The paths toward non-viral CAR-T cell manufacturing: A comprehensive review of state-of-the-art methods.

Although CAR-T cell therapy has emerged as a game-changer in cancer immunotherapy several bottlenecks limit its widespread use as a front-line therapy. Current protocols for the production of CAR-T cells rely mainly on the use of lentiviral/retroviral vectors. Nevertheless, according to the safety concerns around the use of viral vectors, there are several regulatory hurdles to their clinical use. Large-scale production of viral vectors under "Current Good Manufacturing Practice" (cGMP) involves rigorous quality control assessments and regulatory requirements that impose exorbitant costs on suppliers and as a result, lead to a significant increase in the cost of treatment. Pursuing an efficient non-viral method for genetic modification of immune cells is a hot topic in cell-based gene therapy. This study aims to investigate the current state-of-the-art in non-viral methods of CAR-T cell manufacturing. In the first part of this study, after reviewing the advantages and disadvantages of the clinical use of viral vectors, different non-viral vectors and the path of their clinical translation are discussed. These vectors include transposons (sleeping beauty, piggyBac, Tol2, and Tc Buster), programmable nucleases (ZFNs, TALENs, and CRISPR/Cas9), mRNA, plasmids, minicircles, and nanoplasmids. Afterward, various methods for efficient delivery of non-viral vectors into the cells are reviewed.

Dundee Annual Neurosurgery Skills Event (DANSE)-Improving the Availability and Affordability of Neurosurgical Skills Workshops for Medical Students.

Background Neurosurgery can be a daunting career choice for medical students, with preparation for trainee application often being inaccessible and expensive. This article describes a student-led neurosurgical skills event supported by local neurosurgery faculty members. Such event was designed to offer a means to bridge this gap by providing an opportunity to practice neurosurgical techniques in simulation, and learn about what a career in neurosurgery involves. Methods Pre- and postskills laboratory surveys were used to ascertain the baseline confidence and knowledge of common neurosurgical techniques, as well as to what both the application to neurosurgery and the typical workload of a neurosurgeon involves. The conference offered six neurosurgical workshops as well as three lectures to provide practical and theoretical learning opportunities. The session included introduction to the candidates and faculty, identification of learning objectives, and career discussion. Postcourse feedback also was also used to assess learning outcomes. Results Eighteen students attended the event. Postskills event, students were significantly more likely to understand the principles behind all of the relevant neurosurgical skills included on the day. Additionally, students were more likely to understand what a career in neurosurgery involves, and how to approach applying for a training number. Respondents enjoyed the workshops, valued hands-on experience and interactions with consultants, found it affordable, and would recommend to their peers. Conclusions For medical students interested in a career in neurosurgery, opportunities to learn relevant techniques and skills are often expensive and difficult to come across. Here, we highlight affordable methods of simulation to result in significant student satisfaction. Additionally, providing ample opportunity to practice different neurosurgical techniques under almost 1:1 level tutoring enables significant increases in students' confidence and understanding of different neurosurgical concepts. We greatly encourage other medical student groups to develop their own hands-on simulation events to attract medical students to a surgical field often considered daunting and inaccessible, and address gaps in the medical school curriculum.

Efficacy of Adding Sodium Hyaluronate Eye Drops to Tobramycin and Dexamethasone in the Treatment of Post-Cataract Surgery Dry Eye Disease: A Retrospective Analysis and Prospective Questionnaire Assessment.

Purpose: This study aimed to compare the efficacy of using a combination of antibiotic and corticosteroid eye drops to using the same combination in addition to sodium hyaluronate eye drops. Patients and Methods: This study included patients who underwent phacoemulsification for age-related cataract and presented to the ophthalmology department or outpatient clinic of the two hospitals in the study with DED during the period from January 2020 to January 2023. The study involved a two-pronged approach in which we retrospectively analyzed the prospectively maintained data of the patients and prospectively called the patients for an evaluation of the dry eye impact on vision-related function. The study patients were recruited from two hospitals. During the study period, patients who were treated with a combination of antibiotic and corticosteroid eye drops were enrolled in Group A, and those who were treated with the same combination with sodium hyaluronate eye drops were enrolled in Group B. Results: The present study included 143 patients with post-phacoemulsification DED. Group A included 70 patients, and Group B included 73 patients. There was statistically significant improvement 4 weeks after treatment (p < 0.05) in the two groups. Comparing the two groups showed statistically significant improvements in group B compared to group A (p < 0.05). Assessment of the overall efficacy outcome revealed a statistically significant high percentage of cure (35.6% vs 1.4%) and high effectiveness (42.5% vs 13.6%) and a low percentage of effectiveness (21.9% vs 74.3%) and ineffectiveness (0.0% vs 5.7%) in Group B compared to Group A (p < 0.001). Conclusion: Combining sodium hyaluronate eye drops with tobramycin and dexamethasone eye drops yielded obviously better efficacy outcomes compared to using tobramycin and dexamethasone eye drops alone.

Impact of Living with Stigma in Persons with Type 1 Diabetes: A Patient-Physician Perspective.

Type 1 diabetes mellitus (T1D) is an autoimmune disorder characterized by a complete deficiency in insulin due to the destruction of pancreatic beta cells. Globally, T1D accounts for nearly 5-10% of the total diabetes cases. Living with this life-long condition has a significant emotional, psychological, physical, mental, and social impact. Despite extensive research characterizing the underlying physiology of T1D, additional work is needed to address the psychosocial aspects associated with the condition and its effect on the quality of life (QoL) of people living with T1D. One area that warrants further exploration is the stigma-related stereotypes and prejudice of people living with T1D experience in real-life settings. Despite the acknowledgment of stigma for conditions such as obesity, mental illness, and epilepsy, its association with T1D and ensuing psychological distress remains relatively under-investigated. Health-related stigma is a huge barrier to seeking appropriate, timely support for enhanced healthcare management and engagement in such patients. Here, we provide the perspectives of an adult with over 33 years of living with T1D and an expert endocrinologist who details their experience of T1D-related stigma. The self-reported factors explored by the person living with T1D include (but are not limited to) blame, mockery of the condition/person, diabetes-related shame, exclusion, rejection, negative judgments, fear, stereotyping, and discrimination. The lived experience supported by the clinical insights of the endocrinologist highlights the urgent need to decipher the severity, extent, nature, determinants, and consequences of stigma faced by a person living with T1D. Raising societal awareness, increasing education for caregivers, access to counseling for people living with diabetes, and engaging in shared decision-making remain the path forward.

Emotional, Psychological, and Social Well-being Experience of Long-Term Living with Type 1 Diabetes Mellitus: A Patient-Psychiatrist-Endocrinologist Perspective.

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease that impacts blood glucose levels and can also lead to an increased prevalence of psychiatric conditions. Living with T1DM has been associated with a significant impact on a person's social, mental, and psychological quality of life (QoL). Stressors related to T1DM include the demands of managing the condition, acceptance of the diagnosis, and recognition of the sizeable personal responsibility involved in managing the condition. Participating in treatment designed to improve QoL can still take a psychological toll on individuals with T1DM and can lead to a wide range of psychological distress, including anxiety, fear, depression, stress, anger, frustration, and denial (among many others). Ongoing research seeks to investigate the range of psychiatric conditions that are common among people with T1DM. Bringing patient perspectives into research to design and implement workable solutions is the future of a novel holistic approach to managing T1DM-related mental health impact. Connecting with other people living with T1DM, clinicians, counselors/therapists, mental health professionals, and social workers might alleviate some of the challenges of managing the emotional issues and psychological distress associated with T1DM. Here, we provide the perspective of someone with over 33 years of living with T1DM, its impact on his mental health, QoL, the steps undertaken, and the path to successful management. This perspective is complemented by opinions from two expert clinicians-an endocrinologist and a psychiatrist. Sharing the real-life subjective burden experienced by the person living with diabetes could be one step towards increasing awareness of the toll of mental health disorders on people living with T1DM. This patient experience, complemented by expert endocrinologist and psychiatrist opinions, could pave the way for an effective two-way dialogue to manage the condition effectively.

Geographical Diversity in the Age Specific Anti Müllerian Hormone Levels in Infertile Women: A Hospital based Cohort Study.

Background: Serum anti-Mullerian hormone (AMH) is a significant determinant of ovarian reserve. It is still not clear about the rate at which AMH declines with age and varies across populations. Aim: The present study examined the AMH levels specific to the North and South Indian populations and attempted to establish an age-dependent reference parametrically. Settings and Design: This was a prospective study in a tertiary centre. Materials and Methods: Serum samples were collected apparently from 650 infertile women (327 from North and 323 from South Indians). AMH was measured using an electrochemiluminescent technique. Statistical Analysis Used: Comparison of the AMH data between North and South regions was done by independent t-test. For each age, seven empirical percentiles (3rd, 10th, 25th, 50th, 75th, 90th and 95th) were applied. AMH nomograms for the 3rd, 10th, 25th, 50th, 75th, 85th, 90th and 95th percentiles were produced using the lambda-mu-sigma method. Results: AMH levels remarkably decreased with increasing age in the North Indian population, but in the South Indian population, they did not decline beyond 1.5 ng/mL. Further, in the North Indian population, AMH levels were significantly higher in the age group of 22-30 years (4.4 ng/mL) than in the South Indian population (2.04 ng/mL). Conclusion: The present study suggests a major geographical difference in mean AMH levels according to their age and ethnic background, regardless of their subjacent pathologies.

Lesion depth and marrow stimulation results.

AIM: The aim of this study was to study the importance Osteochondral lesion (OCL) depth as a singular factor for treatment outcomes using marrow stimulation. We hypothesized that the clinical outcomes of marrow stimulation would be inferior for lesions with depths of more than 5 mm compared to those less than 5 mm. MATERIALS & METHODS: An interventional prospective cohort study was conducted on 55 ankles in 55 patients who had been diagnosed with full-thickness osteochondral lesions of the talus; stage II, III, IV according to Anderson staging system based on magnetic resonance imaging; depth of 10 mm or less; and area of 150 mm2 or less measured by preoperative computed tomography. According to lesion depth, patients were divided into two groups: group (A) ≤ 5 mm, and group (B) ˃ 5 mm. The mean follow-up period for both groups was 30 months (range, 22-40). RESULTS: For groups A and B the average preoperative Foot and Ankle Outcome Scores (FAOS) were 43.1 ± 8.8 (range, 25-52) and 46 ± 8.5 (range, 32-60), respectively, and improved to 90 ± 4.3 (range, 80-96) (P = 0.001) and 75 ± 6.4 (range, 65-88) (P = 0.001) at the final follow-up. The average time to full weight bearing was 12 weeks (range, 10-16) in group A and 16 weeks (range, 12-20) in group B. CONCLUSIONS: Although treatment of OCLs is still undergoing changes and there are many prognostic factors that affect outcomes during marrow stimulation treatment, depth of OCL was shown to be an independent factor affecting outcomes. OCLs of less than 5 mm in depth were more likely to have superior clinical outcomes compared to OCLs of more than 5 mm. CLINICAL SIGNIFICANCE: The depth of OCL talus is an important factor as it affects the outcome of arthroscopic marrow stimulation inversely. LEVEL OF EVIDENCE: I.

Genetic architecture of seed glycerolipids in Asian cultivated rice.

Glycerolipids are essential for rice development and grain quality but its genetic regulation remains unknown. Here we report its genetic base using metabolite-based genome-wide association study and metabolite-based quantitative traits locus (QTL) analyses based on lipidomic profiles of seeds from 587 Asian cultivated rice accessions and 103 chromosomal segment substitution lines, respectively. We found that two genes encoding phosphatidylcholine (PC):diacylglycerol cholinephosphotransferase (OsLP1) and granule-bound starch synthase I (Waxy) contribute to variations in saturated triacylglycerol (TAG) and lyso-PC contents, respectively. We demonstrated that allelic variation in OsLP1 sequence between indica and japonica results in different enzymatic preference for substrate PC-16:0/16:0 and different saturated TAG levels. Further evidence demonstrated that OsLP1 also affects heading date, and that co-selection of OsLP1 and a flooding-tolerant QTL in Aus results in the abundance of saturated TAGs associated with flooding tolerance. Moreover, we revealed that the sequence polymorphisms in Waxy has pleiotropic effects on lyso-PC and amylose content. We proposed that rice seed glycerolipids have been unintentionally shaped during natural and artificial selection for adaptive or import seed quality traits. Collectively, our findings provide valuable genetic resources for rice improvement and evolutionary insights into seed glycerolipid variations in rice.

Non-penetrating deep sclerectomy versus combined trabeculotomy-trabeculectomy in primary congenital glaucoma.

Background: The primary mode of therapy in children with primary congenital glaucoma (PCG) and mild or no corneal edema is goniotomy, which has a high success rate. However, in developing countries, the diagnosis of PCG is usually delayed, and corneal cloudiness interferes with goniotomy. Therefore, trabeculotomy may be the best choice in such eyes. We compared the short-term efficacy and safety of primary combined trabeculotomy-trabeculectomy (primary CTT) with that of non-penetrating deep sclerectomy (NPDS) in managing PCG. Methods: This prospective, randomized, comparative study included patients with PCG referred to Al-Azhar University Hospitals within a 1-year period. Eyes were randomly allocated to one of two groups: eyes in NPDS group underwent NPDS, and those in primary CTT group underwent primary CTT. Baseline and frequent postoperative assessments of intraocular pressure (IOP), cup-to-disc ratio (C/D ratio), corneal diameter, and axial length were performed for up to 6 months. The success rates were recorded in both groups. Results: Forty eyes of 26 patients were included, with 20 eyes allocated to each group. The mean (standard deviation) age of all patients was 12.9 (9.5) months, with comparable ages and sex ratios between groups (both P > 0.05). Both groups demonstrated a significant reduction in IOP and C/D ratio at each postoperative visit compared to the baseline visit (all P < 0.001), with no significant difference detected between the groups (all P > 0.05), except for a significantly lower IOP in NPDS group at 1 month (P < 0.05). The corneal diameter and axial length were comparable between groups at baseline and remained unchanged at all postoperative visits (all P > 0.05). The groups had comparable success rates (P > 0.05). No serious complications were detected. Conclusions: CTT and NPDS both yielded reasonable IOP control and reversal of cupping in eyes with PCG. We observed equal effectiveness of the surgical procedures without major safety concerns. Further large-scale clinical trials with longer follow-up periods are needed to verify our preliminary findings.

Efficacy of pre-operative silodosin on flexible ureteroscopy procedure: A randomized controlled study.

Objectives: To evaluate the impact of silodosin on stages of flexible ureteroscopy (F-URS) procedures, complications, and stone-free rate (SFR). Patients and Methods: A prospective, randomized, controlled comparison research was conducted on 106 patients who were randomly allocated into two groups: the study group (52 patients) received F-URS with preoperative daily uptake of 8 mg silodosin for 10 days, and the control group (54 patients) received F- URS without silodosin uptake. Two patients were lost during the follow up in the study group and four patients were also lost in the controls. Results: Operative time, application access sheath time (AAST), entrance to ureteric orifice time (ETUOT), and entrance to bladder time (ETBT) were significantly lower in the study group compared to controls. Meanwhile, F-URS time & laser time was higher in the study group compared to controls but without statistically significant difference. Complications were insignificalty different between both studied goups with no impact on SFR. Conclusion: Before ureteroscopy, silodosin, an adjunctive alpha-blocker therapy, was successful in treating stones resulting in shortening the procedural time, with no impact on SFR or complication rate.

Nondegenerate Saturation Mutagenesis: Library Construction and Analysis via MAX and ProxiMAX Randomization.

Protein engineering can enhance desirable features and improve performance outside of the natural context. Several strategies have been adopted over the years for gene diversification, and engineering of modular proteins in particular is most effective when a high-throughput, library-based approach is employed. Nondegenerate saturation mutagenesis plays a dynamic role in engineering proteins by targeting multiple codons to generate massively diverse gene libraries. Herein, we describe the nondegenerate saturation mutagenesis techniques that we have developed for contiguous (ProxiMAX) and noncontiguous (MAX) randomized codon generation to create precisely defined, diverse gene libraries, in the context of other fully nondegenerate strategies. ProxiMAX randomization comprises saturation cycling with repeated cycles of blunt-ended ligation, type IIS restriction, and PCR amplification, and is now a commercially automated process predominantly used for antibody library generation. MAX randomization encompasses a manual process of selective hybridisation between individual custom oligonucleotide mixes and a conventionally randomized template and is principally employed in the research laboratory setting, to engineer alpha helical proteins and active sites of enzymes. DNA libraries generated using either technology create high-throughput amino acid substitutions via codon randomization, to generate genetically diverse clones.

Mitochondrial DNA Levels in Trophectodermal Cells Show No Association with Blastocyst Development and Pregnancy Outcomes.

Background: In patients undergoing assisted reproduction, levels of mitochondrial DNA (mtDNA) in the trophectodermal cells of the developing blastocyst are suggested to be associated with its ability to implant. However, discrepancies exist regarding the use of mtDNA levels as a reliable biomarker to predict outcomes of assisted reproduction. Aims: The aim of the study is to explore the association of trophectodermal mtDNA levels to determine blastocyst quality, implantation potential of blastocyst and clinical outcomes in couples who have undergone pre-implantation genetic testing for aneuploidy (PGT-A). Study Setting: Private fertility centre. Study Design: Retrospective analysis. Materials and Methods: We analysed mtDNA levels in the trophectodermal cells of 287 blastocysts from 61 couples undergoing PGT-A. The levels of mtDNA were estimated by next-generation sequencing method. mtDNA levels were correlated with maternal age, blastocyst morphology, ploidy status, implantation rates, miscarriage rate and live birth rate. Statistical Analysis Used: Linear regression and one-way ANOVA with Tukey's all column comparison test. Results: The trophectodermal mtDNA levels did not correlate with maternal age. There were no significant differences in their levels in grade 1 and grade 2 blastocysts. No significant differences were seen between mtDNA levels of implanted and non-implanted blastocysts or those blastocysts that resulted in miscarriage or live birth. However, significantly lower amounts of mtDNA were seen in euploid blastocysts as compared to that in aneuploid blastocysts. Conclusion: mtDNA levels in the trophectodermal cells of the blastocyst do not associate with blastocyst quality (grade 1 and grade 2), implantation potential and clinical outcomes but can differentiate between aneuploid and euploid blastocysts. Our study does not support the use of trophectodermal mtDNA levels as a biomarker for blastocyst quality and predictor of clinical outcomes.

Severe Hypertriglyceridaemia Leading to Factitious Hypobicarbonataemia.

Anion gap metabolic acidosis is a laboratory finding commonly encountered in patients with sepsis, diabetic ketoacidosis, acute kidney injury and toxic alcohol ingestion. Serum blood chemistry assessment detects this abnormality. However, this can be falsely low in situations of high triglyceride levels due to lipid interference with measurement of the bicarbonate levels and through volume displacement by these large molecules. Arterial blood gas analysis and a lipid panel are required to confirm accurate bicarbonate levels. Clinicians handling acid-base disorders in hospitalized patients need to be aware of this spurious laboratory value to avoid unnecessary tests and to determine accurate total bicarbonate levels. LEARNING POINTS: Elevated triglycerides can cause spurious low blood bicarbonate levels.High anion gap metabolic acidosis is associated with serious clinical illness which can lead to a battery of diagnoses and therapeutics.Accurate knowledge of this condition with falsely low bicarbonate levels will prevent unnecessary medical work-up and guide prompt treatment.

Effects of exogenous C18 unsaturated fatty acids on milk lipid synthesis in bovine mammary epithelial cells.

We determined the effects of a combination of C18 unsaturated fatty acids (C18-UFAs) consisting of oleic, linoleic, and linolenic acids on milk lipogenesis in bovine mammary epithelial cells (BMECs). By orthogonal experiments to determine cellular triacylglycerol (TAG) accumulation, a combination of 200 µmol/l C18 : 1, 50 µmol/l C18 : 2, and 2 µmol/l C18 : 3 was selected as C18-UFAs combination treatment, and culture in medium containing fatty acid-free bovine serum albumin was used as the control. The expression of genes related to milk lipid synthesis and intracellular FA composition was measured. The results showed that cytosolic TAG formation was higher under C18-UFAs treatment than under control treatment. The mRNA expression of acetyl-CoA carboxylase-α (ACACA), fatty acid synthase (FASN), and peroxisome proliferator-activated receptor gamma (PPARG) did not differ between treatments. The abundance of stearoyl-CoA desaturase (SCD) and acyl-CoA synthetase long-chain family member 1 (ACSL1) was higher, whereas that of sterol regulatory element binding transcription factor 1 (SREBF-1) was lower after C18-UFAs treatment compared to control treatment. The C16 : 0 and SFA content was decreased following C18-UFAs treatment compared to control treatment, while the cis-9 C18 : 1 and UFA content was increased. In conclusion, C18-UFAs could stimulate triglyceride accumulation, increase the cellular UFA concentration, and regulate lipogenic genes in BMECs.

Intravitreal ziv-aflibercept in diabetic vitreous hemorrhage.

BACKGROUND: To evaluate the safety and efficacy of intravitreal ziv-aflibercept (IVZ) in the management of vitreous hemorrhage (VH) in eyes with previously lasered proliferative diabetic retinopathy (PDR). METHODS: In a prospective multicenter study, previously lasered eyes who had dense VH from PDR underwent intravitreal injection of ziv-aflibercept (IVZ) (1.25 mg aflibercept). Demographic characteristics of the patients, baseline and final logMar visual acuity, number of injections, VH clearance time, and need for vitrectomy were recorded. RESULTS: Twenty-seven eyes of 21 patients were included in the study. Mean age of study patients was 61.3 ± 14.1 years with mean duration of diabetes mellitus of 22.6 ± 7.8 years. Mean logMAR BCVA at baseline was 1.41 ± 1.26 (Snellen equivalent 20/514) and at the last visit 0.55 ± 0.61 (Snellen equivalent 20/70) with a mean gain of 0.86 EDTRS line (paired student t test = 5.1; p ≤ 0.001). Mean number of IVZ 2.4 ± 1.6 (range 1-6). The mean follow-up time was 11.7 ± 11.1 months (range 1-34). Mean time for visual recovery and/or VH clearance was 5.7 ± 3.3 weeks. Eyes, which required multiple injections, the interval period between injections for recurrent VH was 6.4 ± 5.2 months. No subject required vitrectomy. No ocular or systemic adverse effects were noted. CONCLUSIONS: IVZ injections had good short-term safety and efficacy for the therapy of new or recurrent VH in previously lasered eyes with PDR reducing somewhat the need for vitrectomy.Trial registration: NCT02486484.

Out-of-Hospital 30-day Deaths After Cardiac Surgery Are Often Underreported.

BACKGROUND: Operative mortality (in-hospital during the index admission or within 30 days of the procedure after discharge) is commonly used as a quality of care measure for public reporting of cardiac surgery outcomes, but the ability to capture out-of-hospital deaths accurately remains undetermined. The objective of the study was to estimate the impact of incomplete reporting of out-of-hospital deaths on hospital risk-adjusted mortality and outlier status. METHODS: New York State's 2014 to 2016 cardiac registry data were used to compare the capture of 30-day postprocedure deaths after discharge with and without the use of national and state-level vital statistics data for all 54,442 patients undergoing isolated coronary artery bypass graft, cardiac valve surgery, or both. Hospital risk-adjusted operative mortality rates and mortality outliers were compared based on statistical models that were developed with and without the use of vital statistics data. RESULTS: Thirty-day deaths postprocedure after discharge ranged from 10% to 39% of all operative deaths among cardiac surgical procedures. More than 30% of these deaths were missing without vital statistics confirmation for 7 of the 10 cardiac procedures examined, and more than 40% were missing for 5 of the procedures examined. When vital statistics data were used to confirm 30-day postprocedure deaths after discharge, an additional high outlier for valve surgery was identified. CONCLUSIONS: Operative mortality after cardiac surgery is often underreported owing to a considerable percentage of out-of-hospital cardiac surgery deaths that are missed by reporting centers. This can adversely affect the assessment of hospital risk-adjusted mortality in public reports.

Multiple Versus Single Arterial Coronary Bypass Graft Surgery for Multivessel Disease.

BACKGROUND: Despite recent guideline statements, there is still wide practice variation in the use of multiple arterial grafts (MAGs) versus single arterial grafts (SAGs) for patients with multivessel disease undergoing coronary artery bypass graft surgery. This may be related to differences in findings between observational and randomized controlled studies. OBJECTIVES: This study sought to compare intermediate-term MAG and SAG outcomes with enhanced matching to reduce selection bias. METHODS: New York's cardiac registry identified 63,402 multivessel disease patients undergoing coronary artery bypass graft surgery between January 1, 2005, and December 31, 2014, to compare outcomes (median follow-up 6.5 years) for patients receiving SAGs and MAGs. SAG and MAG patients were propensity matched using 38 baseline characteristics to reduce selection bias. The primary endpoint was mortality, and secondary endpoints included repeat revascularization and a composite endpoint of mortality, acute myocardial infarction, and stroke. RESULTS: Before matching, 20% of procedures employed MAG. At 1 year, there was no mortality difference between matched MAG and SAG patients (2.4% vs. 2.2%, adjusted hazard ratio [AHR]: 1.11; 95% confidence interval [CI]: 0.93 to 1.32). At 7 years, MAG patients had lower mortality (12.7% vs. 14.3%, AHR: 0.86; 95% CI: 0.79 to 0.93), a lower composite outcome (20.2% vs. 22.8%, AHR: 0.88; 95% CI: 0.83 to 0.93), and a lower repeat revascularization rate (11.7% vs. 14.6%, AHR: 0.80; 95% CI: 0.74 to 0.87). At 7 years, the subgroups for which MAG did not have a lower mortality rate included patients with off-pump surgery, 2-vessel disease with right coronary artery disease, recent acute myocardial infarction, renal dysfunction, and patient ≥70 years of age. CONCLUSIONS: Mortality and the composite outcome were similar between MAG and SAG patients at 1 year, but lower for MAG after 7 years. Patients of higher volume MAG surgeons experienced lower MAG mortality.

"For Mass Eye and Ear Special Issue" Adaptive Optics in the Evaluation of Diabetic Retinopathy.

Retinal imaging is a fundamental tool for clinical and research efforts in the evaluation and management of diabetic retinopathy. Adaptive optics (AO) is an imaging technique that enables correction of over 90% of the optical aberrations of an individual eye induced primarily by the tear film, cornea and lens. The two major tasks of any AO system are to measure the optical imperfections of the eye and to then compensate for these aberrations to generate a corrected wavefront of reflected light from the eye. AO scanning laser ophthalmoscopy (AOSLO) provides a theoretical lateral resolution limit of 1.4 µm, allowing the study of microscopic features of the retinal vascular and neural tissue. AOSLO studies have revealed irregularities of the photoreceptor mosaic, vascular loss, and details of vascular lesions in diabetic eyes that may provide new insight into development, regression, and response to therapy of diabetic eye disease.

MULTILEVEL ISCHEMIA IN DISORGANIZATION OF THE RETINAL INNER LAYERS ON PROJECTION-RESOLVED OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To examine the relationship between ischemia and disorganization of the retinal inner layers (DRIL). METHODS: Cross-sectional retrospective study of 20 patients (22 eyes) with diabetic retinopathy presenting to a tertiary academic referral center, who had DRIL on structural optical coherence tomography (OCT) using Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) and OCT angiography with XR Avanti (Optovue Inc, Fremont, CA) on the same day. Optical coherence tomography angiography images were further processed to remove flow signal projection artifacts using a software algorithm adapted from recent studies. Retinal capillary perfusion in the superficial capillary plexuses, middle capillary plexuses, and deep capillary plexuses, as well as integrity of the photoreceptor lines on OCT was compared in areas with DRIL to control areas without DRIL in the same eye. RESULTS: Qualitative assessment of projection-resolved OCT angiography of eyes with DRIL on structural OCT demonstrated significant perfusion deficits compared with adjacent control areas (P < 0.001). Most lesions (85.7%) showed superimposed superficial capillary plexus and/or middle capillary plexus nonperfusion in addition to deep capillary plexus nonflow. Areas of DRIL were significantly associated with photoreceptor disruption (P = 0.035) compared with adjacent DRIL-free areas. CONCLUSION: We found that DRIL is associated with multilevel retinal capillary nonperfusion, suggesting an important role for ischemia in this OCT phenotype.

Safety of 5914 intravitreal ziv-aflibercept injections.

PURPOSE: To analyse the pooled safety data of intravitreal ziv-aflibercept (IVZ) therapy for various retinal conditions. METHODS: This was a retrospective, observational study which included patients from 14 participating centres who received IVZ. The medical records of patients who received IVZ from March 2015 through October 2017 were evaluated. Patient demographics and ocular details were compiled. Ocular and systemic adverse events that occurred within 1 month of IVZ injections were recorded and defined as either procedure-related or drug-related. RESULTS: A total of 1704 eyes of 1562 patients received 5914 IVZ injections (mean±SD: 3.73±3.94) during a period of 2.5 years. The age of patients was 60.6±12.8 years (mean±SD) and included diverse chorioretinal pathologies. Both ocular (one case of endophthalmitis, three cases of intraocular inflammation, and one case each of conjunctival thinning/necrosis and scleral nodule) and systemic adverse events (two cases of myocardial infarction, one case of stroke and two deaths) were infrequent. CONCLUSION: This constitutes the largest pooled safety report on IVZ use and includes patients from 14 centres distributed across the globe. It shows that IVZ has an acceptable ocular and systemic safety profile with incidences of adverse events similar to those of other vascular endothelial growth factor inhibitory drugs. The analysis supports the continued use of IVZ in various retinal disorders.