Purpose: Biomarkers predicting clinically significant prostate cancer (sPC) before biopsy are currently lacking. This study aimed to develop a non-invasive urine test to predict sPC in at-risk men using urinary metabolomic profiles. Materials and Methods: Urine samples from 934 at-risk subjects and 268 treatment-naïve PC patients were subjected to liquid chromatography/mass spectrophotometry (LC-MS)-based metabolomics profiling using both C18 and hydrophilic interaction liquid chromatography (HILIC) column analyses. Four models were constructed (training cohort [n=647]) and validated (validation cohort [n=344]) for different purposes. Model I differentiates PC from benign cases. Models II, III, and a Gleason score model (model GS) predict sPC that is defined as National Comprehensive Cancer Network (NCCN)-categorized favorable-intermediate risk group or higher (Model II), unfavorable-intermediate risk group or higher (Model III), and GS ≥7 PC (model GS), respectively. The metabolomic panels and predicting models were constructed using logistic regression and Akaike information criterion. Results: The best metabolomic panels from the HILIC column include 25, 27, 28 and 26 metabolites in Models I, II, III, and GS, respectively, with area under the curve (AUC) values ranging between 0.82 and 0.91 in the training cohort and between 0.77 and 0.86 in the validation cohort. The combination of the metabolomic panels and five baseline clinical factors that include serum prostate-specific antigen, age, family history of PC, previously negative biopsy, and abnormal digital rectal examination results significantly increased AUCs (range 0.88–0.91). At 90% sensitivity (validation cohort), 33%, 34%, 41%, and 36% of unnecessary biopsies were avoided in Models I, II, III, and GS, respectively. The above results were successfully validated using LC-MS with the C18 column. Conclusions Urinary metabolomic profiles with baseline clinical factors may accurately predict sPC in men with elevated risk before biopsy.

Purpose: Metabolic diseases such as diabetes mellitus may play a role in the development and progression of prostate cancer (PC); however, this association remains to be explored in the context of specific PC stages. The objective of this study was to systematically review the evidence for an association between diabetes and overall, early, or advanced PC risk. Materials and Methods: A systematic review with meta-analysis was performed (MEDLINE, EMBASE, and CINAHL) from inception until September 2023. Cohort and case-control studies that assessed PC risk in adult males (≥18 years) associated with type 2 diabetes mellitus or diabetes (if there was no distinction between diabetes type) were included. The Newcastle-Ottawa Scale (NOS) was used to assess study bias; those with NOS<7 were excluded. Evidence certainty was assessed with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method. Results: Thirty-four studies (n=26 cohorts and n=8 case-controls) were included. Of these, 32 assessed diabetes and all PC stages combined, 12 included early PC stages, and 15 included advanced PC stages. Our meta-analysis showed diabetes had a protective effect against early PC development (n=11, risk ratio [RR]=0.71; 95% confidence interval [CI]=0.61–0.83, I2=84%) but no association was found for combined (n=21, RR=0.95; 95% CI=0.79–1.13, I2=99%) or advanced PC stages (n=15, RR=0.96; 95% CI=0.77–1.18, I2=98%) at diagnosis. According to GRADE, the evidence certainty was very low. Conclusions Diabetes may be protective against early PC stages, yet evidence linking diabetes to risk across all stages, and advanced PC specifically, is less conclusive. High heterogeneity may partially explain discrepancy in findings and was mostly associated with study design, method used for PC diagnosis, and risk measures. Our results may aid risk stratification of males with diabetes and inform new approaches for PC screening in this group, especially considering the reduced sensitivity of prostate-specific antigen values for those with diabetes.

Purpose: The study aimed to comprehensively analyze testosterone and precursor concentrations in the testicular interstitial fluid (TIF) of men with azoospermia, exploring their significance in the testicular microenvironment and their correlation with testicular sperm retrieval outcomes. Materials and Methods: We analyzed 37 TIF samples, including 5 from men with obstructive azoospermia (OA) and 32 from men with non-obstructive azoospermia (NOA). Liquid chromatography with tandem mass spectrometry quantified testosterone and precursor levels. Comparative assessments of the outcomes of testicular sperm retrieval were performed between the OA and NOA groups as well as among men with NOA. Results: Men with NOA who had not undergone hormone treatment exhibited significantly higher intratesticular concentrations of testosterone (median 1,528.1 vs. 207.5 ng/mL), androstenedione (median 10.6 vs. 1.9 ng/mL), and 17-OH progesterone (median 13.0 vs. 1.8 ng/mL) than men diagnosed with OA. Notably, in the subgroup of patients with NOA subjected to medical treatment, men with successful sperm retrieval had significantly reduced levels of androstenedione (median androstenedione 5.7 vs. 18.5 ng/mL, p=0.004). Upon a more detailed analysis of these men who underwent hormone manipulation treatment, the testosterone/androstenedione ratio (indicative of HSD17B3 enzyme activity) was markedly increased in men with successful sperm retrieval (median: 365.8 vs. 165.0, p=0.008) compared with individuals with NOA who had unsuccessful sperm recovery. Furthermore, within the subset of men with NOA who did not undergo medical treatment before microdissection testicular sperm extraction but achieved successful sperm retrieval, the ratio of 17-OH progesterone/progesterone (indicative of CYP17A1 activity) was substantially higher. Conclusions The study suggests distinct testosterone biosynthesis pathways in men with compromised spermatogenesis and those with normal spermatogenesis. Among NOA men with successful retrieval after hormone optimization therapy, there was decreased androstenedione and increased HSD17B3 enzyme activity. These findings have diagnostic and therapeutic implications for the future.

BACKGROUND: Regulatory T cells (Tregs) are essential for maintaining immune homeostasis and facilitating tissue regeneration by fostering an environment conducive to tissue repair. However, in damaged tissues, excessive inflammatory responses can overwhelm the immunomodulatory capacity of Tregs, compromising their functionality and potentially hindering effective regeneration. Mesenchymal stem cells (MSCs) play a key role in enhancing Treg function. MSCs enhance Treg activity through indirect interactions, such as cytokine secretion, and direct interactions via membrane proteins. METHODS: This review examines the regenerative functions of Tregs across various tissues, including bone, cartilage, muscle, and skin, and explores strategies to enhance Treg functionality using MSCs. Advanced techniques, such as the overexpression of relevant genes in MSCs, are highlighted for their potential to further enhance Treg function. Additionally, emerging technologies utilizing extracellular vesicles (EVs) and cell membrane-derived vesicles derived from MSCs offer promising alternatives to circumvent the potential side effects associated with live cell therapies. This review proposes approaches to enhance Treg function and promote tissue regeneration and also outlines future research directions. RESULTS AND CONCLUSION: This review elucidates recent technological advancements aimed at enhancing Treg function using MSCs and examines their potential to improve tissue regeneration efficiency.

BACKGROUND: Soft tissue integration (STI) around dental implant abutments is a prerequisite to prevent bacterial invasion and achieve successful dental implant rehabilitation. However, peri-implant STI is a major challenge after dental abutment placement due to alterations in the immune microenvironment upon surgical dental implant installation. METHODS: Based on known immunomodulatory effects of zinc, we herein deposited zinc/chitosan/gelatin (Zn/CS/Gel) coatings onto titanium substrates to study their effect on macrophages. First, we exposed macrophages to cell culture media containing different zinc ion (Zn2+) concentrations. Next, we explored the immunomodulatory effect of Zn/CS/Gel coatings prepared via facile electrophoretic deposition (EPD). RESULTS: We found that Zn2+ effectively altered the secretome by reducing the secretion of pro-inflammatory and enhancing pro-regenerative cytokine secretion, particularly at a Zn2+ supplementation of approximately 37.5 μM. Zn/CS/Gel coatings released Zn2+ in a concentration range which effectively stimulated pro-regenerative macrophage polarization as demonstrated by M2 macrophage polarization. Additionally, the impact of these Zn2+-exposed macrophages on gingival fibroblasts incubated in conditioned medium showed stimulated adhesion, proliferation, and collagen secretion. CONCLUSION Our promising results suggest that controlled release of Zn2+ from Zn/CS/Gel coatings could be applied to immunomodulate peri-implant STI, and to enhance dental implant survival.

BACKGROUND: Priming strategies that improve the functionality of MSCs may be required to address issues limiting successful clinical translation of MSC therapies. For conditions requiring high trophic support such as brain and spinal cord injuries, priming MSCs to produce higher levels of trophic factors may be instrumental to facilitate translation of current MSC therapies. We developed and tested a novel molecular priming paradigm using docosahexaenoic acid (DHA) to prime adipose tissue-derived mesenchymal stromal cells (ASCs) to enhance the secretome neuroregulatory potential. METHODS: Comprehensive dose–response and time-course assays were carried to determine an optimal priming protocol. Secretome total protein measurements were taken in association with cell viability, density and morphometric assessments. Cell identity and differentiation capacity were studied by flow cytometry and lineage-specific markers. Cell growth was assessed by trypan-blue exclusion and senescence was probed over time using SA-b-gal, morphometry and gene expression. Secretomes were tested for their ability to support differentiation and neurite outgrowth of human neural progenitor cells (hNPCs). Neuroregulatory proteins in the secretome were identified using multiplex membrane arrays. RESULTS: Priming with 40 lM DHA for 72 h significantly enhanced the biosynthetic capacity of ASCs, producing a secretome with higher protein levels and increased metabolic viability. DHA priming enhanced ASCs adipogenic differentiation and adapted their responses to replicative senescence induction. Furthermore, priming increased concentrations of neurotrophic factors in the secretome promoting neurite outgrowth and modulating the differentiation of hNPCs. CONCLUSIONS These results provide proof-of-concept evidence that DHA priming is a viable strategy to improve the neuroregulatory profile of ASCs.

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

Objective: Mobility limitations and falls are common in people with Parkinson’s disease (PwP). Compared with exercise alone, a tailored, multidomain intervention has the potential to be more effective in improving mobility safety and preventing falls. This study aimed to explore the feasibility and potential effectiveness of a multidomain fall prevention intervention (Integrate) designed for PwP who experience frequent falls. Methods: The home-based intervention was delivered over a span of 6 months by occupational therapists and physiotherapists. The personalized intervention included home fall hazard reduction, exercise, and safer mobility behavior training. The participants received 8 to 12 home visits and were supported by care-partners (when necessary) to participate in the intervention. Results: Twenty-nine people (recruitment rate: 49%; drop-out rate: 10%) with moderate to advanced Parkinson’s disease, a history of recurrent falls, and mild to moderate cognitive impairment participated in the study, with 26 people completing the study. A moderate-to-high adherence to the intervention was observed, and there were no adverse events related to the intervention. Twenty-one (81%) participants met or exceeded their safer mobility goal based on the Goal Attainment Scale. The participants exhibited a median 1.0-point clinically meaningful improvement according to the Short Physical Performance Battery. An exploratory analysis revealed that fall rates were reduced by almost 50% in the 6-month follow-up period (incidence rate ratio: 0.51; 95% confidence interval 0.28–0.92). Conclusion A multidomain occupational therapy and physiotherapy intervention for PwP experiencing recurrent falls was feasible and appeared to improve mobility safety. A randomized trial powered to detect the effects of the intervention on falls and mobility is warranted.

Background/Aims: Functional lumen imaging probe (FLIP) Panometry has demonstrated utility in the assessment of esophageal motility as a complement to existing methodologies like high-resolution manometry. However, as FLIP is typically performed with sedation during routine endoscopy, there is potential for impact of sedation agents on esophageal motility. We aim to examine the effects of conscious sedation with midazolam and fentanyl on FLIP Panometry metrics and classification. Methods: A cross-over study was conducted on 12 healthy, asymptomatic volunteers that completed FLIP while sedated with intravenous fentanyl and midazolam and while awake on a separate day. FLIP was performed in the same manner in both conditions with transoral placement of the FLIP and stepwise FLIP filling. During awake FLIP, subjects also rated the presence and intensity of esophageal perception. Results: In both experimental conditions, all subjects demonstrated normal motility. The esophagogastric junction distensibility index was lower (median [interquartile range]: 5.8 [5.15-6.85] vs 8.9 [7.68-9.38] mm 2 /mmHg; P = 0.025), and the FLIP pressure was higher (46.5 [38.125-52.5] vs 33 [26-36.8] mmHg; P = 0.010) in the sedated condition compared to the awake condition. Maximum esophagogastric junction diameter and body distensibility plateau were no different between conditions (P = 0.999 and P = 0.098, respectively). Perception of esophageal sensation during awake FLIP was reported in 7/12 (58%) subjects. Conclusions While numeric differences in FLIP Panometry metrics were observed between sedated and awake FLIP in healthy subjects, these differences did not change the FLIP Panometry diagnosis. Sedated FLIP offers a well-tolerated method to assess esophageal motility during endoscopy.

Background: Cognitive decline is commonly seen in brain tumor (BT) patients and is associatedwith a worsened prognosis. Cognitive rehabilitation (CR) for cancer-related cognitive dysfunction has been widely studied for non-central nervous system cancers; however, recent emerging research has commenced documenting CR strategies for BT patients and survivors. Our objective was to review the current literature on various CR modalities in patients and BT survivors. Methods: The review was conducted in accordance with the PRISMA guidelines. The studieson CR were searched across 3 databases using a predefined search strategy. After removing duplicates, performing initial and full-text screenings, and applying inclusion criteria, relevant articles were selected. The demographic details, CR technique, cognitive tasks/tests administered, cognitive functions assessed, follow-up time, and outcomes of the intervention were assessed. Results: A total of 15 studies were included in the review. Neuropsychologist-guided trainingsessions to improve memory, attention, and executive functioning are effective in improving the mentioned domains. Younger and more educated patients benefited the most. Holistic mnemonic training and neurofeedback were not shown to affect overall cognitive functioning. Computer-based training programs showed improvements in executive functions of pediatric BT survivors, however, feasibility studies showed conflicting results. Aerobic exercises improved executive functions and decreased symptoms of the tumor. Both yoga and combined aerobic and strength training improved overall cognitive functioning. Active video gaming may improve motor and process skills; however, no effect was seen on cognitive functioning. Conclusion Neuropsychologic training, computer-based programs, and physical exercise havebeen found effective in improving or preventing decline in cognitive functions of BT patients. Given the limited trials and methodological variations, a standardized CR program cannot be established at present. Ongoing trials are expected to provide valuable data in the near future.