Injection Interval Research Articles

Numerical Investigation on the Influence of Injection Location and Injection Strategy on a High-Pressure Direct Injection Diesel/Methanol Dual-Fuel Engine

High-pressure direct injection diesel/methanol dual-fuel engines exhibit excellent emission reduction potential, but they are still in the initial stage of research and development. The influences of different methanol injection locations, injection duration, and injection pressures on combustion characteristics, mixture homogeneity, and exhaust emissions are investigated to explore appropriate injection strategies and further optimize the engine performance base using CONVERGE software. The results show that the impact of the methanol injection position on the engine is relatively small, especially on combustion characteristics. A larger axial nozzle distance contributes to the formation of the homogeneous mixture, improving the engine economy. However, the engine performance is remarkably affected by methanol injection duration and methanol injection pressure. A shorter combustion duration is achieved with a decrease in the methanol injection duration and an increase in the methanol injection pressure, as a result of which the fuel economy is improved, with the combustion process more concentrated near the top dead center. Simultaneously, the mixture homogeneity is enhanced, which is conducive to a reduction in soot and CO emissions, yet not to a NOX and HC reduction. The lowest overall emissions of NOX, soot, CO, and HC are achieved when the radial nozzle distance and axial nozzle distance are 2.5 mm and 0.5 mm, respectively. Besides, the combustion characteristics and emissions of the engine are affected significantly under different methanol injection locations and injection pressures. The increased injection interval leads to deteriorating combustion characteristics and economy, i.e., a delayed combustion phase (CA50), an extended ignition delay and combustion duration (CA10–CA90), thereby increasing CO and soot emissions, but decreasing NOX emission. Additionally, the optimal economy and exhaust emissions are obtained when adopting an injection duration of 6 °CA and an injection pressure of 44.4 MPa. The ITE is increased in this case compared to the other injection strategies, thereby improving the engine performance significantly. The results provide parametric feedback and theoretical support for the design of high-pressure direct injection diesel/methanol dual-fuel engines from a time and space perspective, which has certain theoretical significance.

A phase 2, open-label, adaptive, dose-ranging study with long-term extension to evaluate the safety, tolerability, efficacy, and pharmacokinetics of intra-articular AMB-05X injections in patients with tenosynovial giant cell tumor.

TPS11585 Background: CSF1R is a clinically validated target for Tenosynovial Giant Cell Tumor (TGCT). CSF1 is overexpressed in TGCT and, via action at the colony-stimulating factor 1 receptor (CSF1R), leads to the proliferation of synovial-like mononuclear cells and recruitment of multinucleate giant cells, foam cells, siderophages, and inflammatory cells, which compose the bulk of the neoplasm. Although nonmetastatic in nature, TGCT can develop into locally destructive lesions that cause significant local tissue injury, loss of joint function, and impaired quality of life. When complete resection is achievable without significant morbidity, the standard of care for patients with TGCT is surgical resection. Recurrence after surgery occurs in up to 30% of patients with localized TGCT and 83% of patients with diffuse TGCT ( Mastboom 2019, Patel 2017). Repeat surgeries may be necessary but often leads to further morbidity, complications, and reduced function of affected joints. A safe, effective, and convenient pharmacotherapy is a desirable addition to the therapeutic armamentarium for TGCT. AMB-05X is a potent and selective anti-CSF1R monoclonal antibody in development for local treatment of TGCT. Intra-articular (IA) injection of AMB-05X enables high drug concentration at the tumor site while minimizing systemic exposure and toxicity. A proof-of-concept study of IA AMB-05X for TGCT found clinically meaningful improvement in objective response rate, functional (pain, stiffness, range of motion) and quality of life measures after 12 weeks of therapy with no serious and a low number of adverse events associated with targeting CSF1R. This phase 2 study aims to establish the optimal dosing regimen and local administration of AMB-05X and confirm the efficacy and safety of 24 weeks and longer treatment. Methods: AMB-051-07 (NCT05349643) is an open-label, multicenter, phase 2 study of AMB-05X in patients with TGCT. The trial is being conducted at multiple sites in North America, Europe, and Australia. The dosing schedule includes an injection interval of every 4 weeks and longer, including an extended dosing period. Adult patients with histologically confirmed symptomatic TGCT with one joint involvement whether surgically amenable or non-amenable with measurable disease and adequate organ function are being enrolled. After the initial cohort of patients with TGCT of the knee, other joints may be enrolled pending evaluation by the DMC. The primary study outcome measures are objective response rate (ORR) per RECIST v1.1 by central radiology review and safety. Secondary outcome measures include ORR per modified RECIST and Tumor Volume Score, duration of response, time to response, PRO/QOL (including range of motion, stiffness, pain), pharmacodynamics and pharmacokinetics. Clinical trial information: NCT05349643 .

Assessment of Patients Receiving Short-Interval Botulinum Toxin Chemodenervation Treatment for Laryngeal Dystonia and Essential Tremor of the Vocal Tract

The gold-standard treatment for laryngeal dystonia (LD) and essential tremor of the vocal tract (ETVT) is botulinum toxin (BoNT) chemodenervation. Although safe and effective, it is not curative, and periodic injections are required. Some medical insurance companies only cover injections at a 3-month interval, though some patients benefit from injections more frequently. To determine the proportion and characteristics of patients who receive BoNT chemodenervation treatment in intervals shorter than 90 days. This retrospective cohort study across 3 quaternary care neurolaryngology specialty practices in Washington and California recruited patients who underwent at least 4 consecutive laryngeal BoNT injections for LD and/or ETVT in the past 5 years. Data were collected from March through June 2022 and analyzed from June through December 2022. Laryngeal BoNT treatment. Biodemographic and clinical variables, injection characteristics, evolution during the 3 interinjection intervals, and lifetime laryngeal BoNT treatment data were collected from patient medical records. Logistic regression was used to assess association to the short-interval outcome, defined as an average injection interval shorter than 90 days. Of 255 patients included from the 3 institutions, 189 (74.1%) were female, and the mean (SD) age was 62.7 (14.3) years. The predominant diagnosis was adductor LD (n = 199 [78.0%]), followed by adductor dystonic voice tremor (n = 26 [10.2%]) and ETVT (n = 13 [5.1%]). Seventy patients (27.5%) received short-interval injections (<90 days). The short-interval group was younger than the long-interval group (≥90 days), with a mean (SD) age of 58.6 (15.5) years and 64.2 (13.5) years, respectively, and a mean difference of -5.7 years (95% CI, -9.6 to -1.8 years). There were no patient-related differences between the short- and long-interval groups in terms of sex, employment status, or diagnosis. This cohort study demonstrated that while insurance companies often mandate a 3-month or greater interval for BoNT chemodenervation financial coverage, there is a considerable subset of patients with LD and ETVT who receive short-interval treatment to optimize their vocal function. Short-interval chemodenervation injections demonstrate a similar adverse effect profile and do not appear to predispose to resistance through antibody formation.

Evaluation of Intralymphatic Immunotherapy in Allergic Rhinitis Patients: A Systematic Review and Meta-analysis.

Intralymphatic immunotherapy (ILIT) is short-course administration of allergen-specific immunotherapy (AIT). This study is aimed at assessing the clinical efficacy and safety of ILIT in patients with allergic rhinitis (AR). MEDLINE, PUBMED, and Cochrane Library were used to conduct electronic searches for clinical trials comparing ILIT and placebo in patients with AR. The final search took place on August 24, 2022. Cochrane Handbook for Systematic Reviews of Interventions was used to assess the risk of bias in the included studies. The outcomes included combined symptom and medication scores (CSMS), visual analog scale (VAS), allergic rhinoconjunctivitis quality of life (RQLQ), Skin-prick test (SPT), and adverse events (AEs). Data were synthesized as mean difference (MD)/standard mean difference (SMD) or risk difference (RD) and 95% confidence interval (CI). Thirteen studies (454 participants) were included in this study. The ILIT group had better clinical improvement on the CSMS (random effects model, SMD-0.85, 95% CI [-1.58, -0.11], P = 0.02) and RQLQ (fixed-effects model, MD-0.42, 95% CI [0.69, 0.15], P = 0.003) than the placebo group. The booster injection was beneficial for CSMS (P < 0.0001), and the 4-week injection interval was superior to the 2-week injection period for improving VAS (P < 0.0001). Local swelling or erythema was the main AE following injection (random effects model, RD 0.16, 95% CI [0.05, 0.27], P = 0.005). Discussion. For individuals with AR, ILIT is safe and effective. ILIT alleviates clinical symptoms and reduces pharmaceutical consumption without causing severe AEs. However, the validity of this study is compromised by the substantial heterogeneity and risk of bias in the included researches. RegistrationCRD42022355329.

Assessing the viability of CO[formula omitted] storage in offshore formations of the Gulf of Mexico at a scale relevant for climate-change mitigation

We investigate the feasibility of industrial-scale geological carbon sequestration as an effective climate change mitigation technology. We do so by performing numerical simulations of coupled multiphase flow and geomechanics on a representative field-scale geological model in the Gulf of Mexico that could become a typical CO2 storage site. We use our representative model to investigate two potential hazards associated with large-scale CO2 storage: (1) The potential that CO2 might migrate to shallower formations and (2) The potential that CO2 injection might induce seismicity due to destabilization of pre-existing faults. At our study location, we find that extensive distribution of clay minerals in fault zones in combination with large fault throws result in widespread occurrence of low-permeability faults that prevent migration of CO2 outside of the injection interval. Low-permeability faults act as flow barriers and can result in reservoir compartmentalization and pore pressure build-up. For our field-scale geological model, we find that the risk of induced seismicity is controlled by the choice of the injection location with respect to pre-existing low-permeability faults. Our model results indicate that industrial-scale CO2 storage in the Gulf of Mexico is feasible, but that a priori reservoir characterization and the choice of injection location are crucial to mitigate the potential occurrence of induced seismicity and CO2 migration to shallower formations.

Angubindin-1 opens the blood–brain barrier in vivo for delivery of antisense oligonucleotide to the central nervous system (S14.009)

<h3>Objective:</h3> We aimed to verify a novel strategy of blood-brain barrier (BBB)-crossing delivery system for antisense oligonucleotide (ASO) by modulating the tricellular tight junctions (TJ) formed by brain microvascular endothelial cells. <h3>Background:</h3> ASO has increasingly become powerful therapeutic tools for intractable diseases. However, in case of treating disorders in the central nervous system, safe yet efficient methods of delivering ASO across the BBB by systemic administration have not been established. Recently, molecular characteristics of tricellular TJ located at the point where three cells meet in the BBB have been gradually elucidated. <h3>Design/Methods:</h3> We prepared angubindin-1, a recombinant protein fragment that binds to and modulates angulin-1 expressed at the TJs in the BBB, by using an E.coli expression system. Then we intravenously injected angubindin-1 and subsequently fluorescent-labeled ASO to mice, and examined the distribution of the ASO in the brain by immunohistochemical analyses. We also evaluated the effect of intravenously injected angubindin-1 on the silencing effect of the target RNA in the brain and spinal cord by subsequently injected ASO. <h3>Results:</h3> The fluorescent signals of the ASO were apparent in neurons when injected after angubindin-1. Prior administration of angubindin-1 produced a silencing effect of ASO by 30% to 40% in the brain and spinal cord. This silencing effect was dependent on the interval of injection between angubindin-1 and ASO, and was increased in a dose-dependent manner of both angubindin-1 and ASO. We also found that similarly prepared bicellular TJ modulators did not produce such a silencing effect. <h3>Conclusions:</h3> The delivery strategy of modulating the tricellular TJ in the BBB via angubindin-1 provides a novel avenue of development of ASO-based therapeutics for the treatment of various disorders in the central nervous system. <b>Disclosure:</b> Dr. Kuwahara has nothing to disclose. Dr. Zeniya has nothing to disclose. Dr. Nagata has nothing to disclose. Dr. Yokota has nothing to disclose.

One-Year Brolucizumab Outcomes in Neovascular Age-Related Macular Degeneration from a Large United States Cohort in the IRIS® Registry

To evaluate real-world visual acuity and injection intervals in patients with neovascular age-related macular degeneration (nAMD) after 12 months of brolucizumab therapy. Retrospective cohort study. Adults in the US-based IRIS® registry (Intelligent Research in Sight) with nAMD who received brolucizumab exclusively for 12 months (2308 eyes; 2079 patients). Observational study of eyes with a first injection of brolucizumab (index), followed by >2 more brolucizumab injections over the following 12 months without switching to another anti-vascular endothelial growth factor (VEGF) agent. Primary outcomes were change in best recorded visual acuity and, for eyes that had received prior anti-VEGF therapy (treatment-experienced eyes), the difference between the injection interval of brolucizumab at 12 months and the pre-switch anti-VEGF injection interval. Pre-switch interval was defined as the time between the prior anti-VEGF and index brolucizumab injections; brolucizumab interval was the time between the closest injection to day 365 and the previous brolucizumab injection. Secondary outcomes included incident adverse events. Overall visual acuity at index was 61.6±18.4 ETDRS letters; 83.7% of treatment-naïve eyes (184/220) and 86.1% of treatment-experienced eyes (1797/2088) showed stable (<10 letters gained/lost) or improved (10+ letters gained) visual acuity at 12 months. Overall, 90.5% of eyes (n=2088) were treatment-experienced. Among treatment-experienced eyes that had received a prior anti-VEGF injection within 365 days pre-index, 29.5% (594/2015) had a pre-switch interval ≥8 weeks (mean, 7.6±5.5 weeks), while 83.1% (1734/2015) had a brolucizumab injection interval at 12 months of ≥8 weeks (mean, 10.3±4.0 weeks). In all, 77.1% (1554/2015) of treatment-experienced eyes had an interval extension of ≥1 week; of these, 55.4% (861/1554) had an extension of ≥4 weeks. In this real-world study, at 12 months, brolucizumab treatment prolonged the interval between anti-VEGF injections for most treatment-experienced eyes, particularly those with a shorter pre-switch interval, while maintaining or improving visual acuity. With careful balancing of the benefits and risks, switching to brolucizumab treatment may offer the advantage of extending the treatment interval for patients with a high anti-VEGF therapy burden.

A STUDY ON THE INJECTION RATE CHARACTERISTICS OF THE SOLENOID COMMON-RAIL INJECTOR UNDER USING A HIGH-PRESSURE FUEL SYSTEM

The combustion of diesel engines is mainly controlled by fuel injection. Determining the fuel injection flow rate combined with the common-rail fuel injection system is a key solution to effectively improve engine performance and exhaust emissions. This work aims to investigate the influence of high injection pressures with a 6-holes-solenoid common rail injector on the injection rate characteristics in the range of 400 bar to 1600 bar, and a constant injector energizing time of 1.5 ms. The injection rate characteristics were carried out based on the pressure difference in the Zuech measuring chamber and synchronized data in real-time. The results showed that the increase of the mentioned injection pressures caused the decrease of hydraulic injection delay from 0.5 ms to 0.25 ms and expansion of the injector opening angle profile. In addition, the actual opening injection interval was prolonged as compared to the injector control signal. An increasing trend of fuel discharge coefficient was realized as higher injection pressure.

Energy analysis and research on injection control parameter influence mechanism of air assisted spray system

Air assisted spray system is a two-phase flow spray technology, which consists of fuel injector and gas injector. High pressure gas is injected into the air assisted spray system to maintain the high pressure environment. When using, fuel is injected into the system to mix with high pressure gas, and then the mixture is sprayed out through gas injector to complete the atomization process. Because the air assisted spray system can achieve better atomization of high viscosity liquid under lower injection pressure (below 10 bar), it has attracted more attention recently. A geometric model of the air assisted spray system with a complete air assisted nozzle is established. Based on this model, working process of air assisted spray system is investigated by energy analysis method, and influence mechanisms of different injection control parameters are analyzed. As discovered, the energy provided by fuel injection promotes droplet breakup after interacting with gas inside nozzle. Simultaneously, droplet transfers kinetic energy to gas. Afterwards, kinetic energy of gas and droplet is consumed during their interaction, thereby weakening gas–liquid interaction and reducing droplet breakup. After opening needle valve of gas injector, gas can obtain more kinetic energy due to the pressure difference inside and outside the nozzle, which plays a dominant role in the gas–liquid interaction, and promotes the breakup of droplets. However, the kinetic energy of gas and droplets is subsequently transferred to ambient gas, thus weakening the gas–liquid interaction and hindering the breakup of droplets. The fuel injection duration indirectly affects the consumption of gas kinetic energy in gas–liquid interaction by affecting the total amount of droplets, and then affects the characteristics of air assisted spray. The fuel-gas injection interval directly affects the consumption of gas kinetic energy in gas–liquid interaction, and then affects the characteristics of air assisted spray. The influence of gas injection duration on the characteristics of air assisted spray is determined by the influence of the flow inside the nozzle on the external spray.

Use of Injectable Hyaluronic Acid Gel and Injectable Platelet-rich Fibrin in the Treatment of Gingival Black Triangles: A Randomized Clinical Trial

Purpose: The current study aimed to compare the efficacy of injectable hyaluronic acid gel and injectable platelet rich fibrin, either alone or combined; for the reconstruction of defective interdental papilla using clinical approaches. Subjects and Methods: A total sample size of eighteen class I and class II deficient interdental papillae sites were randomly divided in 3 groups. Group 1 included 6 sites that were treated by 0.2ml hyaluronic acid gel injection. Group 2 included 6 sites that were treated by injectable platelet-rich fibrin (i-PRF). Group 3 included 6 sites that were treated by a combination of 0.2ml hyaluronic acid gel injection and iPRF. Each deficient papilla received 3 injections; at 0, 3and 6 weeks intervals. The height of black triangles was recorded at baseline before injection procedure, at each injection interval and during follow ups. Results: A statistically significant difference in all three groups was found in the mean of the black triangle height records between the five time intervals, mainly between baseline and 6 months follow up. Conclusion: Hyaluronic acid injections and injectable platelet rich fibrin can be an alternative non-invasive treatment method for gingival black triangles.

Use of Injectable Hyaluronic Acid Gel and Injectable Platelet-rich Fibrin in the Treatment of Gingival Black Triangles: A Randomized Clinical Trial

Purpose: The current study aimed to compare the efficacy of injectable hyaluronic acid gel and injectable platelet rich fibrin, either alone or combined; for the reconstruction of defective interdental papilla using clinical approaches. Subjects and Methods: A total sample size of eighteen class I and class II deficient interdental papillae sites were randomly divided in 3 groups. Group 1 included 6 sites that were treated by 0.2ml hyaluronic acid gel injection. Group 2 included 6 sites that were treated by injectable platelet-rich fibrin (i-PRF). Group 3 included 6 sites that were treated by a combination of 0.2ml hyaluronic acid gel injection and iPRF. Each deficient papilla received 3 injections; at 0, 3and 6 weeks intervals. The height of black triangles was recorded at baseline before injection procedure, at each injection interval and during follow ups. Results: A statistically significant difference in all three groups was found in the mean of the black triangle height records between the five time intervals, mainly between baseline and 6 months follow up. Conclusion: Hyaluronic acid injections and injectable platelet rich fibrin can be an alternative non-invasive treatment method for gingival black triangles.

Factors Linked to Injection Interval Extension in Eyes with Wet Age-Related Macular Degeneration Switched to Brolucizumab

To evaluate factors associated with anti-vascular endothelial growth factor (VEGF) injection interval extension in patients with neovascular age-related macular degeneration (nAMD) switched to brolucizumab treatment. Retrospective, observational cohort study. Adults in the United States-based IRIS® Registry (Intelligent Research in Sight) with nAMD who switched from another anti-VEGF agent to brolucizumab-only treatment for ≥ 12 months from October 8, 2019, through November 26,2021. Univariable and multivariable analyses examined associations of demographic and clinical characteristics with the likelihood of interval extension after switching to brolucizumab therapy. Eyes were classified as either extenders or nonextenders at 12 months. Extenders were eyes that achieved (1) an extension of ≥ 2 weeks in the brolucizumab injection interval at 12 months versus the interval before switching (time between the last known prior anti-VEGF injection and first [index] brolucizumab injection) and (2) stable (< 10 letters gained or lost) or improved (≥ 10 letters gained) visual acuity (VA) at 12 months versus VA at index injection. Of 2015 eyes among 1890 patients who switched to brolucizumab treatment, 1186 (58.9%) were extenders. In univariable analyses, demographic and clinical characteristics were comparable between extenders and nonextenders, except that extenders had shorter intervals before switching versus nonextenders (mean, 5.9 ± 2.1 weeks vs. 10.1 ± 7.6 weeks, respectively). In multivariable logistic regression modeling, a shorter interval before switching was associated significantly and positively with interval extension with brolucizumab therapy (adjusted odds ratio, 5.6 for interval before switching of < 8 weeks versus ≥ 8 weeks; 95% confidence interval, 4.5-6.9; P < 0.001), and eyes with an index VA of 40 to 65 letters were significantly less likely to be extenders than eyes in the higher (better) index VA categories. Length of the treatment interval before switching was the characteristic associated most strongly with successful interval extension with brolucizumab. Treatment-experienced patients who required more frequent injections (i.e., shorter intervals before switching) showed the greatest extensions when switching to brolucizumab. With careful consideration of benefits and risks, brolucizumab may be a valuable option for patients with higher treatment burdens because of the need for frequent injections. Proprietary or commercial disclosure may be found after the references.

Steps towards implementation of protocolized dose reduction of adalimumab, etanercept and ustekinumab for psoriasis in daily practice

BackgroundDose reduction (DR) of adalimumab, etanercept and ustekinumab has proven to be (cost-)effective in psoriasis patients with low disease activity. Further implementation is needed to establish application of DR for eligible patients.ObjectivesTo evaluate the implementation of protocolized biologic DR in daily practice.MethodsA pilot implementation study was performed in 3 hospitals during 6 months. By combining education and protocol development, involved healthcare providers (HCPs) were directed toward the adoption of protocolized DR. DR of adalimumab, etanercept, and ustekinumab was achieved by stepwise injection interval prolongation. Implementation outcomes (fidelity, feasibility) were assessed. Factors for optimizing implementation were explored in interviews with HCPs. Uptake was measured in patients by chart review.ResultsThe implementation strategy was executed as planned. Implementation fidelity was less than 100% as not all provided tools were used across study sites. HCPs indicated the feasibility of implementing protocolized DR, although time investment was needed. Identified additional factors for successful implementation included support for patients, uptake of DR into guidelines, and supportive electronic health record systems. During the 6 months intervention period, 52 patients were eligible for DR of whom 26 (50%) started DR. The proposed DR protocol was followed in 22/26 patients (85%) on DR.ConclusionAdditional staff for support, extra time during consultations, education on DR for HCPs and patients, and effective tools such as a feasible protocol can lead to more patients on biologic DR.

Changes in Clinical Management of Patients with Schizophrenia Treated with Long-Acting Injectable Antipsychotics (LAIs), Including Telepsychiatry Use, During the COVID-19 Pandemic.

The COVID-19 pandemic substantially impacted care of patients with schizophrenia treated with long-acting injectable antipsychotics (LAIs). This study (OASIS-MAPS) examined how clinical sites adapted operations and used telepsychiatry to maintain standard of care for these patients during the pandemic. Two online surveys (initial: October-November 2020, N = 35; follow-up: July-September 2021, N = 21) were completed by a principal investigator (PI) or PI-appointed designee at sites participating in the OASIS study (NCT03919994). Survey responses were analyzed descriptively. At the time of the initial survey, all 35 participating sites were using variants of telepsychiatry, with 20 sites adopting it after the pandemic started. Most sites reported no negative impacts of the pandemic on medication adherence, although approximately 20% of sites reported decreased adherence for LAIs. Twelve sites (34%) reported switching patients with schizophrenia from LAIs to oral antipsychotic medications, while 11 sites (31%) reported switching patients from shorter to longer injection interval LAIs during the pandemic. Most sites did not experience difficulties in implementing or expanding telepsychiatry services, although lower reimbursement rate for telepsychiatry and patients' lack of access to and training on relevant technologies were the most frequently reported barriers. Changes made by sites after the pandemic onset were viewed by almost all participants as satisfactory for maintaining standard of care. Almost all participants thought that the use of telepsychiatry services would continue after the pandemic in a hybrid manner combining telepsychiatry and office visits. Ensuring that patients have equitable access to telepsychiatry will be important in the post-pandemic future.

Two-year outcomes of treat-and-extend regimen with intravitreal brolucizumab for treatment-naïve neovascular age-related macular degeneration with type 1 macular neovascularization

We previously reported one-year results of a treat-and-extend (TAE) regimen with intravitreal brolucizumab for 68 eyes with treatment-naïve neovascular age-related macular degeneration (nAMD) associated with type 1 macular neovascularization (MNV). In the current study, we evaluated second-year results of the brolucizumab TAE therapy in 45 eyes with type 1 MNV that had completed the first-year treatment. Forty-three eyes (95.6%) received brolucizumab TAE treatment during a period of 96 weeks. The significant improvement of best-corrected visual acuity in the first year was maintained in the second year. Moreover, the significant foveal thickness and central choroidal thickness reductions in the first year were maintained in the second year. The total number of injections over the 96-week study period was 10.0 ± 1.4, with 6.4 ± 0.6 in the first year and 3.6 ± 1.0 in the second year. The intended injection interval at week 96 was 8 weeks in 9 eyes (20.9%), 12 weeks in 3 eyes (7.0%), and 16 weeks in 31 eyes (72.1%), with an average injection interval of 14.0 ± 3.3 weeks. No eyes developed brolucizumab-related intraocular inflammation (IOI) during the second-year treatment. These results indicate that the TAE regimen with intravitreal brolucizumab for treatment-naïve nAMD associated with type 1 MNV effectively maintained the improved visual acuity and the diminished exudative changes in the second year. Moreover, intravitreal brolucizumab has the potential to reduce the treatment burden of nAMD. The risk of developing brolucizumab-related IOI appeared to be very low during the second year of this TAE regimen.

Efficacy and safety of canakinumab as a second line biologic after tocilizumab treatment failure in children with systemic juvenile idiopathic arthritis: A single-centre cohort study using routinely collected health data.

A significant number of systemic juvenile idiopathic arthritis (sJIA) patients discontinue biologic disease-modifying antirheumatic drugs (bDMARDs) due to lack of efficacy or safety concerns. Studies of biologic therapy switch regimens in sJIA are required. Patients with sJIA who switched from tocilizumab (due to lack of efficacy or safety) to canakinumab (4 mg/kg every 4 weeks) and were hospitalized at the rheumatology department from August 2012 to July 2020 were included. Primary efficacy outcomes were 30% or greater improvement based on the paediatric criteria of the American College of Rheumatology (ACR30), achievement of inactive disease (JADAS-71 = 0) and clinical remission (ACR sJIA clinical inactive disease criteria). Follow-up from time first canakinumab dose administered was 12 months or the closest time point (not less than 6 and not more than 18 months). Data were extracted from electronic outpatient medical records. During the study period, 46 patients with sJIA switched from tocilizumab to canakinumab. Median age at baseline was 8.2 [interquartile range (IQR) 4.0-12.9] years, with the median sJIA duration being 1.8 (IQR 0.8-5.8) years; 37 (80%) patients received at least one conventional DMARD (cDMARD; oral corticosteroids, methotrexate and/or cyclosporine A). Study outcomes were followed up in 45 patients (one patient did not attend the follow-up for an unknown reason); median follow-up was 359 (IQR 282-404) days. During the follow-up, 1 patient discontinued canakinumab due to tuberculosis detection and the dose was reduced or the injection interval increased in 4 (9%) patients. In total, 27 (60%) patients continued to receive at least one cDMARD. Improvement according to the ACR30 criteria was achieved in 43 patients [96%; 95% confidence interval (CI) 85-99], inactive disease in 42 (93%; 95%CI 82-98), and remission in 37 (82%; 95% CI 69-91); after adjustment for actual time-at-risk, the rates were 83, 85 and 73 events per 100 person-years, respectively. During follow-up, 23 AEs (most frequently infections) were reported in 19/45 (42%) patients; 5/45 (11%) patients developed macrophage activation syndrome, with a favorable outcome in all cases. One-year canakinumab therapy was found to be potentially effective as second-line biologic therapy after discontinuation of tocilizumab in patients with sJIA.

High-Dose Aflibercept for Neovascular AMD and DME in Suboptimal Responders to Standard-Dose Aflibercept.

Purpose: To assess the effect of higher dose (HD) aflibercept on visual acuity (VA), optical coherence tomography outcomes, and injection burden in eyes with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME) that responded suboptimally to standard-dose aflibercept. Methods: This retrospective analysis included eyes with clinically significant disease activity on monthly therapy (AMT) (injection interval ≤35 days) or clinically significant increased activity on extension (IAE) (injection interval >36 days) that were switched from aflibercept 2 mg to aflibercept HD (3 mg to 4 mg). Outcomes were assessed at baseline, after injections 1 through 4, and at 6, 9, and 12 months. Results: Overall, 318 eyes of 288 adult patients were analyzed (eyes with nAMD: 59 AMT, 147 IAE; eyes with DME: 50 AMT, 62 IAE). Most of the study cohort received aflibercept HD 3 mg (nAMD: 73% AMT and 58% IAE; DME: 49% AMT and 68% IAE); the remainder received 4 mg. The mean best VA improved significantly with AMT and was maintained with IAE. In all groups, the central subfield thickness decreased significantly and the mean injection intervals increased or remained stable. No new safety signals were observed. Conclusions: Aflibercept HD might improve outcomes while decreasing treatment burden for eyes that respond suboptimally to standard dosing.

Switching to brolucizumab: injection intervals and visual, anatomical and safety outcomes at 12 and 18 months in real-world eyes with neovascular age-related macular degeneration

BackgroundThe anti-vascular endothelial growth factor (anti-VEGF) injection interval influences treatment burden and compliance in neovascular age-related macular degeneration (nAMD). This real-world study investigates visual acuity (VA), injection-interval extension, central macular thickness (CMT) and safety in nAMD eyes switched to the anti-VEGF agent brolucizumab and followed for up to 18 months.MethodsThis retrospective study included patients with nAMD who were switched from other anti-VEGF agents to brolucizumab only. Patient eyes were grouped into three nested cohorts with the overall cohort receiving ≥ 1 brolucizumab injection, the second receiving ≥ 3 brolucizumab injections with a follow-up period of ≥ 12 months and the third cohort receiving ≥ 3 brolucizumab injections with a follow-up period of ≥ 18 months. Study endpoints included changes from baseline at 12 or 18 months in VA, injection intervals, and CMT. Sub-group analyses were conducted using baseline injection interval length or baseline VA as qualifiers.ResultsOverall, 482 eyes received ≥ 1 brolucizumab injection; 174 eyes received ≥ 3 brolucizumab injections with ≥ 12 months of follow-up, and 95 eyes received ≥ 3 brolucizumab injections with ≥ 18 months of follow-up. VA (mean [95% confidence intervals]) remained stable relative to baseline after 12 months (− 1.1 [− 3.7, 1.6] letters; p = 0.42) and 18 months (0.0 [− 3.1, 3.1] letters; p = 0.98) of brolucizumab treatment, respectively, and pre-switch injection intervals or baseline VA had no notable effect. Following the switch to brolucizumab, injection intervals were extended from baseline to month 12 by 26.9 (19.7, 34.0) days (p < 0.0001), and eyes with pre-switch injection intervals < 8 weeks were able to have their injection intervals extended by 23.6 days longer than eyes with pre-switch injection intervals ≥ 8 weeks. At 18 months, injection intervals were extended by 36.3 (25.6, 46.9) days (p < 0.0001) compared to baseline. Following switch to brolucizumab, CMT was reduced at both 12 and 18 months (12 months: − 35.2 (− 51.7, − 18.8) µm, p < 0.0001; 18 months: − 38.9 (− 54.3, − 22.0) µm, p < 0.0001). Intraocular inflammation-related adverse events were reported in 4.6% of brolucizumab-treated eyes.ConclusionsThis real-world study demonstrates that injection intervals may be significantly extended with maintained vision and reduced CMT in nAMD eyes switching to brolucizumab therapy from other anti-VEGFs.

CO2 leak detection threshold using vertical seismic profiles

At the Containment and Monitoring Institute Field Research Station in Alberta, Canada, CO2 is being injected into a saline aquifer at 300 m depth to simulate a shallow leak from a deep carbon sequestration operation. The injection interval is a 7 m thick sandstone with a porosity of 11%. The gas-phase CO2 plume was detected with time-lapse vertical seismic profiles (VSP) after 32 tonnes of CO2 had been injected. The VSP surveys had high repeatability with permanent borehole geophones and carefully repeated source locations. A data processing workflow was developed to produce directly comparable baseline and monitor amplitudes while preserving subtle amplitude changes caused by partial CO2 saturation. Seasonal variations in the physical properties of the near-surface glacial tills introduced spectral differences between baseline and monitor datasets that were successfully mitigated by deterministic deconvolution and selected band-pass filters. The 32 t detection threshold represents a lower limit of CO2 detectability with borehole geophones in this geological setting. These results provide a rare field data example of CO2 monitoring at shallow to intermediate depths and demonstrate that VSP surveys are capable of identifying loss of containment in industrial-scale CO2 sequestration operations.

Treatment of neovascular age-related macular degeneration: insights into drug-switch real-world from the Berlin Macular Registry

PurposeBevacizumab, ranibizumab, and aflibercept are commonly used to treat neovascular age-related macular degeneration (nAMD). The results of various interventional, mostly randomized head-to-head studies, indicate statistical non-inferiority of these three drugs. The results of these studies are often interpreted as the three drugs being freely interchangeable, resulting in some health systems to pressure ophthalmologists to preferentially use the less expensive bevacizumab. This study analyzes switching from aflibercept or ranibizumab to bevacizumab and back under real-world conditions in order to investigate the assumption of interchangeability of the drugs.MethodsTreatment data of IVT patients with diagnosed nAMD were extracted from the clinical Berlin Macular Registry database. Patients who underwent a drug switch from aflibercept or ranibizumab to bevacizumab were subject of this study. Statistical comparisons were pre-planned for best corrected visual acuity, central retinal thickness, macular volume, and length of injection interval. Additional endpoints were analyzed descriptively.ResultsMean visual acuity decreased from 0.57 ± 0.05 under aflibercept/ranibizumab to 0.68 ± 0.06 logMAR after the switch (P = 0.001; N = 63). CRT increased from 308 ± 11 µm to 336 ± 16 µm (P = 0.011; N = 63). About half of the subjects were switched back: visual acuity increased from 0.69 ± 0.08 logMAR to 0.58 ± 0.09 logMAR (N = 26). CRT decreased from 396 ± 28 to 337 ± 20 µm (N = 28).ConclusionThe data provides real-world evidence that there is loss of visual acuity and an increase in retinal edema after switching to bevacizumab. Thus, the assumption of free interchangeability cannot be confirmed in this cohort.