Blood pressure in persons with haemophilia with a focus on haemophilia-specific risk factors.

INTRODUCTION: Persons with haemophilia (PWH) have a higher prevalence of hypertension compared to the general population, which cannot be explained entirely by the usual cardiovascular risk factors. Neutralizing antibodies (inhibitors) against clotting factors might have some relation to cardiovascular disease in PWH. However, whether inhibitors facilitate hypertension is unknown. AIM: We investigated the relationship between hypertension/blood pressure and inhibitors in PWH. Additional goals were to determine the relationships with haemophilia type, race, and viral status. METHODS: Records were extracted retrospectively for PWH (age ≥18 years) between 2003 and 2014 from four Hemophilia Treatment Centers in North America and included demographics, weight, height, haemophilia type/severity, HCV and HIV infection status, hypertension, use of anti-hypertensive medications, and inhibitor status. We fitted semiparametric generalized additive models (GAMs) to describe adjusted curves of blood pressure (BP) against age. RESULTS: Among 691 PWH, 534 had haemophilia A and 157 had haemophilia B, with a median age of 39 years (range 18 to 79). Forty-four PWH (6.5%) had a history of inhibitors, without evidence for a higher prevalence of hypertension or higher BP. A higher prevalence of hypertension and higher BP were noted for haemophilia A (vs. haemophilia B), coinfection with HCV/HIV (vs. uninfected), or moderate haemophilia (vs. severe haemophilia). CONCLUSION: While there was no signal to suggest that a history of inhibitors is associated with hypertension, differences based on haemophilia type, severity, and viral infection status were identified, encouraging prospective investigations to better delineate haemophilia-specific risk factors for hypertension.

VISUAL AND ANATOMICAL OUTCOMES AFTER DIABETIC TRACTION AND TRACTION-RHEGMATOGENOUS RETINAL DETACHMENT REPAIR.

PURPOSE: To evaluate visual and anatomical outcomes of diabetic tractional retinal detachment repaired with pars plana vitrectomy. METHODS: Operative records were used to retrospectively identify all patients with tractional retinal detachments secondary to proliferative diabetic retinopathy surgically repaired with pars plana vitrectomy between November 1, 2009, and January 1, 2015 at the LAC + USC (Los Angeles County + University of Southern California) Medical Center. RESULTS: A total of 403 eyes with diabetic tractional retinal detachment in 359 patients were included. Successful reattachment of the retina was achieved in 87.6% of eyes after one surgery and 92.6% of eyes at the final follow-up. Best-corrected visual acuity at the final follow-up improved two or more lines in 56.3% of eyes, was stable in 23.8% of eyes, and decreased two or more lines in 19.9% of eyes. Eyes repaired with 23-gauge and 25-gauge vitrectomy systems had similar success rates as eyes treated with 20-gauge instrumentation (P = 0.73). Eyes receiving silicone oil tamponade had lower single-surgery reattachment rates (77.6% vs. 87.6%; P = 0.013), lower reattachment rates at the final follow-up (85.7% vs. 92.6%; P = 0.048), and higher rates of vision loss (34.7% vs. 19.9%; P < 0.0001) but were more likely to have concurrent rhegmatogenous detachment (47.0% vs. 21.3%; P < 0.0001) and macula involving detachment (74.5% vs. 60.0%; P < 0.0001). CONCLUSION: In this large, single-center retrospective study of patients with advanced diabetic tractional retinal detachment, vitrectomy achieved excellent anatomical outcome and improved or stabilized vision in 80.1% of eyes. Smaller gauge vitrectomy systems were found to have similar outcomes to 20-gauge instrumentation.

Outcomes of Chimeric Antigen Receptor (CAR) T-Cell Therapy in Patients with Large B-Cell Lymphoma (LBCL): A Single-Institution Experience.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of relapsed/refractory (R/R) large B-cell lymphoma (LBCL). We describe the real-world baseline characteristics, efficacy, safety, and post-relapse outcomes of adult patients with R/R LBCL who received CAR T-cell therapy at the University of California San Diego. A total of 66 patients with LBCL were treated with tisagenlecleucel or axicabtagene ciloleucel. The median age was 59.5, and 21% were over 70 years old. Additionally, 20% of the patients had an Eastern Cooperative Oncology Group (ECOG) performance score of ≥2. Cytokine release syndrome incidence was 88%; immune effector cell-associated neurotoxicity syndrome incidence was 56%. All-grade infection occurred in 48% of patients and in 79% of patients > 70 years old. Complete response (CR) was achieved in 53% and partial response in 14%. Median progression-free survival (PFS) was 10.3 months; median overall survival (OS) was 28.4 months. Patients who relapsed post-CAR T-cell therapy had poor outcomes, with a median OS2 of 4.8 months. Upon multivariate analysis, both ECOG (HR 2.65, 95% CI: 1.30-5.41; p = 0.007) and ≥2 sites of extranodal involvement (HR 2.22, 95% CI: 1.15-4.31; p = 0.018) were significant predictors of PFS. Twenty-six patients were R/R to CAR T-cell therapy; six patients were in remission at the time of data cut off, one of whom received allogeneic transplant. Overall, older patients can safely undergo CAR T-cell therapy, despite the increased risk of all-grade infection. In our cohort, ECOG performance score and ≥2 sites of extranodal disease are significant predictors of PFS.

Toxic medications in Leber's hereditary optic neuropathy.

Leber's hereditary optic neuropathy (LHON) is a maternally inherited mitochondrial disorder characterized by acute bilateral vision loss. The pathophysiology involves reactive oxygen species (ROS), which can be affected by medications. This article reviews the evidence for medications with demonstrated and theoretical effects on mitochondrial function, specifically in relation to increased ROS production. The data reviewed provides guidance when selecting medications for individuals with LHON mutations (carriers) and are susceptible to conversion to affected. However, as with all medications, the proven benefits of these therapies must be weighed against, in some cases, purely theoretical risks for this unique patient population.

Optical Coherence Tomography of the Retinal Ganglion Cell Complex in Leber's Hereditary Optic Neuropathy and Dominant Optic Atrophy.

Background: Mitochondrial optic neuropathies such as Leber's Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA) have been shown to produce an optic neuropathy secondary to retinal ganglion cell loss with thinning of the retinal ganglion cell complex (RGCC). Methods: We performed a retrospective analysis assessing the thicknesses of the peripapillary retinal nerve fiber layer (pRNFL) along with the macular retinal ganglion cell-inner plexiform layer (RGC-IPL) using optical coherence tomography (OCT). We compared these changes among acute and chronic LHON, DOA, and normal healthy control patients. Results: Patients with chronic LHON exhibited statistically significant thinning of the RNFL in the superior, nasal, and inferior quadrants of the retina. In acute LHON, the RNFL was relatively thicker in all but the temporal quadrant when compared with respective quadrants in normal eyes; however, statistical significance was not achieved. In DOA, the RNFL was thinnest in the superior and inferior quadrants of the retina, measuring between acute and chronic LHON thickness values. In chronic LHON and DOA, both the pRNFL and RGC-IPL were significantly thinner in all four retinal quadrants relative to controls. Conclusions: This article represents the first comparative study of the RGCC between LHON and DOA. Our findings demonstrated significant thickness reductions in pRNFL and macular RGC-IPL in patients with LHON and DOA, with different specific patterns consistent with the general patterns of thinning classically observed. This study suggests the usefulness of the RGCC as a potential in vivo biomarker for assessing disease in patients with LHON and DOA.

SEVERE BILATERAL RETINAL VASCULAR OCCLUSION AS FIRST PRESENTATION OF SYSTEMIC LUPUS ERYTHEMATOSUS AND ANTIPHOSPHOLIPID SYNDROME.

PURPOSE: To describe a patient with undiagnosed systemic lupus erythematosus and secondary antiphospholipid syndrome presenting with bilateral severe retinal vaso-occlusion on first presentation. METHODS: Retrospective case report. A 42-year-old Hispanic female with no medical history presented with 2 weeks of bilateral decreased vision. RESULTS: At initial presentation, the patient's best-corrected visual acuity was 2 ft/200 and 20/400 in the right and left eyes, respectively. Dilated fundus examination revealed diffuse, confluent cotton-wool spots, and severe vascular occlusions in both eyes. Fluorescein angiography confirmed that the patient had both arterial and venous vascular occlusions and retinal vasculitis. A thorough work-up revealed that the patient had systemic lupus erythematosus and APS with positive antibodies to anticardiolipin, beta-2-glycoprotein, and lupus anticoagulant. The patient was treated with steroids, immunosuppression agents, anticoagulation, and extensive panretinal photocoagulation. One month later, best-corrected visual acuity had improved to 20/200 and 20/40, the vasculitis had substantially improved, and no neovascularization was present. CONCLUSION: Severe retinal vaso-occlusion may be the first presenting signs for patients with systemic lupus erythematosus and APS.

Ultra-Wide-Field Fluorescein Angiography in Microscopic Polyangiitis.

A 25-year-old Hispanic female presented with 5 months of dry eyes and 2 months of bilateral photophobia and decreased vision. On examination, she had bilateral anterior uveitis and mild disc edema of the left eye. A complete infectious and inflammatory work-up was positive for elevated antinuclear antibodies and p-ANCA, leading to a diagnosis of microscopic polyangiitis. One year after initial treatment and steroid taper, an ultra-wide-field fluorescein angiography revealed peripheral vasculitis, outside of the standard traditional field of view, leading to an increase in immunomodulatory therapy and illustrating the utility of wide-field angiography for managing patients with uveitis.

Rif1 regulates initiation timing of late replication origins throughout the S. cerevisiae genome.

Chromosomal DNA replication involves the coordinated activity of hundreds to thousands of replication origins. Individual replication origins are subject to epigenetic regulation of their activity during S-phase, resulting in differential efficiencies and timings of replication initiation during S-phase. This regulation is thought to involve chromatin structure and organization into timing domains with differential ability to recruit limiting replication factors. Rif1 has recently been identified as a genome-wide regulator of replication timing in fission yeast and in mammalian cells. However, previous studies in budding yeast have suggested that Rif1's role in controlling replication timing may be limited to subtelomeric domains and derives from its established role in telomere length regulation. We have analyzed replication timing by analyzing BrdU incorporation genome-wide, and report that Rif1 regulates the timing of late/dormant replication origins throughout the S. cerevisiae genome. Analysis of pfa4Δ cells, which are defective in palmitoylation and membrane association of Rif1, suggests that replication timing regulation by Rif1 is independent of its role in localizing telomeres to the nuclear periphery. Intra-S checkpoint signaling is intact in rif1Δ cells, and checkpoint-defective mec1Δ cells do not comparably deregulate replication timing, together indicating that Rif1 regulates replication timing through a mechanism independent of this checkpoint. Our results indicate that the Rif1 mechanism regulates origin timing irrespective of proximity to a chromosome end, and suggest instead that telomere sequences merely provide abundant binding sites for proteins that recruit Rif1. Still, the abundance of Rif1 binding in telomeric domains may facilitate Rif1-mediated repression of non-telomeric origins that are more distal from centromeres.