Chronic kidney disease increases cost of care and readmission risk after shoulder arthroplasty.

BACKGROUND: Chronic kidney disease (CKD) is associated with adverse outcomes and higher costs after lower extremity arthroplasty from higher rates of infection, aseptic loosening, and transfusion and longer hospital length of stay (LOS). The purpose of this study was to compare health care utilization and 90-day encounter charges after shoulder arthroplasty (SA) in patients with and without renal disease. A secondary aim was to define the characteristics of patients with renal disease. METHODS: We conducted a retrospective cohort study of all patients who underwent primary SA from January 2015 to December 2019 by a single surgeon at a single institution. Patients without a baseline glomerular filtration rate (GFR) were excluded. We evaluated results for patients with CKD (GFR ≤59 mL/min/1.73 m2) and without CKD (GFR ≥60 mL/min/1.73 m2). Univariate regression was performed to assess the influence of CKD on health care utilization, including LOS, transfusion, and risk for emergency department (ED) revisit or readmission during the 90-day postoperative period. In addition, 90-day encounter charges, revisit charges, and ED charges for patients with CKD were compared with those for patients with normal renal function. Last, multivariable linear regression models were used to assess the effect of estimated GFR on total 90-day encounter charges. RESULTS: A total of 514 patients met the study inclusion criteria, with 125 having CKD and 389 having normal GFR. Patients with CKD were more likely to require transfusion (odds ratio: 16.2 [confidence interval: 1.9, 139.7], P = .011) despite similar intraoperative estimated blood loss (156.9 ± 132.5 mL vs. 153.8 ± 89.7 mL; P = .768). In addition, patients with CKD had longer LOS (2.8 ± 1.3 days vs. 2.3 ± 1.0 days; P < .001), had higher 90-day readmission rates (P = .001), were more likely to visit the ED within 90 days after SA (P = .018), and had higher total 90-day encounter charges ($37,769 ± $6901 vs. $35,684 ± $5312; P = .001). Each unit increase in eGFR independently reduced total encounter charges by $67 (-$132, -$2; P = .043); dialysis patients incurred higher total 90-day encounter charges compared with patients with less severe renal disease ($42,733 ± $8985 vs. $37,531 ± $6749; P = .002). Also, patients with CKD were older (73.2 ± 8.9 vs. 68.1 ± 9.4 years; P < .001); had a lower preoperative hemoglobin level (12.4 ± 1.5 g/dL vs. 13.4 ± 1.5 g/dL; P < .001), higher American Society of Anesthesiologists score (P < .001), and more preoperative comorbidities (5.9 ± 2.9 vs. 5.0 ± 3.1; P < .001); and were more likely to use opioids preoperatively (P = .043). CONCLUSION: Patients with CKD have a higher risk for blood transfusion, ED visits, and readmission after SA, with higher total 90-day encounter charges. Identifying and optimizing this patient population before surgery can reduce costs and improve outcomes, which benefits patients, physicians, institutions, and payors.

Modifiable risk factors increase length of stay and 90-day cost of care after shoulder arthroplasty.

BACKGROUND: Baseline health conditions can negatively impact cost of care and risk of complications after joint replacement, necessitating additional care and incurring higher costs. Bundled payments have been used for hip and knee replacement and the Centers for Medicare & Medicaid Services (CMS) is testing bundled payments for upper extremity arthroplasty. The purpose of this study was to determine the impact of predefined modifiable risk factors (MRFs) on total encounter charges, hospital length of stay (LOS), related emergency department (ED) visits and charges, and related hospital readmissions within 90 days after shoulder arthroplasty. METHODS: We queried the electronic medical record (EPIC) for all shoulder arthroplasty cases under DRG 483 within a regional 7-hospital system between October 2015 and December 2019. Data was used to calculate mean LOS, total 90-day charges, related emergency department (ED) visits and charges, and related hospital readmissions after shoulder arthroplasty. Data for patients who had 1 or more MRFs, defined as anemia (hemoglobin < 10 g/dL), malnutrition (albumin < 3.4 g/dL), obesity (BMI > 40), uncontrolled diabetes (random glucose > 180 mg/dL or glycated hemoglobin > 8.0%), tobacco use (International Classification of Diseases, Tenth Revision, code indicating patient is a smoker), and opioid use (opioid prescription within 90 days of surgery), were evaluated as potential covariates to assess the relationship between MRFs and total encounter charges, LOS, ED visits, ED charges, and hospital readmissions. RESULTS: A total of 1317 shoulder arthroplasty patients were identified. Multivariable analysis demonstrated that anemia (+$19,847, confidence interval [CI] $15,743, $23,951; P < .001), malnutrition (+$5850, CI $3712, $7988; P < .001), and obesity (+$2762, CI $766, $4758, P = .007) independently contributed to higher charges after shoulder arthroplasty. Mean LOS was higher in patients with anemia (5.0 ± 4.0 days vs. 2.2 ± 1.6 days, P < .001), malnutrition (3.7 ± 2.8 days vs. 2.2 ± 1.5 days, P < .001), and uncontrolled diabetes (2.8 ± 2.8 days vs. 2.3 ± 1.7 days, P = .019). Univariate risk factors associated with a significant increase in total 90-day encounter charges included anemia (+$19,345, n = 37, P < .001), malnutrition (+$6971, n = 116, P < .001), obesity (+$2615, n = 184, P = .011), and uncontrolled diabetes (+$4377, n = 66, P = .011). Univariate risk for readmission within 90 days was higher in patients with malnutrition (odds ratio 3.0, CI 1.8, 4.9; P < .001). CONCLUSION: Malnutrition, obesity, and anemia contribute to significantly higher costs after shoulder arthroplasty. Medical strategies to optimize patients before shoulder arthroplasty are warranted to reduce total 90-day encounter charges, length of stay, and risk of readmission within 90 days of surgery. Optimizing patient health before shoulder surgery will positively impact outcomes and cost containment for patients, institutions, and payors after shoulder arthroplasty.

Celecoxib significantly reduces opioid use after shoulder arthroplasty.

BACKGROUND: The opioid crisis has illuminated the risks of opioid use for pain management, with renewed interest in reducing opioid consumption after common orthopedic procedures. Anti-inflammatory medication is an important component of multimodal pain management for patients undergoing orthopedic surgery. The purpose of this study was to evaluate the effect of celecoxib on pain control and opioid use after shoulder surgery. METHODS: Patients scheduled for either total shoulder replacement (group 1) or rotator cuff repair (group 2) were candidates for the study. The exclusion criteria included allergy to celecoxib, coagulopathy, use of anticoagulants, baseline use of long-acting opioids, and a history of medical conditions such as myocardial infarction or stroke. Consenting patients were randomized by type of procedure using block randomization to receive either placebo or celecoxib 1 hour prior to the procedure and for 3 weeks postoperatively. The primary outcome measure assessed was opioid utilization as measured by morphine-equivalent dose (MED). Secondary outcome measures included pain scores at 3 and 6 weeks postoperatively. Data were analyzed using multiple linear regression. RESULTS: Of 1081 patients scheduled for either total shoulder replacement or rotator cuff repair from February 2014 to February 2018, 78 were enrolled for arthroplasty (group 1, with 39 receiving celecoxib and 39 receiving placebo) and 79 were enrolled for rotator cuff repair (group 2, with 40 receiving celecoxib and 39 receiving placebo). Compared with the placebo arm, patients prescribed celecoxib took fewer MEDs by -168 (95% confidence interval [CI], -272 to -64; P < .01) at 3 weeks in the total population and by -197.7 (95% CI, -358 to -38; P = .02) in the arthroplasty group. Similarly, at 6 weeks, total MEDs used was -199 (95% CI, -356 to -42; P < .01) in the total population and -270 (95% CI, -524 to -16; P = .04) in the arthroplasty group. No statistically significant differences in opioid consumption were found between study arms in the cuff repair group, at either 3 or 6 weeks. Of note, preoperative opioid use was statistically associated with higher levels of opioid use in the total population and group 1 at 3 and 6 weeks (P < .01 for all) but not in group 2 (P > .05 for both). CONCLUSIONS: Use of morphine equivalents was statistically significantly less at 3 and 6 weeks in patients who took celecoxib in the total population and in the arthroplasty group. Patients prescribed celecoxib for 3 weeks after shoulder surgery took less opioid medication for pain at 3 and 6 weeks. Multimodal pain control using celecoxib is an effective way to reduce postoperative opioid use in shoulder arthroplasty patients. Preoperative opioid use is associated with higher levels of opioid use after shoulder arthroplasty.

Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3ß Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) α.

Non-alcoholic fatty liver disease is the most rapidly growing form of liver disease and if left untreated can result in non-alcoholic steatohepatitis, ultimately resulting in liver cirrhosis and failure. Biliverdin reductase A (BVRA) is a multifunctioning protein primarily responsible for the reduction of biliverdin to bilirubin. Also, BVRA functions as a kinase and transcription factor, regulating several cellular functions. We report here that liver BVRA protects against hepatic steatosis by inhibiting glycogen synthase kinase 3ß (GSK3ß) by enhancing serine 9 phosphorylation, which inhibits its activity. We show that GSK3ß phosphorylates serine 73 (Ser(P)73) of the peroxisome proliferator-activated receptor α (PPARα), which in turn increased ubiquitination and protein turnover, as well as decreased activity. Interestingly, liver-specific BVRA KO mice had increased GSK3ß activity and Ser(P)73 of PPARα, which resulted in decreased PPARα protein and activity. Furthermore, the liver-specific BVRA KO mice exhibited increased plasma glucose and insulin levels and decreased glycogen storage, which may be due to the manifestation of hepatic steatosis observed in the mice. These findings reveal a novel BVRA-GSKß-PPARα axis that regulates hepatic lipid metabolism and may provide unique targets for the treatment of non-alcoholic fatty liver disease.

Endometriosis: where are we and where are we going?

Endometriosis currently affects ~5.5 million reproductive-aged women in the U.S. with symptoms such as painful periods (dysmenorrhea), chronic pelvic pain, pain with intercourse (dyspareunia), and infertility. It is defined as the presence of endometrial tissue outside the uterine cavity and is found predominately attached to sites within the peritoneal cavity. Diagnosis for endometriosis is solely made through surgery as no consistent biomarkers for disease diagnosis exist. There is no cure for endometriosis and treatments only target symptoms and not the underlying mechanism(s) of disease. The nature of individual predisposing factors or inherent defects in the endometrium, immune system, and/or peritoneal cavity of women with endometriosis remains unclear. The literature over the last 5 years (2010-2015) has advanced our critical knowledge related to hormones, hormone receptors, immune dysregulation, hormonal treatments, and the transformation of endometriosis to ovarian cancer. In this review, we cover the aforementioned topics with the goal of providing the reader an overview and related references for further study to highlight the progress made in endometriosis research, while concluding with critical areas of endometriosis research that are urgently needed.

The naturally occurring luteinizing hormone surge is diminished in mice lacking estrogen receptor Beta in the ovary.

Female ESR2-null mice (betaERKO) display defects in ovarian function and are subfertile. Follicular maturation is impaired and explains smaller litters, but betaERKO also produce fewer litters, which may be partially due to inadequate ovulatory signals. To test this, the amplitude and timing of the naturally occurring luteinizing hormone (LH) surge was measured in individual intact betaERKO and wild-type (WT) mice. Vaginal cytology was evaluated daily, and blood samples were taken from mice in proestrus. The amplitude of the LH surge was severely blunted in betaERKO mice compared to WT, but pituitary LH levels revealed no differences. The betaERKO mice did not produce a preovulatory estradiol surge. To determine if the smaller LH surges and the reduced number of litters in betaERKO were due to the lack of ESR2 in the hypothalamic-pituitary axis or due to the absence of ESR2 in the ovary, ovaries were transplanted from WT into betaERKO mice and vice versa. The size of the LH surge was reduced only in mice lacking ESR2 within the ovary, and these mice had fewer litters. Fertility and size of the LH surge were rescued in betaERKO mice receiving a WT ovary. These data provide the first experimental evidence that the LH surge is impaired in betaERKO females and may contribute to their reduced fertility. ESR2 is not necessary within the pituitary and hypothalamus for the generation of a normal LH surge and for normal fertility, but ESR2 is essential within the ovary to provide proper signals.

Anterior Labral Reconstruction With Biceps Autograft for Anterior Shoulder Instability.

Shoulder instability is a common problem, with current research focused on understanding the implications of humeral and glenoid bone loss. Soft tissue injury, including damage to the anterior labrum, deformity of the capsule, and disruption of the inferior glenohumeral ligament, also contributes to the pathology of shoulder dislocation with implications for recurrent instability. Anatomic placement of the labral tissue and restoration of capsular tension are essential components of successful arthroscopic Bankart repair (ABR). Patients who meet criteria for ABR with a diminutive, ruptured, or absent anterior labrum at the time of arthroscopic stabilization present a significant challenge to repair. In this Technical Note, we demonstrate a technique using biceps autograft to reconstruct the anterior labrum.

MAP3K1 regulates female reproductive tract development.

Mitogen-activated protein 3 kinase 1 (MAP3K1) has a plethora of cell type-specific functions not yet fully understood. Herein, we describe a role for MAP3K1 in female reproductive tract (FRT) development. MAP3K1 kinase domain-deficient female mice exhibited an imperforate vagina, labor failure and infertility. These defects corresponded with shunted Müllerian ducts (MDs), the embryonic precursors of FRT, that manifested as a contorted caudal vagina and abrogated vaginal-urogenital sinus fusion in neonates. The MAP3K1 kinase domain is required for optimal activation of the Jun-N-terminal kinase (JNK) and cell polarity in the MD epithelium, and for upregulation of WNT signaling in the mesenchyme surrounding the caudal MD. The MAP3K1-deficient epithelial cells and MD epithelium had reduced expression of WNT7B ligands. Correspondingly, conditioned media derived from MAP3K1-competent, but not -deficient, epithelial cells activated a TCF/Lef-luciferase reporter in fibroblasts. These observations indicate that MAP3K1 regulates MD caudal elongation and FRT development, in part through the induction of paracrine factors in the epithelium that trans-activate WNT signaling in the mesenchyme.

The Role of MAP3K1 in the Development of the Female Reproductive Tract.

Mitogen-Activated Protein 3 Kinase 1 (MAP3K1) is a dynamic signaling molecule with a plethora of cell-type specific functions, most of which are yet to be understood. Here we describe a role for MAP3K1 in the development of female reproductive tract (FRT). MAP3K1 kinase domain-deficient ( Map3k1 ΔKD ) females exhibit imperforate vagina, labor failure, and infertility. These defects correspond to a shunted Müllerian duct (MD), the principle precursor of the FRT, in embryos, while they manifest as a contorted caudal vagina with abrogated vaginal-urogenital sinus fusion in neonates. In epithelial cells, MAP3K1 acts through JNK and ERK to activate WNT, yet in vivo MAP3K1 is crucial for WNT activity in mesenchyme associated with the caudal MD. Expression of Wnt7b is high in wild type, but low in Map3k1 knockout MD epithelium and MAP3K1-deficient keratinocytes. Correspondingly, conditioned media derived from MAP3K1-competent epithelial cells activate TCF/Lef-luciferase reporter in fibroblasts, suggesting that MAP3K1-induced factors released from epithelial cells trans-activate WNT signaling in fibroblasts. Our results reveal a temporal-spatial and paracrine MAP3K1-WNT crosstalk contributing to MD caudal elongation and FRT development. Highlights: MAP3K1 deficient female mice exhibit imperforate vagina and infertilityLoss of MAP3K1 kinase activity impedes Müllerian duct (MD) caudal elongation and fusion with urogenital sinus (UGS) in embryogenesisThe MAP3K1-MAPK pathway up-regulates WNT signaling in epithelial cellsMAP3K1 deficiency down-regulates Wnt7b expression in the MD epithelium and prevents WNT activity in mesenchyme of the caudal MD.

Selective mutations in estrogen receptor alpha D-domain alters nuclear translocation and non-estrogen response element gene regulatory mechanisms.

The three main mechanisms of ERα action are: 1) nuclear, genomic, direct DNA binding, 2) nuclear, genomic, "tethered"-mediated, protein-protein interactions, and 3) non-nuclear, non-genomic, rapid action responses. Reports suggest the D-domain or hinge region of ERα plays an important role in mechanisms 1 and 2 above. Studies demonstrating the functionality of the ERα hinge region have resected the full D-domain; therefore, site directed mutations were made to attribute precise sequence functionality to this domain. This study focuses on the characterization and properties of three novel site directed ERα- D-domain mutants. The Hinge 1 (H1) ERα mutant has disrupted nuclear localization, can no longer perform tethered mediated responses and has lost interaction with c-Jun, but retains estrogen response element (ERE)-mediated functions as demonstrated by confocal microscopy, reporter assays, endogenous gene expression and co-immunoprecipitation. The H2 ERα mutant is non-nuclear, but translocates to the nucleus with estradiol (E2) treatment and maintains ERE-mediated functionality. The H2+NES ERα mutant does not maintain nuclear translocation with hormone binding, no longer activates ERE-target genes, functions in ERE- or tethered-mediated luciferase assays, but does retain the non-genomic, non-nuclear, rapid action response. These studies reveal the sequence(s) in the ERα hinge region that are involved in tethered-mediated actions as well as nuclear localization and attribute important functionality to this region of the receptor. In addition, the properties of these ERα mutants will allow future studies to further dissect and characterize the three main ERα mechanisms of action and determine the mechanistic role each action has in estrogen hormone regulation.

Estrogen receptors and human disease: an update.

A myriad of physiological processes in mammals are influenced by estrogens and the estrogen receptors (ERs), ERα and ERß. As we reviewed previously, given the widespread role for estrogen in normal human physiology, it is not surprising that estrogen is implicated in the development or progression of a number of diseases. In this review, we are giving a 5-year update of the literature regarding the influence of estrogens on a number of human cancers (breast, ovarian, colorectal, prostate, and endometrial), endometriosis, fibroids, and cardiovascular disease. A large number of sophisticated experimental studies have provided insights into human disease, but for this review, the literature citations were limited to articles published after our previous review (Deroo and Korach in J Clin Invest 116(3):561-570, 2006) and will focus in most cases on human data and clinical trials. We will describe the influence in which estrogen's action, through one of or both of the ERs, mediates the aforementioned human disease states.

Unique Sensitivity of Uterine Tissue and the Immune System for Endometriotic Lesion Formation.

Endometriosis is a debilitating disease that affects about 10% of reproductive-aged adolescents and women. The etiology of the disease is unknown; however, a prevailing hypothesis is that endometriosis develops from retrograde menstruation, where endometrial tissue and fluids flow back through the oviducts into the peritoneal cavity. There is no cure for endometriosis, and symptoms are treated palliatively. Despite the advances in knowledge, the complexity of endometriosis etiology is still unknown. Recent work by our group suggests that the initiation of endometriosis is immune-dependent. Using a mouse model of endometriosis, we hypothesized the initiation of endometriosis is immune regulated and uterine endometrium specific. In the absence of a functional immune system non-obese diabetic/severe combined immunodeficiency (NOD/SCID mice), endometriotic lesions did not form. Uterine endometrial tissue forms endometriotic lesions, whereas tissues with differing basal expression levels of estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), similar cellular composition to uterus (i.e. bladder, mammary gland, and lung), and treated with estradiol did not form lesions. As MMP7 is known to play a major role in the organization/reorganization of the endometrium during the menstrual cycle, blocking metalloproteinase (MMP) activity significantly decreased the invasive properties of these cells. Together, these findings suggest that endometriosis is immune and uterine specific and that MMP7 likely plays a role in the ability of uterine tissue and the innate immune system to establish and maintain endometriotic lesions.

Endometriosis in the Mouse: Challenges and Progress Toward a 'Best Fit' Murine Model.

Endometriosis is a prevalent gynecologic condition associated with pelvic pain and infertility characterized by the implantation and growth of endometrial tissue displaced into the pelvis via retrograde menstruation. The mouse is a molecularly well-annotated and cost-efficient species for modeling human disease in the therapeutic discovery pipeline. However, as a non-menstrual species with a closed tubo-ovarian junction, the mouse poses inherent challenges as a preclinical model for endometriosis research. Over the past three decades, numerous murine models of endometriosis have been described with varying degrees of fidelity in recapitulating the essential pathophysiologic features of the human disease. We conducted a search of the peer-reviewed literature to identify publications describing preclinical research using a murine model of endometriosis. Each model was reviewed according to a panel of ideal model parameters founded on the current understanding of endometriosis pathophysiology. Evaluated parameters included method of transplantation, cycle phase and type of tissue transplanted, recipient immune/ovarian status, iterative schedule of transplantation, and option for longitudinal lesion assessment. Though challenges remain, more recent models have incorporated innovative technical approaches such as in vivo fluorescence imaging and novel hormonal preparations to overcome the unique challenges posed by murine anatomy and physiology. These models offer significant advantages in lesion development and readout toward a high-fidelity mouse model for translational research in endometriosis.

Healing rates after rotator cuff repair for patients taking either celecoxib or placebo: a double-blind randomized controlled trial.

BACKGROUND: Use of anti-inflammatory medications (NSAIDs) is an important component of multimodal pain control after orthopedic procedures to avoid opioid overutilization and abuse. However, the deleterious effects of NSAIDs on tendon healing are of particular concern in rotator cuff repair (RCR). The purpose of this study was to evaluate the effect of celecoxib or placebo on healing rates after RCR when administered in the perioperative and immediate postoperative period using MRI evaluation at one year postoperatively. A secondary aim was to determine whether clinical differences existed between patients with intact or non-intact repairs. METHODS: Patients aged ≤65 years with partial- or full-thickness rotator cuff tear (<25x25 mm) were randomized to receive celecoxib 400 mg or placebo 1 hour before the procedure and 200mg bid for 3 weeks postoperatively. All patients were treated as clinically indicated at the time of surgery and followed standard postoperative protocol. Repair integrity was evaluated with MRI using the Sugaya classification for repair integrity. Data were analyzed using multivariable logistic regression by intent to treat. RESULTS: Seventy-nine patients were enrolled; 21 were lost to follow-up, 6 did not have cuff repair, 5 were revised, and 2 declined follow-up, leaving 45 patients with one-year follow-up. Five of these patients did not complete MRI, leaving 40 patients for review. Eighteen of 20 patients (90%) who received celecoxib completed all doses of study medication as did 15 of 20 patients (75%) who received placebo. The patient groups were similar for demographics, clinical results, and healing rate. After adjusting for tear size, no statistically significant difference in healing rate was found between groups, with 10 of 20 celecoxib patients (50%) having intact repair at 1 year compared with 14 of 20 placebo patients (70%) (OR = 0.53, 95% CI: 0.14, 2.08, P = 0.35). CONCLUSION: Half of the patients who received celecoxib had an intact repair compared with 70% intact repair for patients receiving placebo. Although not statistically significant in this small study, larger studies are needed to clarify this important clinical concern. The authors do not recommend use of celecoxib for postoperative pain control after RCR.

Comparability of the small RNA secretome across human biofluids concomitantly collected from healthy adults.

Small extracellular vesicles (sEV) are nano-sized (40-150 nm), membrane-encapsulated vesicles that are released by essentially all cells into the extracellular space and function as intercellular signaling vectors through the horizontal transfer of biologic molecules, including microRNA (miRNA) and other small non-coding RNA (ncRNA), that can alter the phenotype of recipient cells. sEV are present in essentially all extracellular biofluids, including serum, urine and saliva, and offer a new avenue for discovery and development of novel biomarkers of various disease states and exposures. The objective of this study was to systematically interrogate similarities and differences between sEV ncRNA derived from saliva, serum and urine, as well as cell-free small ncRNA (cf-ncRNA) from serum. Saliva, urine and serum were concomitantly collected from 4 healthy donors to mitigate potential bias that can stem from interpersonal and temporal variability. sEV were isolated from each respective biofluid, along with cf-RNA from serum. sEV were isolated from the respective biofluids via differential ultracentrifugation with a 30% sucrose cushion to minimize protein contamination. Small RNA-sequencing was performed on each sample, and cluster analysis was performed based on ncRNA profiles. While some similarities existed in terms of sEV ncRNA cargo across biofluids, there are also notable differences in ncRNA class and ncRNA secretion, with sEV in each biofluid bearing a unique ncRNA profile, including major differences in composition by ncRNA class. We conclude that sEV ncRNA cargo varies according to biofluid, so thus should be carefully selected and interpreted when designing or contrasting translational or epidemiological studies.

Rotator Cuff Repair With Knotless Technique Is Quicker and More Cost-Effective Than Knotted Technique.

PURPOSE: To determine the cost-effectiveness of knotted (KT) versus knotless (KL) methods for rotator cuff surgical repair and to assess differences in patients' outcomes. METHODS: We retrospectively identified all patients who underwent arthroscopic rotator cuff repair at 1 institution by 1 surgeon over 2 6-month periods of time (KT technique from August 1, 2013, through January 31, 2014; and KL technique from December 1, 2014, through May 31, 2015) to calculate the direct and indirect costs associated with arthroscopic KT or KL suture bridge rotator cuff repair. Patient demographics, number of anchors used, tendons repaired, procedure time, operative time, and clinical results were also evaluated. We used univariate generalized linear models with a Gaussian distribution for assessment scores and total and implant cost data. RESULTS: We identified 87 patients for inclusion during the 2 time frames (35 KT, 54 KL). After excluding patients for tear size < 4 cm2 (n = 42), ≤ 3 anchors (n = 5), revision surgery (n = 1), and those in whom additional procedures were performed (n = 2), 37 eligible subjects remained (nKT = 15, nKL = 22). Median implant costs were statistically significantly higher in the KL group than in the KT group (MKL = $2,127, MKT = $1,520, ß = 413.7, 95% CI: 242.8, 584.6, P < .01), and more anchors were used in the KL group, with KT requiring a median of 4 anchors (IQR: 4, 5) and KL requiring a median of 5 anchors (IQR: 5, 5, P = .02). Procedure time was cut in half with KL repair (estimated 43.5 minutes) versus KT repair (80 minutes) (ß = 0.5, 95% CI: 0.4, 0.6, P < .001). Operating room time also was reduced by approximately 40% (79.5 minutes for KL; 121 minutes for KT [ß = 0.6, CI: 0.6, 0.7, P < .001]). Once operating room costs were considered, median costs were found to be significantly lower in the KL group (MKL = $3788.40, MKT = $4262.90, ß = -492.1, 95% CI: -840.0, -144.1, P < .01). No statistically significant differences were found between groups in mean preoperative, postoperative or postpreoperative differences in the visual analog scale, Simple Shoulder Test, American Shoulder and Elbow Surgeons, or University of California at Los Angeles scores (P > 0.05 for all). CONCLUSIONS: Despite using more anchors and incurring higher implant costs, the KL technique for rotator cuff repair required less surgical procedure time and cost less overall than the KT technique and resulted in equivalent clinical results. LEVEL OF EVIDENCE: Level IV Economic and Decision Analyses.

Estimated blood loss and anemia predict transfusion after total shoulder arthroplasty: a retrospective cohort study.

BACKGROUND: Reported blood transfusion rates after total shoulder arthroplasty (TSA) range from 4.5% to 43%, and reported risk factors include race, female sex, prosthesis type (reverse), revision, age, anemia, low preoperative hemoglobin, and number of comorbidities. The purpose of this study was to develop a predictive model for transfusion in anatomic/hemi and reverse shoulder arthroplasty patients and to estimate the transfusion rate in a community hospital setting. METHODS: A retrospective cohort of 265 shoulder arthroplasties (79 anatomic, 182 reverse, and 4 hemiarthroplasties) performed consecutively by 1 surgeon at 1 institution from May 2013 to May 2016 was assembled. Two patients were excluded for insufficient data, leaving 263 patients for analysis. Sensitivity, specificity, area under the curve, and cut points using estimated blood loss (EBL), history of anemia, and preoperative hemoglobin level were calculated, based on a logistic regression model. RESULTS: The overall transfusion rate was 2.3% (6/265). Higher EBL (P = .003), lower preoperative hemoglobin level (P = .030), and history of anemia (P = .088) were predictive of transfusion with a sensitivity of 80.0% and a specificity of 99.6%. In this cohort, patients with a history of anemia had transfusion risk when an EBL of ≥300 mL was combined with a preoperative hemoglobin level <10.9, resulting in a sensitivity of 1.0 and a specificity of 0.96. Factors associated with transfusion in univariate models included arthroplasty for fracture (P < .001), cemented stem (P < .001), length of stay (P < .001), EBL (P < .001), operative time (P < .001), and preoperative hemoglobin (P = .004) and hematocrit levels (P = .004). CONCLUSION: Patients with a history of anemia, a preoperative hemoglobin level <10.9, and an intraoperative EBL ≥300 mL are at high risk for transfusion after TSA.

Elevated serum chemokines are independently associated with both endometriosis and uranium exposure.

Endometriosis is a complex disease impacted by the hormonal and immune systems. Cytokines and chemokines are serum biomarkers that maybe useful to develop a noninvasive disease diagnosis. Individuals in the Fernald Community Cohort were exposed to uranium, a heavy metal with radioactive properties and estrogenic potential; therefore, serum samples from women in this cohort with or without uranium and with or without endometriosis were compared for alterations in chemokine, cytokine, and matrix metalloproteinase (MMP) levels. Control women were matched to endometriosis cases by uranium exposure, age, and body mass index. MMP levels were not altered. Five chemokines and one cytokine significantly increased in endometriosis cases versus controls irrespective of uranium exposure. Uranium exposure alone was associated with an increase in inflammatory chemokines. The majority of the elevated chemokines in endometriosis cases play important roles in attracting T helper-2 cells, which may be vital to understanding the immune response in endometriosis.

Modulation of PPAR activity via phosphorylation.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. Three subtypes of this receptor have been discovered (PPARalpha, beta and gamma), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK- and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.

Early Endometriosis in Females Is Directed by Immune-Mediated Estrogen Receptor α and IL-6 Cross-Talk.

Endometriosis is a gynecological disease that negatively affects the health of 1 in 10 women. Although more information is known about late stage disease, the early initiation of endometriosis and lesion development is poorly understood. Herein, we use a uterine tissue transfer mouse model of endometriosis to examine early disease development and its dependence on estradiol (E2) and estrogen receptor (ER) α within 72 hours of disease initiation. Using wild-type and ERα knockout mice as hosts or donors, we find substantial infiltration of neutrophils and macrophages into the peritoneal cavity. Examining cell infiltration, lesion gene expression, and peritoneal fluid, we find that E2/ERα plays a minor role in early lesion development. Immune-mediated signaling predominates E2-mediated signaling, but 48 hours after the initiation of disease, a blunted interleukin (IL)-6-mediated response is found in developing lesions lacking ERα. Our data provide evidence that the early initiation of endometriosis is predominantly dependent on the immune system, whereas E2/ERα/IL-6-mediated cross-talk plays a partial role. These findings suggest there are two phases of endometriosis-an immune-dependent phase and a hormone-dependent phase, and that targeting the innate immune system could prevent lesion attachment in this susceptible population of women.