Treatment of Persistent Soiling in Hirschsprung Disease With Antegrade Continence Enemas.

INTRODUCTION: Patients with Hirschsprung disease (HD) can experience soiling after their pull-through. We evaluated the use of antegrade continence enema (ACE) for this patient population and investigated the timing and factors associated with getting the patient clean. METHODS: We performed a single-institution retrospective review (from January 2020 to January 2023) of patients with HD and prior pull-through who had persistent soiling, failed laxative treatment or rectal enemas, and were treated with antegrade enemas. The primary outcome was time to become "clean of stool" which was defined as at least one bowel movement per day, no more than one stool accident per week, and no significant stool burden radiographically. Kaplan-Meier survival analysis was performed, and univariate cox proportional hazard regression was used to assess factors associated with time to continence. RESULTS: Thirty patients who met the criteria underwent ACE creation at a median age of 6.5 y (interquartile range 5.3-9.8) with a median follow-up time of 11.5 mo (interquartile range 5.6-16.5). Most patients became clean by 4 mo (13 of 20, 65%) with similar results at 1-y follow-up (16 of 21, 76%). The median time to becoming clean was 4.3 mo (95% confidence interval: 1.7-15.0. Patients with hypermotility were more likely to continue to soil at 1 y (80% versus 13%, P = 0.01). There were no additional factors significantly associated with time to cleanliness. CONCLUSIONS: ACE is a useful modality for HD patients with soiling. Most became clean of stool in 4 mo. The presence of hypermotility was associated with a higher incidence of persistent soiling at 1 y.

Empowering the discovery of novel target-disease associations via machine learning approaches in the open targets platform.

BACKGROUND: The Open Targets (OT) Platform integrates a wide range of data sources on target-disease associations to facilitate identification of potential therapeutic drug targets to treat human diseases. However, due to the complexity that targets are usually functionally pleiotropic and efficacious for multiple indications, challenges in identifying novel target to indication associations remain. Specifically, persistent need exists for new methods for integration of novel target-disease association evidence and biological knowledge bases via advanced computational methods. These offer promise for increasing power for identification of the most promising target-disease pairs for therapeutic development. Here we introduce a novel approach by integrating additional target-disease features with machine learning models to further uncover druggable disease to target indications. RESULTS: We derived novel target-disease associations as supplemental features to OT platform-based associations using three data sources: (1) target tissue specificity from GTEx expression profiles; (2) target semantic similarities based on gene ontology; and (3) functional interactions among targets by embedding them from protein-protein interaction (PPI) networks. Machine learning models were applied to evaluate feature importance and performance benchmarks for predicting targets with known drug indications. The evaluation results show the newly integrated features demonstrate higher importance than current features in OT. In addition, these also show superior performance over association benchmarks and may support discovery of novel therapeutic indications for highly pursued targets. CONCLUSION: Our newly generated features can be used to represent additional underlying biological relatedness among targets and diseases to further empower improved performance for predicting novel indications for drug targets through advanced machine learning models. The proposed methodology enables a powerful new approach for systematic evaluation of drug targets with novel indications.

The morbidity of open tumor biopsy for intraabdominal neoplasms in pediatric patients.

PURPOSE: Tumor biopsy is often essential for diagnosis and management of intraabdominal neoplasms found in children. Open surgical biopsy is the traditional approach used to obtain an adequate tissue sample to guide further therapy, but image-guided percutaneous core-needle biopsy is being used more often due to concerns about the morbidity of open biopsy. We used a national database to evaluate the morbidity associated with open intraabdominal tumor biopsy. METHODS: We identified all patients undergoing laparotomy with tumor biopsy in the National Surgical Quality Improvement Project-Pediatric (NSQIP-P) database from 2012 to 2018 and measured the frequency of complications in the 30 days postoperatively. We tested associations between patient characteristics and outcomes to identify risk factors for complications. RESULTS: We identified 454 patients undergoing laparotomy for biopsy of an intraabdominal neoplasm. Median postoperative hospital stay was 7 days (IQR 4-12) and operative time was 117 min (IQR 84-172). The overall complication rate was 12.1%, with post-operative infection (6%) and bleeding (4.2%) being the most common complications. Several patient characteristics were associated with bleeding, but the only significant association on multivariable analysis was underlying hematologic disorder. CONCLUSION: Open abdominal surgery for pediatric intraabdominal tumor biopsy is accompanied by significant morbidity. Postoperative infection was the most common complication, which can delay initiation of further therapy, especially chemotherapy. These findings support the need to prospectively compare percutaneous image-guided core-needle biopsy to open biopsy as a way to minimize risk and optimize outcomes for this vulnerable population.

Lifting and exertion injuries decrease after implementation of an integrated hospital-wide safe patient handling and mobilisation programme.

OBJECTIVE: With increasing emphasis on early and frequent mobilisation of patients in acute care, safe patient handling and mobilisation practices need to be integrated into these quality initiatives. We completed a programme evaluation of a safe patient handling and mobilisation programme within the context of a hospital-wide patient care improvement initiative that utilised a systems approach and integrated safe patient equipment and practices into patient care plans. METHODS: Baseline and 12-month follow-up surveys of 1832 direct patient care workers assessed work practices and self-reported pain while an integrated employee payroll and injury database provided recordable injury rates collected concurrently at 2 hospitals: the study hospital with the programme and a comparison hospital. RESULTS: Safe and unsafe patient handling practice scales at the study hospital improved significantly (p<0.0001 and p=0.0031, respectively), with no differences observed at the comparison hospital. We observed significant decreases in recordable neck and shoulder (Relative Risk (RR)=0.68, 95% CI 0.46 to 1.00), lifting and exertion (RR=0.73, 95% CI 0.60 to 0.89) and pain and inflammation (RR=0.78, 95% CI 0.62 to 1.00) injury rates at the study hospital. Changes in rates at the comparison hospital were not statistically significant. CONCLUSIONS: Within the context of a patient mobilisation initiative, a safe patient handling and mobilisation programme was associated with improved work practices and a reduction in recordable worker injuries. This study demonstrates the potential impact of utilising a systems approach based on recommended best practices, including integration of these practices into the patient's plan for care.

Posterior Sagittal Approach Provides Optimal Exposure for Urethral Reconstruction in Children With a History of Anorectal Malformations.

OBJECTIVE: To present a unique series of children with previously repaired anorectal malformations (ARM) with subsequent urethral pathology repaired via a posterior sagittal exposure and highlight the associated technical advantages. METHODS: Using a retrospective review of all procedures performed in our pediatric colorectal and pelvic reconstruction program from January 2020 through December 2022, we compiled a case series of patients with a history of ARM and prior posterior sagittal anorectoplasty (PSARP) who had urethral pathology and concurrent indication for redo-PSARP. Clinical features, operative details, and postoperative outcomes were collected. RESULTS: Six male patients presented at a median age of 4.3 years, all born with an ARM of recto-urinary fistula type, of which 3 were recto-prostatic, 1 recto-bladder-neck, and 2 unknown type. In addition to redo-PSARP, 2 underwent remnant of the original fistula excision and 4 had urethral stricture repair. One required post-operative Heineke-Mikulicz anoplasty. Patients underwent cystoscopy 4-6 weeks post-reconstruction, and none showed urethral stricture requiring treatment. Post-procedurally, 5 patients were able to void urethrally and 1 required additional bladder augmentation/Mitrofanoff. CONCLUSION: Redo-PSARP completely mobilizes the rectum, thereby providing excellent exposure to the posterior urethra for repair. This approach also allows the option of a rectal flap for augmented urethroplasty as well as harvest of an ischiorectal fat pad for interposition.

Locum Tenens and Pediatric Surgery: A Position Statement and Practice Guidelines From the American Pediatric Surgical Association (APSA).

The American Pediatric Surgical Association (APSA) Practice Committee endorsed by the Board of Governors presents a Position Statement on the role of locum tenens in the practice of pediatric surgery. The Practice Committee also presents a set of guidelines for locum tenens practice. These recommendations highlight safe practice and quality care that protects the patient as well as the pediatric surgeon by offering best practice standards, defining optimal resources and establishing parameters by which hospitals and locum tenens agencies should abide. These guidelines are intended to foster discussion and contract negotiation as well as inform decision making for a) pediatric surgeons considering locum tenens opportunities, b) host organizations (hospitals and practices) seeking the coverage of a pediatric surgeon, and c) locum tenens companies vetting both surgeons and hospitals for appropriateness of such coverage. This Position Statement and foundational set of guidelines align with APSA's Vision (all children receive the highest quality surgical care) and Mission (to provide the best surgical care to our patients and families by supporting an inclusive community through education, discovery and advocacy).

Prevention of cartilage degeneration and gait asymmetry by lubricin tribosupplementation in the rat following anterior cruciate ligament transection.

OBJECTIVE: To investigate whether cartilage degeneration is prevented or minimized in a rat model of anterior cruciate ligament (ACL) injury following a single dose-escalated intraarticular injection of lubricin derived from human synoviocytes in culture. METHODS: Unilateral ACL transection (ACLT) of the right hind limb was performed in Lewis rats (n = 56). Control animals underwent a capsulotomy alone, leaving the ACL intact (n = 11). Intraarticular injections (50 µl/injection) of phosphate buffered saline (PBS; n = 14 rats) and human synoviocyte lubricin (1,600 µg/ml; n = 14 rats) were performed on day 7 postsurgery. Animals were killed on day 70 postsurgery. Histologic specimens were immunoprobed for lubricin and sulfated glycosaminoglycans. Urinary C-telopeptide of type II collagen (CTX-II) levels were measured on days 35 and 70 postsurgery. Hind limb maximum applied force was determined using a variable resistor walkway to monitor quadruped gait asymmetries. RESULTS: Increased immunostaining for lubricin in the superficial zone and on the surface of cartilage was observed in lubricin-treated and control animals but not in PBS-treated or untreated animals with ACLT. On days 35 and 70 after surgery, urinary CTX-II levels in human synoviocyte lubricin-treated animals were lower than in untreated and PBS-treated animals (P < 0.005 and P < 0.001, respectively). Animals with ACLT treated with human synoviocyte lubricin and control animals distributed their weight equally between hind limbs compared to PBS-treated or untreated animals (P < 0.01). CONCLUSION: Our findings indicate that a single intraarticular injection of concentrated lubricin following ACLT reduces type II collagen degradation and improves weight bearing in the affected rat joint. These findings support the practice of tribosupplementation with lubricin for retarding cartilage degeneration and possibly the development of posttraumatic osteoarthritis.

Clinical and radiologic factors associated with adnexal torsion in premenarchal and menarchal children and adolescents.

BACKGROUND: Adnexal torsion is a gynecologic emergency in children and adolescents but remains a challenging diagnosis, with no consistent clinical or radiologic diagnostic criteria. Our objective was to identify risk factors associated with adnexal torsion in premenarchal and menarchal patients with surgically confirmed torsion compared with those without torsion. METHODS: We conducted a retrospective chart review of all patients who underwent surgery between January 2016 and December 2019 for possible adnexal torsion. Data on demographics, clinical characteristics, radiologic variables, and operative findings were compared using descriptive statistics. Independent predictors of torsion were then examined in multivariate logistic regression models. RESULTS: Of the 291 patients who underwent surgery, 168 (57.7%) had torsion. Patients with torsion were younger than those without torsion (11.9 vs. 14.2 years, P < .01). Vomiting was significantly associated with torsion for all patients (P < .001). Large adnexal volume and absent arterial Doppler flow were associated with torsion for the total population and menarchal subgroup. A logistic regression model for the total population that controlled for age and menarchal status found that vomiting (adjusted odds ratio [aOR] 5.92, 95% confidence interval [CI] 2.87-12.22), highest adnexal volume category (aOR 4.92, 95% CI 2.25-10.75), and absent arterial Doppler flow (aOR 2.674, 95% CI 1.28-5.60) were associated with torsion. CONCLUSIONS: Vomiting, enlarged adnexal volume, and absent arterial Doppler flow were associated with adnexal torsion. However, no single risk factor accurately diagnosed torsion, and multiple factors should be interpreted together. LEVEL OF EVIDENCE: Study of Diagnostic Test, Level II.

Microglia ferroptosis is regulated by SEC24B and contributes to neurodegeneration.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease (PD). Iron-loaded microglia are frequently found in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood. Here we show that human induced pluripotent stem cell-derived microglia grown in a tri-culture system are highly responsive to iron and susceptible to ferroptosis, an iron-dependent form of cell death. Furthermore, iron overload causes a marked shift in the microglial transcriptional state that overlaps with a transcriptomic signature found in PD postmortem brain microglia. Our data also show that this microglial response contributes to neurodegeneration, as removal of microglia from the tri-culture system substantially delayed iron-induced neurotoxicity. To elucidate the mechanisms regulating iron response in microglia, we performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. These data suggest a critical role for microglia iron overload and ferroptosis in neurodegeneration.

Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells, biomarkers, and response to substrate reduction therapy.

Background: Neuronopathic Gaucher disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in GBA and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features; however, the role of GBA in individual cell types and involvement of microglia, blood-derived macrophages, and immune infiltrates in nGD pathophysiology remains enigmatic. Methods: Here, using single-cell resolution of mouse nGD brains, lipidomics, and newly generated biomarkers, we found induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons. Results: Targeted rescue of Gba in microglia and neurons, respectively, in Gba-deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), concomitant with amelioration of neuroinflammation, reduced serum neurofilament light chain (Nf-L), and improved survival. Serum GlcSph concentration was correlated with serum Nf-L and ApoE in nGD mouse models as well as in GD patients. Gba rescue in microglia/macrophage compartment prolonged survival, which was further enhanced upon treatment with brain-permeant inhibitor of glucosylceramide synthase, effects mediated via improved glycosphingolipid homeostasis, and reversal of neuroinflammation involving activation of microglia, brain macrophages, and NK cells. Conclusions: Together, our study delineates individual cellular effects of Gba deficiency in nGD brains, highlighting the central role of neuroinflammation driven by microglia activation. Brain-permeant small-molecule inhibitor of glucosylceramide synthase reduced the accumulation of bioactive glycosphingolipids, concomitant with amelioration of neuroinflammation involving microglia, NK cells, astrocytes, and neurons. Our findings advance nGD disease biology whilst identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials, and illuminate therapeutic targets. Funding: Research grant from Sanofi; other support includes R01NS110354, Yale Liver Center P30DK034989, pilot project grant.

Prevention of cartilage degeneration and restoration of chondroprotection by lubricin tribosupplementation in the rat following anterior cruciate ligament transection.

OBJECTIVE: To investigate whether cartilage degeneration is prevented or minimized following intraarticular injections of lubricin derived from human synoviocytes in culture, recombinant human PRG4 (rhPRG4), or human synovial fluid (SF) in a rat model of anterior cruciate ligament (ACL) injury. METHODS: Unilateral ACL transection (ACLT) was performed in Lewis rats (n = 45). Nine animals were left untreated. The remaining rats were given intraarticular injections (50 microl/injection) of either phosphate buffered saline (PBS) (n = 9), human synoviocyte lubricin (200 microg/ml; n = 9), rhPRG4 (200 microg/ml; n = 9), or human SF lubricin (200 microg/ml; n = 9) twice weekly beginning on day 7 after injury. Joints were harvested on day 32 after injury. Histologic analysis was performed using Safranin O-fast green staining, and articular cartilage degeneration was graded using the Osteoarthritis Research Society International (OARSI)-modified Mankin criteria. Histologic specimens were immunoprobed for lubricin and sulfated glycosaminoglycans. A 24-hour urine collection was performed on days 17 and 29 postinjury, and urinary C-terminal telopeptide of type II collagen (CTX-II) levels were measured. RESULTS: Treatment with human synoviocyte lubricin resulted in significantly lower OARSI scores for cartilage degeneration compared with no treatment or PBS treatment (P < 0.05). Increased immunostaining for lubricin in the superficial zone chondrocytes and on the surface of cartilage was observed in lubricin-treated, but not untreated or PBS-treated, joints. On day 17, urinary CTX-II levels in human synoviocyte lubricin- and human SF lubricin-treated animals were significantly lower than those in untreated animals (P = 0.005 and P = 0.002, respectively) and in PBS-treated animals (P = 0.002 and P < 0.001, respectively). CONCLUSION: After treatment with any of the 3 types of lubricin evaluated in this study, a reduction in cartilage damage following ACLT was evident, combined with a reduction in type II collagen degradation. Our findings indicate that intraarticular lubricin injection following an ACL injury may be beneficial in retarding the degeneration of cartilage and the development of posttraumatic OA.

For Victims of Fatal Child Abuse, Who Has the Right to Consent to Organ Donation?

In rare circumstances, children who have suffered traumatic brain injury from child abuse are declared dead by neurologic criteria and are eligible to donate organs. When the parents are the suspected abusers, there can be confusion about who has the legal right to authorize organ donation. Furthermore, organ donation may interfere with the collection of forensic evidence that is necessary to evaluate the abuse. Under those circumstances, particularly in the context of a child homicide investigation, the goals of organ donation and collection and preservation of critical forensic evidence may seem mutually exclusive. In this Ethics Rounds, we discuss such a case and suggest ways to resolve the apparent conflicts between the desire to procure organs for donation and the need to thoroughly evaluate the evidence of abuse.

Are there still selected applications for resuscitative thoracotomy in the emergency department after blunt trauma?

Resuscitative thoracotomy has an integral role for open cardiac massage and can be preformed after penetrating trauma with cardiovascular collapse. Its role in blunt trauma is questionable. We performed a retrospective chart review of patients who underwent an emergency department (ED) resuscitative thoracotomy. The goal was to define the role of resuscitative thoracotomy in blunt trauma at our institution. Forty-two patients underwent a resuscitative thoracotomy, 26 penetrating trauma (61.9%) and 16 blunt trauma (38.1%). Of these (n=16), there were 13 thoracic injuries (81.2%), eight cardiac injuries (50.0%), seven isolated abdominal injuries (43.7%) and 13 multiple (two or more locations) injuries (81.2%). Therapeutic interventions included pericardiotomy in 14 (87.5%), cardiac repair in three (18.7%), and pulmonary laceration repair in two (12.5%). All study patients had signs of life in the field; 13 maintained signs of life in transit (81.3%) and 12 upon admission to ED (75%). Average time from field to ED was 10.72 +/- 5.74 minutes. There were two survivors after blunt trauma (12.5%) and one after penetrating trauma (3.8%). Signs of life in the field and a cardiac repair were independent predictors of survival after blunt trauma (p=0.001 and p=0.004 respectively). We conclude that in select trauma patients after blunt injury with cardiovascular collapse, resuscitative thoracotomy still has a vital role.

Outcomes in Children Undergoing Surgery for Congenital Pulmonary Airway Malformations in the First Year of Life.

BACKGROUND: Treatment of congenital pulmonary airway malformations (CPAMs) is generally surgical resection; however, there is controversy regarding the optimal timing of surgical intervention, especially in asymptomatic patients. STUDY DESIGN: Using the American College of Surgeons National Surgical Quality Improvement Program-Pediatric Participant Use Files from 2012 to 2015, children who underwent lung resection for CPAMs were identified. Outcomes in children who underwent lung resection during the neonatal period were compared with those who underwent resection beyond the neonatal period, but during the first year of life (non-neonates). RESULTS: A total of 541 patients (20.7% neonates and 79.3% non-neonates) were identified. Neonates had higher rates of preoperative comorbidities and worse postoperative outcomes when compared with non-neonates (morbidity 19.6% vs 5.4%, p < 0.0001). On multivariable regression analysis, the presence of preoperative symptoms (defined as oxygen dependence or ventilatory support) was independently associated with increased morbidity (odds ratio 3.91 [range 1.6 to 9.57], p = 0.003). In a subgroup analysis of asymptomatic neonates compared with asymptomatic non-neonates, there was no difference in overall morbidity (7.4% vs 4.4%, p = 0.33). CONCLUSIONS: These data suggest that lung resection for CPAMs in the neonatal period in asymptomatic children are not associated with increased 30-day morbidity. The presence of preoperative symptoms was independently associated with increased morbidity in a multivariable regression model. More data are needed to better understand the long-term outcomes and better define the optimal timing of surgery in this patient population.

Short-term outcomes in children undergoing restorative proctocolectomy with ileal-pouch anal anastomosis.

INTRODUCTION: Patients with familial adenomatous polyposis (FAP) and ulcerative colitis (UC) commonly undergo restorative proctocolectomy with ileal-pouch anal anastomosis (RP-IPAA). We sought to describe patient characteristics and postoperative outcomes in this patient population. METHODS: Using the National Surgical Quality Improvement Program-Pediatric Participant Use Files from 2012 to 2015, children who were 6-18years old who underwent RP-IPAA for FAP or UC were identified. Postoperative morbidity, including reoperation and readmission were quantified. Associations between preoperative characteristics and postoperative outcomes were analyzed. RESULTS: A total of 260 children met the inclusion criteria, of which 56.2% had UC. Most cases were performed laparoscopically (58.1%), and the operative time was longer with a laparoscopic versus open approach (326 [257-408] versus 281 [216-391] minutes, p=0.02). The overall morbidity was 11.5%, and there were high reoperation and readmission rates (12.7% and 21.5%, respectively). On bivariate analysis, preoperative steroid use was associated with reoperation (22.5% versus 10.9%, p=0.04). On multivariable regression analysis, obesity was independently associated with reoperation (odds ratio: 3.34 [95% confidence intervals: 1.08-10.38], p=0.04). CONCLUSIONS: Children who undergo RP-IPAA have high rates of overall morbidity, reoperation, and readmission. Obesity was independently associated with reoperation. This data can be used by practitioners in the preoperative setting to better counsel families and establish expectations for the postoperative setting. TYPE OF STUDY: Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III.

Associations Among Health Care Workplace Safety, Resident Satisfaction, and Quality of Care in Long-Term Care Facilities.

OBJECTIVE: We performed an integrated cross-sectional analysis of relationships between long-term care work environments, employee and resident satisfaction, and quality of patient care. METHODS: Facility-level data came from a network of 203 skilled nursing facilities in 13 states in the eastern United States owned or managed by one company. K-means cluster analysis was applied to investigate clustered associations between safe resident handling program (SRHP) performance, resident care outcomes, employee satisfaction, rates of workers' compensation claims, and resident satisfaction. RESULTS: Facilities in the better-performing cluster were found to have better patient care outcomes and resident satisfaction; lower rates of workers compensation claims; better SRHP performance; higher employee retention; and greater worker job satisfaction and engagement. CONCLUSION: The observed clustered relationships support the utility of integrated performance assessment in long-term care facilities.

An Ergonomic Assessment of Hospital Linen Bag Handling.

The Joint Commission provides accreditation standards for staging hospital waste, but there are no federal lifting safety standards for linen bags. We evaluated hospital laundry bag lifting using the Revised National Institute for Occupational Safety and Health (NIOSH) Lifting Equation. We hypothesized that the permitted 32-gallon linen container capacity might allow filling to weights above our calculated Recommended Weight Limit (RWL) for some lifting positions and contents. We found that 30- and 40-gallon bags filled with loose dry linen had predicted weights within estimated RWLs only for lifts close to the body. Thirty- and 40-gallon bags filled more than halfway with dry compact linen had predicted weights above estimated RWLs for all lifting positions. Thirty- and 40-gallon bags filled with wet compact linen exceeded estimated RWLs for all positions when less than one-quarter full. Bag volume and filling controls may be considered to ensure linen bags are not excessively heavy.

Outcomes of safe patient handling and mobilization programs: A meta-analysis.

BACKGROUND: Variability in patient care settings and the range of patient handling tasks present challenges in developing and evaluating safe patient handling and mobilization (SPHM) programs. OBJECTIVE: We performed a systematic meta-analysis of SPHM program evaluations. METHODS: Systematic literature review identified published SPHM program evaluations. Injury Rate Ratios (IRR), pre- to post-intervention, were used to estimate intervention effects and to examine the influence of patient care level, program components, and follow-up time using meta-regression. RESULTS: 27 articles reported evaluations from 44 sites. Combined effect estimate for all SPHM programs was 0.44 (95% CI 0.36, 0.54), reflecting substantial injury reductions after program implementation. While specific program components were not associated with greater effectiveness, longer follow-up duration was associated with greater injury rate reduction (p = 0.01) and intervention effects varied by level of care (p = 0.01), with the greatest effect in intensive care unit interventions (IRR 0.14; 95% CI 0.07, 0.30). CONCLUSIONS: SPHM programs appear to be highly effective in reducing injuries. More research is needed to identify the most effective interventions for different patient care levels.

Intra-articular Recombinant Human Proteoglycan 4 Mitigates Cartilage Damage After Destabilization of the Medial Meniscus in the Yucatan Minipig.

BACKGROUND: Lubricin, or proteoglycan 4 (PRG4), is a glycoprotein responsible for joint boundary lubrication. PRG4 has been shown previously to be down-regulated after traumatic joint injury such as a meniscal tear. Preliminary evidence suggests that intra-articular injection of PRG4 after injury will reduce cartilage damage in rat models of surgically induced posttraumatic osteoarthritis. OBJECTIVE: To determine the efficacy of intra-articular injection of full-length recombinant human lubricin (rhPRG4) for reducing cartilage damage after medial meniscal destabilization (DMM) in a preclinical large animal model. STUDY DESIGN: Controlled laboratory study. METHODS: Unilateral DMM was performed in 29 Yucatan minipigs. One week after DMM, animals received 3 weekly intra-articular injections (3 mL per injection): (1) rhPRG4 (1.3 mg/mL; n = 10); (2) rhPRG4+hyaluronan (1.3 mg/mL rhPRG4 and 3 mg/mL hyaluronan [~950 kDA]; n = 10); and (3) phosphate-buffered saline (PBS; n = 9). Hindlimbs were harvested 26 weeks after surgery. Cartilage integrity was evaluated by use of macroscopic (India ink) and microscopic (safranin O-fast green and hematoxylin and eosin) scoring systems. Secondary outcomes evaluated via enzyme-linked immunosorbent assay (ELISA) included PRG4 levels in synovial fluid, carboxy-terminal telepeptide of type II collagen (CTX-II) concentrations in urine and serum, and interleukin 1ß (IL-1ß) levels in synovial fluid and serum. RESULTS: The rhPRG4 group had significantly less macroscopic cartilage damage in the medial tibial plateau compared with the PBS group ( P = .002). No difference was found between the rhPRG4+hyaluronan and PBS groups ( P = .23). However, no differences in microscopic damage scores were observed between the 3 groups ( P = .70). PRG4 production was elevated in the rhPRG4 group synovial fluid compared with the PBS group ( P = .033). The rhPRG4 group presented significantly lower urinary CTX-II levels, but not serum levels, when compared with the PBS ( P = .013) and rhPRG4+hyaluronan ( P = .011) groups. In serum and synovial fluid, both rhPRG4 ( P = .006; P = .017) and rhPRG4+hyaluronan groups ( P = .009; P = .03) presented decreased IL-1ß levels. CONCLUSION: All groups exhibited significant cartilage degeneration after DMM surgery. However, animals treated with rhPRG4 had the least amount of cartilage damage and less inflammation, providing evidence that intra-articular injections of rhPRG4 may slow the progression of posttraumatic osteoarthritis. CLINICAL RELEVANCE: Patients with meniscal trauma are at high risk for posttraumatic osteoarthritis. This study demonstrates that an intra-articular injection regimen of rhPRG4 may attenuate cartilage damage after meniscal injury.