The chondrocyte "mechanome": Activation of the mechanosensitive ion channels TRPV4 and PIEZO1 drives unique transcriptional signatures.

The mechanosensitive ion channels Transient Receptor Potential Vanilloid 4 (TRPV4) and PIEZO1 transduce physiologic and supraphysiologic magnitudes of mechanical signals in the chondrocyte, respectively. TRPV4 activation promotes chondrogenesis, while PIEZO1 activation by supraphysiologic deformations drives cell death. The mechanisms by which activation of these channels discretely drives changes in gene expression to alter cell behavior remain to be determined. To date, no studies have contrasted the transcriptomic response to activation of these channels nor has any published data attempted to correlate these transcriptomes to alterations in cellular function. This study used RNA sequencing to comprehensively investigate the transcriptomes associated with activation of TRPV4 or PIEZO1, revealing that TRPV4 and PIEZO drive distinct transcriptomes and also exhibit unique co-regulated clusters of genes. Notably, activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the interleukin (IL)-1-responsive transcriptome and contained genes associated with cartilage degradation and osteoarthritis progression. However, both TRPV4 and PIEZO1 were also shown to elicit anabolic effects. PIEZO1 expression promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. These findings emphasize the presence of a broad "mechanome" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, suggesting complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of osteoarthritis.

Physician infertility: a structured literature review.

Physician infertility has become a growing concern because of the increasingly high rates of infertility physicians experience associated with their strenuous work schedules, environmental exposures, and delayed family planning due to their necessitated years of training. Fortunately, there has been an increase in awareness, advocacy, and urgency for institutional support alongside this suboptimal association. This awareness is reflected in the vast existing literature regarding physician infertility; in this scoping review, we aggregated and assessed the current data as well as identified gaps in the available research. Including 56 articles regarding various aspects of the current state of physician infertility, we compiled and synthesized the available data to understand the role of infertility in physician family planning, including specific analyses for surgeons and comparisons of male and female physicians. We discussed the utilization and downsides of artificial reproductive technologies for this population in terms of finances and logistics, contributing to this complex and, until recently, neglected issue. Lastly, we reported on a multitude of suggestions aimed at medical training programs to help combat the complex issue of physician infertility.

Current Clinical Aspects of Androgen Deprivation Therapy for Locally Advanced and Metastatic Prostate Cancer: A Scoping Review for Urologists and Medical Providers.

Prostate cancer (PCa) currently stands as the most common malignancy and the second most common cause of death in men worldwide. Dr. C. Huggins revolutionized the field of PCa treatment through his work investigating the therapeutic effects of androgen deprivation. These early surgical castration methods were expanded upon by integrating reversible pharmacologic castration via biologic agonists. Following this, intermittent ADT (iADT) became a medical substitute for its continuous counterpart. This data synthesis aims to highlight and assess the pertinent adverse effects of ADT, to compare mortality for PCa treatment plans, and consequently provide direction for clinicians in choosing the suitable systemic ADT approach. We performed a thorough systematic search across the PubMed database to identify prospective randomized clinical trials (RCTs) comparing continuous and intermittent androgen deprivation therapy (cADT and iADT). Our qualitative analysis aimed to evaluate the potential of iADT as an alternative treatment approach, emphasizing recent clinical outcomes. The analysis of randomized control trials in the literature revealed no discernable statistical difference in PCa-specific mortality in comparison of iADT and cADT treatments. Further, in the analysis of mortality due to non-PCa causes, iADT patients fared more favorably compared to cADT. Due to iADT's characteristics of being more cost-efficient and less likely to cause undesirable side effects, urologic healthcare professionals should be made aware of these findings when counseling patients on the optimal form of ADT and consulting for future treatment guidelines.

Will you go the distance? A satisfaction survey of telemedicine in sexual medicine.

Background: The success of telemedicine depends on patient satisfaction with the care that they receive, which is impacted by the ease of use of the technology, quality of the connection, and perceived effectiveness of care. Aim: The study sought to evaluate patient satisfaction with telemedicine services in a high-volume andrology clinic. Methods: We included all patients who had a telemedicine appointment between January 1, 2020, and August 22, 2022. Demographic information was gathered, and a satisfaction survey was conducted using REDCap software. Data were grouped into 2 age categories, with ≥50 years as the cutoff (19-50 years; >50 years). The data were analyzed according to age, distance from the patient's home to our center, and survey responses. Pearson's chi-square test and ordinal logistic regression analyses were performed. Outcomes: The main outcome is satisfaction with telemedicine in a men's sexual health context. Results: A total of 4071 patients were identified based on attending a telemedicine visit. Hypogonadism was the most common diagnosis. Other diagnoses included erectile dysfunction, varicocele, Peyronie's disease, vasectomy, and infertility. In total, 613 patients completed the survey, with a mean age of 56.6 years. Older patients were less likely to prefer telemedicine (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.36-0.80; P < .001), less likely to agree to a video visit because of privacy concerns (OR, 0.51; 95% CI, 0.35-0.75; P < .001), and less likely to recommend a telemedicine visit compared with their younger counterparts (OR, 0.37; 95% CI, 0.27-0.51; P < .001). The median distance was 22.4 (interquartile range, 7.5-57.5) miles. However, there was no significant association between distance and patients' likelihood of preferring telehealth visits, including reviews of outside laboratories and imaging (OR, 1; 95% CI, 0.99-1; P = .35), belief in the quality of care provided via video visits (OR, 0.99, CI 0.99-1; P = .25), and overall preference for telehealth visits (OR, 0.99; 95% CI, 0.99-1; P = .35). Clinical Implications: Healthcare providers should consider the age of patients when deciding to offer telemedicine while addressing privacy concerns to provide adequate reassurance to patients who may have concerns about the quality of care provided through telemedicine. Strengths and Limitations: Our study achieved a substantial sample size that reached statistical significance. Conducted at a single academic center, our study was constrained, possibly introducing biases related to the institution's advanced telemedicine system. Geographic and diagnostic limitations could lead to regional biases, affecting the generalizability of the findings. Conclusion: Older patients exhibited a lower inclination toward preferring telemedicine, along with decreased odds of endorsing in-person visits.

A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues.

Mechanobiologic signals regulate cellular responses under physiologic and pathologic conditions. Using synthetic biology and tissue engineering, we developed a mechanically responsive bioartificial tissue that responds to mechanical loading to produce a preprogrammed therapeutic biologic drug. By deconstructing the signaling networks induced by activation of the mechanically sensitive ion channel transient receptor potential vanilloid 4 (TRPV4), we created synthetic TRPV4-responsive genetic circuits in chondrocytes. We engineered these cells into living tissues that respond to mechanical loading by producing the anti-inflammatory biologic drug interleukin-1 receptor antagonist. Chondrocyte TRPV4 is activated by osmotic loading and not by direct cellular deformation, suggesting that tissue loading is transduced into an osmotic signal that activates TRPV4. Either osmotic or mechanical loading of tissues transduced with TRPV4-responsive circuits protected constructs from inflammatory degradation by interleukin-1α. This synthetic mechanobiology approach was used to develop a mechanogenetic system to enable long-term, autonomously regulated drug delivery driven by physiologically relevant loading.