Outcomes of slow coagulation transscleral cyclophotocoagulation in a predominantly African American glaucoma population.

Purpose: To evaluate outcomes of slow coagulation transscleral cyclophotocoagulation (SC-TSCPC) in a primarily African American patient population with glaucoma. Methods: A retrospective chart review was performed for 104 consecutive cases of SC-TSCPC by a single surgeon between November 6, 2019-September 7, 2023. Power ranged from 1150 to 1500 mW, duration was 4 s, and number of spots ranged from 10 to 25. Exclusion criteria were diagnosis of neovascular glaucoma, prior CPC, visual acuity (VA) of no light perception or unable to be assessed due to patient's mental status, aphakia, or follow-up <3 months. The primary outcome measure was surgical success defined as an intraocular pressure (IOP) of 6-21 mmHg with a ≥20 % reduction from baseline, no glaucoma re-operation, and no loss of light-perception. Secondary outcome measures included VA, glaucoma medication use, and post-surgical complications. Analysis was also stratified by lens status as literature suggests a greater IOP-lowering effect in pseudophakic eyes after CPC. Results: There were 28 eligible patients (6 phakic, 22 pseudophakic) included in this analysis. Mean follow-up was 11.6 ± 8.3 months, and 14 patients had postoperative year 1 data available. The mean age was 75.2 ± 13.9 years, 42.9 % were female, and 92.9 % were African American, reflective of the demographics of the local community. The cumulative success rate was 68.5 % at 1 year and did not differ significantly between phakic and pseudophakic patients. Mean VA worsened from 20/600 preoperatively to 20/1050 at last follow-up (P = 0.04) and was marginally worse in the phakic group (P = 0.15). Mean IOP decreased from 31.1 ± 13.2 mmHg on 4.0 ± 1.5 medications preoperatively to 13.8 ± 7.1 mmHg on 2.6 ± 1.5 medications at last follow-up (P < 0.001; P < 0.01), with a more pronounced effect among pseudophakic patients. 85.7 % of patients had prolonged anterior chamber (AC) inflammation beyond 1 month, which persisted in 10.7 % at last follow-up. The cystoid macular edema (CME) rate was 21.4 %, with 10.7 % persistent at last follow-up. Conclusions: SC-TSCPC is an effective, non-incisional IOP-lowering procedure in phakic and pseudophakic eyes that may not otherwise be ideal candidates for incisional glaucoma surgery. Pseudophakic eyes may experience larger reductions in IOP, however, laser settings can be titrated on a case-by-case basis depending on individual patients' goals. There was a higher incidence of prolonged AC inflammation and CME in our cohort compared to similar studies which report rates of 12.7 % and 2.7 %, respectively. Although the significance of such complications may differ based on the visual potential of each patient, these findings support existing literature that African American patients can have greater incidence of inflammation and subsequent sequalae after ocular surgery.

Bleb revision with Tenon's transposition flap: Case report.

INTRODUCTION: To describe the use and technique of a Tenon's transposition flap without overlying conjunctiva to cover bare sclera following bleb excision and tube shunt implantation. PRESENTATION OF CASE: A 76-year-old man with severe stage primary open-angle glaucoma in both eyes presented with a nonfunctioning trabeculectomy with a thin-walled, cystic bleb overhanging the cornea. A Baerveldt-350 Glaucoma Implant in the ciliary sulcus was recommended for further lowering of intraocular pressure, along with concurrent excision of the bleb due to patient dissatisfaction with the cosmesis of the bleb and to prevent future bleb-associated complications. Conjunctiva could be closed without tension over the new tube entry site; however, a defect remained at the prior trabeculectomy site. A Tenon's transposition flap without overlying conjunctiva was created to cover this site. By postoperative week 6, new conjunctiva had grown over the Tenon's transposition graft, appearing as if there had never been a bleb. DISCUSSION: This case illustrates the use of a Tenon's transposition flap to cover bare sclera following bleb excision. This technique proves valuable when conjunctiva is limited, offering an alternative when adjacent conjunctiva cannot be mobilized. CONCLUSION: In cases requiring non-water-tight coverage of bare sclera with limited available conjunctiva, a Tenon's transposition flap can be used, permitting new conjunctiva to safely grow over bare Tenon's. This technique is useful during a variety of scenarios, including tube shunt and trabeculectomy revisions, where conjunctival closure may be difficult.

Case study and pilot results: Stepwise approach to teach a resident tube shunt surgery.

Purpose: To illustrate the utility of a previously published stepwise rubric for evaluating a resident's progress learning aqueous tube shunt surgery. Method: Using a stepwise rubric, a single PGY3 ophthalmology resident and attending glaucoma surgeon evaluated the resident's performance after each aqueous tube shunt surgery. The rubric subdivides the surgery into 12 consecutive steps and scores the resident's proficiency in each step with either a 0 (observation), 2 (novice), 3 (beginner), 4 (advanced beginner), or 5 (competent). Results: The resident's cumulative score increased significantly throughout the 17 surgeries performed, with the resident's self-evaluated score and attending's score increasing from 12 to 27 and 14 to 27 from the first to last surgery, respectively. Scores were consistent between the resident and attending; for any given surgery, the resident's own score never deviated from the attending's score by more than 1 point. The resident completed at least 50% of the steps in 11 of the 17 cases. While some surgical steps were mastered earlier on ("tube tying" and "suture implantation"), other steps were more challenging to master ("tunnel in sclera and enter the AC" and "close conjunctiva", as demonstrated by fewer overall attempts or never attaining a score of '5' despite multiple attempts. Conclusions and Importance: This study demonstrates the utility of the stepwise rubric in tracking resident surgical scores chronologically via self and attending assessment. The ability to compare their own scores to that of an attending allows the resident to learn how to effectively evaluate their own performance. Most importantly, statistics obtained for each step provides the resident with personalized and real-time feedback for learning specific surgical steps. In conclusion, the stepwise rubric is a useful add-on to a resident's aqueous tube shunt surgery education.

Baerveldt-350 with 3-0 Prolene Ripcord to Minimize Hypotony-Associated Complications after Spontaneous Ligature Dissolution.

PURPOSE: To describe the technique and demonstrate the utility and outcomes of using a thick 3-0 Prolene ripcord in the lumen of a Baerveldt-350 aqueous shunt until after the ligature suture dissolves. DESIGN: Single-center, noncontrolled, retrospective case series. PARTICIPANTS: A total of 50 eyes from 50 patients with glaucoma undergoing placement of Baerveldt-350 aqueous shunts with 3-0 Prolene ripcords. METHODS: A retrospective chart review was performed for all eyes of adult patients that had undergone a Baerveldt-350 aqueous shunt placement by a single surgeon at a single academic center between October 1, 2019 and June 30, 2022. MAIN OUTCOME MEASURES: Data collected included demographic and clinical characteristics of the patients, preoperative and postoperative clinical data including intraocular pressure (IOP) and glaucoma medications, postoperative timepoints of ligature suture dissolution, and timepoints of 3-0 Prolene ripcord removal or whether they were permanently left in place. RESULTS: In total, 50 eyes from 50 patients were included; mean age was 69.5 years, 54.0% of patients were female, 92% of patients were Black, and 66% of eyes had primary open-angle glaucoma. Twenty-six of 50 (52%) eyes had ripcord removal at the soonest postoperative visit after spontaneous ligature dissolution, 19/50 (38%) eyes had delayed ripcord removal, and 5/50 (10%) eyes had no ripcord removal. There were no cases of hypotony-associated complications (shallow anterior chamber, hypotony maculopathy, choroidal effusion, suprachoroidal hemorrhage) in this subgroup of eyes that underwent no ripcord removal. CONCLUSIONS: Our results demonstrate that routine use of a 3-0 Prolene ripcord to partially occlude the lumen of a Baerveldt-350 is a useful strategy to minimize sudden hypotony-associated complications when the ligature suture dissolves. This strategy allows for a more controlled postoperative course and a safe 2-step decrease in IOP (1: when the ligature dissolves, and 2: when the ripcord is removed). FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Same-quadrant Baerveldt Glaucoma Implant-250 to Baerveldt Glaucoma Implant-350 exchange.

Purpose: In eyes with a prior failed aqueous shunt (or "tube") requiring additional intraocular pressure (IOP) control, options include angle surgery, cyclodestruction, second tube, tube revision, or tube exchange. We present a case of a same-quadrant tube exchange of a Baerveldt-250 (BGI-250) to BGI-350. Observations: The patient is a 71-year-old African American female with severe-stage primary open angle glaucoma of both eyes, and this case focuses on the right eye. This eye had prior cataract surgery with iStent, prior BGI-250 in the anterior chamber (AC), and prior iStent removal with gonioscopy assisted transluminal trabeculotomy (GATT). The visual acuity (VA) was 20/150, and the IOP was 26 mmHg on 3 IOP-lowering medications. The prior superotemporal BGI-250 had its "wings" on top of the superior and lateral rectus muscles and its tube tip in the AC. The implant was removed in its entirety including the superficial and deep layers of its capsule. The new BGI-350 was stented with a 3-0 polypropylene ripcord, ligated with a 7-0 polyglactin suture, and implanted with its wings under the rectus muscles and the tube tip in the sulcus. For early IOP-lowering prior to ligature dissolution, 2 needle stab fenestrations and an additional 7-0 polyglactin wick was used. The capsule from the prior BGI-250 was used as a patch graft for the new BGI-350. The ligature dissolved at postoperative week (POW) 6. By POW8, the IOP was 18 mmHg on 3 IOP-lowering medications and frequent topical steroid, the AC was quiet, and the ripcord was removed. A slow steroid taper finished at postoperative month (POM) 6. By POM 12, the VA was still at baseline 20/150, and the IOP was 14 mmHg on 3 IOP-lowering medications. Conclusions & importance: Patients with a prior failed tube requiring additional IOP-lowering can undergo a same-quadrant tube exchange. BGI-350s may offer more IOP-lowering than BGI-250s, but the IOP-lowering achieved in this patient's case could be attributable to differences in postoperative management in addition to endplate size; longer follow-up is needed. A tube exchange offers the opportunity to reposition the tube tip from the AC to the sulcus and to use the prior tube's capsule as a patch graft for the new tube.

Associations Between Autoimmune Disease and the Development of Age-Related Macular Degeneration.

Purpose: The pathogenesis of age-related macular degeneration (AMD) likely implicates the dysregulation of immune response pathways. Several studies demonstrate that the pathogenic elements of AMD resemble those of autoimmune diseases, yet the association between AMD development and most autoimmune diseases remain unexplored. Methods: We conducted a case-control analysis of patients ages 55 and older with new-onset International Classification of Diseases (ICD) coding of dry, wet, or unspecified AMD between 2005 and 2019 in the Merative MarketScan Commercial and Medicare Databases. The diagnosis of an autoimmune disease was defined by an outpatient or inpatient claim with a relevant ICD code in the 12 months before the index visit. Conditional multivariable logistic regression, adjusted for AMD risk factors, was used to calculate odd ratios and 95% confidence intervals. Results: We identified 415,027 cases with new-onset ICD coding for AMD matched with propensity scores to 414,853 controls. In total, 16.1% of cases and 15.9% of controls were diagnosed with any autoimmune disease. The diagnosis of any autoimmune disease did not affect the odds of new-onset ICD coding for AMD in multivariable regression (OR = 1.01; 95% CI, 0.999-1.02). Discoid lupus erythematosus (OR = 1.29; 95% CI, 1.12-1.48), systemic lupus erythematosus (SLE) (OR = 1.21; 95% CI, 1.15-1.27), giant cell arteritis (OR = 1.19; 95% CI, 1.09-1.30), Sjogren's syndrome (OR = 1.17; 95% CI, 1.09-1.26), and Crohn's disease (OR = 1.13; 95% CI, 1.06-1.22) increased the odds of a new-onset ICD coding for AMD. Conclusions: Most autoimmune diseases do not affect the odds of developing AMD but several common autoimmune disorders such as SLE and Crohn's disease were associated with modestly increased odds of AMD. Further studies are needed to validate and investigate the underlying mechanisms of these associations.

Cyclophotocoagulation in Neovascular Glaucoma with Near-Total Synechial Angle Closure.

Objective: To describe a single surgeon's experience utilizing prompt primary slow-burn transscleral cyclophotocoagulation (CPC) with prior or concurrent anti-VEGF and subsequent aqueous shunt as needed in NVG eyes with near-total synechial angle closure at presentation. Methods: Retrospective chart review of all NVG patients with uncontrolled IOP, active anterior segment NV, near-total synechial angle closure, and no contraindications to prompt anti-VEGF who received CPC within 3 days of presentation with at least 6 months of follow-up. Results: Eight patients with mean age 60.6 years were included. Underlying etiologies were CRVO (N = 3), PDR (N = 2), CRAO (N = 1), BRVO (N = 1), and chronic RD (N = 1). All eyes underwent CPC with intravitreal anti-VEGF within 3 days of presentation. Five patients did not require subsequent aqueous shunts through a mean follow-up of 15 months; most recent visual acuities ranged from 20/40 to LP, and IOPs ranged from 5 to 11 mmHg on 0 to 3 IOP-lowering medications. Three patients who required subsequent tubes had complete regression of active anterior segment NV at the time of surgery. Most recent visual acuities ranged from 20/100 to 20/125, and IOPs ranged from 8 to 14 mmHg on 0 meds at a mean follow-up of 10 months. No eyes developed uncontrolled inflammation, sympathetic ophthalmia, or phthisis. Conclusion: Prompt primary slow-burn CPC with prior or concurrent anti-VEGF may be an effective strategy to immediately lower IOP in acute NVG eyes with active anterior segment NV and near-total synechial angle closure. If IOP becomes uncontrolled later, an aqueous shunt can be implanted in a controlled setting after active anterior segment NV has regressed.

Indirect treatment comparison (ITC) of the efficacy of vutrisiran and tafamidis for hereditary transthyretin-mediated amyloidosis with polyneuropathy.

BACKGROUND: Vutrisiran and tafamidis are approved therapies for treating hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis with polyneuropathy, a rapidly progressive and fatal disease. To assist healthcare decision-makers, an indirect treatment comparison (ITC) was undertaken to explore the comparative efficacy of vutrisiran and tafamidis. RESEARCH DESIGN AND METHODS: Individual patient data (vutrisiran vs. placebo) and published results (tafamidis vs. placebo) from phase 3 randomized controlled trials were used in a Bucher analysis to assess differences in treatment effects between vutrisiran and tafamidis on: Neuropathy Impairment Score-Lower Limbs (NIS-LL), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score, NIS-LL Response, and modified Body Mass Index (mBMI). RESULTS: Greater treatment effects were observed at 18 months with vutrisiran vs. tafamidis for all endpoints, with statistically significant improvements in polyneuropathy (relative mean change in NIS-LL: -5.3 [95% confidence interval (CI): -9.4, -1.2; p = 0.011]), health-related quality of life (HRQOL, relative mean change in Norfolk QOL-DN: -18.3 [95% CI: -28.6, -8.0; p < 0.001]), and nutritional status (relative mean change in mBMI: 63.9 [95% CI: 10.1, 117.7; p = 0.020]). CONCLUSIONS: This analysis suggests vutrisiran has greater efficacy on multiple measures of polyneuropathy impairment and HRQOL compared to tafamidis in patients with ATTRv amyloidosis with polyneuropathy.

Hereditary transthyretin-mediated (ATTRv/hATTR) amyloidosis is a rare genetic disease that runs in families, affecting about 50,000 people worldwide. This condition results in abnormal protein deposits building up, causing damage to multiple nerves (polyneuropathy) and other organs, which can shorten lifespan and have other harmful effects. Polyneuropathy symptoms include weakness, numbness, pain, dizziness, and diarrhea. Over time, everyday activities become more difficult as patients become increasingly disabled and dependent on others. Several treatments have been approved for the polyneuropathy of ATTRv amyloidosis. Many of these work in different ways to impact the disease process. An indirect treatment comparison is a well-established statistical method used by healthcare decision-makers to compare treatments when head-to-head trials are unavailable. Indirect treatment comparisons using a common approach, the Bucher method, yield similar conclusions to head-to-head studies over 90% of the time. This method was used to compare clinical trial data for tafamidis and vutrisiran, two approved treatments for ATTRv amyloidosis with polyneuropathy. The findings show that vutrisiran is more effective than tafamidis at addressing the polyneuropathy of ATTRv amyloidosis as measured by changes to sensory or motor nervous system functioning and nutritional status. Also, vutrisiran showed greater maintenance of health-related quality of life compared to tafamidis. The expected benefits of vutrisiran over tafamidis are large enough to be noticeable and clinically meaningful to a patient or clinician. This highlights the potential advantages of vutrisiran compared to tafamidis with regard to preservation of physical function and quality of life when treating ATTRv amyloidosis with polyneuropathy.

Cost-effectiveness analysis of semaglutide 2.4 mg for the treatment of adult patients with overweight and obesity in the United States.

BACKGROUND: The rising prevalence and associated public health burden of obesity has led to advancements in pharmaceuticals for weight management. Semaglutide 2.4 mg, an anti-obesity medication (AOM) recently approved by the US Food and Drug Administration, has demonstrated clinically relevant weight loss in its phase 3 clinical trials. Economic evaluation comparing semaglutide 2.4 mg with other available weight management therapies is essential to inform payers for decision-making. OBJECTIVES: To assess the cost-effectiveness of semaglutide 2.4 mg in the treatment of adult patients with obesity (ie, body mass index [BMI] ≥ 30) and adult patients who are overweight (ie, BMI 27-29.9) with 1 or more weight-related comorbidities from a US third-party payer perspective. METHODS: A cohort Markov model was constructed to compare semaglutide 2.4 mg with the following comparators: no treatment, diet and exercise (D&E), and 3 branded AOMs (liraglutide 3 mg, phentermine-topiramate, and naltrexone-bupropion). All AOMs, including semaglutide 2.4 mg, were assumed to be taken in conjunction with D&E. Changes in BMI, blood pressure, cholesterol level, experience of acute and chronic obesity-related complications, costs, and quality-adjusted life years (QALYs) were simulated over 30 years based on pivotal trials of the AOMs and other relevant literature. Drug and health care prices reflect 2021 standardized values. Cost-effectiveness was examined with a willingness-to-pay (WTP) threshold of $150,000 per QALY gained. Sensitivity analyses were conducted to test the robustness of the cost-effectiveness results to plausible variation in model inputs. RESULTS: In the base-case analysis, treatment with semaglutide 2.4 mg was estimated to improve QALYs by 0.138 to 0.925 and incur higher costs by $3,254 to $25,086 over the 30-year time horizon vs comparators. Semaglutide 2.4 mg is cost-effective against all comparators at the prespecified WTP threshold, with the incremental cost per QALY gained ranging from $23,556 to $144,296 per QALY gained. In the sensitivity analysis, extended maximum treatment duration, types of subsequent treatment following therapy discontinuation, and weight-rebound rates were identified as key drivers for model results. The estimated probability of semaglutide 2.4 mg being cost-effective compared with comparators ranged from 67% to 100% when varying model parameters and assumptions. CONCLUSIONS: As a long-term weight management therapy, semaglutide 2.4 mg was estimated to be cost-effective compared with no treatment, D&E alone, and all other branded AOM comparators under a WTP threshold of $150,000 per QALY gained over a 30-year time horizon. DISCLOSURES: Financial support for this research was provided by Novo Nordisk Inc. The study sponsor was involved in several aspects of the research, including the study design, the interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication. Dr Kim and Ms Ramasamy are employees of Novo Nordisk Inc. Ms Kumar and Dr Burudpakdee were employees of Novo Nordisk Inc at the time this study was conducted. Dr Sullivan received research support from Novo Nordisk Inc for this study. Drs Wang, Song, Wu, Ms Xie, and Ms Sun are employees of Analysis Group, Inc, who received consultancy fees from Novo Nordisk Inc in connection with this study.

Continuous positive airway pressure for obstructive sleep apnea in children.

QUESTION: A 12-year-old child underwent adenotonsillectomy for treatment of obstructive sleep apnea (OSA) but continues to snore at night and struggles with attentiveness at school. The child's parent uses a continuous positive airway pressure (CPAP) machine at night and wonders whether the same therapy could be used in children. ANSWER: Unlike in adults, pediatric OSA is commonly related to adenotonsillar hypertrophy and is often amenable to treatment with adenotonsillectomy. As an alternative to surgery or in cases of postsurgical persistence of OSA, CPAP has shown effectiveness in improving both polysomnographic parameters and daytime neurobehavioural symptoms in children with OSA. Adherence to CPAP therapy is a challenge in children and requires parental education and special considerations such as a mask acclimatization period.

Indirect treatment comparison of the efficacy of patisiran and inotersen for hereditary transthyretin-mediated amyloidosis with polyneuropathy.

INTRODUCTION: Patisiran and inotersen are two therapies approved for the treatment of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy, a rapidly progressive disease with a substantial clinical burden. This analysis indirectly compares the efficacy of patisiran and inotersen on neuropathy and quality of life (QOL). METHODS: Published results from the NEURO-TTR study of inotersen and individual patient data from the APOLLO study of patisiran were used. Indirect comparisons were conducted for 15-month changes in neuropathy and QOL endpoints: modified Neuropathy Impairment Score +7 (mNIS+7Ionis,), Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire, body mass index (BMI), and Polyneuropathy Disability (PND) score. Analyses were conducted under different assumptions about the impact of missing data and to adjust for baseline differences between studies. RESULTS: Patisiran showed significantly greater treatment effects than inotersen for mNIS+7Ionis (mean difference: -12.3 [95% confidence interval: -21.4, -3.3]), Norfolk QOL-DN (-11.3 [-19.8, -2.9]), and BMI (1.0 [0.4, 1.7]). The proportion of patients with improvement or no change from baseline on PND score was higher for patisiran-treated patients (odds ratio: 8.9 [4.6, 17.5]). Results were consistent and robust across analyses and methods. CONCLUSIONS: Patisiran demonstrated greater treatment effects on neuropathy and QOL than inotersen in patients with hATTR amyloidosis with polyneuropathy.

Inverted Papilloma of the Orbit and Nasolacrimal System.

PURPOSE: Periocular inverted papilloma (IP) is a rare, locally aggressive tumor with a propensity for recurrence and malignant transformation. Historically treated via wide excision, this study examines the characteristics and management of periocular IP, comparing those confined to the nasolacrimal system with those invading the orbit. METHODS: An Institutional Review Board-approved, Health Insurance Portability and Accountability Act-compliant retrospective, comparative case series was conducted in patients with IP of the orbit or nasolacrimal system across 15 clinical sites. RESULTS: Of 25 patients, 22 met inclusion criteria with 9 limited to the nasolacrimal system and 13 invading the orbit. Mean age was 60.4 years, 55% were women, all were unilateral. Mean follow-up was 48 months. Rates of smoking, dust and/or aerosol exposure, human papillomavirus (HPV) status, and inflammatory polyps were elevated compared to rates in the general population (45%, 18%, 18%, and 14%, respectively). Bony erosion on computed tomography scans was statistically significantly associated with orbit-invading IP (p = 0.002). Treatment involved all confined IP undergoing surgery alone while 39% of orbit-invading IP also received radiation therapy and/or chemotherapy (p = 0.054). Orbit-invading IP was more likely to be excised with wide margins than IP confined to the nasolacrimal system (85% vs. 22%, p = 0.007). Overall rates of malignancy, recurrence, and patient mortality from IP were found to be 27%, 23%, and 9%, respectively. CONCLUSIONS: IP invading the orbit typically requires aggressive therapy, while IP confined to the nasolacrimal system may be treated more conservatively. Using risk factors, characteristics, and outcomes, a treatment algorithm was created to guide management.

Prevalence of chronic respiratory morbidity, length of stay, inpatient readmissions, and costs among extremely preterm infants with bronchopulmonary dysplasia.

Objective: To evaluate the prevalence of chronic respiratory morbidity (CRM) in preterm infants (born ≤28 weeks gestational age (GA)) and compare healthcare resource utilization and costs among infants with/without CRM, and with/without bronchopulmonary dysplasia (BPD).Methods: Commercial claims data from the Truven MarketScan database were retrospectively analyzed. Included infants were born ≤28 weeks GA and admitted to a neonatal intensive care unit (January 2009-June 2016). Continuous insurance eligibility was required from birth through 1 year (CRM/no CRM cohorts) or ≥3 months (BPD/no BPD cohorts) CA or death.Results: CRM analysis included 1782 infants; 29.0% had CRM. BPD analysis included 2805 infants; 61.1% had BPD. The mean birth hospital length of stay was longer in infants with CRM versus those with no CRM (p < 0.0001). In infants with CRM or BPD, hospital readmission rates were significantly increased versus those without (both p < 0.0001). Total health care costs were significantly higher in infants with CRM (p = 0.0488) and BPD (p < 0.0001) versus those without. After birth hospitalization, outpatient visits and hospital readmissions accounted for most of the costs for the CRM and BPD cohorts.Conclusion: CRM and BPD following extremely preterm birth impose a significant health care burden.

A large multicentre, randomized, double-blind, cross-over study in healthy volunteers to compare pharmacokinetics, pharmacodynamics and safety of a pegfilgrastim biosimilar with its US- and EU-reference biologics.

AIMS: Recombinant PEGylated human granulocyte colony-stimulating factor (pegfilgrastim) is indicated for the reduction of chemotherapy-induced neutropenia and prevention of febrile neutropenia. Biosimilar pegfilgrastim is expected to reduce the financial burden of this complication of chemotherapy. The aim of this study was to demonstrate biosimilarity between Sandoz biosimilar pegfilgrastim and its US- and EU-approved reference biologics. METHODS: Phase I, randomized, double-blind, single-dose, 3-period, 6-sequence cross-over, multicentre study to evaluate the pharmacokinetics, pharmacodynamics, safety and immunogenicity of Sandoz biosimilar pegfilgrastim with US- and EU-references in healthy adults. RESULTS: Pharmacokinetic and pharmacodynamic similarity was demonstrated between the 3 biologics, as the 90% confidence interval for all primary pharmacokinetic and pharmacodynamic endpoint comparisons were contained within the predefined similarity margins of 0.80-1.25. Safety, immunogenicity and tolerability were also similar. CONCLUSIONS: Sandoz biosimilar pegfilgrastim demonstrated pharmacokinetic and pharmacodynamic similarity to both US- and EU-reference biologics. No meaningful differences in safety, local tolerability and immunogenicity were identified.

Economic Impact of Non-Medical Switching from Originator Biologics to Biosimilars: A Systematic Literature Review.

INTRODUCTION: A systematic literature review was conducted to review and summarize the economic impact of non-medical switching (NMS) from biologic originators to their biosimilars (i.e., switching a patient's medication for reasons irrelevant to the patient's health). METHODS: English publications reporting healthcare resource utilization (HRU) or costs associated with biosimilar NMS were searched in PubMed and EMBASE over the past 10 years and from selected scientific conferences over the past 3 years, along with gray literature for all biologics with an approved biosimilar (e.g., tumor-necrosis factor inhibitors, erythropoiesis-stimulating agents, insulin and hormone therapies). RESULTS: A total of 1311 publications were retrieved, where 54 studies met the selection criteria. Seventeen studies reported increased real-world HRU or costs related to biosimilar NMS, e.g., higher rates of surgery (11%), steroid use (13%) and biosimilar dose escalating (6-35.4%). Among the studies that the estimated cost impact associated with NMS, 33 reported drug costs reduction, 12 reported healthcare costs post-NMS without a detailed breakdown, and 5 reported NMS setup and managing costs. Cost estimation/simulation studies demonstrated the cost reduction associated with NMS. However, variation across studies was substantial because of heterogeneity in study designs and assumptions (e.g., disease areas, scenarios of drug price discount rates, cost components, population size, study period, etc.). CONCLUSION: Real-world studies reporting the economic impact of biosimilar NMS separately from drug costs are emerging, and those that reported such results found increased HRU in patients with biosimilar NMS. Studies of cost estimation have been largely limited to drug prices. Comprehensive evaluation of the economic impact of NMS should incorporate all important elements of healthcare service needs such as drug price, biologic rebates, HRU, NMS program setup, administration and monitoring costs. FUNDING: AbbVie.

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study.

BACKGROUND: Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. METHODS: In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. FINDINGS: Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. INTERPRETATION: Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. FUNDING: US National Institutes of Health.

Safety analysis of proposed pegfilgrastim biosimilar in Phase I and Phase III studies.

Aim: This analysis compares safety data for Sandoz proposed biosimilar (LA-EP2006) and reference pegfilgrastim from a Phase I pharmacokinetic/pharmacodynamic study in healthy volunteers (HVs) and two Phase III confirmatory studies in patients with breast cancer (BC; total n = 808). Patients & methods: Baseline characteristics were summarized, and event rates of bone pain and headache calculated. Results: HVs in the Phase I pharmacokinetic/pharmacodynamic study were generally younger, with lower mean body mass index, versus BC patients in PROTECT-1/-2. Bone pain was the most frequent adverse event with similar incidences with reference versus proposed biosimilar in all studies. Conclusion: No differences in adverse events were found between Sandoz proposed biosimilar and reference pegfilgrastim, notwithstanding some differences between HVs and BC patients.

Evaluation of the single-dose pharmacokinetics and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects.

PURPOSE: This double-blind, placebo-controlled, intra-subject, dose-escalation study assessed single-dose safety, pharmacokinetics, and pharmacodynamics of apixaban in healthy Japanese and Caucasian subjects. SUBJECTS AND METHODS: Sixteen healthy male Japanese and sixteen healthy male Caucasian subjects, matched for age, weight, and smoking status were randomized to receive four sequential single oral doses of either apixaban (2.5, 10, 25, and 50 mg) or matched placebo. Doses were separated by a ≥5-day washout. Blood samples were collected for the determination of apixaban plasma concentration, clotting times (international normalized ratio [INR], activated partial thromboplastin time, and modified prothrombin time [mPT]), and ex vivo thrombin generation (TG). Urine samples were collected for the analysis of apixaban concentration. RESULTS: Ascending single doses of apixaban 2.5-50 mg were safe and well tolerated by all subjects. Apixaban exposure increased the dose proportionally up to 10 mg. Apixaban reached maximum concentrations (C max) 3-4 h postdose, with mean C max ranging from 52.5-485.0 to 44.8-494.3 ng/mL in Japanese and Caucasian subjects. The mean half-life was ~8 and ~13 h and the renal clearance was 1.1 and 0.8 L/h in Japanese and Caucasian subjects, respectively. Pharmacodynamic assessments were similar between ethnic groups, with comparable dose-related prolongation of INR and mPT and inhibition of TG. CONCLUSION: Ascending single doses of apixaban over a 20-fold dose range were safe and well tolerated in Japanese and Caucasian subjects in this study. The consistency between pharmacokinetic and pharmacodynamic measures in Japanese and Caucasian subjects indicates that apixaban may be administered as a fixed dose with no need for adjustment in Japanese patients.

Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects.

AIMS: This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) matches reference pegfilgrastim (Neulasta® ) in healthy subjects. Safety and immunogenicity were also assessed. METHODS: The phase I, randomized, double-blind, two-period crossover study consisted of two treatment periods separated by an 8-week washout period. Healthy subjects aged 18-45 were randomized to either proposed biosimilar/reference pegfilgrastim or reference pegfilgrastim/proposed biosimilar. Proposed biosimilar and reference pegfilgrastim were administered on Day 1 of each treatment period (single 6 mg subcutaneous injection). Blood samples for PK/PD analysis were taken predose and ≤336 h postdose. PK/PD similarity was claimed if 90% (PK) and 95% (PD) confidence intervals (CI) for geometric mean ratios of the area under the serum concentration-time curve (AUC) from time of dosing and extrapolated to infinity (AUC0-inf ), or to the last measurable concentration (AUC0-last ), maximum observed serum concentration (Cmax ), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC0-last ) and ANC maximum effect attributable to the therapy under investigation (Emax ) were completely contained within the predefined margin (0.8 to 1.25). RESULTS: Overall, 169 subjects completed the study. PK/PD similarity was demonstrated; 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC0-inf (1.0559-1.2244), AUC0-last (1.0607-1.2328), Cmax (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC0-last (0.9948-1.0366), Emax (0.9737-1.0169) were completely contained within predefined margin of 0.8 to 1.25. Both biologics had similar safety profiles, were well tolerated and had low incidence of anti-drug antibodies. No neutralizing or clinically relevant antibodies were detected. CONCLUSIONS: PK/PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects.

Upper Eyelid Blepharoplasty: A Novel Method to Predict and Improve Outcomes.

BACKGROUND: In some upper eyelid blepharoplasties, maximal skin removal may not result in desired outcomes; raising crease height can therefore be considered. Currently, there is no method to determine the amount of skin to be excised and/or crease elevation required to achieve a specific outcome. OBJECTIVE: This study extrapolated an equation to determine amount of skin excision and/or lid crease elevation needed to achieve a specific eyelid margin to fold distance (MFD). METHODS: This institutional review board-approved, HIPAA-compliant study was a prospective, nonrandomized clinical trial. Patients were included if aged 30 to 100 years old and underwent upper eyelid blepharoplasty with one surgeon between 2012 and 2014. Exclusion criteria were thyroid eye disease, myasthenia gravis, myotonic dystrophy, pregnancy, blepharoptosis, prior eyelid surgery or trauma, concurrent brow surgery, and topical alpha-agonists. The following data were collected preoperatively and at postoperative months 1 and 6: age, gender, BMI, brow position, MFD, margin to crease distance (distance between eyelid margin and crease, MCD), and vertical skin distance (distance between eyelid margin and brow, VSD). RESULTS: A total 322 eyelids of 164 patients underwent 208 skin excisions, 26 crease elevations, and 88 combined skin excision and crease elevation. Age, gender, and BMI category were all nonsignificant and excluded from the final model. This equation was extrapolated with regression analysis: Change in MFD = -0.40 + (-0.28 × Change VSD) + (0.53 × Change MCD) with |R| = 0.28. CONCLUSION: To better predict and obtain desired upper eyelid blepharoplasty outcomes, the authors created an equation.