Does antithrombotic use enable earlier diagnosis of bladder cancer? A brief institutional assessment.

INTRODUCTION: Wallis et al (JAMA 2017) demonstrated use of antithrombotic medications (ATMs) is associated with increased prevalence of hematuria-related complications and subsequent bladder cancer diagnosis within 6 months. Stage of diagnosis was lacking in this highly publicized study. This study examined the association of ATM use on bladder cancer stage at the time of diagnosis. MATERIALS AND METHODS: We completed a retrospective chart review of patients with a bladder cancer diagnosis at our institution. Patient demographics and bladder cancer work up information were assessed. Patients were stratified based on use of ATMs at time diagnosis. Descriptive statistics were completed to identify association between ATM use and stage of bladder cancer diagnosis, as stratified by non-muscle invasive bladder cancer (NMIBC) versus muscle invasive bladder cancer (MIBC). RESULTS: A total of 1052 patient charts were reviewed. Eight hundred and forty-four were included and 208 excluded due to unavailability of diagnosis history. At diagnosis, 357 (42.3%) patients were taking ATMs. Patients on ATMs presented with NMIBC at similar rates as patients not taking ATMs (81.2% vs. 77.8%, p = 0.23). Subgroup analysis by ATM class similarly demonstrated no statistically significant differences in staging. CONCLUSION: While Wallis et al established that patients on blood thinners who present with hematuria are more likely to be diagnosed with genitourinary pathology, this factor does not appear to enable an earlier diagnosis of bladder cancer. Future study may assess hematuria at presentation (gross, microscopic), type of blood thinners, and low versus high risk NMIBC presentation.

Single-Center Retrospective Analysis of Device-Related Complications Related to Dorsal Root Ganglion Stimulation for Pain Relief in 31 Patients.

INTRODUCTION: Dorsal root ganglion (DRG) stimulation is a form of neuromodulation used to treat neuropathic pain due to a myriad of etiologies. Though this relatively new therapy has been shown to be quite effective, complications associated with the implantation of this therapy have not been well documented. OBJECTIVES: The primary objective of this study was to describe the device-related complications associated with DRG stimulator implantations. MATERIALS AND METHODS: This was a single-center retrospective analysis of 31 patients who underwent full implantation of neuromodulation hardware marketed for DRG stimulation. The predefined endpoints included device-related complications associated with DRG implantations, such as hardware failure, explantation procedures, and revision surgery. Additional endpoints included percentage of patients receiving therapy and pain as measured using the visual analog scale (VAS) pain scale at initial, six-month, and 12-month follow-up after hardware implantation. RESULTS: Thirty-one patients were included out of 42 patients trialed. Baseline VAS in patients was 7.7 (31 patients). At initial follow-up, six-month follow-up, and one-year follow-up, VAS scores were 4.7 (31 patients), 5.3 (20 patients), and 5.5 (13 patients), respectively. Paired t-test between preoperative VAS (mean 7.3) and one-year follow-up VAS (5.5) demonstrated statistical significance (p = 0.027). At initial, six-month, and one-year follow-up, 30/31 (97%), 19/24 (79%), and 18/23 (78%) patients were confirmed to be receiving DRG stimulation therapy after permanent implant. Of the 31 patients who were implanted with a permanent system, 8 (26%) were explanted and an additional 10 (29%) required revision surgery. CONCLUSION: In this study, we examine the various device-related complications associated with DRG stimulation requiring repeat surgery. High rates of hardware failure, revision surgery, and explantation of stimulators illustrate the need for hardware optimization to improve patient outcomes.

Recent advances in diagnosis and management of sympathetic ophthalmia.

PURPOSE OF REVIEW: Sympathetic ophthalmia is a bilateral granulomatous uveitis that occurs following unilateral trauma or surgery and is sight-threatening in the contralateral eye. Despite significant potential morbidity, disease remains poorly understood. Variable presentations and clinical courses, as well as a lack of definitive diagnostic laboratory tests can complicate the diagnosis and result in delayed treatment, which can beget permanent vision loss. This review focuses on recent advances in areas of pathophysiology, classification, diagnosis and treatment. RECENT FINDINGS: Sympathetic ophthalmia is thought to involve a cell-mediated immune response to retinal and uveal antigens exposed through trauma or surgery. Multiple mechanisms have been implicated, including activation of the interleukin-23/IL-17 pathway. Ongoing emphasis is placed on early disease recognition and prompt treatment with multimodal imaging. Multiple authors advocate for the routine use of optical coherence tomography (OCT) for screening and disease monitoring. Systemic steroids and steroids sparing-immunosuppressive agents remain the mainstay of treatment. SUMMARY: Understanding pathophysiology may provide useful targets for drug development, as well as allow for identification of patients at risk. OCT is a useful tool in early diagnosis and management of sympathetic ophthalmia, as OCT changes may precede clinical symptoms and signs, allowing for early disease detection and better visual outcomes.

Artificial tissue creation under microgravity conditions: Considerations and future applications.

Traditional tissue engineering methods often fail to promote robust cell growth and differentiation, limiting the development of functioning tissues. However, the microgravity conditions created by rotating wall vessel bioreactors minimize shear stress and unload the gravitational force usually placed on cells. In a microgravity environment, cell proliferation, cell differentiation, and the 3D organization of cells are altered, potentially encouraging the formation of more biosimilar artificial tissues for certain cell types. Additionally, cells in these engineered tissues display lowered immunogenicity, pointing to the transplantation potential of tissues engineered in microgravity conditions. However, these benefits are not consistent across all cell types, and the long-term impact of microgravity on tissue development and stability remains an unanswered question. Even so, there is potential that with further research, microgravity tissue engineering will have productive clinical applications for medical and pharmaceutical purposes.

Outcomes following repair of early-onset versus delayed-onset rhegmatogenous retinal detachments after acute posterior vitreous detachment.

AIM: To report anatomical and functional outcomes after surgical repair of acute-onset vs delayed-onset rhegmatogenous retinal detachments (RDs) following acute posterior vitreous detachment (PVD). METHODS: A retrospective, comparative interventional cohort study where patients presenting to a single-centre retina practice between October 2015 and March 2020 with delayed RDs (diagnosed ≥42 days after initial presentation of acute PVD) were compared with a 2:1 age-matched and gender-matched acute RD cohort (PVD and RD at initial presentation). The primary outcome was the final attachment rate and single surgery anatomic success (SSAS) at 3 months after RD repair. RESULTS: A total of 210 eyes were analysed-70 in the delayed RD group and 140 in the acute RD group. SSAS was 58/70 (82.9%) for the delayed RD group and 112/140 (80%) for the acute RD group (p=0.71). At the time of RD diagnosis, mean (SD) logarithm of minimum angle of resolution visual acuity (VA) was 0.51 (0.70) (Snellen, 20/65) in the delayed RD group vs 1.04 (0.92) (Snellen, 20/219) in the acute RD group (p<0.001). Mean VA was better at 1 and 3 months post-repair in the delayed RD group (p=0.005 and 0.041, respectively) but similar by 6 months, 12 months and at the final visit post-repair (p=0.48, 0.27, and 0.23, respectively). CONCLUSIONS: Delayed-onset RDs occurring ≥6 weeks after initial presentation to a retina specialist with an acute PVD generally had better VA at the time of RD diagnosis and faster post-surgical visual recovery compared with acute-onset RDs diagnosed at the initial presentation. No significant difference in anatomic outcomes was seen between the two groups.

Association of Mutant KRAS Alleles With Morphology and Clinical Outcomes in Pancreatic Ductal Adenocarcinoma.

CONTEXT.­: Mutant KRAS is the main oncogenic driver in pancreatic ductal adenocarcinomas (PDACs). However, the clinical and phenotypic implications of harboring different mutant KRAS alleles remain poorly understood. OBJECTIVE.­: To characterize the potential morphologic and clinical outcome differences in PDACs harboring distinct mutant KRAS alleles. DESIGN.­: Cohort 1 consisted of 127 primary conventional PDACs with no neoadjuvant therapy, excluding colloid/mucinous, adenosquamous, undifferentiated, and intraductal papillary mucinous neoplasm-associated carcinomas, for which an in-house 42-gene mutational panel had been performed. A morphologic classification system was devised wherein each tumor was assigned as conventional, papillary/large duct (P+LD, defined as neoplastic glands with papillary structure and/or with length ≥0.5 mm), or poorly differentiated (when the aforementioned component was 60% or more of the tumor). Cohort 2 was a cohort of 88 PDACs in The Cancer Genome Atlas, which were similarly analyzed. RESULTS.­: In both cohorts, there was significant enrichment of P+LD morphology in PDACs with KRAS G12V and G12R compared with G12D. In the entire combined cohort, Kaplan-Meier analyses showed longer overall survival (OS) with KRAS G12R as compared with G12D (median OS of 1255 versus 682 days, P = .03) and in patients whose PDACs displayed P+LD morphology as compared with conventional morphology (median OS of 1175 versus 684 days, P = .04). In the adjuvant-only subset, KRAS G12R had the longest OS compared with G12D, G12V, and other alleles (median OS unreached/undefined versus 1009, 1129, and 1222 days, respectively). CONCLUSIONS.­: PDACs with different mutant KRAS alleles are associated with distinct morphologies and clinical outcomes, with KRAS G12R allele associated with P+LD morphology and longer OS when compared with G12D using Kaplan-Meier studies.

Euglycemic diabetic ketoacidosis (EDKA) after pancreaticoduodenectomy: An under-recognized metabolic abnormality with outcome implications.

BACKGROUND: Euglycemic diabetic ketoacidosis is a metabolic condition characterized by relative euglycemia, ketonemia, and metabolic acidosis that occurs through mechanisms resembling starvation. Pancreaticoduodenectomy is a complex abdominal operation that subjects patients to a prolonged fasting and an inflammatory state. This study examined the incidence of euglycemic diabetic ketoacidosis and potential opportunities for early diagnosis and management in patients undergoing pancreaticoduodenectomy. METHODS: A single-institution retrospective review of 350 patients who underwent pancreaticoduodenectomy between 2017 and 2020 was performed. Primary endpoints were peak beta-hydroxybutyrate levels, peak lactate levels, lowest pH, peak base deficits, and urinary output within the first 24 hours, postoperatively. Additional endpoints included incidence of postoperative pancreatic fistula, delayed gastric emptying, total complications, postoperative hospital length of stay, readmission rates, and changes in insulin regimen at discharge. RESULTS: Of the 350 cases reviewed, 39 (11.1%) patients developed euglycemic diabetic ketoacidosis. Male sex and pancreatic cancer were associated with a risk for euglycemic diabetic ketoacidosis (P < .05). Patients with euglycemic diabetic ketoacidosis had significantly higher peak beta-hydroxybutyrate levels than patients without euglycemic diabetic ketoacidosis (mean difference = 19.8 mg/dL, 95% confidence interval = 14.7-24.9, P < .001), and were nearly four times more likely to require insulin at discharge (odds ratio 3.8, 95% confidence interval = 1.1-13.0, P < .05). CONCLUSION: This is the first large descriptive study that investigates euglycemic diabetic ketoacidosis after pancreaticoduodenectomy. Euglycemic diabetic ketoacidosis after pancreaticoduodenectomy is associated with significantly higher beta-hydroxybutyrate levels and new or increased insulin requirement at discharge. Our study demonstrates potential markers for euglycemic diabetic ketoacidosis after pancreaticoduodenectomy, offering an opportunity to identify and successfully treat this disease in a timely manner.

Genitourinary and Sexual Symptoms and Treatments in Transfeminine Individuals: A Qualitative Exploration of Patients' Needs.

INTRODUCTION: Medical providers may not be familiar with the genitourinary and sexual symptoms of transgender and non-binary (TGNB) individuals. This lack of familiarity may hinder a provider's ability to address these issues as patients may hesitate to report symptoms due to fear of stigma, misgendering, and being treated disrespectfully. AIM: To describe the array of genitourinary and sexual symptoms in transfeminine individuals. METHODS: Upon institutional review board approval, researchers used semi-structured interviews with 25 transfeminine individuals assigned male at birth to explore urinary and sexual symptoms on a sample of convenience. Participants were recruited and interviews were conducted until saturation was achieved. Two research assistants independently coded all de-identified transcripts and resolved discrepancies. OUTCOMES: Thematic codes pertaining to genitourinary and sexual symptoms were defined and assessed in this study. RESULTS: Some genitourinary symptoms unrelated to hormone therapy or genital gender-affirming surgery (GGAS) included frequency, urgency, nocturia, and incontinence, while those attributed to GGAS included slow stream, spraying, and retention. Sexual symptoms unrelated to hormone therapy or GGAS included sexually transmitted infections, erectile dysfunction, and low libido. Sexual symptoms related to GGAS included delayed ejaculation, penile pain, scar tissue pain, and pain with receptive vaginal penetration. CLINICAL IMPLICATIONS: Increased provider awareness of and accountability for the treatment of genital and sexual symptoms of transfeminine individuals. STRENGTHS AND LIMITATIONS: Open-ended questions were used to generate a range of responses and perspectives through conversation instead of quantifiable data. Findings are not applicable to all TGNB people since participants were limited to transfeminine adults assigned male at birth only. Recruitment was limited by the sensitive nature of the topic and hard-to-reach populations and relied on convenience through flyers and a chain-referral sampling approach. CONCLUSION: Transfeminine individuals experience a wide array of genitourinary and sexual symptoms both similar and different to their cis gender counterparts. Chung PH, Swaminathan V, Spigner S, et al. Genitourinary and Sexual Symptoms and Treatments in Transfeminine Individuals: A Qualitative Exploration of Patients' Needs. Sex Med 2022;10:100566.

Electrical modulation of transplanted stem cells improves functional recovery in a rodent model of stroke.

Stroke is a leading cause of long-term disability worldwide, intensifying the need for effective recovery therapies. Stem cells are a promising stroke therapeutic, but creating ideal conditions for treatment is essential. Here we developed a conductive polymer system for stem cell delivery and electrical modulation in animals. Using this system, electrical modulation of human stem cell transplants improve functional stroke recovery in rodents. Increased endogenous stem cell production corresponds with improved function. Transcriptome analysis identified stanniocalcin 2 (STC2) as one of the genes most significantly upregulated by electrical stimulation. Lentiviral upregulation and downregulation of STC2 in the transplanted stem cells demonstrate that this glycoprotein is an essential mediator in the functional improvements seen with electrical modulation. Moreover, intraventricular administration of recombinant STC2 post-stroke confers functional benefits. In summation, our conductive polymer system enables electrical modulation of stem cells as a potential method to improve recovery and identify important therapeutic targets.

Factors Associated With Good Visual Acuity Outcomes After Retinectomy in Eyes With Proliferative Vitreoretinopathy.

PURPOSE: To investigate factors associated with good visual acuity (VA) following repair of rhegmatogenous retinal detachments (RD) with proliferative vitreoretinopathy (PVR) undergoing retinectomy. DESIGN: Interventional, retrospective, case-control study. METHODS: This single-institution study evaluated patients who underwent retinectomy during repair of RD with PVR from January 1, 2015 to December 31, 2019. A good VA cohort was identified based on a final VA ≥20/70. A 2:1 age-matched and gender-matched poor VA cohort with VA <20/70 was subsequently identified. Metrics compared between the two cohorts included time from primary and recurrent RD diagnosis to surgery, lens status, initial RD size, macula involvement, PVR grade, and size of retinectomy. RESULTS: A total of 5355 eyes were diagnosed with primary RD during the study period, of which 345 had PVR and underwent retinectomy. The good VA cohort included 62 eyes with a mean final logMAR VA of 0.32 [Snellen 20/42], while the poor VA cohort included 119 eyes with a mean final logMAR VA of 1.54 [Snellen 20/693; P < .0001]. On multivariate analysis, smaller initial RD size (P = .0090), fewer surgeries (P = .0002), shorter time between recurrent RD diagnosis and subsequent surgeries (P = .0006), better preoperative VA (P = .0276), and pseudophakia at final visit (P = .0049) remained significant predictors of good vision. CONCLUSION: Eyes undergoing retinectomy during repair of RD with PVR can achieve good VA outcomes. The primary modifiable factor associated with better VA was shorter delay between redetachment diagnosis and surgery, particularly in the absence of silicone oil tamponade.

Bioengineering lungs - current status and future prospects.

INTRODUCTION: Once pulmonary disease progresses to end-stage pulmonary disease, treatment options are very limited. An important advance in the field is the development of a bioartificial lung derived from a generic matrix scaffold populated with patients' own cells. Significant progress has already been made in the engineering of bioartificial lungs. AREAS COVERED: This review explains how previous and current research contributes to the goal of creating a successful bioartificial lung, and the barriers faced in doing so. We will also highlight some of the design considerations being explored to optimize bioartificial lungs and considerations for clinical translation. EXPERT OPINION: While current bioartificial lungs are able to provide short-term gas exchange in large-animal studies, much work is still required to combine the disciplines of cell biology, materials science, and tissue engineering to create such clinically useful and functioning artificial lungs.

Perspectives and Experiences of Transgender and Non-binary Individuals on Seeking Urological Care.

OBJECTIVE: To describe perspectives and experiences related to urology care-seeking of transgender and non-binary (TGNB) individuals assigned male at birth. MATERIALS AND METHODS: This HIPAA-compliant study was IRB approved and followed Consolidated Criteria for Reporting Qualitative Studies (COREQ) guidelines. Through semistructured interviews, perspectives, and experiences of individuals related to urology care-seeking were explored. Open-ended questions were designed to elicit a range of responses rather than quantifiable data. Thematic codes were developed and explicitly defined. Codes pertaining to patient experiences were assessed and described. RESULTS: Twenty-five TGNB individuals assigned male at birth were interviewed. Participants reported an array of factors that informed and inhibited care-seeking, factors that framed individual urologic care experiences, and their overall impression of the healthcare system's ability to effectively and respectfully serve the TGNB population. Specifically, participants reported that prior negative healthcare experiences dissuaded them from seeking care such as feeling discriminated against and having a lack of trust in providers. Additionally, participants reported feeling a need and responsibility to "educate" providers on both their medical needs and psychosocial experiences. Participants were also unclear how best to identify "trans-friendly" urologists who are culturally competent and have appropriate medical knowledge. CONCLUSION: TGNB individuals face significant barriers to care for unique healthcare needs. TGNB participants described care avoidance and reported experiences of healthcare discrimination. These data highlight the importance for urologists to understand the perspectives and historical experiences of these individuals who may seek urological care.

Modulating the Electrical and Mechanical Microenvironment to Guide Neuronal Stem Cell Differentiation.

The application of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine can be limited by the prolonged times required for functional human neuronal differentiation and traditional 2D culture techniques. Here, a conductive graphene scaffold (CGS) to modulate mechanical and electrical signals to promote human iPSC-derived neurons is presented. The soft CGS with cortex-like stiffness (≈3 kPa) and electrical stimulation (±800 mV/100 Hz for 1 h) incurs a fivefold improvement in the rate (14d) of generating iPSC-derived neurons over some traditional protocols, with an increase in mature cellular markers and electrophysiological characteristics. Consistent with other culture conditions, it is found that the pro-neurogenic effects of mechanical and electrical stimuli rely on RhoA/ROCK signaling and de novo ciliary neurotrophic factor (CNTF) production respectively. Thus, the CGS system creates a combined physical and continuously modifiable, electrical niche to efficiently and quickly generate iPSC-derived neurons.

Long-term core outcomes of patients with simple gastroschisis.

PURPOSE: To report the long-term core outcome set of patients with simple gastroschisis. METHODS: This was a retrospective chart review of all patients with simple gastroschisis managed at our hospital between August 2008 and July 2016. We collected all data included in the core outcome set developed for the standardization of gastroschisis outcomes reporting. We conducted a phone survey of the patients' parents using the PedsQL™ Pediatric Quality of Life Inventory, Cognitive Functioning Scale, and Gastrointestinal Symptoms Scale (GSS). Additionally, parents reported their subjective evaluation of the patients' cosmetic result and overall quality of life. RESULTS: There were 124 patients included in the study. The majority (76.5%) was born prematurely at a median gestational age of 36 (range 27.6-38) weeks. At neonatal discharge (median 36 days [18-150] days) most patients were below the 10th percentile for height (81.4%) and weight (87%). Their growth, however, normalized during early childhood. Seven patients (5.6%) required at some point an operation for acute abdominal complications. One-third of patients required long-term treatment for constipation and one-third of patients required long-term treatment for gastroesophageal reflux disease (GERD). Thirty-five parents participated in the phone survey. Mean parent-reported quality of life score was better than healthy controls (87.5% vs. 82.3%, p = 0.049). Cognitive functions and gastrointestinal symptoms scores were similar to healthy controls. All patients are alive. CONCLUSION: Growth restriction in patients with simple gastroschisis is common at birth and during the neonatal period, but it improves during the first three years of life. Abdominal operations are rarely needed in patients with simple gastroschisis. GERD and constipation, on the other hand, are common and often require long-term medical management. The overall parent-reported quality of life of patients with simple gastroschisis is excellent. LEVEL OF EVIDENCE: Level II.

In utero adenine base editing corrects multi-organ pathology in a lethal lysosomal storage disease.

In utero base editing has the potential to correct disease-causing mutations before the onset of pathology. Mucopolysaccharidosis type I (MPS-IH, Hurler syndrome) is a lysosomal storage disease (LSD) affecting multiple organs, often leading to early postnatal cardiopulmonary demise. We assessed in utero adeno-associated virus serotype 9 (AAV9) delivery of an adenine base editor (ABE) targeting the Idua G→A (W392X) mutation in the MPS-IH mouse, corresponding to the common IDUA G→A (W402X) mutation in MPS-IH patients. Here we show efficient long-term W392X correction in hepatocytes and cardiomyocytes and low-level editing in the brain. In utero editing was associated with improved survival and amelioration of metabolic, musculoskeletal, and cardiac disease. This proof-of-concept study demonstrates the possibility of efficiently performing therapeutic base editing in multiple organs before birth via a clinically relevant delivery mechanism, highlighting the potential of this approach for MPS-IH and other genetic diseases.

Single-Cell Encapsulation via Click-Chemistry Alters Production of Paracrine Factors from Neural Progenitor Cells.

Extracellular matrix (ECM) properties affect multiple cellular processes such as cell survival, proliferation, and protein synthesis. Thus, a polymeric-cell delivery system with the ability to manipulate the extracellular environment can act as a fundamental regulator of cell function. Given the promise of stem cell therapeutics, a method to uniformly enhance stem cell function, in particular trophic factor release, can prove transformative in improving efficacy and increasing feasibility by reducing the total number of cells required. Herein, a click-chemistry powered 3D, single-cell encapsulation method aimed at synthesizing a polymeric coating with the optimal thickness around neural progenitor cells is introduced. Polymer encapsulation of neural stem cells significantly increases the release of neurotrophic factors such as VEGF and CNTF. Cell encapsulation with a soft extracellular polymer upregulates the ADCY8-cAMP pathway, suggesting a mechanism for the increase in paracrine factors. Hence, the described single-cell encapsulation technique can emerge as a translatable, nonviral cell modulation method and has the potential to improve stem cells' therapeutic effect.

Development of Neuroregenerative Gene Therapy to Reverse Glial Scar Tissue Back to Neuron-Enriched Tissue.

Injuries in the central nervous system (CNS) often causes neuronal loss and glial scar formation. We have recently demonstrated NeuroD1-mediated direct conversion of reactive glial cells into functional neurons in adult mouse brains. Here, we further investigate whether such direct glia-to-neuron conversion technology can reverse glial scar back to neural tissue in a severe stab injury model of the mouse cortex. Using an adeno-associated virus (AAV)-based gene therapy approach, we ectopically expressed a single neural transcription factor NeuroD1 in reactive astrocytes in the injured areas. We discovered that the reactive astrocytes were efficiently converted into neurons both before and after glial scar formation, and the remaining astrocytes proliferated to repopulate themselves. The astrocyte-converted neurons were highly functional, capable of firing action potentials and establishing synaptic connections with other neurons. Unexpectedly, the expression of NeuroD1 in reactive astrocytes resulted in a significant reduction of toxic A1 astrocytes, together with a significant decrease of reactive microglia and neuroinflammation. Furthermore, accompanying the regeneration of new neurons and repopulation of new astrocytes, new blood vessels emerged and blood-brain-barrier (BBB) was restored. These results demonstrate an innovative neuroregenerative gene therapy that can directly reverse glial scar back to neural tissue, opening a new avenue for brain repair after injury.