Efficacy of ADIPOR1 and ADIPOR2 peptide-agonist AdipoRon in preventing contracture in a rabbit model of arthrofibrosis.

AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with potential antifibrotic effects. Whether AdipoRon can mitigate joint stiffness in a rabbit model of arthrofibrosis is unknown. We examined the efficacy of intravenous (IV) AdipoRon at mitigating contracture in a rabbit model of knee arthrofibrosis. Fifty-six female New Zealand White rabbits were divided into three dosing groups: vehicle (dimethyl sulfoxide, DMSO), 2.5 mg/kg AdipoRon, and 5 mg/kg AdipoRon. AdipoRon, in DMSO, was administered IV preoperatively and for 5 days postoperatively (30 rabbits, Aim 1). AdipoRon was again dosed similarly after Kirschner wire (K-wire) removal at 8 weeks (26 rabbits; Aim 2). The primary outcome of joint passive extension angle (PEA,°) was measured at 8, 10, 12, 16, and 24 weeks following index surgery. At 24 weeks, rabbits were euthanized and limbs were harvested to measure posterior capsular stiffness (N cm/°). In Aim 1, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 16-week (p < 0.05). In Aim 2, the 5 mg/kg treated rabbits had a significant increase in PEA when compared to controls at 10-week (p < 0.05). In both aims, no significant differences were observed at later time points. Capsular stiffness was no different in any group. We are the first to report the efficacy of IV AdipoRon in a rabbit model of arthrofibrosis. We identified a significant dose-dependent decrease in joint PEA at early time points; however, no differences were observed between groups at later time points. Clinical Significance: The present investigation provided the first assessment of AdipoRon's efficacy in mitigating knee stiffness in the current gold standard rabbit model of arthrofibrosis. Results of this investigation provided further evidence as to the potential role of AdipoRon as a preventative for arthrofibrosis in large mammals.

AdipoRon reduces TGFß1-mediated collagen deposition in vitro and alleviates knee stiffness in vivo.

Arthrofibrosis, which causes joint motion restrictions, is a common complication following total knee arthroplasty (TKA). Key features associated with arthrofibrosis include myofibroblast activation, knee stiffness, and excessive scar tissue formation. We previously demonstrated that adiponectin levels are suppressed within the knee tissues of patients affected by arthrofibrosis and showed that AdipoRon, an adiponectin receptor agonist, exhibited anti-fibrotic properties in human mesenchymal stem cells. In this study, the therapeutic potential of AdipoRon was evaluated on TGFß1-mediated myofibroblast differentiation of primary human knee fibroblasts and in a mouse model of knee stiffness. Picrosirius red staining revealed that AdipoRon reduced TGFß1-induced collagen deposition in primary knee fibroblasts derived from patients undergoing primary TKA and revision TKA for arthrofibrosis. AdipoRon also reduced mRNA and protein levels of ACTA2, a key myofibroblast marker. RNA-seq analysis corroborated the anti-myofibrogenic effects of AdipoRon. In our knee stiffness mouse model, 6 weeks of knee immobilization, to induce a knee contracture, in conjunction with daily vehicle (DMSO) or AdipoRon (1, 5, and 25 mg/kg) via intraperitoneal injections were well tolerated based on animal behavior and weight measurements. Biomechanical testing demonstrated that passive extension angles (PEAs) of experimental knees were similar between vehicle and AdipoRon treatment groups in mice evaluated immediately following immobilization. Interestingly, relative to vehicle-treated mice, 5 mg/kg AdipoRon therapy improved the PEA of the experimental knees in mice that underwent 4 weeks of knee remobilization following the immobilization and therapy. Together, these studies revealed that AdipoRon may be an effective therapeutic modality for arthrofibrosis.

Meteorological drivers of resource adequacy failures in current and high renewable Western U.S. power systems.

Power system resource adequacy (RA), or its ability to continually balance energy supply and demand, underpins human and economic health. How meteorology affects RA and RA failures, particularly with increasing penetrations of renewables, is poorly understood. We characterize large-scale circulation patterns that drive RA failures in the Western U.S. at increasing wind and solar penetrations by integrating power system and synoptic meteorology methods. At up to 60% renewable penetration and across analyzed weather years, three high pressure patterns drive nearly all RA failures. The highest pressure anomaly is the dominant driver, accounting for 20-100% of risk hours and 43-100% of cumulative risk at 60% renewable penetration. The three high pressure patterns exhibit positive surface temperature anomalies, mixed surface solar radiation anomalies, and negative wind speed anomalies across our region, which collectively increase demand and decrease supply. Our characterized meteorological drivers align with meteorology during the California 2020 rolling blackouts, indicating continued vulnerability of power systems to these impactful weather patterns as renewables grow.

A Black feminist youth participatory action research photovoice exploration of Black girls and college women.

Utilizing a Black and Hip Hop feminist and Black girlhood studies theoretical lens, the purpose of this study is to explore how Black girls (14-17) and women (19-22), who are in a youth participatory action research (YPAR) mentoring program, BlackGirlsResearch (pseudonym) express their gendered racial identities and gendered racial experiences through their participation in a YPAR photovoice program. This study seeks to answer the following research question: (1) How do Black girls and college women conceptualize their gendered racial identities and gendered racial lived experiences in predominately white schools using a YPAR methodology and photovoice? Employing a qualitative thematic analysis to explore 36 photovoice narratives, results yielded 3 themes: (1) experiencing challenges at predominately white institutions (PWIs): false inclusivity, continued underrepresentation, and tokenism (2) identifying as "queens of culture": identity and empowerment through art, culture, and breaking conformity and (3) activism, inclusion, and accountability: solutions for PWIs. The results of this study indicate that Black girls and women can not only identify and critically discuss issues related to Black girls and women within PWIs, but through YPAR, they can push for positive youth development and community solutions related to those issues.

Molecular Mechanisms of the Anti-Inflammatory Effects of Epigallocatechin 3-Gallate (EGCG) in LPS-Activated BV-2 Microglia Cells.

Chronic neuroinflammation is associated with many neurodegenerative diseases, such as Alzheimer's. Microglia are the brain's primary immune cells, and when activated, they release various proinflammatory cytokines. Several natural compounds with anti-inflammatory and antioxidant properties, such as epigallocatechin 3-gallate (EGCG), may provide a promising strategy for inflammation-related neurodegenerative diseases involving activated microglia cells. The objective of the current study was to examine the molecular targets underlying the anti-inflammatory effects of EGCG in activated microglia cells. BV-2 microglia cells were grown, stimulated, and treated with EGCG. Cytotoxicity and nitric oxide (NO) production were evaluated. Immunoassay, PCR array, and WES™ Technology were utilized to evaluate inflammatory, neuroprotective modulators as well as signaling pathways involved in the mechanistic action of neuroinflammation. Our findings showed that EGCG significantly inhibited proinflammatory mediator NO production in LPS-stimulated BV-2 microglia cells. In addition, ELISA analysis revealed that EGCG significantly decreases the release of proinflammatory cytokine IL-6 while it increases the release of TNF-α. PCR array analysis showed that EGCG downregulated MIF, CCL-2, and CSF2. It also upregulated IL-3, IL-11, and TNFS10. Furthermore, the analysis of inflammatory signaling pathways showed that EGCG significantly downregulated mRNA expression of mTOR, NF-κB2, STAT1, Akt3, CCL5, and SMAD3 while significantly upregulating the expression of mRNA of Ins2, Pld2, A20/TNFAIP3, and GAB1. Additionally, EGCG reduced the relative protein expression of NF-κB2, mTOR, and Akt3. These findings suggest that EGCG may be used for its anti-inflammatory effects to prevent neurodegenerative diseases.

Nonsteroidal Anti-Inflammatory Drugs and Oral Corticosteroids Mitigated the Risk of Arthrofibrosis After Total Knee Arthroplasty.

BACKGROUND: The role of medications to prevent arthrofibrosis following total knee arthroplasty (TKA) remains unclear. We investigated the effect of common oral medications with reported antifibrotic properties on preventing arthrofibrosis and manipulation under anesthesia (MUA) following primary TKA. METHODS: Using our total joint registry, 9,771 patients (12,735 knees) who underwent TKA with cemented, posterior-stabilized, and metal-backed tibial components from 2000 to 2016 were identified. Arthrofibrosis, defined as range of motion (ROM) ≤90° for ≥12 weeks postoperatively or as ROM ≤90° requiring MUA, was diagnosed in 454 knees (4%) and matched 1:2 to controls. Mean age was 62 years (range, 19 to 87) and 57% were women. The majority of operative diagnoses were osteoarthritis. Perioperative use of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins), angiotensin converting enzyme inhibitors (ACE inhibitors), angiotensin II receptor blockers (ARBs), oral corticosteroids, antihistamines, and nonsteroidal anti-inflammatory drugs (NSAIDs) were manually confirmed. Medication effect in preventing arthrofibrosis and MUA was assessed using adjusted multivariable analyses. Mean follow-up was 8 years (range, 2 to 20). RESULTS: Reduced risk of arthrofibrosis was associated with perioperative NSAID use (odds ratio (OR) 0.67, P = .045). A similar trend was observed with perioperative corticosteroids (OR 0.52, P = .098). Corticosteroids were associated with reduced risk of MUA (OR 0.26, P = .036), and NSAIDs trended towards reducing MUA (OR 0.69, P = .11). CONCLUSION: This investigation determined that perioperative NSAID use was associated with reduced risk of arthrofibrosis and trended towards reduced risk of subsequent MUA. Similarly, oral corticosteroids were associated with reduced risk of MUA and trended towards reduced risk of arthrofibrosis.

The Safety of Adiponectin Receptor Agonist AdipoRon in a Rabbit Model of Arthrofibrosis.

AdipoRon is an adiponectin receptor 1, 2 (ADIPOR1 and ADIPOR2) agonist with numerous reported physiological benefits in murine models of human disease, including a proposed reduction in fibrosis. However, AdipoRon has never been investigated in rabbits, which provide a robust model for orthopedic conditions. We examined the safety of intravenous (IV) AdipoRon in New Zealand White (NZW) female rabbits surgically stressed by a procedure that mimics human arthrofibrosis. Fifteen female NZW rabbits were prospectively studied using increasing AdipoRon doses based on established literature. AdipoRon was dissolved in dimethyl sulfoxide (DMSO), diluted in normal saline, and administered IV preoperatively and for 5 subsequent days postoperatively. The primary outcome was overall toxicity to rabbits, whereas secondary outcomes were change in rabbit weights and hemodynamics and defining acid-base characteristics of the drug formulation. Two rabbits expired during preoperative drug administration at 25 mg/kg. Remaining rabbits received preoperative doses of DMSO (vehicle), 2.5, 5, or 10 mg/kg of AdipoRon without complications. On postoperative day 1, one rabbit sustained a tonic-clonic seizure after their second dose of 10 mg/kg AdipoRon. The remaining 12 rabbits (4 in each group) received six serial doses of vehicle, 2.5, or 5 mg/kg of AdipoRon without adverse effects. All formulations of AdipoRon were within safe physiological pH ranges (4-5). We are the first to report the use of IV AdipoRon in a surgically stressed rabbit model of orthopedic disease. AdipoRon doses of 5 mg/kg or less appear to be well-tolerated in female NZW rabbits. Impact statement We provided the first in vivo toxicity assessment and dose optimization of a new antifibrotic experimental medication, AdipoRon, in a surgically stressed rabbit model of knee arthrofibrosis.

Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives for Neuroprotection, Aging, and Neuroinflammation for the Modern Age.

Alzheimer's and Parkinson's diseases are the two most common forms of neurodegenerative diseases. The exact etiology of these disorders is not well known; however, environmental, molecular, and genetic influences play a major role in the pathogenesis of these diseases. Using Alzheimer's disease (AD) as the archetype, the pathological findings include the aggregation of Amyloid Beta (Aß) peptides, mitochondrial dysfunction, synaptic degradation caused by inflammation, elevated reactive oxygen species (ROS), and cerebrovascular dysregulation. This review highlights the neuroinflammatory and neuroprotective role of epigallocatechin-3-gallate (EGCG): the medicinal component of green tea, a known nutraceutical that has shown promise in modulating AD progression due to its antioxidant, anti-inflammatory, and anti-aging abilities. This report also re-examines the current literature and provides innovative approaches for EGCG to be used as a preventive measure to alleviate AD and other neurodegenerative disorders.

A Sociobehavioral Model of Racism against the Black Community and Avenues for Anti-Racism Research.

Sociological researchers have made immense strides in understanding systemic racism, privilege, and bias against Black people. Relational frame theory provides a contemporary account of human language and cognition that intersects within complex external contingency systems that may provide a provisionally adequate model of racial bias and racism. We propose a reticulated model that includes nested relational frames and external contingency systems that operate at the level of the individual (implicit), communities (white privilege), and system policies (systemic racism). This approach is organized from within the framework of critical race theory as an area of sociological scholarship that captures racial disadvantages at multiple levels of organization. We extend this model by describing avenues for future research to inform anti-racism strategies to dismantle this complex and pervasive sociobehavioral phenomenon. At all levels, police violence against the Black community is provided as a case example of negative social impact of racism in our society.

Complete Genome Sequences of 18 Paenibacillus larvae Phages from the Western United States.

We present here the complete genomes of 18 phages that infect Paenibacillus larvae, the causative agent of American foulbrood in honeybees. The phages were isolated between 2014 and 2016 as part of an undergraduate phage discovery course at Brigham Young University. The phages were isolated primarily from bee debris and lysogens.

Complete Genome Sequences of Paenibacillus larvae Phages BN12, Dragolir, Kiel007, Leyra, Likha, Pagassa, PBL1c, and Tadhana.

We present here the complete genomes of eight phages that infect Paenibacillus larvae, the causative agent of American foulbrood in honeybees. Phage PBL1c was originally isolated in 1984 from a P. larvae lysogen, while the remaining phages were isolated in 2014 from bee debris, honeycomb, and lysogens from three states in the USA.

Bacteriophages as an alternative to conventional antibiotic use for the prevention or treatment of Paenibacillus larvae in honeybee hives.

American Foulbrood (AFB) is an infectious disease caused by the bacteria, Paenibacillus larvae. P. larvae phages were isolated and tested to determine each phages' host range amongst 59 field isolate strains of P. larvae. Three phages were selected to create a phage cocktail for the treatment of AFB infections according to the combined phages' ability to lyse all tested strains of bacteria. Studies were performed to demonstrate the safety and efficacy of the phage cocktail treatment as a replacement for traditional antibiotics for the prevention of AFB and the treatment of active infections. Safety verification studies confirmed that the phage cocktail did not adversely affect the rate of bee death even when administered as an overdose. In a comparative study of healthy hives, traditional prophylactic antibiotic treatment experienced a 38±0.7% decrease in overall hive health, which was statistically lower than hive health observed in control hives. Hives treated with phage cocktail decreased 19±0.8%, which was not statistically different than control hives, which decreased by 10±1.0%. In a study of beehives at-risk for a natural infection, 100±0.5% of phage-treated hives were protected from AFB infection, while 80±0.5% of untreated controls became infected. AFB infected hives began with an average Hitchcock score of 2.25 out of 4 and 100±0.5% of the hives recovered completely within two weeks of treatment with phage cocktail. While the n numbers for the latter two studies are small, the results for both the phage protection rate and the phage cure rate were statistically significant (α=0.05). These studies demonstrate the powerful potential of using a phage cocktail against AFB and establish phage therapy as a feasible treatment.

Impact of Social Support and Pain Coping Abilityon Length of Stay and Discharge Disposition following Hip and Knee Arthroplasty A Prospective Study.

INTRODUCTION: While there are many factors known to predict the outcomes of hip and knee arthroplasty procedures, there is a growing interest in predictors that take into consideration the social and psychological preparedness of patients prior to surgery. This study's aim was to determine whether patients' preoperative social support and pain catastrophizing characteristics are independently associated with the outcomes of postoperative length of stay or discharge disposition following primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). METHODS: Data on a prospective sample of 189 THA and TKA adult patients using the pain catastrophizing scale and the medical outcomes study social support expectation score were analyzed. Demographic characteristics, such as age, gender, and race (Caucasian versus non-Caucasian), which served as covariates, were also collected. Bivariate associations between our outcome variables and covariates using Pearson's and Spearman's rank correlation coefficients and Mann Whitney U test for continuous variables (age, MOS-SSS) and Chi-squared tests for categorical variables (gender, race, ethnicity, procedure, catastrophizing) were employed. Statistical significance was set at p ≤ 0.05. Data are presented as median with range values, frequencies with percentages, or adjusted odds ratios (OR) and betas (ß) with 95% confidence intervals (CI). RESULTS: There were 73 (38.6%) patients categorized as catastrophizers. Median score for social support was 90.8 (range: 3.9 to 100). No statistically significant associations between pain catastrophizing or social support were observed for length of stay (ß: 0.03, 95% CI: - 0.24-0.31, p = 0.81; ß: - 0.002, 95% CI: - 0.010-- 0.006, p = 0.58) and discharge disposition (OR: 1.15, 95% CI: 0.51-2.55, p = 0.74; OR: 0.99, 95% CI: 0.97-1.01, p = 0.37). Significant associations with discharge to a rehabilitation facility included non-Caucasian (OR: 5.4, 95% CI: 2.4-11.8, p < 0.001) and longer length of stay (OR: 1.6, 95% CI: 1.01-2.4, p = 0.04). Female gender and non-Caucasian were associated with longer length of stay (ß: 0.3, 95% CI: 0.03-0.6, p = 0.03; and ß: 0.4, 95% CI: 0.1-0.6, p=0.008, respectively). CONCLUSION: We did not find a significant association between pain catastrophizing behavior and level of social support with length of stay or discharge disposition.

What is the Best Strategy to Minimize After-Care Costs for Total Joint Arthroplasty in a Bundled Payment Environment?

BACKGROUND: The post-acute care strategies after lower extremity total joint arthroplasty including the use of post-acute rehabilitation centers and home therapy services are associated with different costs. Providers in bundled payment programs are incentivized to use the most cost-effective strategies. METHODS: We used decision analysis to examine the impact of extending the inpatient hospital stay to avoid discharge of patients to a post-acute rehabilitation facility. RESULTS: The results of this decision analysis show that extended acute hospital care for up to 5.2 extra days to allow for home discharge, rather than discharge to a post-acute inpatient facility can be financially preferable, provided quality is not negatively impacted. CONCLUSION: The data demonstrate that because the cost of additional acute care hospital days is relatively small and because the cost of an extended post-acute inpatient rehabilitation facility is high, keeping patients in the acute facility for a few extra days and then discharging them directly to home may result in an overall lower cost than discharge after a shorter hospital stay to an expensive post-acute facility. However, this approach will have challenges, and future studies are needed to evaluate this change in strategy.

Orthopedic Implant Waste: Analysis and Quantification.

The steadily increasing demand for orthopedic surgeries and declining rates of reimbursement by Medicare and other insurance providers have led many hospitals to look for ways to control the cost of these surgeries. We reviewed administrative records for a 1-year period and recorded total number of surgical cases, number of cases in which an implant was wasted, and cost of each wasted implant. We determined cost incurred because of implant waste, percentage of cases that involved waste, percentage of total implant cost wasted, and average cost of waste per case. We then analyzed the data to determine if case volume or years in surgical practice affected amount of implant waste. Results showed implant waste represents a significant cost for orthopedic procedures within all subspecialties and is an important factor to consider when developing cost-reduction strategies.

Risk Factors for Infection Following Total Knee Arthroplasty: A Series of 3836 Cases from One Institution.

Higher PJI rates may be related to identifiable risk factors, which may or may not be modifiable. Identifying risk factors preoperatively provides opportunities for modification and potentially decreasing the incidence of PJI. The purposes of this study were to: (1) retrospectively identify and quantify risk factors for PJI following primary TKA, and (2) to classify those significant risk factors as either non-modifiable or modifiable for intervention prior to surgery. Optimization of modifiable risk factors such as Staphylococcus aureus colonization, and tobacco use prior to primary TKA may decrease the incidence of periprosthetic joint infection after primary TKA, thereby reducing morbidity and the costs associated with treating those infections.

Expression of Potential Regulatory Genes in Abdominal Adipose Tissue of Broiler Chickens during Early Development.

The identities of genes that underlie population variation in adipose tissue development in farm animals are poorly understood. Previous studies in our laboratory have suggested that increased fat tissue involves the expression modulation of an array of genes in broiler chickens. Of special interest are eight genes, FGFR3, EPHB2, IGFBP2, GREM1, TNC, COL3A1, ACBD7, and SCD. To understand their expression regulation and response to dietary manipulation, we investigated their mRNA levels after dietary manipulation during early development. Chickens were fed either a recommended standard or a high caloric diet from hatch to eight weeks of age (WOA). The high caloric diet markedly affected bodyweight of the broiler birds. mRNA levels of the eight genes in the abdominal adipose tissue were assayed at 2, 4, 6, and 8 WOA using RT-qPCR. Results indicate that (1) FGFR3 mRNA level was affected significantly by diet, age, and diet:age interaction; (2) COL3A mRNA level was repressed by high caloric diet; (3) mRNA levels of EPHB2, ACBD7, and SCD were affected by age; (4) mRNA level of TNC was modulated by age:diet interaction; (5) changes in GREM1 and IGFBP2 mRNA levels were not statistically different.