Racial Disparities in Glaucoma Vision Outcomes and Eye Care Utilization: An IRIS Registry Analysis.

PURPOSE: To evaluate racial disparities in vision outcomes and eye care utilization among glaucoma patients. DESIGN: Retrospective cohort study. METHODS: In this population-based IRIS Registry (Intelligent Research in Sight) study, we included patients with minimum one diagnosis code for glaucoma at least 6 months prior to January 1, 2015 and at least one eye exam, visual field (VF), optical coherence tomography (OCT), or eye-related inpatient or emergency department (ED) code in 2015. Multivariable logistic and negative binomial regression models were used to assess vision and utilization outcomes, respectively, across race and ethnicity from January 1, 2015 to January 1, 2020. Vision outcomes included cup-to-disc ratio (CDR) progression > 0.80, poor vision (visual acuity 20/200 or worse), low vision codes, and need for glaucoma filtering surgery. Utilization outcomes included outpatient eye exams, OCTs, VFs, inpatient/ED encounters, and lasers/surgeries. RESULTS: Among 996,297 patients, 73% were non-Hispanic White, 15% non-Hispanic Black, 9% Hispanic, 3% Asian/Pacific Islander, and 0.3% Native American/Alaska Native. Compared to White eyes, Black and Hispanic eyes had higher adjusted odds of CDR progression (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 1.08-1.17; OR = 1.28, 95% CI = 1.22-1.34), poor vision (OR = 1.26, 95% CI = 1.22-1.29; OR = 1.26, 95% CI = 1.22-1.31), glaucoma filtering surgery (rate ratio (RR) = 1.47, 95% CI = 1.42-1.51; RR = 1.13, 95% CI = 1.09-1.18). Hispanic eyes also had increased odds of low vision diagnoses (Hispanic OR = 1.18, 95% CI = 1.07-1.30). Black and Hispanic patients were less likely to have eye exams (RR = 0.94, 95% CI = 0.94-0.95; RR = 0.99, 95% CI = 0.99-0.99) and OCTs (RR = 0.86, 95% CI = 0.85-0.86; RR = 0.97, 95% CI = 0.96-0.98), yet Black patients had higher odds of inpatient/ED encounters (RR = 1.64, 95% CI = 1.37-1.96) compared to White patients. Native American patients were more likely to have poor vision (OR = 1.17, 95% CI = 1.01-1.36) and less likely to have outpatient visits (RR = 0.89, 95% CI = 0.86-0.91), OCTs (RR = 0.85, 95% CI = 0.82-0.89), visual fields (RR = 0.91, 95% CI = 0.88-0.94) or lasers/surgeries (RR = 0.87, 95% CI = 0.79-0.96) compared to White patients. CONCLUSIONS: We found that significant disparities in US eye care exist with Black, Hispanic, and Native American patients having worse vision outcomes and less disease monitoring. Glaucoma may be undertreated in these racial and ethnic minority groups, increasing risk for glaucoma-related vision loss.

Perceived Pager Burden Among Trainees Across Medical Specialties.

BACKGROUND: The experiences of pager use among trainees across medical specialties is underexplored. The aim of this study was to assess experiences of pager burden and communication preferences among trainees in different specialties. METHODS: An online survey was developed to assess perceived pager burden (eg, pager volume, mistake pages, sleep, and off-time interruptions) and communication preferences at a tertiary center in the United States. All residents and fellows were eligible to participate. Responses were grouped by specialty: General surgery [GS], Surgical subspecialty [SS], Medicine, Anesthesiology, and Psychiatry. Multivariable linear regression was used to assess factors associated with pager burden. Free text responses were analyzed using open coding methods. RESULTS: Of the total 306 responses, the majority were female (58.8%), 30-39 years (59.2%), and White (70.6%). Specialty breakdown was: Medicine (40.2%), Psychiatry (10.8%), SS (18.0%), GS (5.6%), and Anesthesiology (3.6%). GS respondents reported receiving more mistake pages (P < .001), spending more time redirecting mistake pages (P = .003), and having the highest sleep time disruptions (P < .001). For urgent communications, surgical trainees preferred physical pagers, while nonsurgical trainees preferred smartphone pagers (P = .001). "Receive fewer nonurgent pages" was the most common change respondents desired. DISCUSSION: In this single center study, subjective experiences of pager burden were disproportionately high among GS trainees. Reducing nonurgent and mistake pages are potential targets for improving trainee communication experiences. Hospitals should consider incorporating trainee preferences into paging systems. Additional studies are warranted to increase the sample size, assess generalizability of the findings, and contextualize trainee experiences with objective hospital-level paging data.

A Comparative Analysis of Intraocular Pressure Measurement Accuracy With Reused iCare Probes.

PURPOSE: To assess the accuracy of reused iCare probes after disinfection with 70% isopropyl alcohol and ethylene oxide gas compared to new iCare probes and Goldmann applanation tonometry (GAT). DESIGN: Prospective comparative analysis. PARTICIPANTS: A total of 118 eyes from 59 patients recruited from the Aravind Eye Hospital glaucoma clinic in Tirupati, South India. METHODS: Intraocular pressure (IOP) was measured on each eye using a new iCare tonometer probe, an iCare probe previously used and disinfected 1 time prior (once used probe) and 5 times prior (multiply used probe), as well as with GAT. Probes were disinfected after each use with 70% isopropyl alcohol swabs and ethylene oxide sterilization. MAIN OUTCOME MEASURES: Agreement demonstrated with intraclass correlation coefficients (ICCs), mean difference in IOP values with limits of agreement, and Bland-Altman plots among IOP measurement approaches. RESULTS: Compared to new iCare probes, both once used probes (ICC = 0.989, 95% confidence interval [CI] 0.985-0.993) and multiply used probes (ICC = 0.989, 95% CI 0.984-0.992) showed excellent agreement, and the mean difference in IOP was minimal for both once used probes (0.70 mmHg, 95% CI 0.29-1.11) and multiply used probes (0.75 mmHg, 95% CI 0.66-0.82) compared to new probes. Bland-Altman plots demonstrated minimal differences between new and reused probes across the spectrum of IOP. When comparing multiply used probes to once used probes, there was a high level of agreement (0.993) (95% CI 0.990-0.995) and negligible mean IOP difference 0.04 mmHg (95% CI 0.32-0.40). Additionally, ICC values for new probes (0.966, 95% CI 0.951-0.976), once used probes (0.958, 95% CI 0.940-0.971), and multiply used probes (0.957, 95% CI 0.938-0.970) compared to GAT were similar and all showed excellent agreement. Both new and reused iCare probes underestimated IOP by 2 to 3 mmHg compared to GAT. CONCLUSIONS: In this prospective comparative analysis, we found that reusing iCare probes up to 5 times does not compromise the accuracy of IOP measurements when disinfected with 70% isopropyl alcohol swabs and ethylene oxide. Reusing iCare probes has the potential to transform care by reducing cost, decreasing environmental waste, and allowing for glaucoma screening camps and increased glaucoma monitoring in low resource settings leading to earlier identification and treatment of glaucoma. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Future directions of glaucoma treatment: emerging gene, neuroprotection, nanomedicine, stem cell, and vascular therapies.

PURPOSE OF REVIEW: The aim of this article is to summarize current research on novel gene, stem cell, neuroprotective, nanomedicine, and vascular therapies for glaucoma. RECENT FINDINGS: Gene therapy using viral vectors and siRNA have been shown to reduce intraocular pressure by altering outflow and production of aqueous humor, to reduce postsurgical fibrosis with few adverse effects, and to increase retinal ganglion cell (RGC) survival in animal studies. Stem cells may treat glaucoma by replacing or stimulating proliferation of trabecular meshwork cells, thus restoring outflow facility. Stem cells can also serve a neuroprotective effect by differentiating into RGCs or preventing RGC loss via secretion of growth factors. Other developing neuroprotective glaucoma treatments which can prevent RGC death include nicotinamide, the NT-501 implant which secretes ciliary neurotrophic factor, and a Fas-L inhibitor which are now being tested in clinical trials. Recent studies on vascular therapy for glaucoma have focused on the ability of Rho Kinase inhibitors and dronabinol to increase ocular blood flow. SUMMARY: Many novel stem cell, gene, neuroprotective, nanomedicine, and vascular therapies have shown promise in preclinical studies, but further clinical trials are needed to demonstrate safety and efficacy in human glaucomatous eyes. Although likely many years off, future glaucoma therapy may take a multifaceted approach.

A Retrospective Cohort Study on the Difficulties of Diagnosing and Managing Glaucoma in Patients with Coexistent Neurodegenerative Disease.

Aim: To investigate the limitations of diagnosing glaucoma in patients with coexistent neurodegenerative disease (NDD) by collecting information on demographics, examination findings, optical coherence tomography (OCT), and visual field (VF) tests. Materials and methods: Retrospective cohort study of patients with primary open-angle glaucoma and coexistent dementia, multiple sclerosis (MS), Parkinson's disease (PD), or cerebrovascular accident (CVA) from 2014 to 2020. We included patients with a minimum of 3 years of follow-up. Demographics, ophthalmic exam, OCT, and VF findings were reported and compared across NDD groups using the Chi-squared and analysis of variance tests. Results: We included 199 patients with glaucoma and coexistent NDD, including dementia (51.3%), CVA (11.2%), PD (18.1%), and MS (19.6%). Cupping, neuroretinal rim thinning, pallor, and peripapillary atrophy of the optic nerve were most frequently observed. There was a high number of missing values from OCT to VF tests, and zero patients had a complete OCT or VF test. Additionally, 67.8 and 77.4% of patients received <1 OCT and VF/year, respectively. Retinal nerve fiber layer (RNFL) thinning was observed most frequently in the superior (33.2% OD and 30.7% OS) and inferior (25.6% OD and 30.2% OS) quadrants, with the most significant thinning seen in CVA patients compared to other NDDs (p < 0.05). Glaucoma hemifield tests (GHTs) were abnormal in 23.1% OD and 22.6% OS, and the average mean deviation was -7.43 [standard deviation (SD) 8.23] OD and -8.79 (SD 7.99) OS. Conclusion: The OCT and VF tests are frequently unavailable and may be confounded in patients with coexistent glaucoma and NDDs, complicating glaucoma diagnosis and management. Clinical significance: Diagnosing and managing glaucoma in patients with coexistent NDD is difficult, given the lack of available and reliable OCT and VF testing data. Providers may be forced to rely on intraocular pressure (IOP) and other imperfect measures. How to cite this article: Ciociola EC, Patel K, Blahnik T, et al. A Retrospective Cohort Study on the Difficulties of Diagnosing and Managing Glaucoma in Patients with Coexistent Neurodegenerative Disease. J Curr Glaucoma Pract 2023;17(3):126-133.

Decision Factors for Glaucoma Suspects and Ocular Hypertensive Treatment at an Academic Center.

Aims and background: Practice guidelines assert that high-risk glaucoma suspects should be treated. Yet, there is ambiguity regarding what constitutes a high enough risk for treatment. The purpose of this study was to determine which factors contribute to the decision to treat glaucoma suspects and ocular hypertensive patients in an academic ophthalmology practice. Materials and methods: Retrospective cohort study of glaucoma suspects or ocular hypertensives at an academic ophthalmology practice from 2014 to 2020. Demographics, comorbidities, intraocular pressure (IOP), optical coherence tomography (OCT) findings, and visual field measurements were compared between treated and untreated patients. A multivariable logistic regression model assessed predictors of glaucoma suspected treatment. Results: Of the 388 patients included, 311 (80%) were untreated, and 77 (20%) were treated. There was no statistical difference in age, race/ethnicity, family history of glaucoma, central corneal thickness (CCT), or any visual field parameters between the two groups. Treated glaucoma suspects had higher IOP, thinner retinal nerve fiber layers (RNFL), more RNFL asymmetry, thinner ganglion cell-inner plexiform layers (GCIPL), and a higher prevalence of optic disc drusen, disc hemorrhage, ocular trauma, and proliferative diabetic retinopathy (PDR) (p < 0.05 for all). In the multivariable model, elevated IOP {odds ratio [OR] 1.16 [95% confidence interval (CI) 1.04-1.30], p = 0.008}, yellow temporal [5.76 (1.80-18.40), p = 0.003] and superior [3.18 (1.01-10.0), p = 0.05] RNFL quadrants, and a history of optic disc drusen [8.77 (1.96-39.34), p = 0.005] were significant predictors of glaucoma suspect treatment. Conclusion: Higher IOP, RNFL thinning, and optic disc drusen were the strongest factors in the decision to treat a glaucoma suspect or ocular hypertensive patient. RNFL asymmetry, GCIPL thinning, and ocular comorbidities may also factor into treatment decisions. Clinical significance: Understanding the clinical characteristics that prompt glaucoma suspect treatment helps further define glaucoma suspect disease status and inform when treatment should be initiated. How to cite this article: Ciociola EC, Anderson A, Jiang H, et al. Decision Factors for Glaucoma Suspects and Ocular Hypertensive Treatment at an Academic Center. J Curr Glaucoma Pract 2023;17(3):157-165.

ENDOGENOUS ENDOPHTHALMITIS ASSOCIATED WITH INJECTION DRUG USE COMPARED WITH OTHER ETIOLOGIES.

PURPOSE: To compare features of endogenous endophthalmitis associated with injection drug use (IDU) to endogenous endophthalmitis from other etiologies. METHODS: The authors retrospectively collected data on patients with endogenous endophthalmitis due to IDU or other causes from three academic tertiary care centers over a six-year period. Differences in presenting characteristics, culture results, treatment, and visual acuity were compared between groups. RESULTS: Thirty-eight patients (34%) had IDU-associated endogenous endophthalmitis while 75 patients (67%) had endogenous endophthalmitis from other causes. Compared with patients in the non-IDU group, IDU patients were significantly younger, more frequently male, had longer duration of symptoms at diagnosis, and were less likely to have bilateral disease ( P < 0.05 for all). Injection drug use patients were less likely to have a systemic infection source identified (29% vs. 71%, P < 0.001) or have positive cultures (47% vs. 80%, P < 0.001). The IDU group was less likely to be admitted to the hospital (71% vs. 92%, P = 0.005) and less likely to receive treatment with intravenous antimicrobials (55% vs. 83%, P = 0.003). Visual acuity did not significantly differ between groups. CONCLUSION: Endophthalmitis related to IDU presents in younger patients with less comorbidities and frequently without positive cultures or an identifiable systemic source; therefore, a high index of suspicion is needed to identify this disease.

Effectiveness of Trabeculectomy and Tube Shunt with versus without Concurrent Phacoemulsification: Intelligent Research in Sight Registry Longitudinal Analysis.

OBJECTIVE: To determine the effectiveness of trabeculectomy and glaucoma drainage device (GDD) surgery performed with concurrent phacoemulsification compared with stand-alone procedures. DESIGN: Multicenter retrospective cohort study. PARTICIPANTS: Patients in the Intelligent Research in Sight Registry who underwent trabeculectomy or GDD from 2013 through 2019. METHODS: The Kaplan-Meier survival analysis was used to determine reoperation rates. Reoperation was defined as any subsequent glaucoma surgery occurring 1 month to 3 years after the initial procedure. Multivariable Cox proportional hazard models were used to determine reoperation risk factors. MAIN OUTCOME MEASURES: Reoperation rate, intraocular pressure (IOP), visual acuity, reoperation procedure type, postoperative complications, and predictors of surgical failure. RESULTS: A total of 117 697 eyes undergoing glaucoma surgery alone and 35 657 eyes undergoing surgery with phacoemulsification were included. The cumulative reoperation rates at postoperative years 1 and 3 were 4.9% and 11.5%, respectively, for trabeculectomy alone and 3.0% and 7.3%, respectively, for trabeculectomy combined with phacoemulsification (P < 0.001). The reoperation rates at postoperative 1 and 3 years were 3.8% and 7.8%, respectively, for GDD alone and 2.1% and 5.4%, respectively, for GDD with phacoemulsification (P < 0.001). Stand-alone procedures achieved greater IOP reduction by percentage change from baseline (trabeculectomy alone, 35.3% vs. trabeculectomy with phacoemulsification, 23.1%, P < 0.001; and GDD alone, 36.0% vs. GDD with phacoemulsification, 29.3%; P < 0.001). Visual acuity improved by 0.12 logarithm of the minimum angle of resolution (logMAR) (95% confidence interval [CI], 0.11-0.12) and 0.10 logMAR (95% CI, 0.08-0.11) after trabeculectomy and GDD with phacoemulsification and declined by 0.15 logMAR (95% CI, 0.14-0.15) and 0.12 logMAR (95% CI, 0.11-0.12) after stand-alone trabeculectomy and GDD. The overall documented complication rate was 2.9% for GDD and 1.4% for trabeculectomy. Age, sex, race, ethnicity, baseline IOP, and glaucoma diagnosis and severity were associated with surgical failure risk. The most common reoperation procedure was GDD. CONCLUSIONS: Reoperation rates within the first 3 years after trabeculectomy and GDD with and without phacoemulsification were low. Trabeculectomy and GDD with phacoemulsification had lower reoperation rates than those with stand-alone procedures. However, stand-alone procedures resulted in greater IOP reduction compared with combined procedures. Postoperative complications were uncommon overall. Patient age, sex, race, ethnicity, baseline IOP, and glaucoma diagnosis and severity were associated with surgical success.

Effectiveness of Microinvasive Glaucoma Surgery in the United States: Intelligent Research in Sight Registry Analysis 2013-2019.

PURPOSE: To evaluate the effectiveness of microinvasive glaucoma surgery (MIGS) with and without concurrent phacoemulsification. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: Patients in the Intelligent Research in Sight (IRIS®) Registry who underwent Xen gel stent (ab interno) implantation, endoscopic cyclophotocoagulation (ECP), or goniotomy or canaloplasty from 2013 through 2019. METHODS: Kaplan-Meier survival analysis was used to assess reoperation rates. We defined reoperation as any subsequent glaucoma surgery occurring 1 month to 3 years after the initial procedure. Multivariable Cox proportional hazard models were used to determine factors predictive of reoperation. MAIN OUTCOME MEASURES: Reoperation rate, mean intraocular pressure (IOP) and visual acuity (VA), postoperative complications, predictors of reoperation, and reoperation procedure type. RESULTS: A total of 79 363 eyes from 57 561 patients were included, with 15 118 eyes (19%) receiving stand-alone MIGS and 64 245 eyes (81%) receiving MIGS concurrent with phacoemulsification. Overall, patients who underwent MIGS concurrently with phacoemulsification showed lower reoperation rates compared with stand-alone MIGS, most pronounced in ECP and goniotomy or canaloplasty. At postoperative year 2, the cumulative reoperation rate for stand-alone procedures was 15% for ECP, 24% for Xen implantation, and 24% for goniotomy or canaloplasty compared with 3% for ECP, 19% for Xen implantation, and 6% for goniotomy or canaloplasty concurrent with phacoemulsification (P < 0.001 for each stand-alone MIGS vs. MIGS with phacoemulsification). Black race, older age, moderate and severe glaucoma, higher baseline IOP, and glaucoma subtype were associated with higher reoperation risk. Although IOP decreased in all groups, stand-alone MIGS showed a more substantial decrease in mean IOP. Complication rates from MIGS were low overall: 1% for ECP, 1% for Xen implantation, and 2% for goniotomy or canaloplasty. CONCLUSIONS: In current United States clinical practice, MIGS has substantially lower reoperation rates when performed with phacoemulsification, especially for ECP and goniotomy or canaloplasty. Approximately one-sixth of patients undergoing stand-alone ECP and one-quarter of patients undergoing stand-alone Xen implantation or goniotomy or canaloplasty require reoperation by 2 years. Black race, diagnosis coding of moderate to severe glaucoma, and higher baseline IOP were associated with higher risk of reoperation after MIGS procedures. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Juvenile open angle glaucoma: current diagnosis and management.

PURPOSE OF REVIEW: The aim of this article is to summarize up-to-date research on the diagnosis and management of juvenile open-angle glaucoma (JOAG). RECENT FINDINGS: JOAG can be subclassified into four clinical phenotypes, and faster myopic shift is a risk factor for disease progression. Vessel density is associated with structural damage and worsening visual acuity in JOAG and can be monitored with optical coherence tomography angiography. Genetic studies have revealed molecular causes of JOAG including variants in CPAMD8, MYOC, and CYP1B1. Tube shunt surgeries as well as gonioscopy-assisted transluminal trabeculotomy have been shown to be successful in JOAG. SUMMARY: Although genetic advances may improve future screening, intraocular pressure monitoring and fundoscopic exam remain the current mainstay of diagnosis. Medical treatment alone for JOAG is typically insufficient with patients requiring surgical management. Selective laser trabeculoplasty may delay or decrease the need for surgery. Trabeculectomy has traditionally been shown to be effective in JOAG, but tube shunt surgery and microinvasive glaucoma surgery are effective alternatives.

The Heritability of Primary Angle Closure Anatomic Traits and Predictors of Angle Closure in South Indian Siblings.

PURPOSE: To estimate the heritability of ocular biometric and anterior chamber morphologic parameters and to determine predictors of angle closure concordance in South Indian probands with angle closure and their siblings DESIGN: Prospective observational cohort study METHODS: Subjects received a standardized ophthalmic examination, A-scan ultrasonography, pachymetry, and anterior segment optical coherence tomography (ASOCT) imaging. Heritability was calculated using residual correlation coefficients adjusted for age, sex, and home setting. Concordant sibling pairs were defined as both proband and sibling with angle closure. Predictors of angle closure concordance among siblings were calculated using multivariable logistic regression models. RESULTS: A total of 345 sibling pairs participated. All anterior chamber parameters were highly heritable (P < .001 for all). Similarly, all iris parameters, axial length, lens thickness (LT), central corneal thickness, anterior lens curvature, lens vault (LV), spherical equivalent, and intraocular pressure were moderately to highly heritable (P < .004 for all). LV and LT were more heritable among concordant siblings (P < .05 for both). In contrast, ASOCT angle parameters had statistically insignificant heritability estimates. In multivariable analyses, siblings older than their probands were more likely to be concordant for angle closure (OR 1.05, 95% CI 1.01, 1.09; P = .02) and siblings with deeper anterior chamber depths (ACDs) compared to their proband were less likely to be concordant for angle closure (OR 0.74, 95% CI 0.64, 0.86; P < .001). CONCLUSIONS: Iris, anterior chamber, and lens parameters may be heritable whereas angle parameters were not. LT and LV may play important roles in the pathogenesis of angle closure. Siblings who are older or have a shallower ACD may need more careful disease monitoring.

A systematic review of the evidence supporting post-operative medication use in congenital heart disease.

BACKGROUND: Targeted drug development efforts in patients with CHD are needed to standardise care, improve outcomes, and limit adverse events in the post-operative period. To identify major gaps in knowledge that can be addressed by drug development efforts and provide a rationale for current clinical practice, this review evaluates the evidence behind the most common medication classes used in the post-operative care of children with CHD undergoing cardiac surgery with cardiopulmonary bypass. METHODS: We systematically searched PubMed and EMBASE from 2000 to 2019 using a controlled vocabulary and keywords related to diuretics, vasoactives, sedatives, analgesics, pulmonary vasodilators, coagulation system medications, antiarrhythmics, steroids, and other endocrine drugs. We included studies of drugs given post-operatively to children with CHD undergoing repair or palliation with cardiopulmonary bypass. RESULTS: We identified a total of 127 studies with 51,573 total children across medication classes. Most studies were retrospective cohorts at single centres. There is significant age- and disease-related variability in drug disposition, efficacy, and safety. CONCLUSION: In this study, we discovered major gaps in knowledge for each medication class and identified areas for future research. Advances in data collection through electronic health records, novel trial methods, and collaboration can aid drug development efforts in standardising care, improving outcomes, and limiting adverse events in the post-operative period.

Pre-treatment with high molecular weight free PEG effectively suppresses anti-PEG antibody induction by PEG-liposomes in mice.

Immune responses against polyethylene glycol (PEG) can lead to the rapid clearance of PEGylated drugs and are associated with increased risk of serious adverse events such as infusion reactions and anaphylaxis. Although select PEGylated therapeutics can induce anti-PEG antibodies (APA), there is currently no readily deployable strategy to mitigate their negative effects. Given the large number of PEGylated therapeutics that are either FDA-approved or in clinical development, methods that suppress APA induction to ensure the safety and efficacy of PEGylated drugs in patients would be a valuable clinical tool. We previously showed that infusion of high molecular weight (MW) free PEG can safely and effectively restore the circulation of PEG liposomes in animals with high pre-existing titers of APA, without stimulating additional APA production. Here, we explored the effectiveness of prophylaxis with free PEG or tolerogenic PEGylated liposomes as a strategy to reduce the amount of APA induced by subsequently administered PEGylated liposomes. Surprisingly, we found that a single administration of free PEG alone was capable of markedly reducing the APA response to PEG-liposomes for ~2 months; the effectiveness was comparable to, and frequently exceeded, interventions with different tolerogenic PEG-liposomes. These results support further investigations of free PEG prophylaxis as a potential strategy to ameliorate the APA response to sensitizing PEGylated therapeutics.

Association between preoperative respiratory support and outcomes in paediatric cardiac surgery.

BACKGROUND: Preoperative mechanical ventilation is associated with morbidity and mortality following CHD surgery, but prior studies lack a comprehensive analysis of how preoperative respiratory support mode and timing affects outcomes. METHODS: We retrospectively collected data on children <18 years of age undergoing cardiac surgery at an academic tertiary care medical centre. Using multivariable regression, we examined the association between modes of preoperative respiratory support (nasal cannula, high-flow nasal cannula/noninvasive ventilation, or invasive mechanical ventilation), escalation of preoperative respiratory support, and invasive mechanical ventilation on the day of surgery for three outcomes: operative mortality, postoperative length of stay, and postoperative complications. We repeated our analysis in a subcohort of neonates. RESULTS: A total of 701 children underwent 800 surgical procedures, and 40% received preoperative respiratory support. Among neonates, 243 patients underwent 253 surgical procedures, and 79% received preoperative respiratory support. In multivariable analysis, all modes of preoperative respiratory support, escalation in preoperative respiratory support, and invasive mechanical ventilation on the day of surgery were associated with increased odds of prolonged length of stay in children and neonates. Children (odds ratio = 3.69, 95% CI 1.2-11.4) and neonates (odds ratio = 8.97, 95% CI 1.31-61.14) on high-flow nasal cannula/noninvasive ventilation had increased odds of operative mortality compared to those on room air. CONCLUSION: Preoperative respiratory support is associated with prolonged length of stay and mortality following CHD surgery. Knowing how preoperative respiratory support affects outcomes may help guide surgical timing, inform prognostic conversations, and improve risk stratification models.

Overcoming anti-PEG antibody mediated accelerated blood clearance of PEGylated liposomes by pre-infusion with high molecular weight free PEG.

Antibodies that specifically bind polyethylene glycol (PEG), i.e. anti-PEG antibodies (APA), are associated with reduced efficacy and increased risk of serious adverse events for several PEGylated therapeutics. Here, we explored the concept of using free PEG molecules to saturate circulating APA. Surprisingly, we found that 40 kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48 h in mice. In contrast, lower molecular weight free PEG (≤10 kDa) failed to restore circulation beyond a few hours. These in vivo results were consistent with estimates from a minimal physiologically based pharmacokinetic model. Importantly, the infusion of free PEG appeared to be safe in mice previously sensitized by injection of PEGylated liposomes, and free PEG did not elicit excess APA production even in mice with pre-existing adaptive immunity against PEG. Our results support further investigation of high molecular weight free PEG as a potential method to control and overcome high titers of APA, restoring the prolonged circulation of PEGylated liposomes and possibly other PEGylated therapeutics.