Nanomaterials in the treatment and diagnosis of rheumatoid arthritis: Advanced approaches.

Rheumatoid arthritis (RA), a chronic inflammatory condition that affects persons between the ages of 20 and 40, causes synovium inflammation, cartilage loss, and joint discomfort as some of its symptoms. Diagnostic techniques for RA have traditionally been split into two main categories: imaging and serological tests. However, significant issues are associated with both of these methods. Imaging methods are costly and only helpful in people with obvious symptoms, while serological assays are time-consuming and require specialist knowledge. The drawbacks of these traditional techniques have led to the development of novel diagnostic approaches. The unique properties of nanomaterials make them well-suited as biosensors. Their compact dimensions are frequently cited for their outstanding performance, and their positive impact on the signal-to-noise ratio accounts for their capacity to detect biomarkers at low detection limits, with excellent repeatability and a robust dynamic range. In this review, we discuss the use of nanomaterials in RA theranostics. Scientists have recently synthesized, characterized, and modified nanomaterials and biomarkers commonly used to enhance RA diagnosis and therapy capabilities. We hope to provide scientists with the promising potential that nanomaterials hold for future theranostics and offer suggestions on further improving nanomaterials as biosensors, particularly for detecting autoimmune disorders.

Outcomes and patient tolerability of radical inguinal orchiectomy under deep intravenous sedation.

INTRODUCTION: Radical inguinal orchiectomy (RO ) is indicated for the management of testicular tumors and is universally performed under general anesthetic in the hospital. The need to perform radical orchiectomy in an expeditated fashion can result in logistical difficulties, often necessitating this procedure to happen after-hours on a semi-emergent basis. These logistical difficulties have been exacerbated by the backlog of cases from the COVID-19 pandemic. A similar procedure - inguinal hernia repair - is regularly performed under local anesthesia with minimal complications. Thus, we sought to evaluate the feasibility of performing radical orchiectomy under deep intravenous sedation in an ambulatory surgery center. METHODS: We evaluated our single-surgeon (PP), prospective database of patients who underwent RO between September 2022 and February 2023 at the Men's Health Clinic Manitoba. Patients were given a combination of deep sedation, ilioinguinal nerve block, and local anesthetic. Tolerability was assessed both perioperatively and at 4-6 weeks' followup. We reviewed the medical records for any postoperative complications. RESULTS: Eight patients underwent RO under deep sedation during the study period. All patients tolerated the surgery well and were discharged shortly after surgery. Average operative time was 40 minutes and length of stay was 46 minutes. There were no perioperative complications. CONCLUSIONS: Our pilot study demonstrates that RO can be safely and effectively performed under deep sedation. This anesthetic combination can be used both in-hospital and out-of-hospital settings, thereby resulting in faster recovery, shorter length of stay, and favorable patient and provider satisfaction.

Enhancing CRISPR/Cas systems with nanotechnology.

CRISPR/Cas systems have revolutionized biology and medicine, and have led to new paradigms in disease diagnostics and therapeutics. However, these complexes suffer from key limitations regarding barriers to cellular entry, stability in biological environments, and off-target effects. Integrating nanotechnology with CRISPR/Cas systems has emerged as a promising strategy to overcome these challenges and has further unlocked structures that accumulate preferentially in tissues of interest, have tunable pharmacological properties, and are activated in response to desired stimuli. Nanomaterials can also enhance CRISPR/Cas-mediated detection platforms by enabling faster, more sensitive, and convenient readouts. We highlight recent advances in this rapidly growing field. We also outline areas that need further development to fully realize the potential of CRISPR technologies.

Endothelial Cyp26b1 restrains murine heart valve growth during development.

Endothelial cells (ECs) are critical to proper heart valve development, directly contributing to the mesenchyme of the cardiac cushions, which progressively transform into mature valves. To date, investigators have lacked sufficient markers of valve ECs to evaluate their contributions during valve morphogenesis fully. As a result, it has been unclear whether the well-characterized regional differentiation of valves correlates with any endothelial domains in the heart. Furthermore, it has been difficult to ascertain whether endothelial heterogeneity in the heart influences underlying mesenchymal zones in an angiocrine manner. To identify regionally expressed EC genes in the heart valves, we screened publicly available databases and assembled a toolkit of endothelial-enriched genes. We identified Cyp26b1 as one of many endothelial enriched genes found to be expressed in the endocardium of the developing cushions and valves. Here, we show that Cyp26b1 is required for normal heart valve development. Genetic ablation of Cyp26b1 in mouse embryos leads to abnormally thickened aortic valve leaflets, which is due in part to increased endothelial and mesenchymal cell proliferation in the remodeling valves. In addition, Cyp26b1 mutant hearts display ventricular septal defects (VSDs) in a portion of null embryos. We show that loss of Cyp26b1 results in upregulation of retinoic acid (RA) target genes, supporting the observation that Cyp26b1 has RA-dependent roles. Together, this work identifies a novel role for Cyp26b1 in heart valve morphogenesis and points to a role of RA in this process. Understanding the spatiotemporal expression dynamics of cardiac EC genes will pave the way for investigation of both normal and dysfunctional heart valve development.

Extruded poly (glycerol sebacate) and polyglycolic acid vascular graft forms a neoartery.

In the ongoing search for the optimal biomaterial for tissue engineered vascular grafts (TEVGs), poly (glycerol sebacate) (PGS) has emerged as a new potential candidate. We have utilized a novel method to create unique, pore-free, extruded PGS grafts with and without a supportive exterior layer of polyglycolic acid (PGA). The 1 mm diameter by 5 mm length TEVGs were implanted in a rat model of infrarenal abdominal aorta interposition grafting. Three months after implantation, TEVGs comprised of extruded PGS with an external PGA braid demonstrated a patency rate of 9/10 (90%) with no signs of dilatation, dehiscence, or rupture. The PGS/PGA graft was remodeled into a neoartery with complete endothelialization of the neoartery lumen and formation of smooth muscle actinin multilayers as demonstrated via immunohistochemistry. Formation and maturation of extracellular matrix material were also observed, with amounts of elastin and collagen comparable to native rat aorta. No significant host inflammatory response was observed. These findings suggest the combination of an extruded PGS tube with an external reinforcing PGA braid is a promising material for small diameter TEVGs.

New Technologies for Treatment of Benign Prostatic Hyperplasia.

BPH is a common disease in aging men which impacts quality of life. With advancing age expectation coupled with the rising demand for BPH therapy, new technologies have been developed that target rapid recovery and symptom relief, low complication rates, and the ability to perform the procedure in an outpatient setting with local anesthesia. MIST technologies have fostered BPH medical care with ejaculation preservation. Techniques and outcomes for BPH technologies including Aquablation, Rezum, UroLift, iTind, Optilume BPH, XFLO, Zenflow, and Butterfly are reviewed and evaluated. Given the novelty of these technologies, long-term data are required to assess safety and efficacy.

Office-Based Procedures for BPH.

PURPOSE OF REVIEW: Benign prostatic hyperplasia (BPH) is a common disease in men. A rapidly rising demand for safe and effective therapy for BPH has generated novel minimally invasive surgical treatments (MISTs). With multiple procedural options in the urology armamentarium for BPH therapy, we describe the current therapies and outcomes for office-based procedures for BPH including quality of life, voiding symptoms, and sexual function. RECENT FINDINGS: There are three FDA-approved MISTs (Rezum, Urolift, and iTind) and three emerging MISTs for BPH. Preliminary data suggest improvement in voiding symptoms and quality of life while minimizing unwanted sexual side effects. Long term data is required on the durability and safety of MISTs for BPH. MISTs mark a paradigm shift in BPH management. Sandwiched between conservative medical management and conventional transurethral surgery, these novel technologies promise to combine efficacy approaching that of TURP while sparing the negative side effects. We envision a future where BPH can be diagnosed and treated in an office-based setting with a standard cystoscope in one procedure.

Short term outcomes and unintended benefits of establishing a HPB program at a university-affiliated community hospital.

BACKGROUND: In hepato-pancreato-biliary (HPB) surgery higher volumes are associated with improved outcomes; however, there are limitations to regionalization. Here we report our experience establishing multidisciplinary HPB program at a university-affiliated community hospital. METHODS: This is a retrospective review of patients who underwent HPB surgery between 2015 and 2017. Chief residents' HPB case logs were collected. RESULTS: 61 pancreatic resections and 62 hepatic resections were performed. The morbidity, 30-day mortality and median length of stay following pancreatic resections were 27%, 1.5%, and 8 days, respectively. The morbidity, 90-day mortality, and median length of stay following hepatic resections were 24%, 3%, and 7 days, respectively. The median pancreatic and liver case volumes for graduating chief residents increased from 7 to 8 to 16 and 16, respectively (p < 0.05), after the establishment of a HPB program. Participation in multidisciplinary care (p = 0.08) and clinical trial enrollment increased. CONCLUSION: Our study demonstrates short-term outcomes comparable to high volume centers. Development of a HPB program had a positive impact on resident operative experience, increased multidisciplinary care and increased clinical trial enrollment.

The role of academic achievements and psychometric measures in the ranking process.

INTRODUCTION: Ranking candidates for residency positions is challenging. We hypothesize that applicant academic achievements and performance during the interview are equally important in the ranking process. METHODS: This is a retrospective study. Of 53 candidates interviewed during 2016-2017 cycle, 44 (83%) were ranked for 3 PGY1 positions. Each candidate was interviewed and scored in each of the following: USMLE Step 1 score, USMLE Step 2 score, research (RS), letters of recommendation (LOR), personal statement (PS), the way the candidate represented him/herself (RP), interest in the area (IN), answers to standardized questions (SQ), and degree of connection between the candidate and the interviewer (CN). RESULTS: Correlation and multiple regression analyses indicated an inverse relationship between ranking the candidates and USMLE2 (r = -0.14, p = -0.364), LOR (r = -0.513, p < 0.001), PS (r = -0.414, p = 0.006), RP (r = -0.485, p = 0.001), CN (r = -0.605, p < 0.001), IN (r = -0.349, p = 0.022), and SQ (r = -0.480, p = 0.001), USMLE1 (r = -0.036, p = 0.838) and RS (r = -0.008, p = 0.96). After controlling for the other variables, only CN reached statistical significance (p = 0.033). CONCLUSION: Candidate non-cognitive measures during the interview weigh higher than academic performance in the ranking process.

Formation of Neoarteries with Optimal Remodeling Using Rapidly Degrading Textile Vascular Grafts.

IMPACT STATEMENT: We utilized innovative textile technology to create tissue-engineered vascular grafts (TEVGs) comprised exclusively of rapidly degrading material poly(glycolic acid). Our new technology led to robust neotissue formation in the TEVGs, especially extracellular matrix formation, such as elastin. In addition, the rapid degradation of the polymer significantly reduced complications, such as stenosis or calcification, as seen with the use of slow degrading polymers in the majority of previous studies for aortic small diameter TEVGs.

Coagulation profile following liver resection: Does liver cirrhosis affect thromboelastography?

BACKGROUND: Thromboelastography has called into question the coagulopathy seen following partial hepatectomy. However the coagulation profile in cirrhotic livers has not been studied. Our objective was to determine the coagulation profile following partial hepatectomy in normal and cirrhotic livers. METHODS: Patients undergoing liver resection were prospectively enrolled in the study. The prothrombin time and international normalized ratio, as well as the thromboelastogram, were obtained preoperatively, post-operatively, and on post-operative days 1, 3, and 5. RESULTS: 22 noncirrhotic and 11 cirrhotic patients undergoing liver resection were enrolled. Postoperatively the thromboelastogram demonstrated a hypercoagulable profile in 64%, 33%, 39% and 36% of patients on post-operative days 0, 1, 3 and 5 respectively. There was no difference between patients with cirrhosis and those without underlying liver disease. CONCLUSION: Patients appear to have a similar coagulation profile after liver resection regardless of underlying cirrhosis with many having a hypercoagulable profile.

Kemp Elimination in Cationic Micelles: Designed Enzyme-Like Rates Achieved through the Addition of Long-Chain Bases.

The Kemp elimination is prototypical reaction used to study proton abstraction from carbon. Several hydrophobic systems are known to accelerate this reaction, including two classes of computationally-designed enzymes. However, it is unclear whether these computationally-designed enzymes establish specific interactions with their substrates, as natural enzymes do, or if most of the rate acceleration is due to the hydrophobicity of the substrate. We used a simple system composed of cationic micelles and a long chain base (such as lauryl phosphate or lauric acid) to measure the rate acceleration for the Kemp elimination. Remarkably, we found that this simple system can accelerate the reaction by 4 orders of magnitude, approaching the rates of more complex designed systems. Use of different substrates suggests that the reaction takes place at the interface between the micellar head and water (the Stern layer) with the long-chain base embedded in the micelle and the substrate in the aqueous solution. Thus, we suggest that significant rate accelerations can be achieved regardless of the precise positioning of substrates. Because natural enzymes use specific interactions to position their substrates, we propose that acceleration of the Kemp elimination is not a suitable benchmark for the success of the design process, and we suggest that more complex reactions should be used.

Data describing the swelling behavior and cytocompatibility of biodegradable polyelectrolyte hydrogels incorporating poly(L-lysine) for applications in cartilage tissue engineering.

This data article presents data associated with the research article entitled "Evaluation of cell-laden polyelectrolyte hydrogels incorporating poly(L-lysine) for applications in cartilage tissue engineering" (Lam et al., 2016) [1]. Synthetic hydrogel composites fabricated using oligo(poly(ethylene glycol) fumarate) (OPF) macromers were utilized as vehicles for the incorporation of poly(L-lysine) (PLL) as well as the encapsulation of mesenchymal stem cells (MSCs). PLL-laden and PLL-free hydrogels were fabricated to characterize the main and interaction effects of OPF molecular weight, PLL molecular weight, and PLL loading density on the swelling and degradation of synthetic OPF hydrogels. Cells were then encapsulated within such hydrogels for in vitro culture and examined for viability, biochemical activity, and chondrogenic gene expression. These data, which are supplementary to the associated research article (Lam et al., 2016) [1], are presented here.

Evaluation of Gelatin Microparticles as Adherent-Substrates for Mesenchymal Stem Cells in a Hydrogel Composite.

Due to the lack of cell-adhesive moieties in traditional synthetic hydrogels, the present work investigated the use of degradable gelatin microparticles (GMPs) as temporary adherent substrates for anchorage-dependent mesenchymal stem cells (MSCs). MSCs were seeded onto GMPs of varying crosslinking densities and sizes to investigate their role on influencing MSC differentiation and aggregation. The MSC-seeded GMPs were then encapsulated in poly(ethylene glycol)-based hydrogels and cultured in serum-free, growth factor-free osteochondral medium. Non-seeded MSCs co-encapsulated with GMPs in the hydrogels were used as a control for comparison. Over the course of 35 days, MSCs seeded on GMPs exhibited more cell-cell contacts, greater chondrogenic potential, and a down-regulation of osteogenic markers compared to the controls. Although the factors of GMP crosslinking and size had nominal influence on MSC differentiation and aggregation, GMPs demonstrate potential as an adherent-substrate for improving cell delivery from hydrogel scaffolds by facilitating cell-cell contacts and improving MSC differentiation.

Alpha desynchronization and fronto-parietal connectivity during spatial working memory encoding deficits in ADHD: A simultaneous EEG-fMRI study.

The underlying mechanisms of alpha band (8-12 Hz) neural oscillations are of importance to the functioning of attention control systems as well as to neuropsychiatric conditions that are characterized by deficits of that system, such as attention deficit hyperactivity disorder (ADHD). The objectives of the present study were to test if visual encoding-related alpha event-related desynchronization (ERD) correlates with fronto-parieto-occipital connectivity, and whether this is disrupted in ADHD during spatial working memory (SWM) performance. We acquired EEG concurrently with fMRI in thirty boys (12-16 yrs. old, 15 with ADHD), during SWM encoding. Psychophysiological connectivity analyses indicated that alpha ERD during SWM encoding was associated with both occipital activation and fronto-parieto-occipital functional connectivity, a finding that expands on prior associations between alpha ERD and occipital activation. This finding provides novel support for the interpretation of alpha ERD (and the associated changes in occipital activation) as a phenomenon that involves, and perhaps arises as a result of, top-down network interactions. Alpha ERD was associated less strongly with occipital activity, but associated more strongly with fronto-parieto-occipital connectivity in ADHD, consistent with a compensatory attentional response. Additionally, we illustrate that degradation of EEG data quality by MRI-amplified motion artifacts is robust to existing cleaning algorithms and is significantly correlated with hyperactivity symptoms and the ADHD Combined Type diagnosis. We conclude that persistent motion-related MR artifacts in EEG data can increase variance and introduce bias in interpretation of group differences in populations characterized by hypermobility--a clear limitation of current-state EEG-fMRI methodology.

Evaluation of cell-laden polyelectrolyte hydrogels incorporating poly(L-Lysine) for applications in cartilage tissue engineering.

To address the lack of reliable long-term solutions for cartilage injuries, strategies in tissue engineering are beginning to leverage developmental processes to spur tissue regeneration. This study focuses on the use of poly(L-lysine) (PLL), previously shown to up-regulate mesenchymal condensation during developmental skeletogenesis in vitro, as an early chondrogenic stimulant of mesenchymal stem cells (MSCs). We characterized the effect of PLL incorporation on the swelling and degradation of oligo(poly(ethylene) glycol) fumarate) (OPF)-based hydrogels as functions of PLL molecular weight and dosage. Furthermore, we investigated the effect of PLL incorporation on the chondrogenic gene expression of hydrogel-encapsulated MSCs. The incorporation of PLL resulted in early enhancements of type II collagen and aggrecan gene expression and type II/type I collagen expression ratios when compared to blank controls. The presentation of PLL to MSCs encapsulated in OPF hydrogels also enhanced N-cadherin gene expression under certain culture conditions, suggesting that PLL may induce the expression of condensation markers in synthetic hydrogel systems. In summary, PLL can function as an inductive factor that primes the cellular microenvironment for early chondrogenic gene expression but may require additional biochemical factors for the generation of fully functional chondrocytes.

Polymer-Based Local Antibiotic Delivery for Prevention of Polymicrobial Infection in Contaminated Mandibular Implants.

Antibiotic-releasing porous poly(methyl methacrylate) (PMMA) space maintainers, comprising PMMA with an aqueous porogen and a poly(DL-lactic-co-glycolic acid) (PLGA) antibiotic carrier, have been developed to facilitate local delivery of antibiotics and tissue integration. In this study, clindamycin-loaded space maintainers were used to investigate the effects of antibiotic release kinetics and dose upon bacterial clearance and bone and soft tissue healing in a pathogen-contaminated rabbit mandibular defect. Three formulations were fabricated for either high dose burst release (7 days) or with PLGA microparticles for extended release (28 days) at high and low dose. Although inoculated bacteria were not recovered from any specimens, the burst release formulation showed less inflammation and fibrous capsule formation and more bone formation close to the implant than the low dose extended release formulation by histologic analysis. These results suggest that local antibiotic release kinetics and dose affect soft and hard tissue healing independent from its ability to clear bacteria.

Technical Report: Correlation Between the Repair of Cartilage and Subchondral Bone in an Osteochondral Defect Using Bilayered, Biodegradable Hydrogel Composites.

The present work investigated correlations between cartilage and subchondral bone repair, facilitated by a growth factor-delivering scaffold, in a rabbit osteochondral defect model. Histological scoring indices and microcomputed tomography morphological parameters were used to evaluate cartilage and bone repair, respectively, at 6 and 12 weeks. Correlation analysis revealed significant associations between specific cartilage indices and subchondral bone parameters that varied with location in the defect (cortical vs. trabecular region), time point (6 vs. 12 weeks), and experimental group (insulin-like growth factor-1 only, bone morphogenetic protein-2 only, or both growth factors). In particular, significant correlations consistently existed between cartilage surface regularity and bone quantity parameters. Overall, correlation analysis between cartilage and bone repair provided a fuller understanding of osteochondral repair and can help drive informed studies for future osteochondral regeneration strategies.

Autologously generated tissue-engineered bone flaps for reconstruction of large mandibular defects in an ovine model.

The reconstruction of large craniofacial defects remains a significant clinical challenge. The complex geometry of facial bone and the lack of suitable donor tissue often hinders successful repair. One strategy to address both of these difficulties is the development of an in vivo bioreactor, where a tissue flap of suitable geometry can be orthotopically grown within the same patient requiring reconstruction. Our group has previously designed such an approach using tissue chambers filled with morcellized bone autograft as a scaffold to autologously generate tissue with a predefined geometry. However, this approach still required donor tissue for filling the tissue chamber. With the recent advances in biodegradable synthetic bone graft materials, it may be possible to minimize this donor tissue by replacing it with synthetic ceramic particles. In addition, these flaps have not previously been transferred to a mandibular defect. In this study, we demonstrate the feasibility of transferring an autologously generated tissue-engineered vascularized bone flap to a mandibular defect in an ovine model, using either morcellized autograft or synthetic bone graft as scaffold material.