Advancements in surgical education: exploring animal and simulation models in fetal and neonatal surgery training.

Introduction: Surgical education is undergoing a transformation, moving away from traditional models towards more modern approaches that integrate experiential and didactic methods. This shift is particularly pertinent in the realm of fetal and neonatal surgery, where specialized training is crucial. Historical training methods, such as cadaveric dissection, have been prevalent for centuries, but newer innovations, including animal and non-animal simulation models, are gaining prominence. This manuscript aims to explore the use of both animal and non-animal models in surgical education, with a specific focus on fetal and neonatal surgery. Animal models: The use of animal models in surgical training has a long history, dating back to Halsted's introduction in 1889. These models, often utilizing large animals like swine and dogs, offer valuable insights into fetal and neonatal surgeries. They allow for the study of long-term outcomes and the simulation of various diseases and anomalies, providing essential training experiences not readily available in human surgeries. However, there are notable limitations, including anatomical and physiological differences from humans, ethical considerations, and substantial infrastructure and maintenance costs. Simulation models: Simulation-based training offers several benefits, including standardized and safe learning environments without risks to real patients. Bench models, using synthetic materials or non-living animal tissue, provide cost-effective options for skills development. Virtual reality and 3-D printing technologies further enhance simulation experiences, allowing for the replication of complex clinical scenarios and patient-specific anatomies. While these models offer significant advantages, they lack the complexity of biological systems found in animal models. Conclusion: In conclusion, both animal and non-animal simulation models play crucial roles in enhancing surgical education, particularly in fetal and neonatal surgery. While advancements in non-animal technologies are important for ethical reasons, the continued necessity of animal models in certain areas should be acknowledged. By responsibly integrating these models into training programs, surgical education can be further enriched while upholding ethical standards and ensuring optimal patient outcomes.

Racial Disparities in Sacral Neuromodulation for Idiopathic Fecal Incontinence.

IMPORTANCE: Sacral neuromodulation (SNM) is an effective treatment for fecal incontinence (FI). Previous studies found that Black women undergo SNM for urinary incontinence less than White women, but there is less known about racial disparities for FI. OBJECTIVE: This study assessed differences in Black and White patients' FI treatment; SNM counseling was the primary outcome. STUDY DESIGN: This was a retrospective cohort study of adult non-Hispanic Black and White patients who received FI treatment at an academic institution from 2011 to 2021. Medical records were queried for treatments, testing, and treating specialties for a 2:1 age-matched cohort of White:Black patients. RESULTS: Four hundred forty-seven women were included: 149 Black women and 298 age-matched White women. A total of 24.4% (109) of patients had documented SNM counseling, significantly fewer in Black patients (14.8% vs 29.2%, P < 0.001). A total of 5.1% (23) of patients received SNM, less frequent in Black patients (2.7% vs 6.4%, P = 0.003). Among patients with SNM counseling, there was no difference between cohorts. Black patients were less likely to be referred for physical therapy (59.7% vs 77.2%, P < 0.001), sphincter imaging (0.7% vs 5.7%, P = 0.011), and defecography (8.1% vs 17.1%, P = 0.009). Different specialties managed the 2 cohorts. Black patients were less likely to see urogynecology and colorectal surgery (21.5% vs 34.6%, P = 0.004; 9.4% vs 15.4%, P = 0.077). Patients seen by these surgeons were more likely to discuss SNM (48.6% vs 8.5%, P < 0.001). CONCLUSIONS: There were differences between Black and White patients' FI treatment, including counseling about SNM. Multidisciplinary work is needed to provide equitable education for this life-altering condition.

Retained Tampon Fragment as an Unusual Cause of Vesicovaginal Fistula.

BACKGROUND: Vesicovaginal fistula (VVF) is an uncommon cause of urinary incontinence (UI). Iatrogenic etiologies, especially abdominal hysterectomy, are most common; however, a minority of VVFs are caused by retained foreign bodies. Objects associated with VVF include intrauterine devices, gauze, pessaries, bottle caps, and sexual aids, but retained tampons or other menstrual products have not been commonly reported. CASE: We present the case of a 53-year-old woman, gravida 0, with no prior pelvic surgery, with 2 months of intermittent UI and hematuria. Although initial diagnostic test results were negative, cystoscopy and vaginoscopy eventually confirmed the diagnosis of VVF associated with a retained foreign body. In the operating room, all debris was removed using vaginoscopy, and the VVF was repaired using a modified Latzko technique. At the patient's 9-week follow-up appointment, she was found to have complete healing of the VVF and resolution of associated symptoms. CONCLUSION: This is a case of VVF secondary to a retained tampon fragment. In addition to this uncommon etiology, our patient's presenting symptoms were atypical, leading to a delay in diagnosis and treatment for which vaginoscopy was critical.

Endocrine pancreas-specific Gclc gene deletion causes a severe diabetes phenotype.

Reduced glutathione (GSH) is an abundant antioxidant that regulates intracellular redox homeostasis by scavenging reactive oxygen species (ROS). Glutamate-cysteine ligase catalytic (GCLC) subunit is the rate-limiting step in GSH biosynthesis. Using the Pax6-Cre driver mouse line, we deleted expression of the Gclc gene in all pancreatic endocrine progenitor cells. Intriguingly, Gclc knockout (KO) mice, following weaning, exhibited an age-related, progressive diabetes phenotype, manifested as strikingly increased blood glucose and decreased plasma insulin levels. This severe diabetes trait is preceded by pathologic changes in islet of weanling mice. Gclc KO weanlings showed progressive abnormalities in pancreatic morphology including: islet-specific cellular vacuolization, decreased islet-cell mass, and alterations in islet hormone expression. Islets from newly-weaned mice displayed impaired glucose-stimulated insulin secretion, decreased insulin hormone gene expression, oxidative stress, and increased markers of cellular senescence. Our results suggest that GSH biosynthesis is essential for normal development of the mouse pancreatic islet, and that protection from oxidative stress-induced cellular senescence might prevent abnormal islet-cell damage during embryogenesis.

Combined femoral and acetabular version and synovitis are associated with dGEMRIC scores in people with femoroacetabular impingement (FAI) syndrome.

This study sought to explore, in people with symptoms, signs and imaging findings of femoroacetabular impingement (FAI syndrome): (1) whether more severe labral damage, synovitis, bone marrow lesions, or subchondral cysts assessed on magnetic resonance imaging (MRI) were associated with poorer cartilage health, and (2) whether abnormal femoral, acetabular, and/or combined femoral and acetabular versions were associated with poorer cartilage health. This cross-sectional study used baseline data from the 50 participants with FAI syndrome in the Australian FASHIoN trial (ACTRN12615001177549) with available dGEMRIC scans. Cartilage health was measured using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) score sampled at the chondrolabral junction on three midsagittal slices, at one acetabular and one femoral head region of interest on each slice, and MRI features were assessed using the Hip Osteoarthritis MRI Score. Analyses were adjusted for alpha angle and body mass index, which are known to affect dGEMRIC score. Linear regression assessed the relationship with the dGEMRIC score of (i) selected MRI features, and (ii) femoral, acetabular, and combined femoral and acetabular versions. Hips with more severe synovitis had worse dGEMRIC scores (partial η2 = 0.167, p = 0.020), whereas other MRI features were not associated. A lower combined femoral and acetabular version was associated with a better dGEMRIC score (partial η2 = 0.164, p = 0.021), whereas isolated measures of femoral and acetabular version were not associated. In conclusion, worse synovitis was associated with poorer cartilage health, suggesting synovium and cartilage may be linked to the pathogenesis of FAI syndrome. A lower combined femoral and acetabular version appears to be protective of cartilage health at the chondrolabral junction.

Moderators, Mediators, and Prognostic Indicators of Treatment With Hip Arthroscopy or Physical Therapy for Femoroacetabular Impingement Syndrome: Secondary Analyses From the Australian FASHIoN Trial.

BACKGROUND: Although randomized controlled trials comparing hip arthroscopy with physical therapy for the treatment of femoroacetabular impingement (FAI) syndrome have emerged, no studies have investigated potential moderators or mediators of change in hip-related quality of life. PURPOSE: To explore potential moderators, mediators, and prognostic indicators of the effect of hip arthroscopy and physical therapy on change in 33-item international Hip Outcome Tool (iHOT-33) score for FAI syndrome. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Overall, 99 participants were recruited from the clinics of orthopaedic surgeons and randomly allocated to treatment with hip arthroscopy or physical therapy. Change in iHOT-33 score from baseline to 12 months was the dependent outcome for analyses of moderators, mediators, and prognostic indicators. Variables investigated as potential moderators/prognostic indicators were demographic variables, symptom duration, alpha angle, lateral center-edge angle (LCEA), Hip Osteoarthritis MRI Scoring System (HOAMS) for selected magnetic resonance imaging (MRI) features, and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) score. Potential mediators investigated were change in chosen bony morphology measures, HOAMS, and dGEMRIC score from baseline to 12 months. For hip arthroscopy, intraoperative procedures performed (femoral ostectomy ± acetabular ostectomy ± labral repair ± ligamentum teres debridement) and quality of surgery graded by a blinded surgical review panel were investigated for potential association with iHOT-33 change. For physical therapy, fidelity to the physical therapy program was investigated for potential association with iHOT-33 change. RESULTS: A total of 81 participants were included in the final moderator/prognostic indicator analysis and 85 participants in the final mediator analysis after exclusion of those with missing data. No significant moderators or mediators of change in iHOT-33 score from baseline to 12 months were identified. Patients with smaller baseline LCEA (ß = -0.82; P = .034), access to private health care (ß = 12.91; P = .013), and worse baseline iHOT-33 score (ß = -0.48; P < .001) had greater iHOT-33 improvement from baseline to 12 months, irrespective of treatment allocation, and thus were prognostic indicators of treatment response. Unsatisfactory treatment fidelity was associated with worse treatment response (ß = -24.27; P = .013) for physical therapy. The quality of surgery and procedures performed were not associated with iHOT-33 change for hip arthroscopy (P = .460-.665 and P = .096-.824, respectively). CONCLUSION: No moderators or mediators of change in hip-related quality of life were identified for treatment of FAI syndrome with hip arthroscopy or physical therapy in these exploratory analyses. Patients who accessed the Australian private health care system, had smaller LCEAs, and had worse baseline iHOT-33 scores, experienced greater iHOT-33 improvement, irrespective of treatment allocation.

Comparison between Perianal Swab and Stool Specimens for Detecting Colonization with Extended-Spectrum Beta-Lactamase-Producing and Fluoroquinolone-Resistant Enterobacterales.

Stool specimens are frequently used to detect gastrointestinal tract colonization with antimicrobial-resistant enteric bacteria, but they cannot be rapidly collected. Perianal swab specimens can be collected more quickly and efficiently, but data evaluating their suitability as a specimen type for this purpose are sparse. We performed selective culture for extended-spectrum ß-lactamase-producing Enterobacterales (ESBL-E) and fluoroquinolone-resistant Enterobacterales (FQRE) using paired perianal swab and stool specimens that were collected within 1 day of each other from hematopoietic cell transplant recipients and patients with acute leukemia. Nineteen (7.6%) of 251 stool specimens yielded ESBL-E and 64 (26%) of 246 stool specimens yielded FQRE. The positive percent agreement of perianal swab specimens compared to stool specimens was 95% (18/19; 95% confidence interval [CI], 74% to 100%) for detecting ESBL-E and 95% (61/64; 95% CI, 87% to 99%) for detecting FQRE. The concordance between specimen types was 98% (95% CI, 97% to 100%). Perianal swabs are a reliable specimen type for surveillance of the gastrointestinal tract for ESBL-E and FQRE.

Oxidative stress induces inflammation of lens cells and triggers immune surveillance of ocular tissues.

Recent reports have challenged the notion that the lens is immune-privileged. However, these studies have not fully identified the molecular mechanism(s) that promote immune surveillance of the lens. Using a mouse model of targeted glutathione (GSH) deficiency in ocular surface tissues, we have investigated the role of oxidative stress in upregulating cytokine expression and promoting immune surveillance of the eye. RNA-sequencing of lenses from postnatal day (P) 1-aged Gclcf/f;Le-CreTg/- (KO) and Gclcf/f;Le-Cre-/- control (CON) mice revealed upregulation of many cytokines (e.g., CCL4, GDF15, CSF1) and immune response genes in the lenses of KO mice. The eyes of KO mice had a greater number of cells in the aqueous and vitreous humors at P1, P20 and P50 than age-matched CON and Gclcw/w;Le-CreTg/- (CRE) mice. Histological analyses revealed the presence of innate immune cells (i.e., macrophages, leukocytes) in ocular structures of the KO mice. At P20, the expression of cytokines and ROS content was higher in the lenses of KO mice than in those from age-matched CRE and CON mice, suggesting that oxidative stress may induce cytokine expression. In vitro administration of the oxidant, hydrogen peroxide, and the depletion of GSH (using buthionine sulfoximine (BSO)) in 21EM15 lens epithelial cells induced cytokine expression, an effect that was prevented by co-treatment of the cells with N-acetyl-l-cysteine (NAC), a antioxidant. The in vivo and ex vivo induction of cytokine expression by oxidative stress was associated with the expression of markers of epithelial-to-mesenchymal transition (EMT), α-SMA, in lens cells. Given that EMT of lens epithelial cells causes posterior capsule opacification (PCO), we propose that oxidative stress induces cytokine expression, EMT and the development of PCO in a positive feedback loop. Collectively these data indicate that oxidative stress induces inflammation of lens cells which promotes immune surveillance of ocular structures.

Oxidative stress, glutathione, and CYP2E1 in 1,4-dioxane liver cytotoxicity and genotoxicity: insights from animal models.

1,4-Dioxane (DX) is an emerging drinking water contaminant worldwide, which poses a threat to public health due to its demonstrated liver carcinogenicity and potential for human exposure. The lack of drinking water standards for DX is attributed to undetermined mechanisms of DX carcinogenicity. This mini-review provides a brief discussion of a series of mechanistic studies, wherein unique mouse models were exposed to DX in drinking water to elucidate redox changes associated with DX cytotoxicity and genotoxicity. The overall conclusions from these studies support a direct genotoxic effect by high dose DX and imply that oxidative stress involving CYP2E1 activation may play a causal role in DX liver genotoxicity and potentially carcinogenicity. The mechanistic data derived from these studies can serve as important references to refine the assessment of carcinogenic pathways that may be triggered at environmentally relevant low doses of DX in future animal and human studies.

Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency.

1,4-Dioxane (DX) is a synthetic chemical used as a stabilizer for industrial solvents. Recent occurrence data show widespread and significant contamination of drinking water with DX in the US. DX is classified by the International Agency for Research on Cancer as a group 2B carcinogen with the primary target organ being the liver in animal studies. Despite the exposure and cancer risk, US EPA has not established a drinking water Maximum Contaminant Level (MCL) for DX and a wide range of drinking water targets have been established across the US and by Health Canada. The DX carcinogenic mechanism remains unknown; this information gap contributes to the varied approaches to its regulation. Our recent mice study indicated alterations in oxidative stress response accompanying DNA damage as an early change by high dose DX (5000 ppm) in drinking water. Herein, we report a follow-up study, in which we used glutathione (GSH)-deficient glutamate-cysteine ligase modifier subunit (Gclm)-null mice to investigate the role of redox homeostasis in DX-induced liver cytotoxicity and genotoxicity. Gclm-null and wild-type mice were exposed to DX for one week (1000 mg/kg/day by oral gavage) or three months (5000 ppm in drinking water). Subchronic exposure of high dose DX caused mild liver cytotoxicity. DX induced assorted molecular changes in the liver including: (i) a compensatory nuclear factor erythroid 2-related factor 2 (NRF2) anti-oxidative response at the early stage (one week), (ii) progressive CYP2E1 induction, (iii) development of oxidative stress, as evidenced by persistent NRF2 induction, oxidation of GSH pool, and accumulation of the lipid peroxidation by-product 4-hydroxynonenal, and (iv) elevations in oxidative DNA damage and DNA repair response. These DX-elicited changes were exaggerated in GSH-deficient mice. Collectively, the current study provides additional evidence linking redox dysregulation to DX liver genotoxicity, implying oxidative stress as a candidate mechanism of DX liver carcinogenicity.

Impaired GSH biosynthesis disrupts eye development, lens morphogenesis and PAX6 function.

PURPOSE: The purpose of this study was to elucidate the role and molecular consequences of impaired glutathione (GSH) biosynthesis on eye development. METHODS: GSH biosynthesis was impaired in surface ectoderm-derived ocular tissues by crossing Gclcf/f mice with hemizygous Le-Cre transgenic mice to produce Gclcf/f/Le-CreTg/- (KO) mice. Control mice included Gclcf/fand Gclcwt/wt/Le-CreTg/- mice (CRE). Eyes from all mice (at various stages of eye development) were subjected to histological, immunohistochemical, Western blot, RT-qPCR, RNA-seq, and subsequent Gene Ontology, Ingenuity Pathway Analysis and TRANSFAC analyses. PAX6 transactivation activity was studied using a luciferase reporter assay in HEK293T cells depleted of GSH using buthionine sulfoximine (BSO). RESULTS: Deletion of Gclc diminished GSH levels, increased reactive oxygen species (ROS), and caused an overt microphthalmia phenotype characterized by malformation of the cornea, iris, lens, and retina that is distinct from and much more profound than the one observed in CRE mice. In addition, only the lenses of KO mice displayed reduced crystallin (α, ß), PITX3 and Foxe3 expression. RNA-seq analyses at postnatal day 1 revealed 1552 differentially expressed genes (DEGs) in the lenses of KO mice relative to those from Gclcf/f mice, with Crystallin and lens fiber cell identity genes being downregulated while lens epithelial cell identity and immune response genes were upregulated. Bioinformatic analysis of the DEGs implicated PAX6 as a key upstream regulator. PAX6 transactivation activity was impaired in BSO-treated HEK293T cells. CONCLUSIONS: These data suggest that impaired ocular GSH biosynthesis may disrupt eye development and PAX6 function.

Multi-centre randomised controlled trial comparing arthroscopic hip surgery to physiotherapist-led care for femoroacetabular impingement (FAI) syndrome on hip cartilage metabolism: the Australian FASHIoN trial.

BACKGROUND: Arthroscopic surgery for femoroacetabular impingement syndrome (FAI) is known to lead to self-reported symptom improvement. In the context of surgical interventions with known contextual effects and no true sham comparator trials, it is important to ascertain outcomes that are less susceptible to placebo effects. The primary aim of this trial was to determine if study participants with FAI who have hip arthroscopy demonstrate greater improvements in delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) index between baseline and 12 months, compared to participants who undergo physiotherapist-led management. METHODS: Multi-centre, pragmatic, two-arm superiority randomised controlled trial comparing physiotherapist-led management to hip arthroscopy for FAI. FAI participants were recruited from participating orthopaedic surgeons clinics, and randomly allocated to receive either physiotherapist-led conservative care or surgery. The surgical intervention was arthroscopic FAI surgery. The physiotherapist-led conservative management was an individualised physiotherapy program, named Personalised Hip Therapy (PHT). The primary outcome measure was change in dGEMRIC score between baseline and 12 months. Secondary outcomes included a range of patient-reported outcomes and structural measures relevant to FAI pathoanatomy and hip osteoarthritis development. Interventions were compared by intention-to-treat analysis. RESULTS: Ninety-nine participants were recruited, of mean age 33 years and 58% male. Primary outcome data were available for 53 participants (27 in surgical group, 26 in PHT). The adjusted group difference in change at 12 months in dGEMRIC was -59 ms (95%CI - 137.9 to - 19.6) (p = 0.14) favouring PHT. Hip-related quality of life (iHOT-33) showed improvements in both groups with the adjusted between-group difference at 12 months showing a statistically and clinically important improvement in arthroscopy of 14 units (95% CI 5.6 to 23.9) (p = 0.003). CONCLUSION: The primary outcome of dGEMRIC showed no statistically significant difference between PHT and arthroscopic hip surgery at 12 months of follow-up. Patients treated with surgery reported greater benefits in symptoms at 12 months compared to PHT, but these benefits are not explained by better hip cartilage metabolism. TRIAL REGISTRATION DETAILS: Australia New Zealand Clinical Trials Registry reference: ACTRN12615001177549 . Trial registered 2/11/2015.

Perioperative outcomes following pelvic floor reconstruction in women with hereditary disorders of connective tissue: a retrospective cohort study.

INTRODUCTION AND HYPOTHESIS: Women with hereditary disorders of connective tissue (HDCT) are at increased risk of pelvic organ prolapse (POP) and stress urinary incontinence (SUI). We hypothesized that patients would have increased incidence and severity of perioperative complications up to 6 weeks after surgeries for POP/SUI. Secondary objectives were to compare pre- and post-operative pelvic floor symptoms and anatomical support as well as pelvic floor disorder recurrence. METHODS: In this multi-center retrospective cohort study, we identified patients with HDCTs by patient history and ICD-9 codes over an 11-year period. Controls without HDCTs were matched 2:1 to the primary POP or SUI procedure and surgeon. Demographic characteristics, perioperative pelvic floor information and complications were collected. A sample size of 65 HDCT patients and 130 controls was calculated to detect a 20% difference in complications with 80% power and alpha of 0.05. RESULTS: We identified 59 HDCT patients and 118 controls. Of the women with HDCTs, 49% had Ehlers-Danlos, 22% joint hypermobility syndrome, 15% Marfan syndrome, and 14% had others. Compared with controls, HDCT patients had more total perioperative complications (46% vs 22%, p = 0.002); an age-adjusted relative risk of complications was 1.4 (CI 0.7-2.6). HDCT patients had more Clavien-Dindo grades I and II complications (p = 0.02, 0.03) and more hospital readmissions (14% vs 3%, p = 0.01) than controls. There was no difference in the incidence of specific complications nor was there a difference in recurrence of POP (10%) or SUI (11%) between groups. CONCLUSIONS: Patients with HDCTs had more Clavien-Dindo grade I and II complications following pelvic floor reconstructive surgery and more readmissions.

Colonization With Fluoroquinolone-Resistant Enterobacterales Decreases the Effectiveness of Fluoroquinolone Prophylaxis in Hematopoietic Cell Transplant Recipients.

BACKGROUND: Levofloxacin prophylaxis is recommended to prevent gram-negative bloodstream infections (BSIs) in patients with prolonged chemotherapy-induced neutropenia. However, increasing fluoroquinolone resistance may decrease the effectiveness of this approach. METHODS: We assessed the prevalence of colonization with fluoroquinolone-resistant Enterobacterales (FQRE) among patients admitted for hematopoietic cell transplantation (HCT) from November 2016 to August 2019 and compared the risk of gram-negative BSI between FQRE-colonized and noncolonized patients. All patients received levofloxacin prophylaxis during neutropenia. Stool samples were collected upon admission for HCT and weekly thereafter until recovery from neutropenia, and underwent selective culture for FQRE. All isolates were identified and underwent antimicrobial susceptibility testing by broth microdilution. FQRE isolates also underwent whole-genome sequencing. RESULTS: Fifty-four of 234 (23%) patients were colonized with FQRE prior to HCT, including 30 of 119 (25%) allogeneic and 24 of 115 (21%) autologous HCT recipients. Recent antibacterial use was associated with FQRE colonization (P = .048). Ninety-one percent of colonizing FQRE isolates were Escherichia coli and 29% produced extended-spectrum ß-lactamases. Seventeen (31%) FQRE-colonized patients developed gram-negative BSI despite levofloxacin prophylaxis, compared to only 2 of 180 (1.1%) patients who were not colonized with FQRE on admission (P < .001). Of the 17 gram-negative BSIs in FQRE-colonized patients, 15 (88%) were caused by FQRE isolates that were genetically identical to the colonizing strain. CONCLUSIONS: Nearly one-third of HCT recipients with pretransplant FQRE colonization developed gram-negative BSI while receiving levofloxacin prophylaxis, and infections were typically caused by their colonizing strains. In contrast, levofloxacin prophylaxis was highly effective in patients not initially colonized with FQRE.

Colonization with Gastrointestinal Pathogens Prior to Hematopoietic Cell Transplantation and Associated Clinical Implications.

Infectious diarrhea following hematopoietic cell transplantation (HCT) significantly contributes to morbidity and mortality. Most HCT recipients experience diarrhea in the post-transplantation period, and infectious pathogens are frequently detected during diarrheal episodes. However, little is known about how frequently these patients are colonized with gastrointestinal (GI) pathogens before their transplantation and whether colonization predicts future diarrheal illness. We sought to determine how frequently HCT recipients are colonized with GI pathogens before HCT and the degree to which pre-HCT colonization predicts post-transplantation infectious diarrheal illness. We conducted a prospective cohort study of allogeneic and autologous HCT recipients at a single center between December 2016 and January 2019. Stool samples were collected during the week before HCT, and formed samples were evaluated for the presence of 22 diarrheal pathogens using the BioFire FilmArray GI panel. We determined the frequency with which participants were colonized with each pathogen and identified factors associated with colonization. We then determined how frequently pretransplantation colonization led to post-transplantation diarrheal infections due to the colonizing pathogen and whether colonization was associated with increased number of days of post-transplantation diarrhea during the transplant hospitalization. We enrolled 112 asymptomatic patients (allogeneic, 61%; autologous, 39%) who had a formed stool specimen before HCT, of whom 41 (37%) had a GI pathogen detected. The most commonly detected organisms were Clostridioides difficile (n = 21; 19%), Yersinia enterocolitica (n = 9; 8%), enteropathogenic Escherichia coli (EPEC) (n = 6; 6%), and norovirus (n = 5; 4%). Female sex and previous C. difficile infection were associated with C. difficile colonization, and having non-Hodgkin lymphoma was associated with being colonized with a diarrheal pathogen other than C. difficile. Thirteen of 21 patients (62%) with pretransplantation C. difficile colonization developed a clinical C. difficile infection post-transplantation, and 8 of 10 patients (80%) colonized with EPEC or enteroaggregative E. coli developed post-transplantation infections due to their colonizing pathogen. Pretransplantation C. difficile colonization was also associated with an increased duration of post-transplantation diarrhea (P = .048). Conversely, none of the 9 patients with pretransplantation Yersinia enterocolitica colonization developed a post-transplantation Y. enterocolitica infection. Patients admitted for HCT are frequently colonized with a diverse range of GI pathogens. Colonization with C. difficile colonization and diarrheagenic E. coli is frequently associated with post-transplantation diarrheal infections caused by these organisms, but the clinical significance of colonization with other GI pathogens is not clear.

Overview of PAX gene family: analysis of human tissue-specific variant expression and involvement in human disease.

Paired-box (PAX) genes encode a family of highly conserved transcription factors found in vertebrates and invertebrates. PAX proteins are defined by the presence of a paired domain that is evolutionarily conserved across phylogenies. Inclusion of a homeodomain and/or an octapeptide linker subdivides PAX proteins into four groups. Often termed "master regulators", PAX proteins orchestrate tissue and organ development throughout cell differentiation and lineage determination, and are essential for tissue structure and function through maintenance of cell identity. Mutations in PAX genes are associated with myriad human diseases (e.g., microphthalmia, anophthalmia, coloboma, hypothyroidism, acute lymphoblastic leukemia). Transcriptional regulation by PAX proteins is, in part, modulated by expression of alternatively spliced transcripts. Herein, we provide a genomics update on the nine human PAX family members and PAX homologs in 16 additional species. We also present a comprehensive summary of human tissue-specific PAX transcript variant expression and describe potential functional significance of PAX isoforms. While the functional roles of PAX proteins in developmental diseases and cancer are well characterized, much remains to be understood regarding the functional roles of PAX isoforms in human health. We anticipate the analysis of tissue-specific PAX transcript variant expression presented herein can serve as a starting point for such research endeavors.

Predictors for Pelvic Organ Prolapse Recurrence After Sacrocolpopexy: A Matched Case-Control Study.

OBJECTIVE: This study aimed to identify risk factors for prolapse recurrence after sacrocolpopexy. METHODS: This was a retrospective chart review with cross-sectional follow-up survey of 709 patients who underwent sacrocolpopexy of any modality from 2004 to 2014. Cases were defined as those with a composite failure, defined as having subjective bulge symptoms, retreatment, or anatomic prolapse (≥stage 2 prolapse on the Pelvic Organ Prolapse Quantification system). Controls were patients without composite failure. The cases and controls were matched by surgeon and by date of surgery in a 1:4 ratio. RESULTS: We identified 153 cases and matched them to 487 controls. The overall incidence of prolapse recurrence was 21.6% (95% confidence interval [CI], 18.2%-24.1%). Of the recurrence cases, 34 (22.2%) underwent surgical retreatment; the most common surgical retreatment was a posterior colporrhaphy (n = 16 [47.1%]). On multivariable logistic regression, a preoperative genital hiatus size ≥4 cm (adjusted odds ratio [adjOR], 1.95; 95% CI, 1.18-3.25) and concurrent anterior colporrhaphy (adjOR, 2.11; 95% CI, 1.06-4.18) were associated with increased odds of having a composite failure. Patients who had a concurrent posterior colporrhaphy had lower odds of experiencing a failure (adjOR, 0.62; 95% CI, 0.42-0.94). CONCLUSIONS: In this large retrospective chart review of women who underwent sacrocolpopexy with a cross-sectional survey follow-up time frame of nearly 7 years, patients with a preoperative genital hiatus of 4 cm or greater and need for concurrent anterior colporrhaphy at the time of their index surgery had higher odds of prolapse recurrence. Conversely, women who underwent a concurrent posterior colporrhaphy had lower odds of a recurrence.

Long-term pelvic organ prolapse recurrence and mesh exposure following sacrocolpopexy.

INTRODUCTION AND HYPOTHESIS: Large, long-term studies are needed to compare pelvic organ prolapse (POP) recurrence and mesh exposure following all modes of sacrocolpopexy (open, robotic, and laparoscopic). We hypothesized that the prevalence of recurrent POP and mesh exposure does not differ between modes of sacrocolpopexy. METHODS: This is a retrospective cohort study with a cross-sectional, prospective survey. Participants were surveyed regarding complications, retreatments, and symptoms following sacrocolpopexy. Baseline characteristics, POP recurrence, mesh exposure, and survey responses were compared. RESULTS: A total of 709 participants met the criteria. Median time from sacrocolpopexy to last follow-up for all participants was 0.5 years (2 days to 13.4 years). 15.0% experienced recurrent stage 2 or greater POP or underwent retreatment (open 11.7% [95% CI 7.8-17.2%]; robotic 21.1% [95% CI 15.6-27.9%]; laparoscopic 13.8% [95% CI 10.6-17.9%]; p = 0.03). After adjusting for baseline differences there was no significant difference among groups (p = 0.30). 5.3% experienced mesh and/or suture exposure (mesh n = 19, suture n = 10, mesh and suture n = 8) with no significant difference among groups (open 7.7% [95% CI 4.6-12.5%]; robotic 3.6% [95% CI 1.7-7.6%]; laparoscopic 4.9% [95% CI 3.1-7.7%]; p = 0.20). Median time from sacrocolpopexy to survey completion was 6.5 (1.6-13.4) years. 9.2% reported evaluation or treatment for recurrent POP (open 6.3% [95% CI 2.1-16.8%]; robotic 12.5% [95% CI 6.9-21.5%]; laparoscopic 8.5% [5.1-13.8%]; p = 0.44). 6.9% reported evaluation or treatment for mesh exposure (open 6.0% [95% CI 2.1-16.2%]; robotic 3.9% [95% CI 1.3-10.7%]; laparoscopic 8.6% [5.2-13.9%]; p = 0.38). CONCLUSIONS: Objective and patient-reported long-term prevalence of POP recurrence and mesh exposure are low following all modes of sacrocolpopexy.

A randomized controlled noninferiority trial of reduced vs routine opioid prescription after prolapse repair.

BACKGROUND: Given the accelerating opioid crisis in the United States and evidence that patients use fewer opioid tablets than prescribed, surgeons may choose to decrease prescribed quantities. The effect this may have on patient satisfaction with pain control after hospital discharge is unknown. OBJECTIVE: The primary objective of this study was to compare patient satisfaction with postoperative pain control between patients receiving a routine or reduced quantity opioid prescription after prolapse repair. Secondary objectives included a comparison of opioid-related side-effects, the number of opioid tablets used, and the number of excess tablets prescribed between these groups. STUDY DESIGN: This was a single-center, unmasked, 2-arm, randomized controlled noninferiority trial of women who underwent a prolapse repair with a planned overnight hospitalization. Patients were assigned randomly to 1 of 2 study arms: routine (28 tablets of oxycodone 5 mg) or reduced (5 tablets) prescription of opioid tablets. Patients were eligible if they were at least 18 years of age and undergoing a prolapse repair with an anticipated overnight hospital stay. Exclusion criteria included a history of chronic pain, preoperative opioid use, intolerance to study medication, or a score of ≥30 on the Pain Catastrophizing Scale. In addition to their opioid prescription, all patients received multimodal pain medications at discharge. Patients were asked to complete 6 weeks of diaries to record pain and medication use. The primary outcome (patient satisfaction) was collected as part of a postoperative survey completed at patients' routine postoperative visit 6 weeks after surgery. The sample size for noninferiority was calculated at 59 patients per group for a total of 118 patients. RESULTS: One hundred eighteen patients were assigned randomly; the primary outcome was available for 116. The majority of patients were white, postmenopausal, and nonsmokers; the mean age was 62±10.4 years. The most common surgery was a hysterectomy with native tissue repair (n=71; 60%). One hundred ten patients (93%) were satisfied with postoperative pain control. Statistical analysis constructed for noninferiority showed that the difference between the groups was <15% (93% vs 93%; P=.005). Subjects in the reduced arm reported requiring an additional opioid prescription more frequently than in the routine arm (15% vs 2%; P=.01). Patients in the routine arm used more opioid tablets than the reduced arm (median, 3 [interquartile range, 0-14] vs 1 [interquartile range, 0-3]), but overall opioid utilization was low. As such, patients in the routine arm had significantly more unused opioid tablets (median, 26 [interquartile range, 15-28] vs 4 [interquartile range, 2-5]). CONCLUSION: Patient satisfaction with pain control was noninferior in patients who received a reduced quantity of opioid tablets after prolapse repair compared with those who received a routine prescription. A large quantity of excess opioid tablets was seen in both groups. Surgeons should consider prescribing 5-10 opioid tablets after prolapse repair surgery and consider applying these findings to postoperative prescribing after other gynecologic procedures.

Does concurrent posterior repair for an asymptomatic rectocele reduce the risk of surgical failure in patients undergoing sacrocolpopexy?

PURPOSE: To determine if a concurrent posterior repair for an asymptomatic rectocele at the time of sacrocolpopexy reduces the incidence of surgical failure. METHODS: This is a retrospective chart review with a cross-sectional follow-up survey of all patients who underwent sacrocolpopexy from 2004 to 2014. Demographic and operative data were collected from the medical record. For the cross-sectional portion, patients were contacted to obtain information on symptoms and retreatment after surgery. In this study, we included patients with an asymptomatic rectocele on examination, defined as Ap or Bp ≥ -1 on POP-Q without defecatory dysfunction, which was defined as constipation based on the Rome III criteria, dyschezia, excessive straining and/or splinting to have a bowel movement. The primary outcome was a composite score of subjective bulge symptoms or retreatment for prolapse. RESULTS: Three hundred forty-four patients met the inclusion criteria: 185 (53.8%) had a sacrocolpopexy only (SCP) and 159 (46.2%) had a concurrent posterior repair (SCP + PR). The composite failure rate was 10.2% (95% CI = 7.4-13.8%), with a 13.5% (25) failure rate in the SCP group compared with 6.3% (10) in the SCP + PR group (p = 0.03). On multivariable logistic regression, the adjusted odds of failure was 2.79 in the SCP compared with the SCP + PR group (CI 1.25-6.23; P = 0.01). The rates of de novo defecatory dysfunction following surgery were low (SCP = 5.6% vs. SCP + PR = 7.5%, p = 0.55). CONCLUSIONS: For patients with asymptomatic rectoceles, a concurrent posterior repair at the time of sacrocolpopexy reduces the odds of composite patient-centered failure without an increased rate of dyspareunia or de novo defecatory dysfunction.