The lncRNA KTN1-AS1 co-regulates a variety of Myc-target genes and enhances proliferation of Burkitt lymphoma cells.

Long non-coding RNAs (lncRNAs) are involved in many normal and oncogenic pathways through a diverse repertoire of transcriptional and posttranscriptional regulatory mechanisms. LncRNAs that are under tight regulation of well-known oncogenic transcription factors such as c-Myc (Myc) are likely to be functionally involved in their disease-promoting mechanisms. Myc is a major driver of many subsets of B cell lymphoma and to date remains an undruggable target. We identified three Myc-induced and four Myc-repressed lncRNAs by use of multiple in vitro models of Myc-driven Burkitt lymphoma and detailed analysis of Myc binding profiles. We show that the top Myc-induced lncRNA KTN1-AS1 is strongly upregulated in different types of B cell lymphoma compared with their normal counterparts. We used CRISPR-mediated genome editing to confirm that the direct induction of KTN1-AS1 by Myc is dependent on the presence of a Myc E-box-binding motif. Knockdown of KTN1-AS1 revealed a strong negative effect on the growth of three BL cell lines. Global gene expression analysis upon KTN1-AS1 depletion shows a strong enrichment of key genes in the cholesterol biosynthesis pathway as well as co-regulation of many Myc-target genes, including a moderate negative effect on the levels of Myc itself. Our study suggests a critical role for KTN1-AS1 in supporting BL cell growth by mediating co-regulation of a variety of Myc-target genes and co-activating key genes involved in cholesterol biosynthesis. Therefore, KTN1-AS1 may represent a putative novel therapeutic target in lymphoma.

Association of Left Atrial Hemodynamics by Magnetic Resonance Imaging With Long-Term Outcomes in Patients With Cardiac Amyloidosis.

BACKGROUND: Left atrial (LA) function and strain patterns by magnetic resonance imaging (MRI) have been investigated as markers of several cardiovascular pathologies, including cardiac amyloidosis (CA). However, associations with clinical outcomes have not been investigated. PURPOSE: To compare LA function and strain by MRI in CA patients to a matched cohort of patients without cardiovascular disease (CVD) and evaluate the association with long-term clinical outcomes in CA patients. STUDY TYPE: Retrospective case control. POPULATION: A total of 51 patients with CA and 51 age-, gender-, and race-matched controls without CVD who underwent MRI in sinus rhythm. FIELD STRENGTH/SEQUENCE: ECG-gated balanced steady-state free precession sequence at 1.5 T. ASSESSMENT: All measurements were completed by one investigator (M.M.B.). LA function and strain parameters were measured including LA indexed minimum and maximum volumes, LA reservoir (R), contractile (CT), and conduit (CD) strain. We compared groups after adjusting for age, hypertension, New York Heart Association class, modified staging system (troponin-I, BNP, estimated GFR) and left ventricular ejection fraction (LVEF) for an endpoint of all-cause mortality and a composite endpoint of heart failure hospitalization (HFH) or death. STATISTICAL TESTS: Differences between groups were evaluated with t tests for continuous variables or χ2 tests for categorical variables. A multivariable regression model was used to assess the associations of the P values-two-sided tests-<0.05 were considered statistically significant. RESULTS: CA patients with median follow up of 4.9 (8.5) months had significantly lower LA strain and higher LA volumes in comparison to the matched cohort. In the multivariable analysis, only LVEF was significantly associated with death while ƐCT (OR 0.6, CI: 0.41-0.89), indexed minimum LA volume (OR 1.06, CI: 1.02-1.13) and indexed maximum LA volume (OR 1.08, CI: 1.01-1.15) were significantly associated with the composite outcome of death or HFH. CONCLUSION: In this retrospective study of CA patients, ƐCT and indexed minimum and maximum LA volumes were significantly associated with the composite outcome of death or HFH. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 3.

Tobacco smoke exacerbates Filifactor alocis pathogenicity.

AIM: Filifactor alocis has recently emerged as a periodontal pathobiont that appears to thrive in the oral cavity of smokers. We hypothesized that identification of smoke-responsive F. alocis genes would provide insight into adaptive strategies and that cigarette smoke would enhance F. alocis pathogenesis in vivo. MATERIALS AND METHODS: F. alocis was grown in vitro and cigarette smoke extract-responsive genes determined by RNAseq. Mice were exposed, or not, to mainstream 1R6F research cigarette smoke and infected with F. alocis, or not, in an acute ligature model of periodontitis. Key clinical, infectious, and immune data were collected. RESULTS: In culture, F. alocis growth was unaffected by smoke conditioning and only a small number of genes were specifically regulated by smoke exposure. Reduced murine mass, differences in F. alocis-cognizant antibody production, and altered immune profiles as well as altered alveolar bone loss were all attributable to smoke exposure and/or F. alocis infection in vivo. CONCLUSIONS: F. alocis is well-adapted to tobacco-rich conditions and its pathogenesis is enhanced by tobacco smoke exposure. A smoke-exposed ligature model of periodontitis shows promise as a tool with which to further unravel mechanisms underlying tobacco-enhanced, bacteria-induced disease.

27-GAUGE PARS PLANA/PLICATA VITRECTOMY FOR PEDIATRIC VITREORETINAL SURGERY.

PURPOSE: To report on the feasibility of 27-gauge (G) vitrectomy for pediatric patients. METHODS: This study is an international, multicenter, retrospective, interventional case series. Participants were patients 17 years or younger who underwent 27-G vitrectomy for various indications. RESULTS: The records of 56 eyes from 47 patients were reviewed. Mean age was 5.7 ± 5.2 years. Diagnoses included retinopathy of prematurity (Stages 3 with vitreous hemorrhage, 4A, 4B, and 5), Terson's syndrome, traumatic macular hole, posterior capsular opacification, endophthalmitis, and others. Instruments used were the 27-G infusion, 27-G vitreous cutter, 27-G light pipe, and 27-G internal limiting membrane forceps. Instrument bending was noted in one (1.8%) case. There were no cases with intraoperative complications, infusion issues, or postoperative endophthalmitis. There were 67/145 (46%) sclerotomies that required suturing, of which most (51/145) were sutured out of precaution. There were four cases (7.1%) that required conversion to a larger gauge and three cases (5.3%) that developed postoperative hypotony. Mean visual acuity improved from logarithm of the minimum angle of resolution 1.32 (20/420) to 0.72 (20/105), after a mean follow-up of 125.1 days (P = 0.01). Anatomic success was achieved in 96.4% of eyes after a single surgery. CONCLUSION: Twenty-seven-gauge vitrectomy was safe and feasible in selected pediatric vitreoretinopathies. Further studies are warranted to examine indications and outcomes.

Liver fibrosis for the dermatologist: a review.

Methotrexate-induced liver fibrosis is not a well-defined pathology, and many of the reported cases can instead be classified as nonalcoholic fatty liver disease by current diagnostic criteria, which is particularly common in the psoriasis cohort. Liver fibrosis usually takes many years to progress; therefore, screening for liver fibrosis should be done no more regularly than annually at the very most in dermatology practice. An algorithm is presented about how to investigate abnormal liver blood tests and screening tools for liver fibrosis are compared.

Association of left atrial strain by cardiovascular magnetic resonance with recurrence of atrial fibrillation following catheter ablation.

BACKGROUND: Atrial fibrillation (AF) is a progressive condition, which is characterized by inflammation/fibrosis of left atrial (LA) wall, an increase in the LA size/volumes, and decrease in LA function. We sought to investigate the relationship of anatomical and functional parameters obtained by cardiovascular magnetic resonance (CMR), with AF recurrence in paroxysmal AF (pAF) patients after catheter ablation. METHODS: We studied 80 consecutive pAF patients referred for ablation, between January 2014 and December 2019, who underwent pre- and post-ablation CMR while in sinus rhythm. LA volumes were measured using the area-length method and included maximum, minimum, and pre-atrial-contraction volumes. CMR-derived LA reservoir strain (ℇR), conduit strain (ℇCD), and contractile strain (ℇCT) were measured by computer assisted manual planimetry. We used a multivariate logistical regression to estimate the independent predictors of AF recurrence after ablation. RESULTS: Mean age was 58.6 ± 9.4 years, 75% men, mean CHA2DS2-VASc score was 1.7, 36% had prior cardioversion and 51% were taking antiarrhythmic drugs. Patients were followed for a median of 4 years (Q1-Q3 = 2.5-6.2 years). Of the 80 patients, 21 (26.3%) patients had AF recurrence after ablation. There were no significant differences between AF recurrence vs. no recurrence groups in age, gender, CHA2DS2-VASc score, or baseline comorbidities. At baseline, patients with AF recurrence compared to without recurrence had lower LV end systolic volume index (32 ± 7 vs 37 ± 11 mL/m2; p = 0.045) and lower ℇCT (7.1 ± 4.6 vs 9.1 ± 3.7; p = 0.05). Post-ablation, patients with AF recurrence had higher LA minimum volume (68 ± 32 vs 55 ± 23; p = 0.05), right atrial volume index (62 ± 20 vs 52 ± 19 mL/m2; p = 0.04) and lower LA active ejection fraction (24 ± 8 vs 29 ± 11; p = 0.05), LA total ejection fraction (39 ± 14 vs 46 ± 12; p = 0.02), LA expansion index (73.6 ± 37.5 vs 94.7 ± 37.1; p = 0.03) and ℇCT (6.2 ± 2.9 vs 7.3 ± 1.7; p = 0.04). Adjusting for clinical variables in the multivariate logistic regression model, post-ablation minimum LA volume (OR 1.09; CI 1.02-1.16), LA expansion index (OR 0.98; CI 0.96-0.99), and baseline ℇR (OR 0.92; CI 0.85-0.99) were independently associated with AF recurrence. CONCLUSION: Significant changes in LA volumes and strain parameters occur after AF ablation. CMR derived baseline ℇR, post-ablation minimum LAV, and expansion index are independently associated with AF recurrence.

Assessment of Intraparenchymal Injection of 1% Patent Blue Dye in the Upper Outer Quadrant of the Breast to Identify Sentinel Lymph Node in Early Retro-Areolar Breast Cancer in Women: A Tertiary Centre Experience in Egypt.

BACKGROUND: Sentinel lymph node biopsy is the gold standard for axillary assessment of patients with clinically node negative breast cancer. The current internationally accepted methods comprise of the usage of either a radioactive tracer, vital stains or the combination of both. However, in developing countries radioactive tracer is not widely used due to its high cost and limited availability. In addition, the classic retro-areolar blue dye injection has a high failure rate. OBJECTIVE: Our study aimed to assess the efficacy of patent blue dye injection in the upper outer quadrant of the breast after validation by concurrent usage of radioactive nanocolloid, in comparison with the classic retro-areolar injection in identifying the sentinel node. METHODS: A randomized control study involving 279 patients randomly divided into two groups. In group A lateral injection of 1% patent blue dye (validated by radioactive nanocolloid) was used, while subdermal patent blue dye injection in the retro-areolar space was performed in group B. RESULTS: The new technique showed the promising results with lower failure rate (3.4%) in comparison with the classic retro-areolar patent blue injection (13.7%). CONCLUSIONS: The lateral injection technique can be result in comparable results to the combination technique with the added benefit of being widely available and a cheaper option especially in developing countries.

Drotaverine Hydrochloride Superporous Hydrogel Hybrid System: a Gastroretentive Approach for Sustained Drug Delivery and Enhanced Viscoelasticity.

This study aims to prepare drotaverine hydrochloride superporous hydrogel hybrid systems (DSHH systems) to prolong its residence time in the stomach, provide extended release and reduce its frequency of administration. Drotaverine hydrochloride (DRH) is a spasmolytic drug that suffers from brief residence due to intestinal hypermotility during diarrheal episodes associated with gastrointestinal colics resulting in low bioavailability and repeated dosing. Eight DSHH systems were prepared using gas blowing technique. The prepared DSHH systems were evaluated regarding their morphology, incorporation efficiency, density, porosity, swelling ratio, viscoelastic property, erosion percentage and release kinetics. The FH8 formula containing equal proportion of chitosan (3%) /polyvinyl alcohol (3%) as strengthener and crosslinked with tripolyphosphate showed the highest incorporation efficiency (91.83 ± 1.33%), good swelling ratio (28.32 ± 3.15% after 24 h), optimum viscoelastic properties (60.19 ± 3.82 kPa) and sustained release profile (88.03 ± 2.15% after 24 h). A bioequivalence study was done to compare the bioavailability of the candidate formula versus Spasmocure®. Statistical analysis showed significant (P < 0.05) increase in bioavailability 2.7 folds with doubled Tmax (4 h) compared to the marketed product (2 h). These results declared that the superporous hydrogel hybrid systems could be a potential gastroretentive approach for the sustained delivery of drugs with short residence time with enhanced viscoelasticity.

[Bilateral periostitis and arthritis: about a case of hypertrophic osteoarthropathy]. / Périostite bilatérale et polyarthrite : à propos d'un cas d'ostéoarthropathie hypertrophique pneumique.

We report the case of a 67-year-old female patient presenting swelling of the hands and feet and pain in both legs. Clinical examination and bone scintigraphy identify the triad "digital clubbing - arthritis - bilateral periostitis of the long bones", leading to a diagnosis of hypertrophic osteoarthropathy, a syndrome usually associated with pulmonary neoplasia. The thoracic CT-scan, followed by a biopsy, effectively diagnosed a right upper lobe adenocarcinoma. Surgical treatment of the neoplasia allowed the resolution of the clinical complaints and the pathological scintigraphic findings.

Nous rapportons le cas d'une patiente de 67 ans présentant des gonflements des mains et des pieds ainsi que des douleurs des deux jambes. L'examen clinique et la scintigraphie osseuse identifient la triade «hippocratisme digital - arthrites - périostite bilatérale des os longs¼, permettant de poser un diagnostic d'ostéoarthropathie hypertrophique, un syndrome habituellement associé à une néoplasie pulmonaire. Le scanner thoracique, suivi d'une biopsie, ont en effet diagnostiqué un adénocarcinome localisé au niveau du lobe supérieur droit. La prise en charge chirurgicale de la néoplasie a permis la résolution des plaintes cliniques et de l'aspect scintigraphique pathologique.

In-hospital outcomes of percutaneous mitral valve repair in patients with chronic obstructive pulmonary disease: insights from the national inpatient sample database.

OBJECTIVES: We aimed to assess the in-hospital outcomes in patients with mitral regurgitation treated with percutaneous mitral valve repair (PMVR) among patients with chronic obstructive pulmonary disease (COPD). BACKGROUND: There is lack of data on the outcomes of PMVR for mitral regurgitation in patients with COPD. METHODS: We analyzed the national inpatient sample (NIS) database from January 2012 to December 2016. RESULTS: A total of 9125 patients underwent PMVR in the period between January 2012 and December 2016, of whom 2,495 (27.3%) patients had concomitant COPD. Comparing COPD patients to non-COPD patients, COPD patients had higher proportion of females (48.3% vs. 46.6%, p = .16), were younger (75.8 ± 10.0 years vs. 76.4 ± 12.2 years; p = .04), had higher prevalence of peripheral vascular disease (17.4% vs. 13.5%; p < .01) and renal failure (39.3% vs. 37%; p < .01). After propensity matching, there was no significant difference in mortality among the COPD group versus non-COPD patients (2.6% vs. 2.9%; p = .6). Patients with COPD had higher proportion of in-hospital morbidities including St-segment elevation myocardial infarction (1.8% vs. 1.0%; p = .02), cardiogenic shock (1.4% vs. 0.4%; p < .01), vascular complications (2% vs. 0.8; p < .01), pneumothorax (1% vs. 0.4%; p < .01), and septic shock (1.2% vs. 0.4%; p < .01). Moreover, surrogates of severe disability (mechanical intubation and non-home discharges), cost of hospitalization, and length of stay were higher in the COPD group. CONCLUSIONS: There was no difference in mortality between the COPD and non-COPD patients after PMVR. Moreover, we observed higher rates of in-hospital morbidities, surrogates of severe disability, and higher resources utilization by the COPD group.

Maternal and neonatal outcomes in planned versus emergency cesarean delivery for placenta accreta spectrum: A multinational database study.

INTRODUCTION: Placenta accreta spectrum (PAS) is a condition often resulting in severe maternal morbidity. Scheduled delivery by an experienced team has been shown to improve maternal outcomes; however, the benefits must be weighed against the risk of iatrogenic prematurity. The aim of this study is to investigate the rates of emergency delivery seen for antenatally suspected PAS and compare the resulting outcomes in the 15 referral centers of the International Society for PAS (IS-PAS). MATERIAL AND METHODS: Fifteen centers provided cases between 2008 and 2019. The women included were divided into two groups according to whether they had a planned or an emergency cesarean delivery. Delivery was defined as "planned" when performed at a time and date to suit the team. All the remaining cases were classified as "emergency". Maternal characteristics and neonatal outcomes were compared between the two groups according to gestation at delivery. RESULTS: In all, 356 women were included. Of these, 239 (67%) underwent a planned delivery and 117 (33%) an emergency delivery. Vaginal bleeding was the indication for emergency delivery in 41 of the 117 women (41%). There were no significant differences in terms of blood loss, transfusion rates or major maternal morbidity between planned and emergency deliveries. However, the rate of maternal intensive therapy unit admission was increased with emergency delivery (45% vs 33%, P = .02). Antepartum hemorrhage was the only independent predictor of emergency delivery (aOR: 4.3, 95% confidence interval 2.4-7.7). Emergency delivery due to vaginal bleeding was more frequent with false-positive cases (antenatally suspected but not confirmed as PAS at delivery) and the milder grades of PAS (accreta/increta). The rate of infants experiencing any major neonatal morbidity was 25% at 34+1 to 36+0  weeks and 19% at >36+0  weeks. CONCLUSIONS: Emergency delivery in centers of excellence did not increase blood loss, transfusion rates or maternal morbidity. The single greatest risk factor for emergency delivery was antenatal hemorrhage. When adequate expertise and resources are available, to defer delivery in women with no significant antenatal bleeding and no risk factors for pre-term birth until >36+0  weeks can be considered to improve fetal outcomes. Further studies are needed to investigate this fully.

ENDOPHTHALMITIS AFTER INTRAVITREAL INJECTIONS DURING THE COVID-19 PANDEMIC WITH IMPLEMENTATION OF UNIVERSAL MASKING.

PURPOSE: To evaluate the rates of postintravitreal injection-related endophthalmitis during the COVID-19 pandemic with institution of both physician and patient face masking. METHODS: All eyes receiving intravitreal injections of any kind from a single large tertiary retina practice in Houston, TX before (August 2017-March 22, 2020) and after (March 23, 2020-September 2020) COVID-19 pandemic universal masking protocols. The total number of injections and cases of acute injection-related endophthalmitis were determined from billing records and subsequent retrospective chart review. The primary outcome was the rate of endophthalmitis after intravitreal injection. Secondary outcomes included visual acuity, time until initial presentation, patient age, and differences in the overall number of injections performed monthly pre-COVID-19 and post-COVID-19. RESULTS: A total of 134, 097 intravitreal injections were performed during the study period (111,679 pre-COVID-19 and 22,418 post-COVID-19 masking protocols). A total of 41 cases of acute endophthalmitis occurred in the pre-COVID group (0.04%, one in 2,500) and 7 cases in the post-COVID group (0.03%, one in 3,333) P = 0.85. CONCLUSION: In this single center, retrospective study, the implementation of universal patient and physician masking as practiced during the COVID-19 pandemic did not significantly affect the rate of postintravitreal injection endophthalmitis.

Characteristic Visual Field Defect From Lateral Geniculate Body Stroke.

ABSTRACT: A 58-year-old man presented with a complaint of subjective visual field loss on the right side and hypertensive emergency. Examination revealed a right homonymous hemianopia. Computed tomography imaging revealed an acute stroke of the left lateral geniculate body. A few months later, automated perimetry revealed characteristic visual field changes associated with this lesion. In this report, the anatomy, pathophysiology, clinical findings, and previously reported etiologies of lateral geniculate body lesions are reviewed.

Eyebrow supraorbital keyhole craniotomy for olfactory groove meningiomas with endoscope assistance: case series and systematic review of extent of resection, quantification of postoperative frontal lobe injury, anosmia, and recurrence.

BACKGROUND: Olfactory groove meningiomas (OGMs) are commonly treated with open craniotomy. Endonasal approaches have also been described. OBJECTIVE: To present clinical and radiographic outcomes for the minimally invasive eyebrow incision supraorbital keyhole approach with endoscopic assistance for OGMs. METHODS: We performed a retrospective single-center cohort study and a systematic literature review. RESULTS: Fifteen patients were identified, all with Grade I meningiomas. Radiographic gross total resection of enhancing tumor was achieved in all patients. Mean frontal lobe fluid-attenuated inversion recovery volume decreased from 11.1 ± 18.3 cm3 preoperatively to 9.9 ± 11.4 cm3 immediately postoperatively, and there was minimal new restricted diffusion (3.2 ± 2.2 cm3; max 7.5 cm3). Median length of stay was 3 days (range 2-8). Vision was improved in 4 (80%) and stable in 1 (20%) of 5 patients with a preoperative deficit. New postoperative anosmia occurred in 3 (23%) of 13 patients with any preoperative olfaction. All patients were satisfied with their cosmetic result at 3 months. After a median follow-up of 32.2 months, there were 2 (13.3%) asymptomatic radiographic recurrences, 1 treated with radiosurgery and the other with endoscopic endonasal approach (EEA). No patients required further craniotomy. Systematic review revealed the present series to be the largest to date reporting disaggregated outcomes for the eyebrow approach to OGM. CONCLUSION: The eyebrow incision supraorbital keyhole craniotomy with endoscopic assistance is a safe and effective approach to OGM with tumor control rates similar to more invasive open approaches and better than the endonasal approach. Rates of frontal lobe injury, CSF leak and anosmia are comparatively low.

Induced Hypothermia in Patients with Cardiac Arrest and a Non-shockable Rhythm: Meta-analysis and Trial Sequential Analysis.

BACKGROUND: Controversy surrounds utilization of induced hypothermia (IHT) in comatose cardiac arrest (CA) survivors with a non-shockable rhythm. METHODS: We conducted a meta-analysis and trial sequential analysis (TSA) comparing IHT with no IHT approaches in patients with CA and a non-shockable rhythm. The primary outcome of interest was favorable neurological outcomes (FNO) defined using the Cerebral Performance Category (CPC) score of 1 or 2. Secondary endpoints were survival at discharge and survival beyond 90 days. RESULTS: A total of 9 studies with 10,386 patients were included. There was no difference between both groups in terms of FNO (13% vs. 13%, RR 1.34, 95% CI 0.96-1.89, p = 0.09, I2 = 88%), survival at discharge (20% vs. 22%, RR 1.09, 95% CI 0.88-1.36, p = 0.42, I2 = 76%), or survival beyond 90 days (16% vs. 15%, RR 0.92, 95% CI 0.61-1.40, p = 0.69, I2 = 83%). The TSA showed firm evidence supporting the lack of benefit of IHT in terms of survival at discharge. However, the Z-curves failed to cross the conventional and TSA (futility) boundaries for FNO and survival beyond 90 days, indicating lack of sufficient evidence to draw firm conclusions regarding these outcomes. CONCLUSION: In this meta-analysis of 9 studies, the utilization of IHT was not associated with a survival benefit at discharge. Although the meta-analysis showed lack of benefit of IHT in terms of FNO and survivals beyond 90 days, the corresponding TSA showed high probability of type-II statistical error, and therefore more randomized controlled trials powered for these outcomes are needed.

Gastric cancer during pregnancy: A report on 13 cases and review of the literature with focus on chemotherapy during pregnancy.

INTRODUCTION: Gastric cancer during pregnancy is extremely rare and data on optimal treatment and possible chemotherapeutic regimens are scarce. The aim of this study is to describe the obstetric and maternal outcome of women with gastric cancer during pregnancy and review the literature on antenatal chemotherapy for gastric cancer. MATERIAL AND METHODS: Treatment and outcome of patients registered in the International Network on Cancer, Infertility and Pregnancy database with gastric cancer diagnosed during pregnancy were analyzed. RESULTS: In total, 13 women with gastric cancer during pregnancy were registered between 2002 and 2018. Median gestational age at diagnosis was 22 weeks (range 6-30 weeks). Twelve women were diagnosed with advanced disease and died within 2 years after pregnancy, most within 6 months. In total, eight out of 10 live births ended in a preterm delivery because of preeclampsia, maternal deterioration, or therapy planning. Two out of six women who initiated chemotherapy during pregnancy delivered at term. Two neonates prenatally exposed to chemotherapy were growth restricted and one of them developed a systemic infection with brain abscess after preterm delivery for preeclampsia 2 weeks after chemotherapy. No malformations were reported. CONCLUSIONS: The prognosis of gastric cancer during pregnancy is poor, mainly due to advanced disease at diagnosis, emphasizing the need for early diagnosis. Antenatal chemotherapy can be considered to reach fetal maturity, taking possible complications such as growth restriction, preterm delivery, and hematopoietic suppression at birth into account.

Drusen in patient-derived hiPSC-RPE models of macular dystrophies.

Age-related macular degeneration (AMD) and related macular dystrophies (MDs) are a major cause of vision loss. However, the mechanisms underlying their progression remain ill-defined. This is partly due to the lack of disease models recapitulating the human pathology. Furthermore, in vivo studies have yielded limited understanding of the role of specific cell types in the eye vs. systemic influences (e.g., serum) on the disease pathology. Here, we use human induced pluripotent stem cell-retinal pigment epithelium (hiPSC-RPE) derived from patients with three dominant MDs, Sorsby's fundus dystrophy (SFD), Doyne honeycomb retinal dystrophy/malattia Leventinese (DHRD), and autosomal dominant radial drusen (ADRD), and demonstrate that dysfunction of RPE cells alone is sufficient for the initiation of sub-RPE lipoproteinaceous deposit (drusen) formation and extracellular matrix (ECM) alteration in these diseases. Consistent with clinical studies, sub-RPE basal deposits were present beneath both control (unaffected) and patient hiPSC-RPE cells. Importantly basal deposits in patient hiPSC-RPE cultures were more abundant and displayed a lipid- and protein-rich "drusen-like" composition. Furthermore, increased accumulation of COL4 was observed in ECM isolated from control vs. patient hiPSC-RPE cultures. Interestingly, RPE-specific up-regulation in the expression of several complement genes was also seen in patient hiPSC-RPE cultures of all three MDs (SFD, DHRD, and ADRD). Finally, although serum exposure was not necessary for drusen formation, COL4 accumulation in ECM, and complement pathway gene alteration, it impacted the composition of drusen-like deposits in patient hiPSC-RPE cultures. Together, the drusen model(s) of MDs described here provide fundamental insights into the unique biology of maculopathies affecting the RPE-ECM interface.

Imaging individual neurons in the retinal ganglion cell layer of the living eye.

Although imaging of the living retina with adaptive optics scanning light ophthalmoscopy (AOSLO) provides microscopic access to individual cells, such as photoreceptors, retinal pigment epithelial cells, and blood cells in the retinal vasculature, other important cell classes, such as retinal ganglion cells, have proven much more challenging to image. The near transparency of inner retinal cells is advantageous for vision, as light must pass through them to reach the photoreceptors, but it has prevented them from being directly imaged in vivo. Here we show that the individual somas of neurons within the retinal ganglion cell (RGC) layer can be imaged with a modification of confocal AOSLO, in both monkeys and humans. Human images of RGC layer neurons did not match the quality of monkey images for several reasons, including safety concerns that limited the light levels permissible for human imaging. We also show that the same technique applied to the photoreceptor layer can resolve ambiguity about cone survival in age-related macular degeneration. The capability to noninvasively image RGC layer neurons in the living eye may one day allow for a better understanding of diseases, such as glaucoma, and accelerate the development of therapeutic strategies that aim to protect these cells. This method may also prove useful for imaging other structures, such as neurons in the brain.

Acellular dermal matrix as an alternative to autologous fascia lata for skull base repair following extended endoscopic endonasal approaches.

BACKGROUND: Skull base reconstruction after extended endoscopic endonasal approaches (EEAs) can be challenging. In addition to the nasoseptal flap, which has been adopted by most centers, autologous fascia lata is also often utilized. Harvesting of fascia lata requires a separate thigh incision, may prolong recovery, and results in a visible scar. In principal, the use of non-autologous materials would be preferable to avoid a second incision and maintain the minimally invasive nature of the approach, assuming the CSF leak rate is not compromised. OBJECTIVE: To assess the efficacy of acellular dermal matrix (ADM) as a non-autologous alternative to autologous fascia lata graft for watertight closure of the cranial base following EEAs. METHODS: A retrospective chart review of extended EEAs performed before and after the transition from fascia lata to ADM was performed. Cases were frequency matched for approach, pathology, BMI, use of lumbar drainage, and tumor volume. Power analysis was performed to estimate the sample size needed to demonstrate non-inferiority. RESULTS: ADM was used for watertight closure of the cranial base in 19 consecutive extended endoscopic endonasal approaches (16 gasket-seals and 3 buttons) with 1 postoperative CSF leak at the last follow-up (median 5.3, range 1.0-12.6 months). All patients had high-flow intraoperative leaks. The cohort included 8 meningiomas, 8 craniopharyngiomas, 2 chordomas, and 1 pituicytoma ranging in size from 0.2 to 37.2cm3 (median 5.5, IQR 2.8-13.3 cm3). In 19 historical controls who received fascia lata, there were 2 postoperative CSF leaks. CONCLUSIONS: Preliminary results suggest that ADM provides a non-inferior non-autologous alternative to fascia lata for watertight gasket-seal and button closures following extended EEAs, potentially reducing or eliminating the need to harvest autologous tissue.

The slope of the learning curve in 600 consecutive endoscopic transsphenoidal pituitary surgeries.

BACKGROUND: Endonasal endoscopic transsphenoidal surgery (EETS) for pituitary adenoma has become a mainstay of treatment over the last two decades and it is generally accepted that once this learning curve is achieved, a plateau is reached with little incremental improvement. OBJECTIVE: The objective of this study was to assess the slope of the learning curve over a long period of time for a variety of outcomes measures. METHODS: We examined outcomes and complications in a consecutive series of 600 EETS for pituitary adenoma grouped into quartiles based on date of surgery. RESULTS: GTR significantly increased across quartiles from 55 to 79% in the last quartile (p < 0.005). The rate of intraoperative CSF leak significantly decreased from 60% in the first quartile to 33% in the last quartile and the rate of lumbar drain placement from 28% in the first quartile to 6% in the last quartile (p < 0.005). Hormonal remission for secreting adenomas increased from 68% in the first quartile to 90% in the last quartile (p < 0.05). The rate of post-operative CSF leak trended lower (3% in first quartile to 0.7% in last two quartiles). The greatest improvement in outcome occurred between the first and second quartiles (19.9%), but persistent improvement occurred between the second and third (6.7%) and third and fourth quartiles (8.0%). CONCLUSION: Although the slope of the learning curve is steeper earlier in a surgeon's experience, the slope does not plateau and continues to increase even over more than a decade.