeiro state, Brazil. We aim to estimate the percentage of each taxon of insects found in feces either, hypothesizing that there are a greater variety of insect species in the diet of S. nigritus that inhabit preserved forested areas. A fecal screening was conducted using a light microscopy and the insects were identified based on their external morphology. Insect fragments were found in eight out of ten fecal samples of S. nigritus, revealing that they belonged to insects from five orders: Hymenoptera, Hemiptera, Orthoptera, Coleoptera and Blattodea, suggesting a good conservation status of the sampling areas.

Identification of novel broad host-range promoter sequences functional in diverse Pseudomonadota by a promoter-trap approach.

Finding novel promoter sequences is a cornerstone of synthetic biology. To contribute to the expanding catalog of biological parts, we employed a promoter-trap approach to identify novel sequences within an Antarctic microbial community that act as broad host-range promoters functional in diverse Pseudomonadota. Using Pseudomonas putida KT2440 as host, we generated a library comprising approximately 2,000 clones resulting in the identification of thirteen functional promoter sequences, thereby expanding the genetic toolkit available for this chassis. Some of the discovered promoter sequences prove to be broad host-range as they drove gene expression not only in P. putida KT2440 but also in Escherichia coli DH5α, Cupriavidus taiwanensis R1T, Paraburkholderia phymatum STM 815T, Ensifer meliloti 1021, and an indigenous Antarctic bacterium, Pseudomonas sp. UYIF39. Our findings enrich the existing catalog of biological parts, offering a repertoire of broad host-range promoter sequences that exhibit functionality across diverse members of the phylum Pseudomonadota, proving Antarctic microbial community as a valuable resource for prospecting new biological parts for synthetic biology.

Role of Nasal Surgery in Adult Obstructive Sleep Apnea: A Systematic Review.

Objective To perform a systematic review to determine if isolated nasal surgery has any impact on subjective or objective parameters in adult obstructive sleep apnea (OSA) patients. Materials and Methods From December 2022 to March 2023, we conducted a search on the PubMed, Cochrane, Scopus, and Web of Science databases. Two independent investigators performed a study selection according to the established criteria, as well as data collection, including the study design, the subjective and objective parameters addressed, the type of intervention, and the outcomes, considering the methodological quality and risk of bias. Results In total, 25 studies met the selection criteria, and they showed that there is a significant improvement in sleep quality, sleepiness, nasal resistance, and snoring after isolated nasal surgery. Still, there is no relevant modification of other polysomnographic parameters. It also reduces the required titration pressures of continuous positive airway pressure (CPAP) and increases the duration of its use. Conclusion Isolated nasal surgery is not a primary treatment for OSA. Still, it improves the subjective parameters and can lead to CPAP therapy success by enhancing its effectiveness and long-term compliance.

Fungal Infections in Hospitalized Patients of Systemic Lupus Erythematosus: A United States Nationwide Cohort Analysis.

Introduction/objective Immunosuppressive therapy is the cornerstone of management in patients with systemic lupus erythematosus (SLE). Patients on immunosuppressive therapy are at increased risk of developing opportunistic fungal infections. We conducted this analysis to describe the epidemiology, including incidence, risk factors, and outcomes, of fungal infections in hospitalized patients with SLE in the United States. Method A retrospective cohort study was performed by analyzing the National Inpatient Sample (NIS) 2016-2020 for all patients with a discharge diagnosis of SLE and fungal infections, including histoplasmosis, pneumocystosis, cryptococcosis, aspergillosis, and blastomycosis, as a primary or secondary diagnosis via ICD-10 (International Classification of Diseases 10th Revision) codes. Frequencies, demographics, and trends were determined and compared between hospitalized patients with SLE and those without SLE. STATA version 17 was used for data analysis. A p-value of ≤0.05 was considered statistically significant. Results In hospitalized SLE patients, there were lower odds of developing fungal infections in females (odds ratio (OR): 0.63 (95% confidence interval (CI): 0.49-0.80)) and higher odds in Hispanic (OR: 1.52 (95% CI: 1.16-1.98) and Asian (OR: 1.78 (95% CI: 1.15-2.75) populations. Steroid use (OR: 1.96 (95% CI: 1.58-2.42)), concomitant HIV infection(OR: 22.39 (95% CI: 16.06-31.22)), and the presence of leukemias (OR: 3.56 (95% CI: 1.67-7.59)) and lymphomas (OR: 3.29 (95% CI: 1.78-6.09)) in hospitalized SLE patients were significant predictors of fungal infection (p < 0.01). There were differences in the incidence of fungal infections based on geographical areas in the US, with blastomycosis being more common in the Midwest. From 2016 to 2020, there was a decline in the incidence rate of hospitalization per 100,000 for non-SLE patients with fungal infections (10.7 per 100,000 hospitalizations in 2016 versus 9.6 per 100,000 hospitalizations in 2020), whereas this rate remained steady for the SLE cohort (0.1 per 100,000 hospitalizations in 2016 versus 0.2 per 100,000 hospitalizations in 2020). Conclusions Hospitalized patients with SLE are at an increased risk of developing fungal infections, and this risk is increased further in patients who are males, are on steroid therapy, and have HIV or leukemia and lymphomas. Further studies can be done to explain the increased risk of fungal infections associated with these patient characteristics.

Spin-Orbit-Lattice Entangled State in A_{2}MgReO_{6} (A=Ca, Sr, Ba) Revealed by Resonant Inelastic X-Ray Scattering.

The 5d^{1} ordered double perovskites present an exotic playground for studying novel multipolar physics due to large spin-orbit coupling. We present Re L_{3} edge resonant inelastic x-ray scattering (RIXS) results that reveal the presence of the dynamic Jahn-Teller effect in the A_{2}MgReO_{6} (A=Ca, Sr, Ba) family of 5d^{1} double perovskites. The spin-orbit excitations in these materials show a strongly asymmetric line shape and exhibit substantial temperature dependence, indicating that they are dressed with lattice vibrations. Our experimental results are explained quantitatively through a RIXS calculation based on a spin-orbit-lattice entangled electronic ground state with the dynamic Jahn-Teller effect taken into consideration. We find that the spin-orbit-lattice entangled state is robust against magnetic and structural phase transitions as well as against significant static Jahn-Teller distortions. Our results illustrate the importance of including vibronic coupling for a complete description of the ground state physics of 5d^{1} double perovskites.

Forensic application of sandpaper spray ionization mass spectrometry (SPS-MS): Direct analysis of solid pharmaceutical formulations and edible cannabis products.

In this work, we employed a new ambient ionization mass spectrometry technique, sandpaper spray mass spectrometry (SPS-MS), as an efficient tool to analyze pills and tablets of pharmaceutical formulations. The following samples were analyzed: regulators of blood pressure, cholesterol, and diabetes, and drugs for the treatment of erectile dysfunction (ED). Additionally, a hard candy of Cannabis sativa containing Δ9-tetrahydrocannabinol (Δ9-THC) and its related isomer cannabidiol (CBD) was also evaluated. The surfaces of the samples, without any prior treatment, were sanded onto triangular-cut sandpaper, and full MS scans (and MS/MS) were acquired in both positive and negative ionization modes. SPS-MS (and MS/MS) allowed for prompt detection of the active pharmaceutical ingredients (APIs) in each formulation. Other components of the formulations, added as excipients, were also tentatively identified. The results described herein indicate that the SPS-MS technique can be applied to fast screening of pills and tablets being potentially used as an efficient tool to detect counterfeit pharmaceutical and illicit products, a current issue of increasing concern.

Preventive medicine in OSA-A systematic review and a call to action.

STUDY OBJECTIVES: The purpose of this systematic review is to evaluate the modifiable risk factors associated with OSA and analyze extant publications solely focused on prevention of the disease. METHODS: Studies focused on prevention strategies for OSA and modifiable risk factors were eligible for inclusion. A detailed individual search strategy for each of the following bibliographic databases was developed: Cochrane, EMBASE, MEDLINE, PubMed and LILACS. The references cited in these articles were also crosschecked and a partial grey literature search was undertaken using Google Scholar. The methodology of selected studies was evaluated using the 14-item Quality Assessment Tool for Diagnostic Accuracy Studies. RESULTS: Search resulted in 720 publications examining risk factors and prevention of OSA, as well as lifestyle modifications. Of these, a thorough assessment of the abstracts and content of each of these manuscripts led to the rejection of all but four papers, the latter being included in this systematic review. In contrast, a search regarding 'Therapeutics' showed that 23,674 articles on OSA were published, clearly illustrating the imbalance between the efforts in prevention and those focused on therapeutics. CONCLUSIONS: Notwithstanding the importance and benefits of technological advances in medicine, consideration of the needs of people with OSA and its consequences prompts advocacy for the prevention of the disease. Thus, despite the economic interests that focus only on diagnosis and treatment, strategies preferentially aimed at overall avoidance of OSA emerge as a major priority. Thus, public and healthcare provider education, multidimensional prevention, and early diagnosis of OSA should be encouraged worldwide.

Association of operative time and approach on postoperative complications for esophagectomy.

BACKGROUND: Minimally invasive esophagectomy is associated with decreased postoperative complications compared with open esophagectomy. However, the risks of complications for minimally invasive esophagectomy compared with open esophagectomy may be affected by operative time. The objectives of this study are to (1) compare the incidence of postoperative complications for minimally invasive esophagectomy and open esophagectomy and (2) evaluate the association of postoperative complications on operative approach and operative time. METHODS: A retrospective cohort analysis of patients who underwent an esophagectomy in the American College of Surgeons National Surgical Quality Improvement Program Procedure-Targeted Data File was performed from 2016 to 2020. For analysis, minimally invasive esophagectomy and open esophagectomy were stratified into tertiles of operative time. A bivariate analysis of postoperative complications comparing minimally invasive esophagectomy with open esophagectomy was performed. Multivariable Poisson regression models were estimated evaluating the association of the likelihood of postoperative complications with operative approach and operative time. RESULTS: In total, 8,574 patients who underwent esophagectomy were included: 5,369 patients underwent minimally invasive esophagectomy, and 3,205 patients underwent open esophagectomy. Median operative time was 402 minutes for minimally invasive esophagectomy and 321 minutes for open esophagectomy. The incidence of postoperative complications and 30-day mortality was lower in the minimally invasive esophagectomy group than the open esophagectomy group within the same tertiles of operative time. When we compared patients who underwent short open esophagectomy with those who underwent long minimally invasive esophagectomy, there were no significant differences in complications. CONCLUSION: There is no significant association of postoperative complications for short open esophagectomy compared with long minimally invasive esophagectomy. Patients should be selected for minimally invasive esophagectomy when there is appropriate surgeon experience and hospital resources.

EUFOREUM Berlin 2023: Optimizing care for type 2 inflammatory diseases from clinic to AI: A pediatric focus.

The European Forum for Research and Education in Allergy and Airways diseases (EUFOREA) organized its bi-annual forum EUFOREUM in Berlin in November 2023. The aim of EUFOREUM 2023 was to highlight pediatric action plans for prevention and optimizing care for type 2 inflammatory conditions starting in childhood, with a focus on early-stage diagnosis, ensuring neither under- nor overdiagnosis, optimal care, and suggestions for improvement of care. EUFOREA is an international not-for-profit organization forming an alliance of all stakeholders dedicated to reducing the prevalence and burden of chronic respiratory diseases through the implementation of optimal patient care via educational, research, and advocacy activities. The inclusive and multidisciplinary approach of EUFOREA was reflected in the keynote lectures and faculty of the virtual EUFOREUM 2023 (www.euforea.eu/euforeum) coming from the pediatric, allergology, pulmonology, ENT, dermatology, primary health care fields and patients around the central theme of type 2 inflammation. As most type 2 inflammatory conditions may start in childhood or adolescence, and most children have type 2 inflammation when suffering from a respiratory or skin disease, the moment has come to raise the bar of ambitions of care, including prevention, remission and disease modification at an early stage. The current report provides a comprehensive overview of key statements by the faculty of the EUFOREUM 2023 and the ambitions of EUFOREA allowing all stakeholders in the respiratory field to be updated and ready to join forces in Europe and beyond.

Structure-guided drug design targeting Abl kinase: how structure and regulation can assist in designing new drugs.

The human protein Abelson kinase (Abl), a tyrosine kinase, plays a pivotal role in developing chronic myeloid leukemia (CML). Abl's involvement in various signaling pathways underscores its significance in regulating fundamental biological processes, including DNA damage responses, actin polymerization, and chromatin structural changes. The discovery of the Bcr-Abl oncoprotein, resulting from a chromosomal translocation in CML patients, revolutionized the understanding and treatment of the disease. The introduction of targeted therapies, starting with interferon-alpha and culminating in the development of tyrosine kinase inhibitors (TKIs) like imatinib, significantly improved patient outcomes. However, challenges such as drug resistance and side effects persist, indicating the necessity of research into novel therapeutic strategies. This review describes advancements in Abl kinase inhibitor development, emphasizing rational compound design from structural and regulatory information. Strategies, including bivalent inhibitors, PROTACs, and compounds targeting regulatory domains, promise to overcome resistance and minimize side effects. Additionally, leveraging the intricate structure and interactions of Bcr-Abl may provide insights into developing inhibitors for other kinases. Overall, this review highlights the importance of continued research into Abl kinase inhibition and its broader implications for therapeutic interventions targeting kinase-driven diseases. It provides valuable insights and strategies that may guide the development of next-generation therapies.

Sphaerotilus uruguayifluvii sp. nov., a novel filamentous bacterium isolated from river water.

Strain C29T, a Gram-staining-negative, straight rod occurring singly, in pairs or short chains, was isolated from floating filamentous biomass of the Uruguay River. The strain was catalase and oxidase positive, chemoorganotrophic, strictly aerobic, non-motile, and grew at pH 6.0-9.0, 15-45 °C, and 0-0.5% (w/v) NaCl. Polyhydroxybutyrate was accumulated in nutrient-limited conditions. Phylogenetic analysis based on the 16S rRNA gene revealed that strain C29T had the highest sequence similarity with Leptothrix discophora SS-1T (97.82%), Ideonella livida TBM-1T (97.82%), Vitreoscilla filiformis L1401-2T (97.52%), Sphaerotilus sulfidivorans D-501T (97.50%) and Sphaerotilus natans DSM 6575T (97.46%). Other type strains with validly published names had similarities below 97.46%. Further phylogenomic analysis showed that strain C29T was affiliated to the family Sphaerotilaceae. Average nucleotide identity (ANI) and in silico DNA-DNA hybridization (dDDH) values with its phylogenetic relatives were lower than 91 and 41%, respectively, revealing that strain C29T represented a new species. The DNA G + C content of strain C29T was 70.9%. The annotation of the genome of the novel strain shows it possessed genes for the degradation of aromatic compounds. It also contained genes that encode sigma factors involved in response regulation of stress resistance, which is an important function for adaptation and survival in natural niches. Based on the results of the phylogenetic and phenotypic analyses, we propose that strain C29T represents a novel species, for which the name Sphaerotilus uruguayifluvii sp. nov. is proposed. The type strain is C29T (= CCM 9043T = DSM 113250T).

The interaction of the azetidine thiazole side chain with the active site loop (ASL) 3 drives the evolution of IMP metallo-ß-lactamase against tebipenem.

Imipenemase (IMP) metallo-ß-lactamases (MBLs) hydrolyze almost all available ß-lactams including carbapenems and are not inhibited by any commercially available ß-lactamase inhibitor. Tebipenem (TP) pivoxil is the first orally available carbapenem and possesses a unique bicyclic azetidine thiazole moiety located at the R2 position. TP has potent in vitro activity against Enterobacterales producing extended-spectrum and/or AmpC ß-lactamases. Thus far, the activity of TP against IMP-producing strains is understudied. To address this knowledge gap, we explored the structure activity relationships of IMP MBLs by investigating whether IMP-6, IMP-10, IMP-25, and IMP-78 [MBLs with expanded hydrolytic activity against meropenem (MEM)] would demonstrate enhanced activity against TP. Most of the Escherichia coli DH10B strains expressing IMP-1 variants displayed a ≥twofold MIC difference between TP and MEM, while those expressing VIM or NDM variants demonstrated comparable MICs. Catalytic efficiency (kcat/KM) values for the TP hydrolysis by IMP-1, IMP-6, IMP-10, IMP-25, and IMP-78 were significantly lower than those obtained for MEM. Molecular dynamic simulations reveal that V67F and S262G substitutions (found in IMP-78) reposition active site loop 3, ASL-3, to better accommodate the bicyclic azetidine thiazole side chain, allowing microbiological/catalytic activity to approach that of comparison MBLs used in this study. These findings suggest that modifying the R2 side chain of carbapenems can significantly impact hydrolytic stability. Furthermore, changes in conformational dynamics due to single amino acid substitutions should be used to inform drug design of novel carbapenems.

Advancing ethanol content determination in hydrogels: non-destructive and operational methods for health and criminal inspections.

The significance of accurate determination of ethanol content in hydrogel formulations was accentuated during COVID-19 pandemic coinciding with the heightened demand for sanitizing agents. The present article proposes three robust methodologies for this purpose: Fourier Transform Infrared Spectroscopy (FTIR), Raman spectroscopy, and Densitometry with matrix effect correction by Near-Infrared Spectroscopy (NIR). All three methods demonstrated outstanding linearity (R2 ≥ 0.99) and minimal errors (< 1.7%), offering simplicity and operational efficiency. FTIR and Raman, being non-destructive and requiring minimal preparation, enable practical on-site analysis capabilities, underscoring the potential of the spectroscopic methods to expedite health investigations and inspections, empowering on-site ethanol determination, and relieving the burden on official laboratories. Additionally, the densitometry with NIR-based approach showcased superior accuracy and precision compared to spectroscopic methods, meeting validation criteria while offering operational advantages over the costly official distillation-based method. Therefore, it stands as a reliable and reproducible technique for comprehensive health and criminal compliance assessments, making it a compelling alternative for both industry and official laboratories.

Ecological transcriptomics reveals stress response pathways of a ground-herb species in a waterlogging gradient of Amazonian riparian forests.

Environmental stress is a fundamental facet of life and a significant driver of natural selection in the wild. Gene expression diversity may facilitate adaptation to environmental changes, without necessary genetic change, but its role in adaptive divergence remains largely understudied in Neotropical systems. In Amazonian riparian forests, species distribution is predominantly influenced by species' waterlogging tolerance. The flooding gradient delineates distinct wetland forest types, shaping habitats and species characteristics. Here we investigated the molecular basis of environmental stress response in a tropical ground-herb species (Ischnosiphon puberulus) to environmental variation in Amazonian riparian forests. We compared environmental variables and gene expression profiles from individuals collected in two forest types: Igapó and Terra firme in the Amazonian riparian forests. Predictable seasonal flooding poses a significant challenge in Igapó compared to Terra firme environments, with the former presenting higher water column height and longer flooding duration. Our findings suggest that contrasting environmental conditions related to flooding regimes are important drivers of population genetic differentiation and differential gene expression in I. puberulus. Enriched gene ontology terms highlight associations with environmental stresses, such as defence response, water transport, phosphorylation, root development, response to auxin, salicylic acid and oxidative stress. By uncovering key environmental stress response pathways conserved across populations, I. puberulus offers novel genetic insights into the molecular basis of plant reactions to environmental constraints found in flooded areas of this highly biodiverse neotropical ecosystem.

Immune Competence and Pain: A Narrative Review.

PURPOSE OF REVIEW: This review aims to summarize current knowledge on the pathophysiology of pain and the role of neuro-immune crosstalk in the development of acute and chronic pain (CP). Specifically, the review focuses on the role of immune cells involved in the innate and acquired immune response, emphasizing their bidirectional interactions with the nervous systems and discussing the implications of this crosstalk on acute and CP management. RECENT FINDINGS: In the last two decades, multiple studies have uncovered the important role of the immune system in initiating, maintaining, and resolving pain stimuli. Furthermore, researchers discovered that the immune system interacts tightly with the nervous system, creating a bidirectional crosstalk in which immune cells influence the response of peripheral and central nerve fibers while neurotransmitters and neuropeptides released by nociceptors directly and indirectly modulate the immune response. The neuro-immune crosstalk in acute and CP is a complex and not fully understood process that comprise the interactions of multiple diverse molecules, bidirectional interferences, and numerous redundant processes. Despite the complexity, important steps have been taken in recent years toward explaining the specific roles of each immune cell type and molecule in the initiation, maintenance and resolution of pain. These findings may set the basis for innovative therapeutic options that target the immune system, overcoming the limitations of current treatments in providing pain relief and the disadvantages associated with opioid therapy.

Clinical Validation of the Intermediate-risk Non-muscle-invasive Bladder Cancer Scoring System and Substratification Model Proposed by the International Bladder Cancer Group: A Multicenter Young Academic Urologists Urothelial Working Group Collaboration.

BACKGROUND AND OBJECTIVE: Intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) encompasses a broad spectrum of disease, with heterogeneous outcomes in terms of disease recurrence and progression. The International Bladder Cancer Group (IBCG) recently proposed an updated scoring model for IR substratification that is based on five key risk factors. Our aim was to provide a clinical validation of the IBCG scoring system and substratification model for IR NMIBC. METHODS: This was an international multicenter retrospective study. Patients diagnosed with IR NMIBC between 2012 and 2022 and treated with transurethral resection of the bladder and adjuvant intravesical chemotherapy were included. According to the presence or absence of risk factors, patients with IR NMIBC were further categorized in IR-low (no risk factors), IR-intermediate (1-2 risk factors), and IR-high (≥3 risk factors) groups. The 1-yr and 3-yr rates for recurrence-free survival (RFS) and progression-free survival (PFS) were evaluated for each subgroup. Cox regression analyses were used to compare oncological outcomes between the groups. KEY FINDINGS AND LIMITATIONS: Of the 677 patients with IR NMIBC included in the study, 231 (34%), 364 (54%), and 82 (12%) were categorized in the IR-low, IR-intermediate, and IR-high groups, respectively. There were significant differences in RFS and PFS rates between these groups. CONCLUSIONS AND CLINICAL IMPLICATIONS: We provide the first clinical validation of the IBCG scoring system and model for substratification of IR NMIBC. PATIENT SUMMARY: Our study demonstrates that patients with intermediate-risk non-muscle-invasive bladder cancer can be correctly classified into three distinct subgroups according to their risk of both disease recurrence and progression. Our results support use of this scoring system in clinical practice.