IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rßγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.

International Nosocomial Infection Control Consortium (INICC) report of health care associated infections, data summary of 45 countries for 2015 to 2020, adult and pediatric units, device-associated module.

BACKGROUND: Reporting on the International Nosocomial Infection Control Consortium study results from 2015 to 2020, conducted in 630 intensive care units across 123 cities in 45 countries spanning Africa, Asia, Eastern Europe, Latin America, and the Middle East. METHODS: Prospective intensive care unit patient data collected via International Nosocomial Infection Control Consortium Surveillance Online System. Centers for Disease Control and Prevention/National Health Care Safety Network definitions applied for device-associated health care-associated infections (DA-HAI). RESULTS: We gathered data from 204,770 patients, 1,480,620 patient days, 936,976 central line (CL)-days, 637,850 mechanical ventilators (MV)-days, and 1,005,589 urinary catheter (UC)-days. Our results showed 4,270 CL-associated bloodstream infections, 7,635 ventilator-associated pneumonia, and 3,005 UC-associated urinary tract infections. The combined rates of DA-HAIs were 7.28%, and 10.07 DA-HAIs per 1,000 patient days. CL-associated bloodstream infections occurred at 4.55 per 1,000 CL-days, ventilator-associated pneumonias at 11.96 per 1,000 MV-days, and UC-associated urinary tract infections at 2.91 per 1,000 UC days. In terms of resistance, Pseudomonas aeruginosa showed 50.73% resistance to imipenem, 44.99% to ceftazidime, 37.95% to ciprofloxacin, and 34.05% to amikacin. Meanwhile, Klebsiella spp had resistance rates of 48.29% to imipenem, 72.03% to ceftazidime, 61.78% to ciprofloxacin, and 40.32% to amikacin. Coagulase-negative Staphylococci and Staphylococcus aureus displayed oxacillin resistance in 81.33% and 53.83% of cases, respectively. CONCLUSIONS: The high rates of DA-HAI and bacterial resistance emphasize the ongoing need for continued efforts to control them.

CD8 cis-targeted IL-2 drives potent antiviral activity against hepatitis B virus.

CD8+ T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying CD8+ T cell dysfunction showed that interleukin-2 (IL-2)-based treatment, unlike programmed cell death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential against HBV. However, IL-2's effectiveness is hindered by its pleiotropic nature, because its receptor is found on various immune cells, including regulatory T (Treg) cells and natural killer (NK) cells, which can counteract antiviral responses or contribute to toxicity, respectively. To address this, we developed a cis-targeted CD8-IL2 fusion protein, aiming to selectively stimulate dysfunctional CD8+ T cells in chronic HBV. In a mouse model, CD8-IL2 boosted the number of HBV-reactive CD8+ T cells in the liver without substantially altering Treg or NK cell counts. These expanded CD8+ T cells exhibited increased interferon-γ and granzyme B production, demonstrating enhanced functionality. CD8-IL2 treatment resulted in substantial antiviral effects, evidenced by marked reductions in viremia and antigenemia and HBV core antigen-positive hepatocytes. In contrast, an untargeted CTRL-IL2 led to predominant NK cell expansion, minimal CD8+ T cell expansion, negligible changes in effector molecules, and minimal antiviral activity. Human CD8-IL2 trials in cynomolgus monkeys mirrored these results, achieving a roughly 20-fold increase in peripheral blood CD8+ T cells without affecting NK or Treg cell numbers. These data support the development of CD8-IL2 as a therapy for chronic HBV infection.

An international prospective study of INICC analyzing the incidence and risk factors for catheter-associated urinary tract infections in 235 ICUs across 8 Asian Countries.

BACKGROUND: Identify urinary catheter (UC)-associated urinary tract infections (CAUTI) incidence and risk factors (RF) in 235 ICUs in 8 Asian countries: India, Malaysia, Mongolia, Nepal, Pakistan, the Philippines, Thailand, and Vietnam. METHODS: From January 1, 2014, to February 12, 2022, we conducted a prospective cohort study. To estimate CAUTI incidence, the number of UC days was the denominator, and CAUTI was the numerator. To estimate CAUTI RFs, we analyzed 11 variables using multiple logistic regression. RESULTS: 84,920 patients hospitalized for 499,272 patient days acquired 869 CAUTIs. The pooled CAUTI rate per 1,000 UC-days was 3.08; for those using suprapubic-catheters (4.11); indwelling-catheters (2.65); trauma-ICU (10.55), neurologic-ICU (7.17), neurosurgical-ICU (5.28); in lower-middle-income countries (3.05); in upper-middle-income countries (1.71); at public-hospitals (5.98), at private-hospitals (3.09), at teaching-hospitals (2.04). The following variables were identified as CAUTI RFs: Age (adjusted odds ratio [aOR] = 1.01; 95% CI = 1.01-1.02; P < .0001); female sex (aOR = 1.39; 95% CI = 1.21-1.59; P < .0001); using suprapubic-catheter (aOR = 4.72; 95% CI = 1.69-13.21; P < .0001); length of stay before CAUTI acquisition (aOR = 1.04; 95% CI = 1.04-1.05; P < .0001); UC and device utilization-ratio (aOR = 1.07; 95% CI = 1.01-1.13; P = .02); hospitalized at trauma-ICU (aOR = 14.12; 95% CI = 4.68-42.67; P < .0001), neurologic-ICU (aOR = 14.13; 95% CI = 6.63-30.11; P < .0001), neurosurgical-ICU (aOR = 13.79; 95% CI = 6.88-27.64; P < .0001); public-facilities (aOR = 3.23; 95% CI = 2.34-4.46; P < .0001). DISCUSSION: CAUTI rate and risk are higher for older patients, women, hospitalized at trauma-ICU, neurologic-ICU, neurosurgical-ICU, and public facilities. All of them are unlikely to change. CONCLUSIONS: It is suggested to focus on reducing the length of stay and the Urinary catheter device utilization ratio, avoiding suprapubic catheters, and implementing evidence-based CAUTI prevention recommendations.

Survival Benefits of Therapeutic Plasma Exchange in Severe Sepsis and Septic Shock: A Systematic Review and Meta-analysis.

OBJECTIVES: To summarize the role of therapeutic plasma exchange (TPE) in critically ill adults and children with severe sepsis. DATA COLLECTION: A systematic search was performed using the following databases: Medline, EMBASE, CINAHL, and Cochrane from January 1990 till December 2022. Comparative studies of TPE in severe sepsis were selected. Adult and pediatric data were analyzed separately. DATA SYNTHESIS: Eight randomized control trials and 6 observational studies (n = 50,142 patients) were included. Centrifugal TPE was the most common modality (209/280, 74.6% adults and 952/1026, 92.7% children). Every TPE study utilized different volume exchanges. Most TPE sessions (1173/1306, 89.8%) employed fresh frozen plasma (FFP) as replacement fluid and heparin as anticoagulant. Adults with severe sepsis supported with TPE using FFP had lower mortality (risk ratio, RR: 0.64 [95% confidence interval, CI: 0.49, 0.84]) compared to those who did not. In contrast, TPE was associated with increased mortality in septic children without thrombocytopenia-associated multiorgan failure (RR: 2.23, 95% CI: 1.93, 2.57). There was no difference in outcomes in patients supported with centrifugal and membrane TPE. In both populations, patients supported on TPE as a continuous regime had poorer outcome. CONCLUSION: Current evidence indicates that TPE is a potential adjunct therapy in adults with severe sepsis but not in children.

Soil nutrients and plant uptake parameters as related to greenhouse gas emissions.

Fertilizer and water management practices have short- and long-term effects on soil chemical and physical properties and, in turn, greenhouse gas (GHG) emissions. The goal of this 4-yr field study was to establish the relationships between soil properties, agronomic practices, and GHG (CO2 and N2 O) emissions under different fertilizer and water table management practices. There were two fertilizer treatments: inorganic fertilizer (IF) and a mix of solid cattle manure and inorganic fertilizer (SCM), combined with tile drainage(DR) and controlled drainage with subirrigation(CDS). The cropping system was a maize (Zea mays L.)-soybean [Glycine max (L.) Merr.] rotation. Nitrogen in biomass (BMN) and N in grain (GRN) were measured and used to calculate other plant N parameters. Nitrous oxide and CO2 fluxes were collected weekly, and their respective cumulative emissions were calculated. The results show that soil organic matter (OM), soil total carbon (C), and soil total nitrogen (N) were greater in SCM than IF by 23.7, 35.2, and 24.4%, respectively. Water table management did not significantly affect soil N and C. Increased CO2 emissions were witnessed under higher soil OM, soil total C, and total N. Plant N uptake parameters were negatively correlated with N2 O and CO2 emissions. Higher plant N uptake can reduce environmental pollution by limiting N2 O and CO2 emissions.

Phosphorus characteristics of Canada-wide animal manures and implications for sustainable manure management with a cleaner environment.

Animal manure can be a serious environmental concern if improperly managed, particularly with regard to phosphorus (P). A good understanding on manure P chemistry is required for improving manure management in an environmentally sustainable manner. In the study, 102 representative manure samples collected from farms of major intensive livestock areas of Canada were sequentially fractionated with H2O, 0.5 M NaHCO3, 0.1 M NaOH, and 1.0 M HCl, respectively, for measuring inorganic (Pi) and organic P (Po). Across the manures, total P (TP) ranged from 3.71 to 17.3 g kg-1, with total Pi and available P (i.e., the sum of H2O-Pi and NaHCO3-Pi) accounting for 67.0-92.4 % and 35.6-67.3 % of TP, respectively. Composting reduced the percentages of available P and Po in TP, and meanwhile increased the percentages of moderately stable HCl-Pi. Compared to other P fractions, manure available P increased more rapidly with increases in TP; once manure TP reached 7.8-9.6 g kg-1, further TP increase enhanced transformation to more recalcitrant P (i.e., NaOH-Pi and HCl-Pi). Under Canadian conditions, manure application to meet the demand of crops for N would lead to P buildup in the soil at rates of 6.1-41.6 kg P ha-1 yr-1, increasing runoff P loss risk. Manure compost and poultry manure tend to cause rapid P buildup in the soil after land application and become a long-term P source for runoff losses. The results help to develop scientifically-sound manure-specific P management technologies which would enable farmers to achieve sustainable crop production with improved environment.

Surgical site infection and development of antimicrobial sutures: a review.

Sutures are used to facilitate wound healing and play an important role in ensuring the success of surgical interventions in healthcare facilities. Suture-associated surgical site infection (SSI) may develop when bacterial contaminants colonize the suture surface and establish biofilms that are highly resistant to antibiotic treatment. The outcome of SSI affects postoperative care, leading to high rates of morbidity and mortality, prolonged hospitalization, and increased financial burden. Antimicrobial sutures coated with antiseptics such as triclosan and chlorhexidine have been used to minimize the occurrence of SSI. However, as the efficacy of antiseptic-based sutures may be affected due to the emergence of resistant strains, new approaches for the development of alternative antimicrobial sutures are necessary. This review provides an update and outlook of various approaches in the design and development of antimicrobial sutures. Attaining a zero SSI rate will be possible with the advancement in suturing technology and implementation of good infection control practice in clinical settings.

Patterns of Athlete Medication Use at the 2018 PyeongChang Paralympic Games: A Descriptive Cohort Study.

OBJECTIVE: Medication use among elite athletes has received growing attention over the past decades. However, only limited studies have focused on para athletes, and trends in medication use among this cohort remain unclear. The aims of this study were (1) to describe the pattern of medication use in elite Paralympic athletes, with a particular focus on analgesics, (2) to analyze whether medications declared by athletes were included in the 2018 World Anti-Doping Agency's prohibited list and monitoring program, (3) to report on a variety of novel supplements, and (4) to review whether athlete analgesic needs will be met by the new Olympic & Paralympic Model Formulary. DESIGN: This is a retrospective, descriptive cohort study. RESULTS: Of all athletes who underwent doping control, 21% declared the use of an analgesic medication. Athletes with limb deficiency and para snowboarders declared the most analgesic medications in their respective categories. It was determined that 84% of the athletes' analgesic medication needs were provided from the new Olympic & Paralympic Model Formulary. CONCLUSIONS: Analgesic use among athletes who participated at the 2018 PyeongChang Winter Paralympics was high. Para snowboarders and athletes with limb deficiency declared the most analgesics. The new Olympic & Paralympic Model Formulary adequately addressed the medication needs of the athletes attending the 2018 games.

Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury.

The signaling of cells by scaffolds of synthetic molecules that mimic proteins is known to be effective in the regeneration of tissues. Here, we describe peptide amphiphile supramolecular polymers containing two distinct signals and test them in a mouse model of severe spinal cord injury. One signal activates the transmembrane receptor ß1-integrin and a second one activates the basic fibroblast growth factor 2 receptor. By mutating the peptide sequence of the amphiphilic monomers in nonbioactive domains, we intensified the motions of molecules within scaffold fibrils. This resulted in notable differences in vascular growth, axonal regeneration, myelination, survival of motor neurons, reduced gliosis, and functional recovery. We hypothesize that the signaling of cells by ensembles of molecules could be optimized by tuning their internal motions.

Evaluation of Atmospheric 3-Day Waves as a Source of Day-to-Day Variation of the Ionospheric Longitudinal Structure.

We report for the first time the day-to-day variation of the longitudinal structure in height of the F2 layer (hmF2) in the equatorial ionosphere using multi-satellite observations of electron density profiles by the Constellation Observing System for Meteorology, Ionosphere and Climate-2 (COSMIC-2). These observations reveal a ~3-day modulation of the hmF2 wavenumber-4 structure viewed in a fixed local time frame during January 30-February 14, 2021. Simultaneously, ~3-day planetary wave activity is discerned from zonal wind observations at ~100 km by the Ionospheric Connection Explorer (ICON) Michelson Interferometer for Global High-Resolution Thermospheric Imaging (MIGHTI). This signature is not observed at ~180-250 km altitudes, suggesting the dissipation of this wave below the F-region. We propose that the 3-day variation identified in h mF2 is likely caused by the planetary wave-tide interaction through the E-region dynamo.

The efficacy of intense pulse light among patients with skin type III-IV in acute facial acne: The Malaysian experience.

INTRODUCTION: Twenty-seven adult patients, skin type III -V with mild to moderate acne, were recruited. IPL at wavelengths range of 420 - 600nm with triple pulses was administered every two weeks for a total of 3 sessions. Assessment of acne severity and improvement of treatment was based on Global Acne Grading System (GAGS), scoring before and after treatment for each session and patient satisfaction's using a 5-item Likert scale range at the end of session three. RESULTS: Of the 27 patients, 77.8% were female. Their ages group ranged from 18 to 35 years, and all patients had skin type III or IV. There were 14 mild acne patients and 13 moderate ones. There was a statistically significant improvement in mean acne severity score from 18.1± 4.3 at baseline to 14.3 ± 4.6 after two weeks post-IPL and 12.3 ± 4.9 after four weeks post-IPL. The result on satisfaction level of patients showed 'satisfied' in 3 patients, "very satisfied" in 5 patients; and, half of the patients (11) answered "fair" at the end of the study. Most patients tolerated well the procedure, and only 5 patients developed either post-inflammatory hyperpigmentation or skin hyperpigmentation. CONCLUSION: The IPL of wavelength of 400-600nm offers effective, safe, and well-tolerated treatment of mild to moderate acne lesions in Malaysians with skin types III-IV. The majority of subjects had a fair score on treatment satisfaction. It is recommended that reasonable expectations for clinical results be addressed with patients before hands to prevent over-expectation.

Postfilament supercontinuum on 100 m path in air.

Pulses at 744 nm with 90 fs duration, 6 mJ energy, and a weakly divergent wavefront propagate for more than 100 m and generate a filament followed by an unprecedently long high intensity (≥1TW/cm2) light channel. Over a 20 m long sub-section of this channel, the pulse energy is transferred continuously to the infrared wing, forming spectral humps that extend up to 850 nm. From 3D+time carrier-resolved simulations of 100 m pulse propagation, we show that spectral humps indicate the formation of a train of femtosecond pulses appearing at a predictable position in the propagation path.

An influenza A (H3N2) virus outbreak in the Kingdom of Cambodia during the COVID-19 pandemic of 2020.

BACKGROUND: Global influenza virus circulation decreased during the COVID-19 pandemic, possibly due to widespread community mitigation measures. Cambodia eased some COVID-19 mitigation measures in June and July 2020. On 20 August a cluster of respiratory illnesses occurred among residents of a pagoda, including people who tested positive for influenza A but none who were positive for SARS-CoV-2. METHODS: A response team was deployed on 25 August 2020. People with influenza-like illness (ILI) were asked questions regarding demographics, illness, personal prevention measures, and residential arrangements. Respiratory swabs were tested for influenza and SARS-Cov-2 by real-time reverse transcription PCR, and viruses were sequenced. Sentinel surveillance data were analyzed to assess recent trends in influenza circulation in the community. RESULTS: Influenza A (H3N2) viruses were identified during sentinel surveillance in Cambodia in July 2020 prior to the reported pagoda outbreak. Among the 362 pagoda residents, 73 (20.2%) ILI cases were identified and 40 were tested, where 33/40 (82.5%) confirmed positive for influenza A (H3N2). All 40 were negative for SARS-CoV-2. Among the 73 residents with ILI, none were vaccinated against influenza, 47 (64%) clustered in 3/8 sleeping quarters, 20 (27%) reported often wearing a mask, 27 (36%) reported often washing hands, and 11 (15%) reported practicing social distancing. All viruses clustered within clade 3c2.A1 close to strains circulating in Australia in 2020. CONCLUSIONS: Circulation of influenza viruses began in the community following the relaxation of national COVID-19 mitigation measures, and prior to the outbreak in a pagoda with limited social distancing. Continued surveillance and influenza vaccination are required to limit the impact of influenza globally.

Correlation and accuracy of contrast-enhanced computed tomography in assessing depth of invasion of oral tongue carcinoma.

The aim of this study was to evaluate the correlation and accuracy of depth of invasion (DOI) measurement from preoperative contrast-enhanced computed tomography (CECT) scans in comparison to histopathological examination (HPE) in oral tongue squamous cell carcinoma (OTSCC). Preoperative CT scans of 18 OTSCC patients were reviewed retrospectively by a single observer to measure the DOI on axial and coronal sections; these were then compared to the HPE report. Mean DOI was compared between CECT and HPE using repeated measures ANOVA. The strength of correlation of CT-derived tumour depth was determined using the intra-class correlation coefficient (ICC) followed by assessment of accuracy by Bland-Altman plot. In general, the measurement of DOI was smaller on CECT, with a mean difference of 0.743mm on axial CT and 1.106mm on coronal CT. Regarding the correlation between CECT and HPE tumour depths, ICC was 0.956 for axial CT and 0.965 for coronal CT. Bland-Altman analysis showed that DOI from CECT and histopathological depth were in agreement with each other. In conclusion, there was excellent correlation and accurate measurement of DOI from CECT.

Modeling of phosphorus loss from field to watershed: A review.

Phosphorus (P) losses from nonpoint sources into surface water resources through surface runoff and tile drainage play a significant role in eutrophication. Accordingly, the number of studies involving the modeling of agricultural P losses, the uncertainties of such models, and the best management practices (BMPs) supported by the modeling of hypothetical P loss reduction scenarios has increased significantly around the world. Many improvements have been made to these models: separate manure P pools, variable source areas allowing the determination of critical source areas of P loss, analyses of modeling uncertainties, and understanding of legacy P. However, several elements are still missing or have yet to be sufficiently addressed: the incorporation of preferential flow into models, the modification of P sorption-desorption processes considering recent research data (e.g., pedotransfer functions for labile, active, or stable P, along with P sorption coefficients), BMP parameterization, and scale-up issues, as well as stakeholder-scientist and experimentalist-modeler interactions. The accuracy of P loss modeling can be improved by (a) incorporating dynamic P sorption-desorption processes and new P subroutines for direct P loss from manure, fertilizer, and dung, (b) modeling preferential flow, connectivity between field and adjacent water bodies, and P in-stream processes, (c) including an assessment of model uncertainty, (d) integrating field and watershed models for BMP calibration and scaling field results up to larger areas, and (e) building a holistic interaction between stakeholders, experimentalists, and modelers.

Bioequivalence and pharmacokinetic comparison of two fixed dose combination of Metformin/ Glibenclamide formulations in healthy subjects under fed condition.

AIM: This study is conducted to compare the pharmacokinetic profiles of two fixed dose combination of metformin/glibenclamide tablets (500mg/5 mg per tablet). MATERIALS AND METHODS: This is a single-center, single-dose, open-label, randomized, 2-treatment, 2-sequence and 2- period crossover study with a washout period of 7 days. All 28 adult male subjects were required to fast for at least 10 hours prior to drug administration and they were given access to water ad libitum during this period. Thirty minutes prior to dosing, all subjects were served with a standardized high-fat and high-calorie breakfast with a total calorie of 1000 kcal which was in accordance to the EMA Guideline on the Investigation of Bioequivalence. Subsequently, subjects were administered either the test or reference preparation with 240mL of plain water in the first trial period. During the second trial period, they received the alternate preparation. Plasma levels of glibenclamide and metformin were analysed separately using two different high performance liquid chromatography methods. RESULTS: The 90% confidence interval (CI) for the ratio of the AUC0-t, AUC0-∞, and Cmax of the test preparation over those of the reference preparation were 0.9693-1.0739, 0.9598- 1.0561 and 0.9220 - 1.0642 respectively. Throughout the study period, no serious drug reaction was observed. However, a total of 26 adverse events (AE)/side effects were reported, including 24 that were definitely related to the study drugs, namely giddiness (n=17), while diarrheoa (n=3), headache (n=2) and excessive hunger (n=2) were less commonly reported by the subjects. CONCLUSION: It can be concluded that the test preparation is bioequivalent to the reference preparation.

COVID-19: Four Paediatric Cases in Malaysia.

OBJECTIVE: This is a brief report of 4 paediatric cases of COVID-19 infection in Malaysia BACKGROUND: COVID-19, a coronavirus, first detected in Wuhan, China has now spread rapidly to over 60 countries and territories around the world, infecting more than 85000 individuals. As the case count amongst children is low, there is need to report COVID-19 in children to better understand the virus and the disease. CASES: In Malaysia, until end of February 2020, there were four COVID-19 paediatric cases with ages ranging from 20 months to 11 years. All four cases were likely to have contracted the virus in China. The children had no symptoms or mild flu-like illness. The cases were managed symptomatically. None required antiviral therapy. DISCUSSION: There were 2 major issues regarding the care of infected children. Firstly, the quarantine of an infected child with a parent who tested negative was an ethical dilemma. Secondly, oropharyngeal and nasal swabs in children were at risk of false negative results. These issues have implications for infection control. Consequently, there is a need for clearer guidelines for child quarantine and testing methods in the management of COVID-19 in children.

An Optimized Full-Length FLT3/CD3 Bispecific Antibody Demonstrates Potent Anti-leukemia Activity and Reversible Hematological Toxicity.

FLT3 (FMS-like tyrosine kinase 3), expressed on the surface of acute myeloid leukemia (AML) blasts, is a promising AML target, given its role in the development and progression of leukemia, and its limited expression in tissues outside the hematopoietic system. Small molecule FLT3 kinase inhibitors have been developed, but despite having clinical efficacy, they are effective only on a subset of patients and associated with high risk of relapse. A durable therapy that can target a wider population of AML patients is needed. Here, we developed an anti-FLT3-CD3 immunoglobulin G (IgG)-based bispecific antibody (7370) with a high affinity for FLT3 and a long half-life, to target FLT3-expressing AML blasts, irrespective of FLT3 mutational status. We demonstrated that 7370 has picomolar potency against AML cell lines in vitro and in vivo. 7370 was also capable of activating T cells from AML patients, redirecting their cytotoxic activity against autologous blasts at low effector-to-target (E:T) ratio. Additionally, under our dosing regimen, 7370 was well tolerated and exhibited potent efficacy in cynomolgus monkeys by inducing complete but reversible depletion of peripheral FLT3+ dendritic cells (DCs) and bone marrow FLT3+ stem cells and progenitors. Overall, our results support further clinical development of 7370 to broadly target AML patients.

Modeling and Mitigating Phosphorus Losses from a Tile-Drained and Manured Field Using RZWQM2-P.

Prediction of P losses from manured agricultural fields through surface runoff and tile drainage is necessary to mitigate widespread eutrophication in water bodies. However, present water quality models are weak in predicting P losses, particularly in tile-drained and manure-applied cropland. We developed a field-scale P management model, the Root Zone Water Quality Model version 2-Phosphorus (RZWQM2-P), whose accuracy in simulating P losses from manure applied agricultural field is yet to be tested. The objectives of this study were (i) to assess the accuracy of this new model in simulating dissolved reactive phosphorus (DRP) and particulate phosphorus (PP) losses in surface runoff and tile drainage from a manure amended field, and (ii) to identify best management practices to mitigate manure P losses including water table control, manure application timing, and spreading methods by the use of model simulation. The model was evaluated against data collected from a liquid cattle manure applied field with maize ( L.)-soybean [ (L.) Merr.] rotation in Ontario, Canada. The results revealed that the RZWQM2-P model satisfactorily simulated DRP and PP losses through both surface runoff and tile drainage (Nash-Sutcliffe efficiency > 0.50, percentage bias within ±25%, and index of agreement > 0.75). Compared with conventional management practices, manure injection reduced the P losses by 18%, whereas controlled drainage and winter manure application increased P losses by 13 and 23%, respectively. The RZWQM2-P is a promising tool for P management in manured and subsurface drained agricultural field. The injection of manure rather than controlled drainage is an effective management practice to mitigate P losses from a subsurface-drained field.