Disorders with Ophthalmic and Thoracic Involvement.

A variety of systemic conditions involve the thorax and the eyes. While subtle or nonspecific eye symptoms can be the initial clinical manifestation of some disorders, there can be additional manifestations in the thorax that lead to a specific diagnosis and affect patient outcomes. For instance, the initial clinical manifestation of Sjögren syndrome is dry eye or xerophthalmia; however, the presence of Sjögren lung disease represents a fourfold increase in mortality. Likewise, patients with acute sarcoidosis can initially present with pain and redness of the eye from uveitis in addition to fever and parotitis. Nearly 90% of patients with sarcoidosis have thoracic involvement, and the ophthalmologic symptoms can precede the thoracic symptoms by several years in some cases. Furthermore, a diagnosis made in one system can result in the screening of other organs as well as prompt genetic evaluation and examination of family members, such as in the setting of Marfan syndrome or Ehlers-Danlos syndrome. Multimodality imaging, particularly CT and MRI, plays a vital role in identification and characterization of these conditions. While it is helpful for ophthalmologists to be knowledgeable about these conditions and their associations so that they can order the pertinent radiologic studies, it is also important for radiologists to use the clues from ophthalmologic examination in addition to imaging findings to suggest a specific diagnosis. Systemic conditions with thoracic and ophthalmologic manifestations can be categorized as infectious, inflammatory, autoimmune, neoplastic, or hereditary in origin. The authors describe a spectrum of these conditions based on their underlying cause. ©RSNA, 2024.

Heterogeneity in the progression of retinal pathologies in mice harboring patient mimicking Impg2 mutations.

Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Toward this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with a homozygous frameshift mutation (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of subretinal deposits near the optic disc, disruption of the outer retina, and neurosensorial detachment, whereas the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP and provide a toolkit and preclinical data for advancing therapeutic approaches.

Disease progression joint model predicts time to type 1 diabetes onset: Optimizing future type 1 diabetes prevention studies.

Clinical trials seeking type 1 diabetes prevention are challenging in terms of identifying patient populations likely to progress to type 1 diabetes within limited (i.e., short-term) trial durations. Hence, we sought to improve such efforts by developing a quantitative disease progression model for type 1 diabetes. Individual-level data obtained from the TrialNet Pathway to Prevention and The Environmental Determinants of Diabetes in the Young natural history studies were used to develop a joint model that links the longitudinal glycemic measure to the timing of type 1 diabetes diagnosis. Baseline covariates were assessed using a stepwise covariate modeling approach. Our study focused on individuals at risk of developing type 1 diabetes with the presence of two or more diabetes-related autoantibodies (AAbs). The developed model successfully quantified how patient features measured at baseline, including HbA1c and the presence of different AAbs, alter the timing of type 1 diabetes diagnosis with reasonable accuracy and precision (<30% RSE). In addition, selected covariates were statistically significant (p < 0.0001 Wald test). The Weibull model best captured the timing to type 1 diabetes diagnosis. The 2-h oral glucose tolerance values assessed at each visit were included as a time-varying biomarker, which was best quantified using the sigmoid maximum effect function. This model provides a framework to quantitatively predict and simulate the time to type 1 diabetes diagnosis in individuals at risk of developing the disease and thus, aligns with the needs of pharmaceutical companies and scientists seeking to advance therapies aimed at interdicting the disease process.

Molecular and behavioral consequences of Ube3a gene overdosage in mice.

Chromosome 15q11.2-q13.1 duplication syndrome (Dup15q syndrome) is a severe neurodevelopmental disorder characterized by intellectual disability, impaired motor coordination, and autism spectrum disorder. Chromosomal multiplication of the UBE3A gene is presumed to be the primary driver of Dup15q pathophysiology, given that UBE3A exhibits maternal monoallelic expression in neurons and that maternal duplications typically yield far more severe neurodevelopmental outcomes than paternal duplications. However, studies into the pathogenic effects of UBE3A overexpression in mice have yielded conflicting results. Here, we investigated the neurodevelopmental impact of Ube3a gene overdosage using bacterial artificial chromosome-based transgenic mouse models (Ube3aOE) that recapitulate the increases in Ube3a copy number most often observed in Dup15q. In contrast to previously published Ube3a overexpression models, Ube3aOE mice were indistinguishable from wild-type controls on a number of molecular and behavioral measures, despite suffering increased mortality when challenged with seizures, a phenotype reminiscent of sudden unexpected death in epilepsy. Collectively, our data support a model wherein pathogenic synergy between UBE3A and other overexpressed 15q11.2-q13.1 genes is required for full penetrance of Dup15q syndrome phenotypes.

Leveraging Real-World Data for EMA Qualification of a Model-Based Biomarker Tool to Optimize Type-1 Diabetes Prevention Studies.

The development of therapies to prevent or delay the onset of type 1 diabetes (T1D) remains challenging, and there is a lack of qualified biomarkers to identify individuals at risk of developing T1D or to quantify the time-varying risk of conversion to a diagnosis of T1D. To address this drug development need, the T1D Consortium (i) acquired, remapped, integrated, and curated existing patient-level data from relevant observational studies, and (ii) used a model-based approach to evaluate the utility of islet autoantibodies (AAs) against insulin/proinsulin autoantibody, GAD65, IA-2, and ZnT8 as biomarkers to enrich subjects for T1D prevention. The aggregated dataset was used to construct an accelerated failure time model for predicting T1D diagnosis. The model quantifies presence of islet AA permutations as statistically significant predictors of the time-varying probability of conversion to a diagnosis of T1D. Additional sources of variability that greatly improved the accuracy of quantifying the time-varying probability of conversion to a T1D diagnosis included baseline age, sex, blood glucose measurements from the 120-minute timepoints of oral glucose tolerance tests, and hemoglobin A1c. The developed models represented the underlying evidence to qualify islet AAs as enrichment biomarkers through the qualification of novel methodologies for drug development pathway at the European Medicines Agency (EMA). Additionally, the models are intended as the foundation of a fully functioning end-user tool that will allow sponsors to optimize enrichment criteria for clinical trials in T1D prevention studies.

Ureteroarterial fistula embolization by transradial approach: A case report.

Ureteroarterial fistula is a rare condition wherein a communication develops between a ureter and the common, internal, or external iliac artery. Localizing the fistula can be difficult, as cystoscopy, CT angiography, and conventional angiography have low sensitivity in identifying the fistula. Provocative maneuvers within the ureter, however, can aid in the visualization of fistulae on angiography. Prior reports of endovascular repair have utilized transfemoral access, which makes performing concurrent provocative maneuvers in the ureter challenging. We present a case of successful endovascular ureteroarterial fistula localization and embolization in an 80-year-old woman with recurrent gross hematuria by the transradial approach, aided by concurrent provocative maneuvers performed via cystoscopy. The transradial endovascular approach facilitated a multi-disciplinary joint procedure that resulted in effective treatment of the patient.

Urinary Catheter Management Approaches Among Women Undergoing Benign Gynecologic Surgery: A Randomized Trial.

OBJECTIVE: The objective of this study was to identify differences in voiding trial success rates between delayed (postoperative day 1) and day of surgery catheter removal ("fast track") among women undergoing benign gynecologic surgery. Rates of urinary tract infection, patient satisfaction, and lower urinary tract symptoms were compared between catheter management schemes. METHODS: Women undergoing benign gynecologic surgery were randomized to either "conventional" delayed urinary catheter care removal on postoperative day 1 or day of surgery catheter removal (fast track) 4 hours after surgery. Subjects were asked to complete a brief survey recording bladder function before and during their hospitalization and satisfaction with their catheter management. Subjects were contacted by phone 2 to 3 weeks after the index surgery to survey their bladder function including symptoms (eg, dysuria) or treatment indicative of a bladder infection. RESULTS: The median dwell time for Foley catheters in the "fast-track" group was 8.15 hours (SD = 375 minutes), whereas the median dwell time in the conventional group was 20.6 hours (SD = 265 minutes), which was significantly different (P < 0.001). Overall, 153 (93%) patients passed their voiding trial with significantly more patients passing their voiding trial in the conventional management group (P = 0.01). There was no difference in the Urogenital Distress Inventory scores at 2 weeks between catheter management cohorts (P = 0.81). CONCLUSIONS: Foley dwell time is significantly reduced in the fast-track cohort. Voiding trial failure is higher with same-day catheter removal but that rate of failure rate is low. Patient satisfaction, the Urogenital Distress Inventory score, and postoperative urinary tract infection rates are not significantly different between cohorts.

Nationwide salpingectomy rates for an indication of permanent contraception before and after published practice guidelines.

OBJECTIVE: To identify the nationwide rate of salpingectomy for permanent contraception before and after the January 2015 American College of Obstetricians and Gynecologists (ACOG) Committee Opinion, Salpingectomy for Ovarian Cancer Prevention. STUDY DESIGN: Using ICD-9/10 diagnosis and procedure codes within the Vizient database, we identify permanent contraception procedures with and without salpingectomy, among females 18-50 years old between January 2013 and January 2017. Subject, hospital characteristics and costs information were recorded. To determine the changes in salpingectomy rates over time analysis was conducted using the Cochran-Armitage trend test and logistic regression models. RESULTS: A total of 211,312 women across 303 Vizient-member hospitals underwent a permanent contraception procedure over the study period. Of these, 174,930 subjects were selected from 160 hospitals that contributed data over the full 49-month period. Overall, 25,882 (14.8%) subjects underwent a salpingectomy for an indication of permanent contraception. Higher salpingectomy rates were identified among larger (p<.0001), teaching (p<.0001) hospitals versus smaller, non-teaching hospitals and in subjects with commercial/private payers (p<.0001). A lower salpingectomy rate was observed in Northeast hospitals (p<.0001). Median total hospital costs differed by $25 between permanent contraceptions performed with and without salpingectomy. The proportion of salpingectomies was <1% in January 2013 slowly rising to 20.6% in October 2015 and then 61.5% by January 2017 (p<.0001). During the pre-opinion period (Jan 2013-Dec 2014) the monthly increase in the odds of salpingectomy was 6% (OR 1.06, 95% CI 1.05, 1.06) compared to a monthly increase of 18% (OR 1.18, 95% CI 1.18, 1.18) during the post-opinion period (Jan 2015-Jan 2017). CONCLUSIONS: The nationwide rate of salpingectomies for permanent contraception has steadily increased among Vizient-member hospitals since the ACOG committee opinion. IMPLICATIONS: Salpingectomy as an approach to permanent contraception in the United States is increasing since the ACOG Committee Opinion with differing utilization rates by hospital type, region, size, and patient payer types. Physician behavior may be influenced by practice guidelines but other factors mitigate the effect.

Association of the Length of the Third Stage of Labor and Blood Loss Following Vaginal Delivery.

OBJECTIVES: The length of the third stage of labor is correlated with blood loss following a vaginal delivery. We aimed to accurately measure blood loss following a vaginal delivery and examine the relation between blood loss and length of the third stage of labor. METHODS: This was a prospective observational study of singleton pregnancies ≥24 weeks undergoing a vaginal delivery. Blood loss was meticulously measured and the length of the third stage of labor was recorded. RESULTS: The median blood loss of the 600 women was 125 mL (interquartile range 175) and the median length of the third stage of labor was 5 minutes (interquartile range 4). Total blood loss (P = 0.0263) and length of the third stage of labor (P = 0.0120) were greater in pregnancies ≥37 weeks versus <37 weeks. Women with a third stage of labor ≥15 minutes had a significantly greater risk of blood loss >500 mL (relative risk 5.8, 95% confidence interval 8.36-29.88). CONCLUSIONS: The median blood loss following a vaginal delivery is 125 mL and the median length of the third stage of labor is 5 minutes. Total blood loss and the length of the third stage of labor are greater in pregnancies >37 weeks. Women with a third stage of labor >15 minutes are 15.8 times more likely to have total blood loss ≥500 mL. As such, it is prudent to consider manual extraction of the placenta at 15 minutes rather than 30 minutes to minimize the risk of excessive blood loss.

A New Way to Treat Brain Tumors: Targeting Proteins Coded by Microcephaly Genes?: Brain tumors and microcephaly arise from opposing derangements regulating progenitor growth. Drivers of microcephaly could be attractive brain tumor targets.

New targets for brain tumor therapies may be identified by mutations that cause hereditary microcephaly. Brain growth depends on the repeated proliferation of stem and progenitor cells. Microcephaly syndromes result from mutations that specifically impair the ability of brain progenitor or stem cells to proliferate, by inducing either premature differentiation or apoptosis. Brain tumors that derive from brain progenitor or stem cells may share many of the specific requirements of their cells of origin. These tumors may therefore be susceptible to disruptions of the protein products of genes that are mutated in microcephaly. The potential for the products of microcephaly genes to be therapeutic targets in brain tumors are highlighted hereby reviewing research on EG5, KIF14, ASPM, CDK6, and ATR. Treatments that disrupt these proteins may open new avenues for brain tumor therapy that have increased efficacy and decreased toxicity.

Road to recovery after transvaginal surgery for urethral mesh perforation: evaluation of outcomes and subsequent procedures.

INTRODUCTION AND HYPOTHESIS: Urethral injury resulting from transvaginal mesh slings is a rare complication with an estimated incidence of <1%. Our objective was to review the surgical management and functional outcomes of women presenting with urethral mesh perforation following midurethral sling (MUS) placement. METHODS: This was a retrospective multicenter review of women who from January 2011 to March 2016 at two institutions underwent mesh sling excision for urethral perforation with Female Pelvic Medicine and Reconstructive Surgery fellowship-trained surgeons. Data comprising preoperative symptoms, operative details, and postoperative outcomes were collected by telephone (n 13) or based on their last follow-up appointment. RESULTS OBTAINED: Nineteen women underwent transvaginal sling excision for urethral mesh perforation. Eight (42%) patients had undergone previous sling revision surgery. Sixty percent of women had resolution of their pelvic pain postoperatively. At follow-up, 92% reported urinary incontinence (UI), and three had undergone five additional procedures for vaginal prolapse mesh exposure (n 1), incontinence (onabotulinum toxin injection n 1, rectus fascia autologous sling n 1), prolapse (colpopexy n 1), and pain (trigger-point injection n 1). Patient global impression of improvement data was available for 13 patients, of whom seven (54%) rated their postoperative condition as Very much better or Much better. CONCLUSIONS: The management of urethral mesh perforation is complex. Most women reported resolution of their pelvic pain and a high rate of satisfaction with their postoperative condition despite high rates of incontinence.

Fractional CO2 laser of the vagina for genitourinary syndrome of menopause: Is the out-of-pocket cost worth the outcome of treatment?

OBJECTIVES: The purpose of this study is to assess patient's satisfaction treatment outcomes and out-of-pocket expense for the fractional CO2 laser (SmartXide) in the treatment of genitourinary symptoms of menopause (GSM). MATERIALS AND METHODS: A multicenter retrospective cohort study of patients who completed a course of three vaginal treatments with the SmartXide11 Fractional CO2 laser. Patients contacted via telephone and asked to participate in questionnaires to evaluate for adverse outcomes since last treatment, symptom severity before and after treatment, patient satisfaction with treatment, patient satisfaction with out-of-pocket expense, and sexual function. RESULTS: Of the 368 patients contacted, 122 agreed to be interviewed. No patients reported seeking emergent medical treatment. Patient reported vaginal dryness significantly improved following treatment (P < 0.05). The frequency of intercourse increased from "once a month" to "few times a month" (P < 0.001). The vast majority of patients reported being satisfied with their treatment results (86%) and with the cost of treatment (78%). Satisfaction with the out-of-pocket expense did not correlate with household income (P = 0.07). CONCLUSION: The SmartXide Fractional CO2 laser is a safe and efficacious treatment for GSM. This treatment is associated with a high level of patient satisfaction with both treatment results and out-of-pocket expense. Lasers Surg. Med. 49:882-885, 2017. © 2017 Wiley Periodicals, Inc.

Anterior compartment prolapse: what's new?

PURPOSE OF REVIEW: The purpose of this review is to summarize the treatment options for anterior compartment prolapse, describe the role that apical suspension plays in the correction of anterior vaginal wall prolapse, and assess the risks and benefits of biologic and synthetic graft use in anterior compartment repair. RECENT FINDINGS: In 2016, The Cochrane Review published a review of 37 trials including 4023 participants finding that compared to native tissue repair, the use of synthetic mesh resulted in reduced symptomatic prolapse recurrence, anatomic recurrence, and repeat prolapse surgery. There was insufficient evidence regarding quality of life improvement or the use of biologic grafts. Of note the differences between native tissue and mesh kit repairs were not large. SUMMARY: A strong consideration should be on the correction of apical prolapse when present; isolated anterior wall repairs should be pursued with caution. The surgeon may consider the use of augmenting materials in their repair of anterior vaginal wall prolapse, although the available evidence is not strongly supportive of their use given potential risks.

Lasers for pelvic floor dysfunctions: is there evidence?

PURPOSE OF REVIEW: The purpose of this review is to discuss the available energy sources used in the vaginal canal that are currently being promoted for certain pelvic floor conditions and explore the body of peer-reviewed literature supporting their use. RECENT FINDINGS: The majority of research has focused on the use of fractional CO2 laser treatment for genitourinary syndrome of menopause (GSM). Most of these studies are nonrandomized prospective studies, but their data consistently shows an improvement in symptoms without significant side effects. SUMMARY: Vaginal laser treatment for GSM is of particular interest to gynecologists as it provides patients with a history of estrogen receptor positive breast cancer, thromboembolic event, or other contraindication to hormone therapy, an effective treatment option. Currently, we are in the early stages of scientific investigation into the use of lasers in the treatment of pelvic floor dysfunction, but the emerging data is encouraging. The existing data is limited to mostly observational studies with additional quality randomized controlled trials and sham studies needed to ensure that physicians are providing the optimum evidence-based treatments to their patients. At the present time there is insufficient data to promote these therapies for stress incontinence, vaginal tightening, or other pelvic floor abnormalities.

Entry into the peritoneal cavity in posthysterectomy prolapse: an educational video.

INTRODUCTION AND HYPOTHESIS: Entry into the peritoneal cavity can be challenging in patients with posthysterectomy prolapse; however, it is important for vaginal surgeons to be able to enter the peritoneal cavity using various techniques to perform an intraperitoneal vaginal vault suspension. METHODS: We present surgical footage of various methods of accessing the peritoneal cavity in posthysterectomy prolapse using posterior, anterior and apical approaches. RESULTS: This video highlights surgical techniques that can be used to enter the peritoneal cavity in posthysterectomy prolapse in a safe and reliable manner. CONCLUSIONS: Vaginal surgeons should be able to safely and confidently identify and enter the peritoneal cavity using various approaches to perform an intraperitoneal vaginal vault suspension.

ATR maintains chromosomal integrity during postnatal cerebellar neurogenesis and is required for medulloblastoma formation.

Microcephaly and medulloblastoma may both result from mutations that compromise genomic stability. We report that ATR, which is mutated in the microcephalic disorder Seckel syndrome, sustains cerebellar growth by maintaining chromosomal integrity during postnatal neurogenesis. Atr deletion in cerebellar granule neuron progenitors (CGNPs) induced proliferation-associated DNA damage, p53 activation, apoptosis and cerebellar hypoplasia in mice. Co-deletions of either p53 or Bax and Bak prevented apoptosis in Atr-deleted CGNPs, but failed to fully rescue cerebellar growth. ATR-deficient CGNPs had impaired cell cycle checkpoint function and continued to proliferate, accumulating chromosomal abnormalities. RNA-Seq demonstrated that the transcriptional response to ATR-deficient proliferation was highly p53 dependent and markedly attenuated by p53 co-deletion. Acute ATR inhibition in vivo by nanoparticle-formulated VE-822 reproduced the developmental disruptions seen with Atr deletion. Genetic deletion of Atr blocked tumorigenesis in medulloblastoma-prone SmoM2 mice. Our data show that p53-driven apoptosis and cell cycle arrest - and, in the absence of p53, non-apoptotic cell death - redundantly limit growth in ATR-deficient progenitors. These mechanisms may be exploited for treatment of CGNP-derived medulloblastoma using ATR inhibition.

Titin stiffness modifies the force-generating region of muscle sarcomeres.

The contractile units of striated muscle, the sarcomeres, comprise the thick (myosin) and thin (actin) filaments mediating active contraction and the titin filaments determining "passive" elasticity. We hypothesized that titin may be more active in muscle contraction by directly modulating thick-filament properties. We used single-myofibril mechanical measurements and atomic force microscopy of individual sarcomeres to quantify the effects of sarcomere strain and titin spring length on both the inter-filament lattice spacing and the lateral stiffness of the actin-myosin overlap zone (A-band). We found that strain reduced the lattice spacing similarly in sarcomeres with stiff (rabbit psoas) or compliant titin (rabbit diaphragm), but increased A-band lateral stiffness much more in psoas than in diaphragm. The strain-induced alterations in A-band stiffness that occur independently of lattice spacing effects may be due to titin stiffness-sensing by A-band proteins. This mechanosensitivity could play a role in the physiologically important phenomenon of length-dependent activation of striated muscle.

Rectal perforation at the time of vaginal mesh placement and subsequent abdominal mesh removal.

INTRODUCTION: We present an uncommon complication of vaginally placed synthetic prolapse mesh and demonstrate repair of rectal mesh perforation. METHODS: A 41-year-old was referred with multiple complaints following rectocele repair using a posterior vaginal mesh kit 5 months earlier. In the immediate postoperative period, she experienced severe pain radiating down her right leg, pelvic pain, dyspareunia, dyschezia, diarrhea, and new onset fecal incontinence. Our examination revealed tight, tender mesh arms palpable at the vaginal apex with no evidence of erosion or rectovaginal fistula. Rectal examination revealed intrarectal mesh traversing the rectal lumen 6 cm from the anal verge. Pelvic MRI demonstrated a possible rectovaginal fistula with inflammation surrounding the right sciatic nerve plexus. The patient underwent exploratory laparotomy, removal of the mesh, primary repair of two perforating rectal defects and diverting loop ileostomy. Postoperatively she experienced immediate improvement in pain and later underwent successful take-down of her ileostomy. She did well with improvement of bowel function, continence of feces, improvement of pain, and no recurrence of prolapse. CONCLUSION: Our video shows an abdominal approach for mesh removal and repair of rectal mesh injury occurring from vaginal mesh placement. We discuss the rationale for the abdominal approach and review techniques for proper placement of posterior vaginal mesh.