Detailed Phenotype Supports Pathogenicity of Hypomorphic Variant in ABCC6-Associated Pattern Dystrophy.

Introduction: We report a case of pseudoxanthoma elasticum (PXE) with an atypical phenotype likely related to a hypomorphic variant in ABCC6. Case Presentation: A 66-year-old Caucasian female with a history of a maculopathy interpreted as either age-related macular degeneration or a pattern dystrophy underwent a detailed ophthalmic evaluation. Visual acuities were 20/25, OD, and 20/20, OS. Spectral domain optical coherence and fluorescein angiography demonstrated outer retinal disruptions and breaks in retinal pigment epithelium (RPE)/Bruch's membrane bilaterally, consistent with angioid streaks. A large area of hypo- and hyperautofluorescence extending from the central retina into the peripapillary retina was documented with short-wavelength excitation autofluorescence. The area of hypoautofluorescence, which was much larger on near-infrared excitation, spared the temporal retina. Two-color dark-adapted perimetries documented severe rod sensitivity losses and less severe cone sensitivity abnormalities co-localizing with the RPE abnormalities. No obvious skin findings were observed, and initial dermatologic biopsy was negative. Gene screening identified a pathogenic ABCC6 gene variant c.1552C>T and a previously reported variant of uncertain significance c.1171A>G. A second dermatologic biopsy demonstrated positive findings consistent with PXE. Conclusion: Although this patient had minimal skin findings, this patient had characteristic structural and functional abnormalities of a pattern dystrophy with angioid streaks and histologic evidence of PXE, suggesting compound heterozygous variants involving the hypomorphic ABCC6 c.1171A>G variant. These findings support the pathogenic role of both variants.

FACTORS ASSOCIATED WITH OUTCOMES OF SUPRACHOROIDAL HEMORRHAGE: An Individual Participant Data Systematic Review.

PURPOSE: To determine factors associated with visual and anatomic outcomes of suprachoroidal hemorrhage in studies published between 1990 and 2022. METHODS: Individual participant data systematic review. The protocol was prospectively registered on Open Science Framework ( https://osf.io/69v3q/ ). PubMed, EMBASE, Web of Science, and Google Scholar were searched for peer-reviewed studies of suprachoroidal hemorrhage with ≥3 patients published between January 1, 1990, and September 1, 2022. The primary outcome was the change in logarithm of the minimum angle of resolution visual acuity from the time of suprachoroidal hemorrhage diagnosis to last follow-up. RESULTS: Four hundred thirteen eyes from 49 studies were included, with mean (SD) age 60.8 (22.4) years and mean (SD) follow-up of 13.8 (12.6) months. Among 145 eyes with at least 6 months of follow-up, the mean (SD) gain in visual acuity was -0.98 (0.89) logarithm of the minimum angle of resolution. In multivariable regression, treatment with systemic steroids was associated with greater improvement in logarithm of the minimum angle of resolution visual acuity (adjusted mean [SE] -1.29 [0.09] vs. -0.16 [0.30] for no systemic steroids; P < 0.001) and greater odds of achieving anatomic success (adjusted OR 10.59, 95% confidence interval 2.59-43.3; P = 0.001). CONCLUSION: The use of systemic steroids was associated with better visual and anatomic outcomes for suprachoroidal hemorrhage.

A Scan of Pleiotropic Immune Mediated Disease Genes Identifies Novel Determinants of Baseline FVIII Inhibitor Status in Hemophilia-A.

Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called "FVIII-inhibitors (FEIs)" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and F8-mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects-206 with black-African-ancestry and 244 with white-European-ancestry-was the dependent variable. The F8-mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to NOS2A (rs117382854; p=3.2E-6) and B3GNT2 (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with CTLA4 assigned SNPs (p=2.2E-5). The F8-mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of F8-mutation-effects and non-F8-genetics.

OUTER RETINOPATHY AND MICROANGIOPATHY IN ACUTE MYELOGENOUS LEUKEMIA.

PURPOSE: To describe a patient with acute myelogenous leukemia who presented with a recurrent, bilateral, outer retinopathy, before and after consolidative peripheral blood stem cell transplantation complicated by chronic graft-versus-host disease. METHODS: This is a retrospective review of records from a 23-year-old woman with acute myelogenous leukemia who underwent comprehensive ophthalmic evaluations for over a year including chromatic perimetry and multifocal electroretinograms, imaging with spectral domain optical coherence tomography, near-infrared and short-wavelength fundus reflectance and autofluorescence, fluorescein and optical coherence tomography angiography. RESULTS: The patient presented with recurrent, unilateral paracentral scotomas. There was localized loss of inner segment ellipsoid (EZ) and photoreceptor outer segment signals (IZ) in the pericentral retina of both eyes co-localizing with hyperreflective lesions on near-infrared reflectance. She subsequently lost vision (visual acuity = 20/200) in the right eye a year after consolidative peripheral blood stem cell transplantation complicated by steroid-resistant-chronic graft-versus-host disease. There was loss of the EZ and IZ signals corresponding to a dense central cone scotoma and multifocal electroretinograms depression. Near-infrared autofluorescence, fluorescein and optical coherence tomography angiography were within normal limits. Visual acuity (20/20) and retinal sensitivities improved with restoration of the EZ/IZ signals after oral prednisone and intravenous rituximab, but left a residual photoreceptor loss and paracentral scotoma. CONCLUSION: We propose that an immune-mediated microangiopathy may explain the protracted, recurrent course of primary photoreceptor abnormalities in our patient, which was further complicated by manifestations of chronic graft-versus-host disease following consolidative peripheral blood stem cell transplantation. Outer retinal findings previously documented in leukemia may be explained by a similar mechanism.

Bilateral retinal hemorrhages after sequential endovascular treatment of bilateral unruptured cerebral aneurysms.

PURPOSE: To report a case of bilateral retinal hemorrhages in a patient undergoing two separate endovascular interventions for bilateral cerebral aneurysms. METHODS: A comprehensive ophthalmic examination was performed after the patient underwent each of two separate endovascular interventions for bilateral cerebral aneurysms. Multimodal imaging including widefield pseudocolor fundus photography, optical coherence tomography, and widefield fluorescein angiography (FA) was obtained. A systemic workup including genetic testing and hypercoagulability studies was performed. RESULTS: Dilated fundus examination revealed new visually significant ipsilateral retinal hemorrhages after each endovascular procedure. FA showed evidence of a peripheral retinal microangiopathy present in both eyes before the patient underwent her second endovascular procedure. Systemic workup revealed persistently elevated serum anticardiolipin IgM antibody levels at >99th percentile. CONCLUSION: Retinal complications after endovascular intracranial interventions are uncommon. This patient who developed bilateral retinal complications was found to have persistently elevated anticardiolipin antibody levels, a risk factor for thrombosis. Patients who develop retinal complications after endovascular intracranial intervention may benefit from systemic workup for hypercoagulable conditions.

Comparison of satisfaction with penile prosthesis implantation in patients with prostate cancer radiation therapy versus radical prostatectomy.

Background: Penile prosthesis surgery (PPS) is a commonly used treatment for erectile dysfunction (ED), either as first-line therapy or in cases refractory to other treatment options. In patients with a urologic malignancy such as prostate cancer, surgical interventions like radical prostatectomy (RP) as well as non-surgical treatments such as radiation therapy can all induce ED. PPS as a treatment for ED has high satisfaction rates in the general population. Our aim was to compare sexual satisfaction in patients with prosthesis implantation for ED following RP versus ED following radiation therapy for prostate cancer. Methods: A retrospective chart review from our institutional database was conducted to identify patients who underwent PPS at our institution from 2011 to 2021. Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire data at least 6 months from implant operative date available was required for inclusion. Eligible patients were placed in one of two groups depending on etiology of ED-following RP or prostate cancer radiation therapy. To prevent crossover confounding; patients with history of pelvic radiation were excluded from the RP group and patients with history of RP were excluded from the radiation group. Data were obtained from 51 patients in the RP group and 32 patients in the radiation therapy group. Mean EDITS scores and additional survey questions were compared between the radiation and RP groups. Results: There was a significant difference in mean survey responses for 8 of the 11 questions in the EDITS questionnaire between the RP group and the radiation group. Additional survey questions administered also found RP patients reported significantly higher rate of satisfaction with size of penis post-operatively versus the radiation group. Conclusions: These preliminary findings, while requiring large-scale follow-up, suggest that there is greater sexual satisfaction and penile prosthesis device satisfaction in patients undergoing IPP placement following RP versus radiation therapy for prostate cancer. Use of validated questionnaires should continue to be utilized in quantifying device and sexual satisfaction following PPS.

Using Immersive Virtual Reality to Enhance Social Interaction Among Older Adults: A Cross-Site Investigation.

Background and Objectives: Virtual reality (VR) applications are increasingly being targeted toward older adults as a means to maintain physical and cognitive skills and to connect with others, especially during the coronavirus disease 2019 era. Our knowledge about how older adults interact with VR is limited, however, since this is an emerging area and the related research literature is still rather slim. The current study focused specifically on older adults' reactions to a social-VR environment, examining participant's views about the possibility of meaningful interactions in this format, the impacts of social-VR immersion on mood and attitude, and features of the VR environment that affected these outcomes. Research Design and Methods: The researchers designed a novel social-VR environment with features intended to prompt conversation and collaborative problem-solving among older adults. Participants were recruited from 3 diverse geographic locations (Tallahassee, FL; Ithaca, NY; and New York City, NY), and were randomly assigned to a partner from one of the other sites for social-VR interaction. The sample consisted of 36 individuals aged 60 and older. Results: Reactions to the social VR were quite positive. Older adults reported high levels of engagement in the environment and perceived the social VR to be enjoyable and usable. Perceived spatial presence was found to be a central driver of positive outcomes. A majority of the participants indicated a willingness to reconnect with their VR partner in the future. The data also identified important areas for improvement that were of concern to older adults, such as the use of more realistic avatars, larger controllers more suited to aging hands, and more time for training/familiarization. Discussion and Implications: Overall, these findings suggest that VR can be an effective format for social engagement among older adults.

COMBINED RHEGMATOGENOUS RETINAL AND CHOROIDAL DETACHMENT: A Systematic Review.

PURPOSE: To review the literature on eyes with concurrent rhegmatogenous retinal and choroidal detachment (RRD-CD). METHODS: Several databases were searched for "rhegmatogenous retinal detachment" and "choroidal detachment" through October 2022. All English language primary literature was reviewed. RESULTS: Studies demonstrated that eyes with RRD-CD were very uncommon and had diminished baseline visual acuity (VA) and intraocular pressure (IOP) compared with eyes with RRD only. Although no randomized trials have been performed, pars plana vitrectomy with or without scleral buckle (SB) have reported higher surgical success rates than SB alone. Reattachment rates were affected by age, IOP, adjuvant steroids, and grade of proliferative vitreoretinopathy. CONCLUSION: Low IOP and poor initial VA are salient features of eyes with RRD-CD. Steroids can be useful adjuvants administered safely using several routes including periocular and intravitreal injection. PPV ± SB may result in best surgical outcomes.

Retinal photoreceptor layer thickness has disease specificity and distinguishes predicted FTLD-Tau from biomarker-determined Alzheimer's disease.

While Alzheimer's disease (AD) is associated with inner retina thinning (retinal nerve fiber layer and ganglion cell layer), we have observed photoreceptor outer nuclear layer (ONL) thinning in patients with frontotemporal lobar degeneration tauopathy (FTLD-Tau) compared to normal controls. We hypothesized that ONL thinning may distinguish FTLD-Tau from patients with biomarker evidence of AD neuropathologic change (ADNC) and will correlate with FTLD-Tau disease severity. Predicted FTLD-Tau (pFTLD-Tau; n = 21; 33 eyes) and predicted ADNC (pADNC; n = 24; 46 eyes) patients were consecutively enrolled, underwent optical coherence tomography macula imaging, and disease was categorized (pFTLD-Tau vs. pADNC) with cerebrospinal fluid biomarkers, genetic testing, and autopsy data when available. Adjusting for age, sex, and race, pFTLD-Tau patients had a thinner ONL compared to pADNC, while retinal nerve fiber layer and ganglion cell layer were not significantly different. Reduced ONL thickness correlated with worse performance on Folstein Mini-Mental State Examination and clinical dementia rating plus frontotemporal dementia sum of boxes for pFTLD-Tau but not pADNC. Photoreceptor ONL thickness may serve as an important noninvasive diagnostic marker that distinguishes FTLD-Tau from AD neuropathologic change.

Visual and Anatomic Outcomes of Suprachoroidal Hemorrhage: A Systematic Review and Meta-Analysis.

TOPIC: To characterize the presentation, management, and outcomes of suprachoroidal hemorrhage (SCH). CLINICAL RELEVANCE: Suprachoroidal hemorrhage is a potentially devastating condition but there is no high-quality evidence for the prognosis or management of SCH. METHODS: We performed a systematic review and meta-analysis of peer-reviewed studies of SCH published in PubMed, EMBASE, Web of Science, or Google Scholar between January 1, 1990, and September 1, 2022. The protocol was prospectively registered on the Open Science Framework (https://osf.io/69v3q/). Random-effects models were used to calculate the pooled estimate and 95% confidence intervals (CIs) for visual acuity (VA) and anatomic outcomes. Univariable and multivariable random-effects meta-regressions were performed to determine factors associated with VA outcomes and anatomic success, defined as the retina attached at the last follow-up. RESULTS: Sixty-eight studies comprising 1246 eyes of 1245 patients were included, with mean (standard deviation [SD]) follow-up of 14.0 (9.4) months. The pooled estimate (95% CI) for mean change in logarithm of the minimum angle of resolution (logMAR) VA from baseline to the last follow-up was -0.98 (-1.22 to -0.74) (I2 = 88.4%), with 72.0% (63.5%-80.5%) (I2 = 74.3%) achieving VA improvement of ≥ 0.3 logMAR (3-line improvement in ETDRS VA), 39.6% (32.5%-46.7%) (I2 = 83.2%) achieving final VA of 1.0 logMAR (Snellen equivalent 20/200) or better, and 75.5% (68.4%-82.7%) (I2 = 74.7%) achieving anatomic success. Studies with predominantly nonspontaneous SCH and greater percent of eyes receiving systemic steroids were associated with greater improvement in logMAR VA, a greater proportion of eyes with VA improvement ≥ 0.3 logMAR, and greater proportion of eyes achieving anatomic success (all P < 0.05 univariable meta-regression). Studies with greater percent of eyes treated surgically were associated with greater proportion of eyes with VA improvement of ≥ 0.3 logMAR in (P < 0.05, univariable and multivariable analysis). The mean (SD) quality score across studies was 13.9 (2.3) out of 24, and outcomes were of very low certainty of evidence. CONCLUSION: Although limited by heterogeneous observational studies, published reports of SCH indicate that most eyes with SCH experience some degree of VA improvement and anatomic success. However, final VA outcomes remain poor, with most cases resulting in severe visual impairment or blindness. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

UTILITY OF OCULAR ß- d -GLUCAN TESTING IN PATIENTS WITH FUNGAL ENDOPHTHALMITIS.

PURPOSE: To assess the diagnostic utility of (1→3)-ß- d -glucan (BDG) in ocular fluid of patients with fungal endophthalmitis. METHODS: This prospective pilot single-center study evaluated aqueous and vitreous humor BDG levels of suspected fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls with the standard Fungitell assay and the Fungitell STAT assay. ß- d -Glucan levels were compared using generalized linear models followed by post hoc pairwise comparisons. RESULTS: Seven fungal endophthalmitis, 6 bacterial endophthalmitis, and 17 noninfectious ocular samples were evaluated. Mean aqueous BDG concentrations were 204, 11.0, and 9.6 pg/mL for fungal endophthalmitis, bacterial endophthalmitis, and noninfectious controls, respectively ( P = 0.01, fungal vs. bacterial; P = 0.0005, fungal vs. noninfectious controls). Mean vitreous BDG concentrations were 165, 30.3, and 5.4 pg/mL, respectively ( P = 0.001 for fungal vs. bacterial; P < 0.0001 for fungal vs. noninfectious controls). Mean vitreous BDG index (Fungitell STAT) values were 1.7, 0.4, and 0.3, respectively ( P = 0.001, fungal vs. bacterial; P = 0.0004, fungal vs. noninfectious controls). The Pearson correlation between BDG levels and BDG index was high (correlation coefficient = 0.99, P < 0.001). CONCLUSION: Significantly elevated ocular BDG levels were found in fungal endophthalmitis compared with bacterial endophthalmitis and noninfectious controls. Our study suggests a potential utility for BDG testing in the diagnosis of fungal endophthalmitis, and a larger study is warranted.

Remission and Relapse of Dyslipidemia After Vertical Sleeve Gastrectomy vs Roux-en-Y Gastric Bypass in a Racially and Ethnically Diverse Population.

Importance: The comparative effectiveness of the most common operations in the long-term management of dyslipidemia is not clear. Objective: To compare 4-year outcomes associated with vertical sleeve gastrectomy (VSG) vs Roux-en-Y gastric bypass (RYGB) for remission and relapse of dyslipidemia. Design, Setting, and Participants: This retrospective comparative effectiveness study was conducted from January 1, 2009, to December 31, 2016, with follow-up until December 31, 2018. Participants included patients with dyslipidemia at the time of surgery who underwent VSG (4142 patients) or RYGB (2853 patients). Patients were part of a large integrated health care system in Southern California. Analysis was conducted from January 1, 2018, to December 31, 2021. Exposures: RYGB and VSG. Main Outcomes and Measures: Dyslipidemia remission and relapse were assessed in each year of follow-up for as long as 4 years after surgery. Results: A total of 8265 patients were included, with a mean (SD) age of 46 (11) years; 6591 (79.8%) were women, 3545 (42.9%) were Hispanic, 1468 (17.8%) were non-Hispanic Black, 2985 (36.1%) were non-Hispanic White, 267 (3.2%) were of other non-Hispanic race, and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 44 (7) at the time of surgery. Dyslipidemia outcomes at 4 years were ascertained for 2168 patients (75.9%) undergoing RYGB and 3999 (73.9%) undergoing VSG. Remission was significantly higher for those who underwent RYGB (824 [38.0%]) compared with VSG (1120 [28.0%]) (difference in the probability of remission, 0.10; 95% CI, 0.01-0.19), with no differences in relapse (455 [21.0%] vs 960 [24.0%]). Without accounting for relapse, remission of dyslipidemia after 4 years was 58.9% (1279) for those who underwent RYGB and 51.9% (2079) for those who underwent VSG. Four-year differences between operations were most pronounced for patients 65 years or older (0.39; 95% CI, 0.27-0.51), those with cardiovascular disease (0.43; 95% CI, 0.24-0.62), or non-Hispanic Black patients (0.13; 95% CI, 0.01-0.25) and White patients (0.13; 95% CI, 0.03-0.22). Conclusions and Relevance: In this large, racially and ethnically diverse cohort of patients who underwent bariatric and metabolic surgery in clinical practices, RYGB was associated with higher rates of dyslipidemia remission after 4 years compared with VSG. However, almost one-quarter of all patients experienced relapse, suggesting that patients should be monitored closely throughout their postoperative course to maximize the benefits of these operations for treatment of dyslipidemia.

Survey of Lifestyle, Past Medical History and Complementary and Alternative Medicine Use Among Adult Patients Participating in the National Cancer Institute's Exceptional Responders Initiative.

INTRODUCTION: The Exceptional Responders Initiative (ERI) at the National Cancer Institute attempts to correlate unusually good outcomes in patients with cancer with genetic targets in tumors and the therapies the patients received. It is not known if other factors might contribute to exceptional responses or outcomes. We explored aspects of the medical history, lifestyle changes, complementary and alternative medicine (CAM) use and communication between health care practitioners and patients who experienced an exceptional response following cancer treatment. METHODS: All subjects whose case was submitted to the ERI were eligible to participate in the survey. A 121-question survey questionnaire was developed to assess aspects of the subject's past medical history, lifestyle (e.g., diet, exercise, spirituality) and use of CAM. RESULTS: Thirty subjects completed and returned the questionnaire from approximately 88 patients invited to participate (approximate response rate = 34%). Approximately 68% were female and 32% were male. Fifty percent of subjects changed their diet after their cancer diagnosis. Eighteen patients (60%) reported using a CAM therapy (not including oral vitamins/minerals or spiritual practices) during their Exceptional Response (ER). CONCLUSION: Multiple factors, including features of the tumor itself, the patient, or the environment, could affect tumor response or patient survival, either solely or in combination with the treatments received. Many patients use other medications, change their diet or physical activity or use CAM interventions after their cancer diagnosis. Investigators attempting to understand the exceptional response phenomenon should acquire rich data sets of their subjects that include information about these factors.

Emerging opportunities for C3 inhibition in the eye.

The eye presents a unique opportunity for complement component 3 (C3) therapeutics. Drugs can be delivered directly to specific parts of the eye, and growing evidence has established a pivotal role for C3 in age-related macular degeneration (AMD). Emerging data show that C3 may be important to the pathophysiology of other eye diseases as well. This article will discuss the location of C3 expression in the eye as well as the preclinical and clinical data regarding C3's functions in AMD. We will provide a comprehensive review of developing C3 inhibitors for the eye, including the Phase 2 and 3 data for the C3 inhibitor pegcetacoplan as a treatment for the geographic atrophy of AMD. Developing evidence also points toward C3 as a therapeutic target for stages of AMD preceding geographic atrophy. We will also discuss data illuminating C3's relationship to other eye diseases, such as Stargardt disease, diabetic retinopathy, and glaucoma. In addition to being a converging point and centerpiece of the complement cascade, C3 has broad effects as a multifaceted controller of opsonophagocytosis, microglia/macrophage recruitment, and downstream terminal pathway activity. C3 is a crucial player in the pathophysiology of AMD but also seems to have importance in other diseases that are major causes of blindness. Directions for further investigation will be highlighted, as culminating evidence suggests that we may be approaching an era of C3 therapeutics for the eye.

Application of in-vitro-cultured primary hepatocytes to evaluate species translatability and AAV transduction mechanisms of action.

Recombinant adeno-associated virus (AAV) is an effective platform for therapeutic gene transfer; however, tissue-tropism differences between species are a challenge for successful translation of preclinical results to humans. We evaluated the use of in vitro primary hepatocyte cultures to predict in vivo liver-directed AAV expression in different species. We assessed whether in vitro AAV transduction assays in cultured primary hepatocytes from mice, nonhuman primates (NHPs), and humans could model in vivo liver-directed AAV expression of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), an experimental gene therapy for hemophilia A with a hepatocyte-selective promoter. Relative levels of DNA and RNA in hepatocytes grown in vitro correlated with in vivo liver transduction across species. Expression in NHP hepatocytes more closely reflected expression in human hepatocytes than in mouse hepatocytes. We used this hepatocyte culture model to assess transduction efficacy of a novel liver-directed AAV capsid across species and identified which of 3 different canine factor VIII vectors produced the most transgene expression. Results were confirmed in vivo. Further, we determined mechanisms mediating inhibition of AAV5-hFVIII-SQ expression by concomitant isotretinoin using primary human hepatocytes. These studies support using in vitro primary hepatocyte models to predict species translatability of liver-directed AAV gene therapy and improve mechanistic understanding of drug-drug interactions.

Comparative effectiveness of gastric bypass and sleeve gastrectomy on predicted 10-year risk of cardiovascular disease 5 years after surgery.

BACKGROUND: Comparative evidence is needed when deciding which bariatric operation to undergo for long-term cardiovascular risk reduction. OBJECTIVES: The Effectiveness of Gastric Bypass vs. Gastric Sleeve for Cardiovascular Disease (ENGAGE CVD) study compared the effectiveness of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) operations for reduction of the American College of Cardiology and the American Heart Association-predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk 5 years after surgery. SETTING: Data for this study came from a large integrated healthcare system in the Southern California region of the United States. This is one of the most ethnically diverse (64% non-White) bariatric populations in the literature. METHODS: The ENGAGE CVD cohort consisted of 22,095 patients who underwent VSG or RYGB from 2009-2016. The VSG and RYGB were compared using a local instrumental variable approach to address observed and unobserved confounding, as well as to conduct heterogeneity of treatment effects for patients of different age groups, baseline-predicted 10-year CVD risk using the ASCVD risk score, and those who had type 2 diabetes (T2D) at the time of surgery. RESULTS: Patients (2771 RYGB and 6256 VVSG) were primarily women (80.6%), Hispanic or non-Hispanic Black (63.7%), and 46 ± 10 years of age, with a body mass index of 43.40 ± 6.5 kg/m2. The predicted 10-year ASCVD risk at surgery was 4.1% for VSG and 5.1% for RYGB, decreasing to 2.6% for VSG and 2.8% for RYGB 1 year postoperatively. By 5 years after surgery, patients remained with relatively low risk levels (3.0% for VSG and 3.3% for RYGB) and there were no significant differences in predicted 10-year ASCVD risk between VSG and RYGB at any time. CONCLUSION: Predicted 10-year ASCVD risk was low in this population and remained low up to 5 years for those with diabetes, Black and Hispanic patients, and older adults. Literature reporting significant differences between VSG and RYGB in 10-year ASCVD risk may be a result of residual confounding.

Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A.

Factor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.6-4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability.

Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study. METHODS: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results. RESULTS: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants. CONCLUSIONS: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).