Real-World Ravulizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population

Introduction: Current management of patients diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) includes C5 complement inhibitors such as ravulizumab. The ravulizumab dosage regimen varies by patient body weight and consists of a single loading dose followed by maintenance doses administered every 8 weeks via intravenous infusion (see Table for label-recommended loading and maintenance dosing regimens by patient body weight category). Given its recent 2018 FDA approval, real-world data on the dosing patterns of ravulizumab are limited. This study investigated the real-world dosing patterns of patients with PNH treated with ravulizumab in a large US population. Methods: This retrospective longitudinal cohort study was conducted using provider-based claims data from the Symphony Health Integrated Dataverse ® (IDV). Patients were ≥12 years of age and received ≥2 infusions of ravulizumab between June 21, 2019 and May 6, 2021. The index date was defined as the 1st medical claim for ravulizumab infusion with ≥6 months of continuous clinical activity prior to the index (the baseline period). Patients with ≥1 diagnosis of atypical hemolytic uremic syndrome (another indication for ravulizumab) during the baseline period or on the index date were excluded to identify those with PNH. Patient baseline demographic and clinical characteristics including PNH-related comorbidities and symptoms were described. Because Symphony IDV does not record patient weight, it was assumed that all patients had a weight ≥60 and <100 kg (ie, "medium body weight"), consistent with mean weights reported in recent clinical trials of ravulizumab (~70 kg) and in the US population (men: 91 kg; women: 77 kg). Mean and mode loading and maintenance doses as well as the proportion of patients with high, label-recommended, and low loading and mean maintenance doses were calculated. To test the weight assumptions, 2 sets of sensitivity analyses were carried out to account for alternative dosing pattern scenarios, with all patients classified as "low body weight" (≥40 and <60 kg) or "high body weight" (≥100 kg). Results: A total of 433 patients with PNH were included in the study; the mean age was 47 years and 52% were female. The mean treatment period was 11.8 months; and 54%, 40%, and 6% of patients initiated ravulizumab in 2019, 2020, and 2021, respectively. Most patients (76%) were insured through a commercial insurance plan. Aplastic anemia and myelodysplastic syndrome were present at baseline in 22% and 5% of patients, respectively. The most frequent comorbidities were coagulopathy (13%), deficiency anemias (12%), and hypertension (11%); and 40% of patients had anemia (other than aplastic anemia) at baseline. Prior to initiating ravulizumab, 42% of patients had previously received ≥1 infusion of eculizumab during the baseline period. The mean (standard deviation [SD]) and mode loading doses were 3,316 (2,932) and 3,300 mg, respectively. The proportion of patients with a high, label-recommended, and low loading dose was 59%, 28%, and 13%, respectively (Table). During the maintenance phase, the mean (SD) and mode doses were 3,404 (1,024) and 3,300 mg, respectively; the proportion of patients with a high, label-recommended, and low mean dose during this phase was 27%, 51%, and 23%, respectively (Table). The sensitivity analyses revealed similar trends: nearly half or more than half of patients received a high loading dose; the proportion with a high mean dose during the maintenance phase was substantial when it was assumed that all patients had "low body weight" and negligible when assuming "high body weight" (Table). Conclusions: Most patients with PNH treated with ravulizumab received a higher than label-recommended loading dose regardless of weight category. Additionally, the mean dose received during the maintenance phase was higher than the label-recommended dose of 3,300 mg in more than one-quarter of patients (≥60 - <100 kg). The deviations from label-recommended dosing regimens-especially dosages exceeding recommendations-suggest that in some patients, PNH is not controlled by ravulizumab. Alternative weight scenarios will be tested in future analyses to account for weight distribution in the US. Future budget impact analyses of ravulizumab in patients with PNH should consider real-world dosing patterns in order to determine cost vs benefit. Figure 1 Figure 1. Disclosures Cheng: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study.. Fishman: Apellis: Current Employment, Current equity holder in publicly-traded company. Sarda: Apellis: Current Employment, Current equity holder in publicly-traded company. Krishnan: Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Vu: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Yenikomshian: Apellis: Other: Employee of Analysis Group, Inc., Research Funding. Duh: Novartis: Other: I am an employee of Analysis Group, a consulting company that received funding from Novartis for this research study..

EVALUATION OF PYRETHROID AND BOTANICAL BARRIER INSECTICIDES AGAINST AEDES ALBOPICTUS IN THE LABORATORY AND FIELD

Outdoor residual insecticide applications are useful for preventing or reducing mosquito populations at focal areas. Until recently, pyrethroids have been the only option for barrier sprays in mosquito control. In this study, three pyrethroid (Onslaught, Cyzmic CS, DeltaGard) and two botanical (Nature-Cide, Essentria IC3 ) outdoor residual insecticides were comparatively tested at low, mid, and high label rates against adult Aedes albopictus in both laboratory bioassays and field trials in St. Augustine, FL, from May-August 2017. Bioassays indicated NatureCide and Cyzmic CS were the most toxic across all three dilution ratios followed by DeltaGard, Onslaught, and Essentria IC3 , respectively. In field trials Nature-Cide and Onslaught were the only products that reduced mosquito abundance at the low rate. However, at the mid rate NatureCide and Onslaught caused ~90% percent reduction of adult female Ae. albopictus in the field, the highest of all tested products. The performance of DeltaGard (79% reduction in field counts), Essentria IC 3 (64%), and Cyzmic CS (36%) in the field were not similar to the laboratory results. The universally high performance of Nature-Cide indicates that mosquito control operations should expand consideration to botanical based insecticides for field operations.

Real-World Eculizumab Dosing Patterns Among Patients with Paroxysmal Nocturnal Hemoglobinuria in a US Population

INTRODUCTION Current pharmacologic management of patients who are diagnosed with paroxysmal nocturnal hemoglobinuria (PNH) includes C5 complement inhibitors, such as eculizumab. The standard dosage of eculizumab, administered via intravenous infusion, is 600 mg/week for the first 4 weeks (induction phase), 900 mg for the fifth dose 1 week later, and 900 mg biweekly thereafter (maintenance phase). There is limited information describing dosing patterns of eculizumab in clinical practice. The purpose of this study was to conduct a comprehensive assessment of the real-world dosing patterns of patients with PNH treated with eculizumab in a large US population. METHODS A retrospective longitudinal cohort study using provider-based claims data from the Symphony Health Integrated Dataverse® was conducted. Patients were ≥12 years of age and received ≥2 infusions of eculizumab between October 1, 2014, and September 30, 2019. The index date was defined as the first medical claim for eculizumab infusion with ≥3 months of prior continuous clinical activity, defined as ≥1 claim of any type per quarter (ie, the baseline period). Patients with ≥1 diagnosis of another indication for eculizumab, including atypical hemolytic uremic syndrome, generalized myasthenia gravis, and neuromyelitis optica spectrum disorder, during the baseline period or on the index date were excluded to identify patients with PNH. Patient baseline demographic and clinical characteristics, including PNH-related comorbidities and PNH-symptoms, were described. Mean starting dose and the proportion with high (>600 mg), label-recommended (600 mg), and low (<600 mg) starting dose during the induction phase were calculated. In addition, the mean and mode dose during the induction and maintenance phases, as well as the proportion of patients with high, label-recommended, and low mean dose during the induction and maintenance phases, were described. RESULTS A total of 707 patients with PNH who had ≥2 infusions of eculizumab during the study period were included in this analysis; mean observation period was 23.9 months. Mean age was 45.4 years, 55.7% were female, and 35.9% were from the South. The majority of patients (77.1%) were insured through a commercial insurance plan. Respectively, 32.5% and 6.8% of patients had a diagnosis for aplastic anemia and myelodysplastic syndrome during baseline. The most frequent comorbidities in this sample included hypertension (26.6%), coagulopathy (26.6%), and renal failure (20.5%). In addition, 85.1% of patients experienced anemia (other than aplastic anemia) at baseline. The mean (standard deviation) starting dose during the induction phase was 862 (412) mg; the proportion of patients with high, label-recommended, and low starting dose was 64.1%, 30.6%, and 5.4%, respectively. The mean (standard deviation) and mode dose was 859 (391) mg and 900 mg during the induction phase, and 1011 (333) mg and 900 mg during the maintenance phase. Respectively, 67.9%, 25.9%, and 6.2% of patients had a high, label-recommended, and low mean dose during the induction phase, and 45.9%, 41.6%, and 12.5% had a high, label-recommended, and low mean dose during the maintenance phase. CONCLUSIONS This study demonstrates that the majority of patients with PNH treated with eculizumab were started on a dose in the induction phase that was higher than the label-recommended dose of 600 mg, and the mean dose received during the maintenance phase was higher than the label-recommended dose of 900 mg in approximately half of all patients. Future analyses that investigate budget impact of eculizumab in patients with PNH should account for real-world dosing patterns in order to comprehensively assess costs and benefits. Disclosures Cheng: Apellis: Research Funding. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Yenikomshian:Apellis: Research Funding. Scoble:Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler:Apellis: Research Funding. Vu:Apellis: Research Funding. Cheung:Apellis: Research Funding. Duh:Merck: Research Funding; Pharmacyclics: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Apellis: Research Funding.

Efficacy of triclopyr and synthetic auxin herbicide mixtures for common blue violet (Viola sororia) control

Common blue violet is a widely distributed, perennial broadleaf that is difficult to control in lawns. Two experiments were conducted to evaluate the efficacy of synthetic auxin herbicides and their mixtures or rate for common blue violet control. A herbicide comparison experiment was conducted with treatments including a nontreated check; 2,4-D dimethylamine; 2,4-D isooctyl ester (2,4-D ester); dichlorprop (2,4-DP) ethylhexyl ester, MCPA dimethylamine; mecoprop dimethylamine; triclopyr butoxyethyl ester; quinclorac; and mixtures of triclopyr + quinclorac; 2,4-D ester + 2,4-DP; 2,4-D ester + triclopyr; 2,4-D ester + 2,4-DP + triclopyr. All herbicides were applied at 1.12 kg ae ha−1 except quinclorac (0.84 kg ha−1). Additionally, a triclopyr dose-response experiment was conducted using rates of 0, 0.14, 0.28, 0.56, 0.84, and 1.12 kg ha−1. Epinasty ranged from 80% to 99% at 21 d after application for triclopyr-containing treatments and no more than 28% for all other treatments. Plant mass from harvest and regrowth data from the comparison experiment indicated triclopyr-containing treatments provided the highest common blue violet control. Mixtures containing triclopyr did not differ from triclopyr alone, indicating there was no added effect between herbicide mixtures. The triclopyr dose-response experiment confirmed triclopyr efficacy across data collection types. As triclopyr dose increased, violet epinasty increased and chlorophyll content and dry weight decreased. Triclopyr applied at 0.81 kg ha−1 or greater concentration provided 75% or greater control, as indicated by regrowth data. Many herbicides containing triclopyr are registered for use in turf, but most apply a concentration not greater than 0.56 kg ha−1 triclopyr when applied at the high label rate. Thus, to achieve good (75%) common blue violet control, turf managers should select products that contain triclopyr and apply doses of at least 0.81 kg ha−1 when used according to the label.

Pengelompokan Notifikasi Alert Intrusion Detection System Snort Pada Bot Telegram Menggunakan Algoritma K-Means

AbstrakDengan semakin luasnya pengetahuan dan meningkatnya kejahatan internet maka dibutuhkan Intrusion Detection System (IDS) salah satunya adalah Snort yang dapat mendeteksi serangan. Dibutuhkan notifikasi serangan agar administrator tahu jika adanya serangan. Pengelompokan alert menggunakan metode K-Means untuk membagi 2 kelompok alert yaitu low dan high. Bot Telegram akan mengirimkan alert yang memiliki label high saja. Notifikasi akan muncul pada aplikasi Telegram. Dataset 4SICS digunakan untuk proses penegelompokan agar menghasilkan 2 centroid yang akan digunakan pada serangan real. Proses pengujian serangan real dilakukan selama 2 hari. Terdapat total 10352 serangan diantaranya 1096 memiliki label high dan 9256 memiliki label low serta terdapat 771 notifikasi yang dikirimkan.Persentase hasil serangan selama satu jam berdasarkan label serangan. 60,38% serangan memiliki label “high” dan 39,62% memiliki label “low”. Persentase hasil serangan selama dua hari berdasarkan label serangan. 89% serangan memiliki label “low” dan 11% memiliki label “high”.Abstract With the increasing knowledge and cybercrime, Intrusion Detection System (IDS) is needed. One of which is Snort that can detect the attack. Notification when there is attack is needed so the administrator knows. Alert clustering uses K-Means to divide 2 cluster of alerts namely “low” and “high”. Telegram Bots will send alerts that having a “high” label only. Dataset from 4SICS is used for the grouping process to produce 2 centroid that will be used in real attacks. The real attack testing process is carried out for 2 days. There were a total of 10352 attacks including 1096 having a “high” label and 9256 having a “low” label and there were 771 notifications sent. Percentage of results of one hour attack results based on attack labels was 60.38% of attacks had the label “high” and 39.62% had the label ”low”. Percentage of results of two days attack results based on attack labels was 89% of attacks had the label “low” and 11% had the label ”high”.

Residual Effects of Insecticides on Deraeocoris brevis (Hemiptera: Miridae)

Deraeocoris brevis (Uhler) is a key predatory natural enemy of insects and mites in pear orchards in the United States. Insecticides used for crop protection in pear orchards and their residues can negatively affect populations of D. brevis. The focus of this study was to investigate the field-aged residual effects of lambda-cyhalothrin, spinetoram, and chlorantraniliprole insecticides on D. brevis through contact exposure. An airblast sprayer was used to apply the high label rate of insecticides on pear trees. Leaves were collected from the experimental trees at 1 d after treatment (DAT) and then at 7-d intervals up to 21 DAT. Adults and nymphs were exposed to leaves with insecticide residues or untreated control for 72 h in the laboratory. The nymphs that survived the treatments were reared until they emerged as adults. The surviving paired adults were reared until death. The treated nymphs were assessed for acute mortality, survival, developmental time, and the sex ratio if they emerged as adults. The treated adults were assessed for acute and chronic mortality, fecundity, fertility, and longevity. Both nymphs and adults exposed to leaf residues of lambda-cyhalothrin had significantly higher acute mortality compared with the insects exposed to the control. When compared with the control treatment, the toxicity of field-aged residues of lambda-cyhalothrin, chlorantraniliprole, and spinetoram can persist over a longer period of time. Similar patterns were observed in previous laboratory and field experiments on D. brevis. We discuss the residual effects of three insecticides through contact exposure of D. brevis.

Field-Aged Insecticide Residues on Chrysoperla johnsoni (Neuroptera: Chrysopidae)

We studied the direct (lethal) and indirect (sublethal) effects of field-aged insecticide residues of spinetoram, chlorantraniliprole and lambda-cyhalothrin on adults and larvae of the green lacewing, Chrysoperla johnsoni Henry, Wells and Pupedis an important generalist predator in western United States pear orchards. We applied formulated pesticides using their high label rates mixed with 935 liters/ha of water on pear trees utilizing an airblast sprayer. We collected leaves from the experiment trees at 1, 7, 14, 21 days after treatment (DAT) and exposed C. johnsoni adults and second instars to insecticide residues or untreated control for 72 h. We monitored larvae that survived the treatments until adult emergence (for larvae) or adults until death (for paired adults). We assessed the adults for acute and chronic mortality, longevity, fecundity, and fertility, and larvae for acute mortality, sex ratio, developmental time, and survival of adults emerged from treated second instars, to determine lethal and sublethal effects. The field-exposed insecticide residues of chlorantraniliprole exhibited higher lethal and sublethal toxicities on C. johnsoni during the 21-d leaf collection period when compared with the field-exposed residue toxicities of lambda-cyhalothrin and spinetoram. The field-exposed residue of lambda-cyhalothrin and spinetoram exhibited moderate toxicities on C. johnsoni during the 21-d leaf collection period. Results from this study show similar trends with previous studies using multiple routes of exposure laboratory assays and field experiments on Chrysoperla sp. The direct and indirect effects of field-aged residues of spinetoram, chlorantraniliprole, and lambda-cyhalothrin on C. johnsoni are discussed.

Limited impacts of truck-based ultra-low-volume applications of mosquito adulticides on mortality in honey bees (Apis mellifera)

Adulticides applied against mosquitoes can reduce vector populations during times of high arbovirus transmission. However, impacts of these insecticides on pollinators and other non-target organisms are of concern to mosquito control professionals, beekeepers and others. We evaluated mortality of Culex quinquefasciatus and Apis mellifera when caged insects were exposed to low and high label rates of four common adulticides (Aqua-Pursuit™ [permethrin], Duet® [prallethrin + sumithrin], Fyfanon® [malathion] and Scourge® [resmethrin]) at six distances up to 91.4 m from a truck-mounted ultra-low-volume sprayer. Honey bee mortality was both absolutely low (<10%) and low relative to mosquito mortality for most products, distances, and application rates. Exceptions were at the high rate of Fyfanon (honey bee mortality of 22–100% at distances ≤61 m) and the low rate of Scourge (mortality <10% for both insects). The greatest ratios of mosquito-to-honey bee mortality were found for the low rate of Fyfanon (30× greater) and the high rate of Duet (50× greater). Aqua-Pursuit and Fyfanon tended to increase mortality of both species at closer distances and at higher application rate; this was related to increased number and size of spray droplets. Wind speed and temperature had inconsistent effects on mortality of mosquitoes only. In this bioassay designed to have insects directly intercept insecticide droplets, mosquito adulticides applied at low rates and at >61 m had limited impacts on honey bee mortality while providing effective mosquito control.

Selective microwave sensors exploiting the interaction of analytes with trap states in TiO2 nanotube arrays

Vertically oriented metal oxide nanotube arrays integrated with planar microwave resonators can be used to generate selectivity in addition to high label-free sensitivity through the unique interactions of charge carrier traps with surface-adsorbed analytes.

Late Fall and Early Spring Application of Granular Preemergence Herbicide on a Fertilizer Carrier for Season-Long Crabgrass Control

Though sprayable preemergence herbicides will provide season-long control of crabgrass when applied in fall or early spring in the northern states, little work has been done with the now popular granular formulations of preemergence herbicide on a fertilizer carrier. Dimension (dithiopyr) or Barricade (prodiamine) on a fertilizer carrier were applied in October, November, March, April, May, or June in three trials and crabgrass control was monitored the summer following application. A single granular application of 0.56 kg ai·ha−1 (0.5 lb ai·A−1) of Dimension in November or March can provide control equivalent to that expected from typical mid-April applications. Barricade at 0.72 kg ai·ha−1 (0.65 lb ai·A−1) applied in November or March provided season-long crabgrass control equivalent to traditional mid-April application timing, though season-long crabgrass control from a November application of Barricade at 0.72 kg ai·ha−1 (0.65 lb ai·A−1) can be improved by a sequential May application of 0.28 kg ai·ha−1 (0.25 lb ai·A−1). Adding a sequential May application of Dimension at 0.28 kg ai·ha−1 (0.25 lb ai·A−1) only minimally improved crabgrass control over a November Dimension application at 0.56 kg ai·ha−1 (0.5 lb ai·A−1). Granular formulations of preemergence herbicide on a fertilizer carrier applied in November or March can provide season-long control similar to when applied at the traditional timing in mid-April in the Midwest and Mid-Atlantic regions of the United States. However, it is important for season-long crabgrass control to use the high label rate or follow with a sequential application in early summer if lower rates are used in the fall.