Subsequent Maintenance Research Articles

A Dual-Guided Adaptive Decomposition Method of Fault Information and Fault Sensitivity for Multi-Component Fault Diagnosis Under Varying Speeds

Fault diagnosis is essential for the safe operation and subsequent maintenance of mechanical equipment. However, multifault mutual interference brings great challenges to fault diagnosis when multicomponent faults occur simultaneously. Furthermore, since multiple components operate under different varying-speed conditions, it is difficult to match fault information from different components to their respective speeds, making fault diagnosis even more difficult. A dual-guided adaptive decomposition method of fault information and fault sensitivity (FIFS-ADM) is proposed to address the above issues. First, a fault information-driven empirical wavelet transform whose segmentation boundaries are optimized by fault richness index is presented to separate multicomponent faults, thereby eliminating multifault interference. Then, multiorder tracking that refers to using multiple speed signals to resample the decomposed subsignals, respectively, is performed to convert these speed-varying subsignals into angular-domain stationary signals. Finally, a health recognition matrix composed of multicomponent fault sensitivity indicators is introduced to achieve not only the matching of fault component and speed but also fault location and health assessment of multiple components. Furthermore, simulated signals and actual signals are built to validate the proposed method, which shows the effectiveness and superiority of FIFS-ADM.

The Beneficial Effect of Combination of Mycophenolate with Low-Dose Corticosteroids and Calcineurin-Inhibitor as Well as Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Blocker in Induction and Maintenance of Remission in Corticosteroid- and Rituximab-Resistant Minimal Change Nephrotic Syndrome in Adults

Management of steroid-resistant minimal change disease remains elusive with international guidelines suggesting high-dose corticosteroids and/or Calcineurin inhibitors for months similar to those with refractory idiopathic FSGS. Unfortunately, with such approach, the overall remission rates were 47% - 66%. Moreover, complete remission rates were 32% - 47% and partial remission ones were 19% - 29%. Those limited options of treatment and their poor outcomes led us to conduct the present study to assess the efficacy and safety of a new combined drug-therapy at induction and subsequent maintenance of such disease. The regimen consisted of an initial induction phase of 3-month Prednisone, Calcineurin-inhibitor, Mycophenolate and ACEI/ARB. The latter was followed by a maintenance phase of minimal dose Prednisone and nearly 1/2 the induction dose of Calcineurin inhibitors to decrease their long-term side effects. The results were satisfactory with 14 of the 22 patients, had complete remission. Moreover, 5 patients manifested partial remission and only 3 did not respond. Creatinine clearance was maintained in patients with complete remission yet, was mildly reduced in the partial and non-responsive ones. The safety and efficacy of such new combined drug-therapy provide new tool and future prospective in management of such relentless disease.

BMRHTA: Balanced Multipath Routing and Hybrid Transmission Approach for Lifecycle Maximization in WSNs

In this article, a balanced multipath routing and hybrid transmission approach (BMRHTA) is proposed to effectively alleviate the imbalance of the forwarding load in a sink connection area (SCA) and prolong the network lifecycle for wireless sensor networks (WSNs). To achieve the energy efficient and balanced WSNs, three design issues, including the multipath, multihop, and single-hop transmissions, are jointly optimized to maximize the overall network lifecycle. First, the path load aggregation phenomenon in the SCA, which makes the forwarding packet load unevenly distributed among hotspots, is examined. In order to achieve the load balance in SCA, multiple shortest balanced paths are generated in the BMRHTA model. In the first stage, two uncorrelated shortest paths are discovered from each node to the sink and the optimal path selection cycle can be determined to achieve the SCA load balance. Afterward, a network equilibrium policy is offered to resolve the optimal transmission period of energy balance via hybrid transmission. As a result, the balanced shortest paths, the path selection cycle and the transmission period can be determined in the network formation phase to avoid the excessive load concentration in the subsequent maintenance phase. Simulation results show that the joint two uncorrelated balanced routing and the proposed network equilibrium policy can nearly quadruple the network lifecycle extension, as compared to a conventional node power policy. Also, the proposed BMRHTA achieves better performance than the current state-of-the-art competitive approaches in terms of energy efficiency and lifecycle.

Induction of mucosal healing by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids in patients with ulcerative colitis: long-term remission maintenance after induction by GMA and efficacy of GMA re-treatment upon relapse.

This study examined the long-term maintenance rate after inducing remission by intensive granulocyte/monocyte adsorptive apheresis (GMA) without use of corticosteroids (CS) and GMA re-treatment efficacy in the same patients upon relapse with ulcerative colitis. Patients who achieved clinical remission and mucosal healing (MH) by first-time intensive GMA (first GMA) without CS were enrolled. The cumulative non-relapse survival rate up to week 156 was calculated. Patients with relapse during the maintenance period underwent second-time intensive GMA (second GMA) without CS. Clinical remission and MH rates following second GMA were compared to those following first GMA in the same patients. Of the 84 patients enrolled, 78 were followed until week 156 and 34 demonstrated relapse. The cumulative non-relapse survival rate by week 156 was 56.4%. Clinical remission and MH rates after second GMA did not differ from those after first GMA in the same patients (week 6: clinical remission, 100% vs 88.4%, p = 0.134; MH, 100% vs 84.8%, p = 0.074). In conclusion, MH induction by intensive GMA without use of CS in ulcerative colitis patients contributes to subsequent long-term clinical remission maintenance. GMA re-treatment efficacy was comparable to that of first GMA in the same patients who had relapse.

ბინათმესაკუთრეთა გაერთიანების მართვის თავისებურებები - მიზანი, პასუხისმგებლობა, კონტროლი

Although the legal platform for improving the living conditions of the owners of multi-apartment houses, sharing common interests and creating the desired well-being has been in place since 2007, neighborhood law still faces many difficulties and challenges. Prior to the current legal regulation, there was a need for obedience, mutual respect and empathy among the neighbors, and an obligation arose from long ago, which included the housing regulations in the Soviet space and the rights and obligations under the Civil Code. Given that this legal regulation obliges each resident to understand the importance of individual property and common use status and their share of responsibility in the common case, the current case law is rich in disputes over the ownership and use of space managed by landlords. This article: "Features of the management of the homeowners 'association - Purpose, Responsibility, Control", presents the history of the origin and development of homeowners' associations, the preconditions, needs and importance of creating a relevant legislative platform. In addition, the partnership is discussed as a model of cooperation, the scope of responsibilities of members and the chairman, the goals of the union and control mechanisms at both the state and local self-government levels. The author believes that great attention should be paid to the training of chairpersons to take on this responsibility, however, it is necessary to have material support, as such an environment increases competition and the quality of work performed. It should be noted that the article focuses on the organizational aspects of the partnership, its legal regulation and neighborhood relations, where the moral values of the members and the management of individual property are no less important, so as not to infringe on property, restrict and damage the rights of others. Free disposal of property is inadmissible only in accordance with the views of the person, it is necessary to define the area of free action and to understand that the management of individual property should not be harmful to third parties. The author focuses on the basic tools of partnership management, the typology of condominiums and the legal status of members. The article covers the following important issues: a member of the partnership as a necessary data, "forced membership" and its constitutionality, the scope of authority of owner and non-owner members, the legal entity as a member of the partnership, the responsibility of the state as a member of the partnership and the controlling entity. Institution of rightful owner. The article discusses the organizational aspects of a condominium, which includes assessing the authority, role and importance of the convention assembly in the process of confirming ownership of the item and subsequently registering ownership of it. It is assessed whether the number of votes currently in the law is sufficient in the process of disposing of the property, whether the partnership assumes responsibility for its subsequent maintenance, whether there is a further control mechanism. Describes the institution of the chairman of the partnership as a manager and a representative of the neighborhood union. Where the chairman's responsibilities begin and end, whether it is appropriate to end their responsibilities solely by disposing of common space. However, a comparative legal study presented in the article, based on the example of the United States and various European countries, highlights the value of effective management of owners' associations, both legally and practically. The article summarizes the main challenges of the issue, the factors hindering the development of the partnership as a neighborhood union, and the issues of redistribution of responsibilities. Emphasis is placed on the importance of each member's role and function in good faith.

The Role of Leptin in the Development of Energy Homeostatic Systems and the Maintenance of Body Weight.

LEP is a pleiotropic gene and the actions of leptin extend well beyond simply acting as the signal of the size of adipose tissue stores originally proposed. This is a discussion of the multi-system interactions of leptin with the development of the neural systems regulating energy stores, and the subsequent maintenance of energy stores throughout the lifespan. The prenatal, perinatal, and later postnatal effects of leptin on systems regulating body energy stores and on the energy stores themselves are heavily influenced by the nutritional environment which leptin exposure occurs. This review discusses the prenatal and perinatal roles of leptin in establishing the neuronal circuitry and other systems relevant to the adiposity set-point (or “threshold”) and the role of leptin in maintaining weight homeostasis in adulthood. Therapeutic manipulation of the intrauterine environment, use of leptin sensitizing agents, and identification of specific cohorts who may be more responsive to leptin or other means of activating the leptin signaling pathway are ripe areas for future research.

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control

Outcome of patients with mantle cell lymphoma after autologous stem cell transplantation in the pre‐CAR T‐cell era

Mantle cell lymphoma (MCL) patients can be treated with intensive induction therapy, followed by high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) for consolidation and subsequent anti-CD20 maintenance. For patients relapsing after bruton tyrosine kinase (BTK) inhibitors, CAR T-cell therapy became available in late 2020 fueling the interest in outcomes of relapsing MCL patients. We retrospectively analyzed the outcome of MCL patients receiving HDCT/ASCT at our center between 2000 and 2021, thus, before availability of CAR-T cells. We identified 97 MCL patients undergoing HDCT/ASCT in this period with a median follow-up of 52months. 43 (44%) patients ultimately relapsed, and 29 (30%) have died. The median progression-free survival (PFS) for the entire cohort was 48months and overall survival (OS) was 202months. Relapsing patients had a median PFS of only 28months and median OS of 105months. The OS of relapsing patients receiving BTK inhibitors was 148 versus 78months in patients who never received BTK inhibitors (p=0.1175). Even after HDCT/ASCT, a substantial proportion of MCL patients will relapse and ultimately die of the disease, emphasizing the need for new therapeutic options including CAR T-cell treatment for this lymphoma subtype.

A Theory- and Evidence-Based Digital Intervention Tool for Weight Loss Maintenance (NoHoW Toolkit): Systematic Development and Refinement Study.

BackgroundMany weight loss programs show short-term effectiveness, but subsequent weight loss maintenance is difficult to achieve. Digital technologies offer a promising means of delivering behavior change approaches at low costs and on a wide scale. The Navigating to a Healthy Weight (NoHoW) project, which was funded by the European Union’s Horizon 2020 research and innovation program, aimed to develop, test, and evaluate a digital toolkit designed to promote successful long-term weight management. The toolkit was tested in an 18-month, large-scale, international, 2×2 factorial (motivation and self-regulation vs emotion regulation) randomized controlled trial that was conducted on adults with overweight or obesity who lost ≥5% of their body weight in the preceding 12 months before enrollment into the intervention.ObjectiveThis paper aims to describe the development of the NoHoW Toolkit, focusing on the logic models, content, and specifications, as well as the results from user testing.MethodsThe toolkit was developed by using a systematic approach, which included the development of the theory-based logic models, the selection of behavior change techniques, the translation of these techniques into a web-based app (NoHoW Toolkit components), technical development, and the user evaluation and refinement of the toolkit.ResultsThe toolkit included a set of web-based tools and inputs from digital tracking devices (smart scales and activity trackers) and modules that targeted weight, physical activity, and dietary behaviors. The final toolkit comprised 34 sessions that were distributed through 15 modules and provided active content over a 4-month period. The motivation and self-regulation arm consisted of 8 modules (17 sessions), the emotion regulation arm was presented with 7 modules (17 sessions), and the combined arm received the full toolkit (15 modules; 34 sessions). The sessions included a range of implementations, such as videos, testimonies, and questionnaires. Furthermore, the toolkit contained 5 specific data tiles for monitoring weight, steps, healthy eating, mood, and sleep.ConclusionsA systematic approach to the development of digital solutions based on theory, evidence, and user testing may significantly contribute to the advancement of the science of behavior change and improve current solutions for sustained weight management. Testing the toolkit by using a 2×2 design provided a unique opportunity to examine the effect of motivation and self-regulation and emotion regulation separately, as well as the effect of their interaction in weight loss maintenance.

RESEARCH OF CONCRETE OF REINFORCED CONCRETE SLEEPERS, WHICH DECIDED DAMAGE DURING OPERATION

Purpose. On the railways of Ukraine in some areas there is an intensive premature exit sleepers due to the formation of defects that can affect the safety of trains and cause significant material losses due to a single replacement of a significant number of sleepers. The purpose of the study is to establish the causes of damage reinforced concrete sleepers on a characteristic section of the railway with their intense premature exit. Methodology. The condition of reinforced concrete sleepers of SB3 type under unlined substrate fastenings on 324-332 km of the pair track of the Odnorobivka-Bukine section of the Southern Railway was studied, where since 2007 their intensive output was observed due to defects. Findings. It is established that for 15 years of operation, as 236.3 million tons were put into operation, about 2.8 % of sleepers were replaced due to defects (44 pieces per 1 km of track). Typical defects (damages), due to which the sleepers were removed from the track, were mainly 13.2 and 13.2 according to the classification of CP-0150 – cracks and fractures of sleepers, including ones with crushing concrete. These defects were preceded by the formation of a network of thin cracks on the visible surfaces of sleepers. 3 sleepers with an initial compressive strength of 68…77 MPa produced by the Korosten Reinforced Concrete Sleeper Plant and the Gnivan Special Reinforced Concrete Plant, removed from the track due to characteristic defects, were selected and investigated. Samples were selected from the sleepers, with the help of which there was determined the final strength of concrete and microscopic examinations, including luminescence flaw detection method, were performed. It was found that the network of cracks in sleepers is spatial, mostly developed mostly beneath their top edge, the least developed above the bottom edge, and causes a decrease in compressive strength of concrete by 47…72 %. It is noted that the destruction of concrete during loading occurred behind these cracks. On the inner surfaces of the cracks there are individual grains of aggregates, which have signs of active silica content, that together with the nature of the cracks may indicate that the cause of their formation is corrosion of concrete from the interaction of cement alkali with reactive aggregates. On the surfaces of the cracks in the lower part of the sleepers leaching products were found, apparently leached by electro migration, which may indicate that corrosion processes were promoted by leakage currents on electrified DC tracks. Originality Thus, in the study area, the main cause of defects, which caused the replacement of the sleepers – was the corrosion of concrete due to the interaction of cement alkali with reactive aggregates, promoted by leakage currents, as well as a small diagram of sleepers and the use of unlined anchor intermediate rail fasteners. Practical value. The results of the study allow to establish the causes of cracks and other damage in reinforced concrete sleepers during operation and, in turn, reduce the losses of fasteners manufacturers and sleepers from defects and complaints, optimize the total cost of track repairs and subsequent track maintenance due to rational purpose of track construction, reduction of damage and replacement of sleepers during track operation.

Changes in Circulating Metabolites during Weight Loss and Weight Loss Maintenance in Relation to Cardiometabolic Risk.

(1) Background: There is a substantial lack of knowledge of the biochemical mechanisms by which weight loss and weight regain exert their beneficial and adverse effects, respectively, on cardiometabolic outcomes. We examined associations between changes in circulating metabolites and changes in cardiometabolic risk factors during diet-induced weight loss and weight loss maintenance. (2) Methods: This prospective analysis of data from the Satiety Innovation (SATIN) study involved adults living with overweight and obesity (mean age=47.5). One hundred sixty-two subjects achieving ≥8% weight loss during an initial 8-week low-calorie diet (LCD) were included in a 12-week weight loss maintenance period. Circulating metabolites (m=123) were profiled using a targeted multiplatform approach. Data were analyzed using multivariate linear regression models. (3) Results: Decreases in the concentrations of several phosphatidylcholines (PCs), sphingomyelins (SMs), and valine were consistently associated with decreases in total (TChol) and low-density lipoprotein cholesterol (LDL-C) levels during the LCD. Increases in PCs and SMs were significantly associated with increases in TChol and LDL-C during the weight loss maintenance period. Decreases and increases in PCs during LCD and maintenance period, respectively, were associated with decreases in the levels of triglycerides. (4) Conclusions: The results of this study suggest that decreases in circulating PCs and SMs during weight loss and the subsequent weight loss maintenance period may decrease the cardiovascular risk through impacting TChol and LDL-C.

Detraining Slows and Maintenance Training Over 6 Years Halts Parkinsonian Symptoms-Progression.

Introduction: There are scant data to demonstrate that the long-term non-pharmaceutical interventions can slow the progression of motor and non-motor symptoms and lower drug dose in Parkinson's disease (PD).Methods: After randomization, the Exercise-only (E, n = 19) group completed an initial 3-week-long, 15-session supervised, high-intensity sensorimotor agility exercise program designed to improve the postural stability. The Exercise + Maintenance (E + M, n = 22) group completed the 3-week program and continued the same program three times per week for 6 years. The no exercise and no maintenance control (C, n = 26) group continued habitual living. In each patient, 11 outcomes were measured before and after the 3-week initial exercise program and then, at 3, 6, 12, 18, 24, 36, 48, 60, and 72 months.Results: The longitudinal linear mixed effects modeling of each variable was fitted with maximum likelihood estimation and adjusted for baseline and covariates. The exercise program strongly improved the primary outcome, Motor Experiences of Daily Living, by ~7 points and all secondary outcomes [body mass index (BMI), disease and no disease-specific quality of life, depression, mobility, and standing balance]. In E group, the detraining effects lasted up to 12 months. E+M group further improved the initial exercise-induced gains up to 3 months and the gains were sustained until year 6. In C group, the symptoms worsened steadily. By year 6, levodopa (L-dopa) equivalents increased in all the groups but least in E + M group.Conclusion: A short-term, high-intensity sensorimotor agility exercise program improved the PD symptoms up to a year during detraining but the subsequent 6-year maintenance program was needed to further increase or sustain the initial improvements in the symptoms, quality of life, and drug dose.

Real-time monitoring and diagnosis scheme for IoT-enabled devices using multivariate SPC techniques

This article is aimed at condition monitoring and fault identification for Internet of Things (IoT) devices, and proposes a multivariate statistical process control scheme. The new method aims to detect sparse mean shifts using spatial rank and an improved adaptive elastic net algorithm, which can monitor the high-dimension data stream collected by IoT devices and pinpoint faulty variables. The new method is also applicable in the presence of a non-normal distribution and insufficient reference samples. Numerical simulations verify that the proposed method has clear advantages over existing methods. The case of wind turbines shows that the method can be applied to real-time monitoring and diagnosis of real IoT devices, which could provide valuable diagnosis of root cause and optimize subsequent maintenance strategies.

Transcriptional Control of Apical-Basal Polarity Regulators.

Cell polarity is essential for many functions of cells and tissues including the initial establishment and subsequent maintenance of epithelial tissues, asymmetric cell division, and morphogenetic movements. Cell polarity along the apical-basal axis is controlled by three protein complexes that interact with and co-regulate each other: The Par-, Crumbs-, and Scrib-complexes. The localization and activity of the components of these complexes is predominantly controlled by protein-protein interactions and protein phosphorylation status. Increasing evidence accumulates that, besides the regulation at the protein level, the precise expression control of polarity determinants contributes substantially to cell polarity regulation. Here we review how gene expression regulation influences processes that depend on the induction, maintenance, or abolishment of cell polarity with a special focus on epithelial to mesenchymal transition and asymmetric stem cell division. We conclude that gene expression control is an important and often neglected mechanism in the control of cell polarity.

Determining the Optimal Biomass of Macrophytes during the Ecological Restoration Process of Eutrophic Shallow Lakes

Many studies have shown that macrophytes play a significant role in controlling eutrophication; however, only a few of these are based on macrophyte biomass. Based on the growth characteristic of macrophytes, we propose an approach for the assessment of the optimal biomass of macrophytes in the decay and growth periods in Lake Datong (a shallow lake), using a lake ecological model. The results showed that the pollution load of the lake should be reduced by 50% while conforming to the Environmental Quality Standards for Surface Water (EQSSW) Class Ⅲ. In contrast, with an increase in the pollution load of 5%, the results indicate that the lake may deteriorate to a turbid state over the next few years. The macrophyte biomass should be harvested during the decay period, when 80% biomass is beneficial to the water quality of the eutrophic shallow lake. Based on macrophyte simulation from 2020–2024, the wet biomass of macrophytes should be controlled at 5.5 kg/m2. The current macrophyte biomass in Lake Datong is four-fold higher than the simulated optimal biomass. This study provides a reference for the adequate ecological restoration of the lake and its subsequent maintenance, as well as scientific support for improving the comprehensive evaluation standard of healthy lakes and the theoretical basis of lake ecological restoration.

Evaluation of Serviceability of Canal Lining Based on AHP–Simple Correlation Function Method–Cloud Model: A Case Study in Henan Province, China

In the process of sustainable development within modern agriculture, in order to ensure that agricultural production has adequate water resources, canal lining (CL) is often used to transport water in order to reduce water seepage, thus promoting the sustainable utilization of water resources. However, due to the influence of the terrain, environment, human factors and other factors, the CL often suffers a certain degree of damage. Therefore, it is necessary to evaluate the serviceability of the CL, so to realize the sustainable use of the CL strategy. Aiming at the weight assignment of CL evaluation indices that are subjective and not combined with actual index data, a weight calculation method based on the Analytic Hierarchy Process (AHP)–simple correlation function (SCF) method was proposed, and game theory was used to achieve combination weighting. For the evaluation indices with the characteristics of fuzziness and randomness, the cloud model (CM) was used to comprehensively consider these characteristics in order to realize the evaluation. Finally, a method to measure serviceability of CL based on AHP–SCF–CM was proposed. Taking a CL project in China as an example, this method was used to evaluate the serviceability of the CL. The evaluation result showed that the serviceability of the CL was poor, and the qualitative evaluation result was consistent with the actual damage condition of the project; meanwhile, a comparative study was performed in combination with the AHP–Entropy Weight (EW)–unascertained measurement theory (UMT). The quantitative evaluation results of the two methods displayed the same grade of serviceability, which verifies that the method proposed in this paper is more reasonable, objective and feasible from both qualitative and quantitative perspectives. Furthermore, the evaluation results lay the foundation for subsequent maintenance and fault prevention of the canal.

Two Currently Recruiting Randomized Phase III Trials: COMMODORE 1 and 2 Evaluating Crovalimab Vs Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Current Anti-Complement Therapy

Two Currently Recruiting Randomized Phase III Trials: COMMODORE 1 and 2 Evaluating Crovalimab Vs Eculizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Current Anti-Complement Therapy

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

Sustained Residual Disease Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Has Strong Predictive Relevance for Survival in Newly Diagnosed Multiple Myeloma Patients on Maintenance Therapy after Autologous Stem Cell Transplantation (ASCT)

Atezolizumab Combined with Immunogenic Salvage Chemoimmunotherapy (R-GemOx+Atezo) in Patients with Transformed Diffuse Large B-Cell Lymphoma

Atezolizumab Combined with Immunogenic Salvage Chemoimmunotherapy (R-GemOx+Atezo) in Patients with Transformed Diffuse Large B-Cell Lymphoma

Evaluation of the Long-Term Safety and Efficacy of Pegcetacoplan Treatment for Paroxysmal Nocturnal Hemoglobinuria Patients: An Extension Study

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, potentially life-threatening disease characterized by complement mediated hemolysis and thrombosis. Current C5-inhibitors, such as eculizumab and ravulizumab, are able to partially treat these symptoms by controlling intravascular but not extravascular hemolysis, manifesting as persistent anemia in up to 72% of treated patients and transfusion dependence in up to 36% of patients.Pegcetacoplan (PEG) is a Food and Drug Administration (FDA)-approved C3-inhibitor that controls both intravascular and extravascular hemolysis (IVH and EVH). In the PEGASUS phase 3, multi- center, active-comparator controlled, randomized trial (NCT03500549), improvements in hemoglobin levels from baseline to Week 16 demonstrated the superiority of PEG over eculizumab; 85% of the patients receiving PEG achieved transfusion independence when compared with the 15% of patients on eculizumab. The extension study will evaluate the long-term safety and efficacy of PEG in patients with PNH.Acute hemolytic (AH) events occurred during the PEG clinical development program. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with PEGAims: Determine the long-term safety and efficacy of PEG for PNH treatment, as well as evaluate a treatment regimen to address acute hemolytic (AH) events in these patients.Study Design: The PEG extension study (NCT03531255) is an active, multi-center, open-label, non-randomized trial with an estimated enrollment of up to160 adult PNH patients (≥18 years), who have completed prior PEG trials - phase 1b PADDOCK (NCT02588833) and PHAROAH (NCT02264639), phase 2a PALOMINO (NCT03593200), and the phase 3 PEGASUS (NCT03500549) and PRINCE (NCT04085601) trials. The main study will determine long-term safety and efficacy of PEG dosing on complement-mediated hemolytic activity, hemoglobin levels, and transfusion independence in PNH patients. For enrolled subjects experiencing AH episodes, a substudy to evaluate safety and efficacy of intensive SC or IV dosing of PEG acute treatments will be offered. Dose adjustments will be offered for AH subjects declining to enter the substudy, but continuing to participate in the main study.Inclusion criteria for the management of AH substudy specify that lactate dehydrogenase (LDH) levels in patients must be >2 times the upper limit of normal, accompanied by new or worsening clinical signs of hemolysis (hemoglobinuria, fatigue, decreased hemoglobin, etc.). Notable exclusion criteria include subjects who have withdrawn from a previous PEG trial, co-morbidities and infections that can enhance risk profiles for adverse events or confound study interpretation, and complement deficiency.The safety population consisting of patients that will receive at least one dose of the drug will be used for all efficacy analyses. Descriptive statistics will be used in documenting changes from baseline, along with qualitative descriptors (improved, maintained, or worsened).Intervention: Patients in the long-term extension study receive subcutaneous (SC) administration of 1080 mg PEG twice weekly, every 3 days, or 3 times weekly. For AH events substudy, patients with steady-state PEG dose of 1080 mg SC twice weekly will receive a loading dose of 1080 mg IV once, or 1080 mg SC every 24 hours for 3 doses, followed by increase in maintenance dose to 1080 mg SC every 3 days; for those receiving 1080 mg SC every 3 days, identical loading dose will be followed by subsequent maintenance dose of 1080 mg SC 3 times weekly.Primary and Secondary Outcome Measures: The study will monitor safety outcomes such as occurrence and severity of adverse events within a 2-year timeframe from baseline. Additional biomarkers include recurrent acute hemolysis, thromboembolism, laboratory and electrocardiogram (ECG) parameters. Efficacy endpoint measurements over a 48-week timeframe include mean change from baseline levels of hemoglobin, LDH, and indirect bilirubin, absolute reticulocyte counts, RBC transfusions, and functional assessment of fatigue scale scores.Results: Trial results are anticipated in 2022, upon study completion. DisclosuresHoffman: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Machaidze: Apellis Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Yeh: Apellis Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Weitz: Alexion: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Novartis Corporation: Consultancy, Honoraria; Sanofi Genxyme: Consultancy, Honoraria. OffLabel Disclosure:Pegcetacoplan is a Food and Drug Administration approved C3-inhibitor that controls both intravascular and extravascular hemolysis. As part of the long-term extension study, we aim to better understand how to manage acute hemolytic events through dose adjustments in patients treated with pegcetacoplan.