Effects of Obesity on Urogynecologic Prolapse Surgery Outcomes: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review the literature on outcomes of pelvic organ prolapse (POP) surgery in patients from various body mass index (BMI) categories to determine the association between obesity and surgical outcomes. DATA SOURCES: PubMed, EMBASE, and Cochrane databases were searched from inception to April 12, 2022; ClinicalTrials.gov was searched in September 2022 (PROSPERO 2022 CRD42022326255). Randomized and nonrandomized studies of urogynecologic POP surgery outcomes were accepted in which categories of BMI or obesity were compared. METHODS OF STUDY SELECTION: In total, 9,037 abstracts were screened; 759 abstracts were identified for full-text screening, and 31 articles were accepted for inclusion and data were extracted. TABULATION, INTEGRATION, AND RESULTS: Studies were extracted for participant information, intervention, comparator, and outcomes, including subjective outcomes, objective outcomes, and complications. Outcomes were compared among obesity categories (eg, BMI 30-34.9, 35-40, higher than 40), and meta-analysis was performed among different surgical approaches. Individual studies reported varying results as to whether obesity affects surgical outcomes. By meta-analysis, obesity (BMI 30 or higher) is associated with an increased odds of objective prolapse recurrence after vaginal prolapse repair (odds ratio [OR] 1.38, 95% CI, 1.14-1.67) and after prolapse repair from any surgical approach (OR 1.31, 95% CI, 1.12-1.53) and with complications such as mesh exposure after both vaginal and laparoscopic POP repair (OR 2.10, 95% CI, 1.01-4.39). CONCLUSION: Obesity is associated with increased likelihood of prolapse recurrence and mesh complications after POP repair. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022326255.

Health Care Disparities in Patients Undergoing Hysterectomy for Benign Indications: A Systematic Review.

OBJECTIVE: To explore how markers of health care disparity are associated with access to care and outcomes among patients seeking and undergoing hysterectomy for benign indications. DATA SOURCES: PubMed, EMBASE, and ClinicalTrials.gov were searched through January 23, 2022. METHODS OF STUDY SELECTION: The population of interest included patients in the United States who sought or underwent hysterectomy by any approach for benign indications. Health care disparity markers included race, ethnicity, geographic location, insurance status, and others. Outcomes included access to surgery, patient level outcomes, and surgical outcomes. Eligible studies reported multivariable regression analyses that described the independent association between at least one health care disparity risk marker and an outcome. We evaluated direction and strengths of association within studies and consistency across studies. TABULATION, INTEGRATION, AND RESULTS: Of 6,499 abstracts screened, 39 studies with a total of 46 multivariable analyses were included. Having a Black racial identity was consistently associated with decreased access to minimally invasive, laparoscopic, robotic, and vaginal hysterectomy. Being of Hispanic ethnicity and having Asian or Pacific Islander racial identities were associated with decreased access to laparoscopic and vaginal hysterectomy. Black patients were the only racial or ethnic group with an increased association with hysterectomy complications. Medicare insurance was associated with decreased access to laparoscopic hysterectomy, and both Medicaid and Medicare insurance were associated with increased likelihood of hysterectomy complications. Living in the South or Midwest or having less than a college degree education was associated with likelihood of prior hysterectomy. CONCLUSION: Studies suggest that various health care disparity markers are associated with poorer access to less invasive hysterectomy procedures and with poorer outcomes for patients who are undergoing hysterectomy for benign indications. Further research is needed to understand and identify the causes of these disparities, and immediate changes to our health care system are needed to improve access and opportunities for patients facing health care disparities. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021234511.

A novel porcine model of CLN3 Batten disease recapitulates clinical phenotypes.

Mouse models of CLN3 Batten disease, a rare lysosomal storage disorder with no cure, have improved our understanding of CLN3 biology and therapeutics through their ease of use and a consistent display of cellular pathology. However, the translatability of murine models is limited by disparities in anatomy, body size, life span and inconsistent subtle behavior deficits that can be difficult to detect in CLN3 mutant mouse models, thereby limiting their use in preclinical studies. Here, we present a longitudinal characterization of a novel miniswine model of CLN3 disease that recapitulates the most common human pathogenic variant, an exon 7-8 deletion (CLN3Δex7/8). Progressive pathology and neuron loss is observed in various regions of the CLN3Δex7/8 miniswine brain and retina. Additionally, mutant miniswine present with retinal degeneration and motor abnormalities, similar to deficits seen in humans diagnosed with the disease. Taken together, the CLN3Δex7/8 miniswine model shows consistent and progressive Batten disease pathology, and behavioral impairment mirroring clinical presentation, demonstrating its value in studying the role of CLN3 and safety/efficacy of novel disease-modifying therapeutics.

Extracellular vesicles: an emerging player in retinal homeostasis.

Extracellular vesicles (EVs) encompass secreted membrane vesicles of varied sizes, including exosomes (-30-200 nm) and microvesicles (MVs) that are ∼100-1,000 nm in size. EVs play an important role in autocrine, paracrine, and endocrine signaling and are implicated in myriad human disorders including prominent retinal degenerative diseases, like age related macular degeneration (AMD) and diabetic retinopathy (DR). Studies of EVs in vitro using transformed cell lines, primary cultures, and more recently, induced pluripotent stem cell derived retinal cell type(s) (e.g., retinal pigment epithelium) have provided insights into the composition and function of EVs in the retina. Furthermore, consistent with a causal role of EVs in retinal degenerative diseases, altering EV composition has promoted pro-retinopathy cellular and molecular events in both in vitro and in vivo models. In this review, we summarize the current understanding of the role of EVs in retinal (patho)physiology. Specifically, we will focus on disease-associated EV alterations in specific retinal diseases. Furthermore, we discuss the potential utility of EVs in diagnostic and therapeutic strategies for targeting retinal diseases.

Patient-Reported Outcome Measures for Use in Women With Pelvic Organ Prolapse: A Systematic Review.

OBJECTIVE: To describe the psychometric properties of existing patient-reported outcome measures for women with prolapse using the COSMIN (Consensus-Based Standards for the Selection of Health Measurement Instruments) framework. Additional objectives were to describe the patient-reported outcome scoring method or interpretation, methods of administration, and to compile a list of the non-English languages in which the patient-reported outcomes are reportedly validated. DATA SOURCES: PubMed and EMBASE was searched through September 2021. Study characteristics, patient-reported outcome details, and psychometric testing data were extracted. Methodologic quality was assessed with COSMIN guidelines. METHODS OF STUDY SELECTION: Studies reporting the validation of a patient-reported outcome in women with prolapse (or women with pelvic floor disorders that included a prolapse assessment) and reporting psychometric testing data on English-language patient-reported outcome for at least one measurement property per COSMIN and the U.S. Department of Health and Human Services definitions were included, as well as studies reporting the translation of an existing patient-reported outcome into another language, a new method of patient-reported outcome administration, or a scoring interpretation. Studies reporting only pretreatment and posttreatment scores, only content or face validity, or only findings for nonprolapse domains of the patient-reported outcome were excluded. TABULATION, INTEGRATION, AND RESULTS: Fifty-four studies covering 32 patient-reported outcomes were included; 106 studies assessing translation into a non-English language were excluded from the formal review. The number of validation studies per patient-reported outcome (one version of one questionnaire) ranged from 1 to 11. Reliability was the most reported measurement property, and most measurement properties received an average rating of sufficient. The condition-specific patient-reported outcomes had on average more studies and reported data across more measurement properties compared with adapted and generic patient-reported outcomes. CONCLUSION: Although measurement property data vary on patient-reported outcomes for women with prolapse, most data were of good quality. Overall, condition-specific patient-reported outcomes had more studies and reported data across more measurement properties. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42021278796.

AMD recapitulated in a 3D biomimetic: A breakthrough in retina tissue engineering.

Song et al. (Nature Methods, 2022) engineered a 3D model of the human outer blood-retina barrier (oBRB) that recapitulates key features of healthy and age-related macular degeneration (AMD)-affected eyes.1 We shine a spotlight on this tissue-engineering triumph that has the potential to transform preclinical studies of AMD and other eye diseases.

Prescription Opioid Use for Acute Pain and Persistent Opioid Use After Gynecologic Surgery: A Systematic Review.

OBJECTIVE: To assess the amount of opioid medication used by patients and the prevalence of persistent opioid use after discharge for gynecologic surgery for benign indications. DATA SOURCES: We systematically searched MEDLINE, EMBASE, and ClinicalTrials.gov from inception to October 2020. METHODS OF STUDY SELECTION: Studies with data on gynecologic surgical procedures for benign indications and the amount of outpatient opioids consumed, or the incidence of either persistent opioid use or opioid-use disorder postsurgery were included. Two reviewers independently screened citations and extracted data from eligible studies. TABULATION, INTEGRATION, AND RESULTS: Thirty-six studies (37 articles) met inclusion criteria. Data were extracted from 35 studies; 23 studies included data on opioids consumed after hospital discharge, and 12 studies included data on persistent opioid use after gynecologic surgery. Average morphine milligram equivalents (MME) used in the 14 days after discharge were 54.0 (95% CI 39.9-68.0, seven tablets of 5-mg oxycodone) across all gynecologic surgery types, 35.0 (95% CI 0-75.12, 4.5 tablets of 5-mg oxycodone) after a vaginal hysterectomy, 59.5 (95% CI 44.4-74.6, eight tablets of 5-mg oxycodone) after laparoscopic hysterectomy, and 108.1 (95% CI 80.5-135.8, 14.5 tablets of 5-mg oxycodone) after abdominal hysterectomy. Patients used 22.4 MME (95% CI 12.4-32.3, three tablets of 5-mg oxycodone) within 24 hours of discharge after laparoscopic procedures without hysterectomy and 79.8 MME (95% CI 37.1-122.6, 10.5 tablets of 5-mg oxycodone) from discharge to 7 or 14 days postdischarge after surgery for prolapse. Persistent opioid use occurred in about 4.4% of patients after gynecologic surgery, but this outcome had high heterogeneity due to variation in populations and definitions of the outcome. CONCLUSION: On average, patients use the equivalent of 15 or fewer 5-mg oxycodone tablets (or equivalent) in the 2 weeks after discharge after major gynecologic surgery for benign indications. Persistent opioid use occurred in 4.4% of patients who underwent gynecologic surgery for benign indications. Our findings could help surgeons minimize overprescribing and reduce medication diversion or misuse. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42020146120.

Multisystem Inflammatory Syndrome in Children (MIS-C) Related to SARS-CoV-2 and 1-Year Follow-up.

OBJECTIVE: To study the demographics, clinical profile, management, outcome and 1-y follow-up of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This was a retrospective observational study of 54 Children satisfying the WHO MIS-C criteria admitted during the study period. RESULTS: Fifty-four children were included in the study, median age was 5.5 (IQR 8.75), 68.5% were males. PICU admissions were 77%. Most involved organ was gastrointestinal (92%), followed by cardiovascular 85%, central nervous system (CNS) 74%, respiratory 72%, mucocutaneous 59%, and renal 31%, and hypotension was the presenting symptom in 43%. Coronary artery dilatation was seen in 1 (1.8%) child. All patients presented with more than three organs involvement. Raised procalcitonin was seen in 100%, raised BNP in 31.5%, low ejection fraction in 83.3%, and abnormal radiograph in 59%. All children were positive for anti-SARS-CoV-2 antibodies and negative for cultures. Methylprednisolone or intravenous immunoglobulin (IVIg) was used in 77%, mechanical ventilation in 18.5%, and inotropic support in 77%. Aspirin was used in 48% and low molecular weight heparin (LMWH) in 54%. The median stay in hospital was 7 d (IQR 2). There was 1 mortality (1.8%). On 7-d follow-up, 98% children had a normal echocardiography; on 6 mo and 1-y follow-up, all children had normal echocardiography. CONCLUSION: MIS-C is an important complication of COVID-19 infection. Cardiac involvement resolves completely. Coronary artery involvement is not common.

Sexual function after pelvic organ prolapse surgery: a systematic review comparing different approaches to pelvic floor repair.

OBJECTIVE: Women consider preservation of sexual activity and improvement of sexual function as important goals after pelvic organ prolapse surgery. This systematic review aimed to compare sexual activity and function before and after prolapse surgery among specific approaches to pelvic organ prolapse surgery including native tissue repairs, transvaginal synthetic mesh, biologic grafts, and sacrocolpopexy. DATA SOURCES: MEDLINE, Embase, and ClinicalTrials.gov databases were searched from inception to March 2021. STUDY ELIGIBILITY CRITERIA: Prospective comparative cohort and randomized studies of pelvic organ prolapse surgeries were included that reported the following specific sexual function outcomes: baseline and postoperative sexual activity, dyspareunia, and validated sexual function questionnaire scores. Notably, the following 4 comparisons were made: transvaginal synthetic mesh vs native tissue repairs, sacrocolpopexy vs native tissue repairs, transvaginal synthetic mesh vs sacrocolpopexy, and biologic graft vs native tissue repairs. METHODS: Studies were double screened for inclusion and extracted for population characteristics, sexual function outcomes, and methodological quality. Evidence profiles were generated for each surgery comparison by grading quality of evidence for each outcome across studies using a modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS: Screening of 3651 abstracts was performed and identified 77 original studies. The overall quality of evidence was moderate to high. There were 26 studies comparing transvaginal synthetic mesh with native tissue repairs, 5 comparing sacrocolpopexy with native tissue repairs, 5 comparing transvaginal synthetic mesh with sacrocolpopexy, and 7 comparing biologic graft with native tissue repairs. For transvaginal synthetic mesh vs native tissue repairs, no statistical differences were found in baseline or postoperative sexual activity, baseline or postoperative total dyspareunia, persistent dyspareunia, and de novo dyspareunia. Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire short form change scores were not different between transvaginal synthetic mesh and native tissue repairs (net difference, -0.3; 95% confidence interval, -1.4 to 0.8). For sacrocolpopexy vs native tissue repairs, baseline or postoperative sexual activity, baseline or postoperative total dyspareunia, de novo dyspareunia, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire short form score differences were not different. For biologic graft vs native tissue repairs, baseline or postoperative sexual activity, baseline or postoperative total dyspareunia, and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire short form changes were also not different. For transvaginal synthetic mesh vs sacrocolpopexy, there was no difference in sexual activity and sexual function score change. Based on 2 studies, postoperative total dyspareunia was more common in transvaginal synthetic mesh than sacrocolpopexy (27.5% vs 12.2%; odds ratio, 2.72; 95% confidence interval, 1.33-5.58). The prevalence of postoperative dyspareunia was lower than preoperative dyspareunia after all surgery types. CONCLUSION: Sexual function comparisons are most robust between transvaginal synthetic mesh and native tissue repairs and show similar prevalence of sexual activity, de novo dyspareunia, and sexual function scores. Total dyspareunia is higher after transvaginal synthetic mesh than sacrocolpopexy. Although sexual function data are sparse in the other comparisons, no other differences in sexual activity, dyspareunia, and sexual function score change were found.

Relationship of postoperative vaginal anatomy and sexual function: a systematic review with meta-analysis.

INTRODUCTION AND HYPOTHESIS: This was a planned secondary analysis of a systematic review that described sexual function outcomes following pelvic organ prolapse (POP) surgery. We aimed to describe the relationship of pre- and postoperative vaginal anatomic measures with sexual function outcomes. Data Sources included the Medline, Embase, and clinicaltrials.gov databases from inception to April 2018. METHODS: The original systematic review included prospective, comparative studies that reported sexual function outcomes before and following POP surgery. Studies were extracted for population characteristics, sexual function outcomes, and vaginal anatomy, including total vaginal length (TVL) and genital hiatus. By meta-regression, we analyzed associations across studies between vaginal anatomic measurements and sexual function using the Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire-12 (PISQ-12) and dyspareunia outcomes. RESULTS: We screened 3124 abstracts and identified 74 papers representing 67 original studies. Among these, 14 studies reported TVL and PISQ-12 outcomes. Nine studies reported TVL and dyspareunia outcomes, eight studies reported GH and PISQ-12 outcomes, and seven studies reported GH and dyspareunia outcomes. We found no associations between anatomic measures and PISQ-12 or dyspareunia, although, we found a statistically significant association found between preoperative TVL and change in PISQ-12. CONCLUSION: Across studies, the evidence does not support an association between vaginal anatomy and either validated, condition-specific sexual function questionnaires or dyspareunia. However, no study has directly analyzed these associations in the setting of pelvic floor reconstructive surgery.

3D iPSC modeling of the retinal pigment epithelium-choriocapillaris complex identifies factors involved in the pathology of macular degeneration.

The retinal pigment epithelium (RPE)-choriocapillaris (CC) complex in the eye is compromised in age-related macular degeneration (AMD) and related macular dystrophies (MDs), yet in vitro models of RPE-CC complex that enable investigation of AMD/MD pathophysiology are lacking. By incorporating iPSC-derived cells into a hydrogel-based extracellular matrix, we developed a 3D RPE-CC model that recapitulates key features of both healthy and AMD/MD eyes and provides modular control over RPE and CC layers. Using this 3D RPE-CC model, we demonstrated that both RPE- and mesenchyme-secreted factors are necessary for the formation of fenestrated CC-like vasculature. Our data show that choroidal neovascularization (CNV) and CC atrophy occur in the absence of endothelial cell dysfunction and are not necessarily secondary to drusen deposits underneath RPE cells, and CC atrophy and/or CNV can be initiated systemically by patient serum or locally by mutant RPE-secreted factors. Finally, we identify FGF2 and matrix metalloproteinases as potential therapeutic targets for AMD/MDs.

A human model of Batten disease shows role of CLN3 in phagocytosis at the photoreceptor-RPE interface.

Mutations in CLN3 lead to photoreceptor cell loss in CLN3 disease, a lysosomal storage disorder characterized by childhood-onset vision loss, neurological impairment, and premature death. However, how CLN3 mutations cause photoreceptor cell death is not known. Here, we show that CLN3 is required for phagocytosis of photoreceptor outer segment (POS) by retinal pigment epithelium (RPE) cells, a cellular process essential for photoreceptor survival. Specifically, a proportion of CLN3 in human, mouse, and iPSC-RPE cells localized to RPE microvilli, the site of POS phagocytosis. Furthermore, patient-derived CLN3 disease iPSC-RPE cells showed decreased RPE microvilli density and reduced POS binding and ingestion. Notably, POS phagocytosis defect in CLN3 disease iPSC-RPE cells could be rescued by wild-type CLN3 gene supplementation. Altogether, these results illustrate a novel role of CLN3 in regulating POS phagocytosis and suggest a contribution of primary RPE dysfunction for photoreceptor cell loss in CLN3 disease that can be targeted by gene therapy.

Risk factors predicting the loss of functional independence after obliterative procedures for pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: To determine the risk factors associated with loss of functional independence after obliterative procedures for pelvic organ prolapse (POP). METHODS: The American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database was used to collect data on women who underwent obliterative vaginal procedures from 2011 to 2016, using current procedural terminology (CPT) codes for LeFort colpocleisis (57120) and vaginectomy (57110). The criterion for loss of functional independence was a transition from a functionally independent status to a dependent status (discharge to a post-care facility) or death within the 30-day postoperative period. Multivariate regression analysis was utilized to determine factors associated with loss of functional independence. RESULTS: A total of 1847 women were included in the analysis. A loss of functional independence was noted in 50 of the 1847 women (2.6%). The women who suffered loss of functional independence were older than those who were independent postoperatively (mean age 79.3 years, SD 7.47 vs. 76.7 years, SD 8.1, respectively). On multiple logistic regression analysis, age ≥ 80 years (OR 2.8, 95% CI 1.4-5.5), American Society of Anesthesiologists (ASA) classification ≥ 3 (OR 2.3, CI 1.1-4.7) and length of stay ≥ 5 days (OR 15.2, 95% CI 6.2-37.1) remained significantly associated with an increased risk of loss of functional independence. CONCLUSIONS: Age ≥ 80 years, ASA classification ≥ 3 and longer length of stay are associated with an increased risk of loss of functional independence after an obliterative procedure for pelvic organ prolapse. Consideration of these factors during the preoperative decision-making process may help improve outcomes in this cohort.

Changes in Sexual Activity and Function After Pelvic Organ Prolapse Surgery: A Systematic Review.

OBJECTIVE: We aimed to systematically review the literature to describe sexual activity and function before and after prolapse surgery. DATA SOURCES: We searched MEDLINE, EMBASE, and ClinicalTrials.gov databases from inception to April 2018. METHODS OF STUDY SELECTION: Prospective, comparative studies of reconstructive pelvic organ prolapse (POP) surgeries that reported sexual function outcomes were included. Studies were extracted for population characteristics, sexual function outcomes, and methodologic quality. Data collected included baseline and postoperative sexual activity, dyspareunia, and validated sexual function questionnaire scores. Change in validated scores were used to categorize overall sexual function as improved, unchanged, or worsened after surgery. TABULATION, INTEGRATION, AND RESULTS: The search revealed 3,124 abstracts and identified 74 articles representing 67 original studies. The overall quality of evidence was moderate to high. Studies reporting postoperative results found higher rates of sexual activity than studies reporting preoperative sexual activity in all POP surgeries except sacrospinous suspension, transvaginal mesh, and sacrocolpopexy. The prevalence of dyspareunia decreased after all prolapse surgery types. The risk of de novo dyspareunia ranged from 0% to 9% for all POP surgeries except posterior repair, which lacked sufficient data. Overall sexual function based on PISQ-12 (Pelvic Organ Prolapse/Incontinence Sexual Questionnaire-12) scores improved for mixed native tissue repairs, anterior repairs, uterosacral suspensions, sacrospinous suspensions, and sacrocolpopexy; scores were similar for posterior repairs, transvaginal mesh, and biologic grafts. Sexual function did not worsen after any POP surgeries. CONCLUSION: Sexual function improves or remains unchanged after all types of reconstructive POP surgeries and does not worsen for any surgery type. Prevalence of total dyspareunia was lower after all POP surgery types, and de novo dyspareunia was low ranging 0-9%. This information can help surgeons counsel patients preoperatively. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42019124308.

Pluripotent Stem Cells to Model Degenerative Retinal Diseases: The RPE Perspective.

Pluripotent stem cell technology, including human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs), has provided a suitable platform to investigate molecular and pathological alterations in an individual cell type using patient's own cells. Importantly, hiPSCs/hESCs are amenable to genome editing providing unique access to isogenic controls. Specifically, the ability to introduce disease-causing mutations in control (unaffected) and conversely correct disease-causing mutations in patient-derived hiPSCs has provided a powerful approach to clearly link the disease phenotype with a specific gene mutation. In fact, utilizing hiPSC/hESC and CRISPR technology has provided significant insight into the pathomechanism of several diseases. With regard to the eye, the use of hiPSCs/hESCs to study human retinal diseases is especially relevant to retinal pigment epithelium (RPE)-based disorders. This is because several studies have now consistently shown that hiPSC-RPE in culture displays key physical, gene expression and functional attributes of human RPE in vivo. In this book chapter, we will discuss the current utility, limitations, and plausible future approaches of pluripotent stem cell technology for the study of retinal degenerative diseases. Of note, although we will broadly summarize the significant advances made in modeling and studying several retinal diseases utilizing hiPSCs/hESCs, our specific focus will be on the utility of patient-derived hiPSCs for (1) establishment of human cell models and (2) molecular and pharmacological studies on patient-derived cell models of retinal degenerative diseases where RPE cellular defects play a major pathogenic role in disease development and progression.

Surgical interventions for posterior compartment prolapse and obstructed defecation symptoms: a systematic review with clinical practice recommendations.

INTRODUCTION AND HYPOTHESIS: Several posterior compartment surgical approaches are used to address posterior vaginal wall prolapse and obstructed defecation. We aimed to compare outcomes for both conditions among different surgical approaches. METHODS: A systematic review was performed comparing the impact of surgical interventions in the posterior compartment on prolapse and defecatory symptoms. MEDLINE, Embase, and ClinicalTrials.gov were searched from inception to 4 April 2018. Randomized controlled trials, prospective and retrospective comparative and single-group studies of women undergoing posterior vaginal compartment surgery for vaginal bulge or bowel symptoms were included. Studies had to include both anatomical and symptom outcomes both pre- and post-surgery. RESULTS: Forty-six eligible studies reported on six surgery types. Prolapse and defecatory symptoms improved with native-tissue transvaginal rectocele repair, transanal rectocele repair, and stapled transanal rectocele repair (STARR) surgeries. Although prolapse was improved with sacrocolpoperineopexy, defecatory symptoms worsened. STARR caused high rates of fecal urgency postoperatively, but this symptom typically resolved with time. Site-specific posterior repairs improved prolapse stage and symptoms of obstructed defecation. Compared with the transanal route, native-tissue transvaginal repair resulted in greater improvement in anatomical outcomes, improved obstructed defecation symptoms, and lower chances of rectal injury, but higher rates of dyspareunia. CONCLUSIONS: Surgery in the posterior vaginal compartment typically has a high rate of success for anatomical outcomes, obstructed defecation, and bulge symptoms, although these may not persist over time. Based on this evidence, to improve anatomical and symptomatic outcomes, a native-tissue transvaginal rectocele repair should be preferentially performed.

Environmental stress impairs photoreceptor outer segment (POS) phagocytosis and degradation and induces autofluorescent material accumulation in hiPSC-RPE cells.

Retinal pigment epithelium (RPE) cell dysfunction is central to the pathogenesis of age-related macular degeneration (AMD), a leading cause of adult blindness. Aging, the single biggest risk factor for AMD development, favors increase in RPE autofluorescent material due to accumulation of POS-digestion by-products through lysosomal dysfunction and impaired POS degradation. Apart from aging, environmental agents affect lysosomal function in multiple model systems and are implicated in AMD. Iron (Fe) overload and cigarette smoke exposure are the two environmental factors that are known to affect the lysosomal pathway and impact RPE cell health. However, the impact of Fe and cigarette smoke, on POS processing and its consequence for autofluorescent material accumulation in human RPE cells are yet to be established. Human induced pluripotent stem cell (hiPSC)-derived RPE, which phagocytoses and degrades POS in culture and can be derived from control individuals (no history/susceptibility for retinal disease), provides a model system to investigate the singular effect of excess Fe and/or cigarette smoke on POS processing by RPE cells. Using at least three distinct control hiPSC lines, we show that, compared to untreated hiPSC-RPE cells, POS uptake is reduced in both Fe (ferric ammonium citrate or FAC) and FAC + CSE (cigarette smoke extract)-treated hiPSC-RPE cells. Furthermore, exposure of hiPSC-RPE cultures to FAC + CSE leads to reduced levels of active cathepsin-D (CTSD), a lysosomal enzyme involved in POS processing, and causes delayed degradation of POS. Notably, delayed degradation of POS over time (2 weeks) in hiPSC-RPE cells exposed to Fe and CSE was sufficient to increase autofluorescent material build-up in these cells. Given that inefficient POS processing-mediated autofluorescent material accumulation in RPE cells has already been linked to AMD development, our results implicate a causative role of environmental agents, like Fe and cigarette smoke, in AMD.

The Role of FGF9 in the Production of Neural Retina and RPE in a Pluripotent Stem Cell Model of Early Human Retinal Development.

PURPOSE: To investigate the role of fibroblast growth factors (FGFs) in the production of neural retina (NR) and retinal pigmented epithelium (RPE) in a human pluripotent stem cell model of early retinal development. METHODS: Human induced pluripotent stem cell (hiPSC) lines from an individual with microphthalmia caused by a functional null mutation (R200Q) in visual system homeobox 2 (VSX2), a transcription factor involved in early NR progenitor cell (NRPC) production, and a normal sibling were differentiated along the retinal and forebrain lineages using an established protocol. Quantitative and global gene expression analyses (microarray and RNAseq) were used to investigate endogenous FGF expression profiles in these cultures over time. Based on these results, mutant and control hiPSC cultures were treated exogenously with selected FGFs and subjected to gene and protein expression analyses to determine their effects on RPE and NR production. RESULTS: We found that FGF9 and FGF19 were selectively increased in early hiPSC-derived optic vesicles (OVs) when compared to isogenic cultures of hiPSC-derived forebrain neurospheres. Furthermore, these same FGFs were downregulated over time in (R200Q)VSX2 hiPSC-OVs relative to sibling control hiPSC-OVs. Interestingly, long-term supplementation with FGF9, but not FGF19, partially rescued the mutant retinal phenotype of the (R200Q)VSX2 hiPSC-OV model. However, antagonizing FGF9 in wild-type control hiPSCs did not alter OV development. CONCLUSIONS: Our results show that FGF9 acts in concert with VSX2 to promote NR differentiation in hiPSC-OVs and has potential to be used to manipulate early retinogenesis and mitigate ocular defects caused by functional loss of VSX2 activity. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.