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Traumatic perineal injuries are rare but can result in significant morbidity, particularly when the anal sphincter is injured. The management of such injuries in the pediatric population is rarely noted in the literature. We aimed to describe reconstruction in such patients using lessons learned in reoperative anorectal malformation surgery. This is a single-institution retrospective case series of three pediatric patients who were referred to our institution with pelvic trauma who underwent anal sphincter reconstruction. Three patients aged 5 (female), 12 (male), and 13 (female) years were referred for reconstruction following pelvic trauma involving the anal sphincter, perineal body, and genitourinary system. All three underwent multidisciplinary evaluation with urology and gynecology (for females) and a subsequent repair with anal sphincter reconstruction utilizing a posterior sagittal approach. Two patients had ostomy reversal with appendicostomy for antegrade continence enemas and regained voluntary fecal control. The third patient is awaiting colostomy reversal but has regained volitional urinary control after urethral reconstruction. The experience gained from using the posterior sagittal anorectoplasty approach in reoperations for patients with anorectal malformations can be applied to cases of rectal trauma. Key aspects include mobilizing the rectum, repairing the sphincters, and placing them around the anus, and in females, reconstructing the perineal body. Pediatric pelvic trauma can cause devastating disruptions of physiology and are difficult to treat. Experience from reoperations for anorectal malformations can be applied to these cases, including the use of a multidisciplinary team and posterior sagittal approach., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest All authors have no disclosures or conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

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., Competing Interests: CB, SN, GB, SM, JR, DK, KK, PM No competing interests declared, JG "JG is an employee of Sanofi and received stock and options as part of compensation. JG received tissues samples from Yale for data generation. The author has no other competing interests to declare", ET "ET is an employee of Sanofi. The author has no other competing interests to declare", TN T-H N was previously an employee of Sanofi. The author has no other competing interests to declare", LG LG is an employee of Sanofi and holds stocks in Sanofi. The author has no other competing interests to declare, MK MK was previously an employee of Sanofi and holds stocks in Sanofi. The author has no other competing interests to declare, HW HW was previously an employee of Sanofi. The author has no other competing interests to declare, MD HW (now retired) was previously an employee of Sanofi and holds stocks in Sanofi. The author has no other competing interests to declare, DV BZ is an employee of Sanofi. The author has no other competing interests to declare, BZ KK is an employee of Sanofi. The author has no other competing interests to declare, (© 2022, Boddupalli, Nair et al.)

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., (© 2022. The Author(s).)

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.

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.

Objective: Meniscal tears occur frequently in patients with knee osteoarthritis (OA). The aim of our study was to determine whether meniscal damage identified on magnetic resonance imaging (MRI) is associated with the severity of knee pain or the frequency of meniscal symptoms in patients with knee OA., Methods: We performed a cross-sectional study using data from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial. We characterized meniscal damage hierarchically as: root tear; maceration; long and short complex or horizontal tears; and simple tears. Subjects completed the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Scale and a survey of frequency of meniscal symptoms. We used multivariable general linear models to assess the relationships between meniscal damage and 1) pain severity; and 2) meniscal symptoms, after adjusting for demographic and radiographic features. In further analysis root tear was considered as a binary variable., Results: Analysis included 227 knees. Root tears were present in 19%, maceration in 14%, long complex or horizontal tears in 22%, short complex or horizontal tears in 30%, and simple tears in 14%. Root tears were associated with higher WOMAC pain scores. The adjusted mean WOMAC pain score was 45.2 (standard error (SE) 2.7) for those with root tear and 38.7 (SE 1.2) for subjects without root tear (P = 0.03). We did not find statistically significant associations between meniscal morphology and frequency of meniscal symptoms., Conclusion: Root tears were associated with greater pain than meniscal tears or maceration. We did not find a relationship between meniscal damage and meniscal symptoms., (Copyright © 2017 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)