ABSTRACT Objective To evaluate the impact of screening and treating asymptomatic pregnant women for C. trachomatis and N. gonorrhoeae infections on the frequency of preterm birth or low birth weight infants in Botswana. Design Non-randomized, cluster-controlled trial. Setting Four antenatal care clinics in Gaborone, Botswana. Population Pregnant women aged ≥15 years, attending a first antenatal care visit, ≤27 weeks gestation, and without urogenital symptoms were eligible. Methods Participants in the intervention clinics received screening (GeneXpert®, Cepheid) during pregnancy and at the post-natal visit. Participants in the standard-of-care clinics received screening at the postnatal visit only. We used multivariable logistic regression and post-estimation predictive margins analysis. Post-hoc analysis was conducted among sub-samples stratified by parity. Main outcome measures Preterm birth (<37 weeks gestation) and low birth weight (<2500g). Results After controlling for parity, hypertension, antenatal care visits, and clinic site, the predicted prevalence of preterm or low birth weight was lower in the intervention arm (11%) compared to the standard-of-care (16%) (AOR: 0.59; 95% CI: 0.28 to 1.24), but confidence intervals were wide. In post-hoc analysis, the intervention was more effective than the standard-of-care (AOR: 0.20; 95% CI: 0.07-0.64) among nulliparous participants. Conclusion A C. trachomatis and N. gonorrhoeae infection screening and treatment intervention among asymptomatic pregnant women did not significantly reduce preterm or low birth weight outcomes. Post hoc analysis found the intervention reduced adverse outcomes among nulliparous participants.

Many clinical and research efforts aim to develop antidepressant drugs for those suffering from major depressive disorder (MDD). Yet even today, the available treatments are suboptimal and unpredictable, with a significant proportion of patients enduring multiple drug attempts and adverse side effects before a successful response; and for many patients, no response at all. Thus, a clearer understanding of the mechanisms underlying MDD is necessary. In the “Brain Development and Disease” class of our Master’s program in Cognitive Sciences, we ask students to collect data about the expression of a gene whose altered expression and/or function is related to a brain disorder. The students’ final exam assignment consists of writing a research article in which the collected data are discussed in relation to the relevant disorder. In the course of one of these assignments, we identified the FKBP5 gene as a key player uniting two major hypotheses of MDD pathogenesis and treatment response. FKBP5 controls biological processes including immunoregulation and glucocorticoid function, both of which are separately implicated in the development and prognosis of MDD. Gene expression analyses from the human, non-human primate, and mouse Allen Brain Atlases revealed that FKBP5 is expressed in brain regions involved in MDD, particularly at ages susceptible to early-life stressors. Data re-analysis from published studies confirmed that FKBP5 expression is upregulated in relevant brain regions in human MDD and preclinical mouse models of MDD. Our experience shows that classes engaging students in data collection and analysis projects may effectively result in novel data-driven hypotheses.

Intercropping herbage promoted the availability ofsoil phosphorus by improving the bacterial genus structure and the abundance of key bacterial-fungal taxa in theacidic soil of mango (Mangifera indica L.) orchardsChengming Yan a, b, c, 1, Dongsheng Ana, c, 1, Baoshan Zhao a, c, Zhiling Ma a, b, Haiyang Ma a, b, d, Qiufang Zhao a, Ran Kong a, Junbo Su a, c, *a South Subtropical Crops Research Institute, Chinese Academy of Tropical Agricultural Sciences (CATAS), Zhanjiang, Guangdong, 524091, Chinab Key Laboratory of Tropical Fruit Biology, Ministry of Agriculture and Rural Affairs of China, Zhanjiang, Guangdong, 524091, ChinacZhanjiang Experimental and Observation Station for National Long-Term Agricultural Green Development, Zhanjiang, Guangdong, 524091, Chinad Key Laboratory of Tropical Crops Nutrition of Hainan province, Zhanjiang, Guangdong, 524091, China*Corresponding Author, South Subtropical Crops Research Institute, Chinese Academy of Tropical Agricultural Sciences (CATAS), Zhanjiang, Guangdong, 524091, China. Tel No: +86-0759-2859194, Fax No: +86-0759-2859194, E-mail Address: junbosu@126.com.1 Made an equal contribution to this article.

The hybrid nanofluids are effective in terms of cooling where the range of temperature is high and includes a significant range of thermal applications, such as cooling electrical equipment, heat exchangers, automotive industry, heat pipes, manufacturing industry, and solar energy. As a result of these facts, this particular research emphasizes on the silver- titanium oxide /water hybrid nanofuid flow through an exponentially stretching sheet. The impacts such as viscous dissipation, magneto hydrodynamics, porosity, thermal radiation and heat generation have been also taken into account. By utilizing non-dimensional quantities and similarity functions, the flow model is transformed and simplified to a system of ordinary differential equations. With the help of the numerical method Runge-Kutta with shooting technique in Matlab script, the desired system is solved. It has been discovered that stronger the porosity parameter raises the temperature while diminishing the velocity. It additionally emphasizes that augmentations in the magnetic parameter, Eckert number, radiation parameter, and volume percentage of T i O 2 and A g nanoparticles proportional to the temperature profile. The results demonstrate satisfactory congruence’s when compared to the current literature.

This paper addresses the construction of Cauchy operators and related identities from R( p,q)-deformed quantum algebras. The generating function, Mehler and Rogers formulae, and their extended identities for the homogeneous Rogers-Szegö polynomials are computed and discussed. Relevant particular identities extracted from known quantum algebras are highlighted.

Busulfan is commonly used in the conditioning regimen for hematopoietic stem cell transplantation. Due to the risk of seizures associated with its use, prophylaxis with an anti-seizure drug is required. We prospectively evaluated the effectiveness of oral levetiracetam in children and adolescents for the prevention of busulfan-induced seizures. None of the 64 patients included in the study experienced seizures during the conditioning therapy or side effects that required discontinuation of the drug. Our results suggest that oral levetiracetam is effective in this setting.

All animals and plants respond to changes in the environment during their life cycle. This flexibility is known as phenotypic plasticity and allows organisms to cope with variable environments. A common source of environmental variation is predation risk, which describes the likelihood of being attacked and killed by a predator. Some species can respond to the level of predation risk by producing morphological defences against predation. A classic example is the production of pedestals and head spikes in the water flea, Daphnia pulex, which defend against predation from Chaoborus midge larvae. Previous studies of these defences have focussed on changes in pedestal size and the number of spikes along a gradient of predation risk. Although these studies have provided a model for continuous plasticity, they do not capture the whole-organism shape response to predation risk. In contrast, studies in fish and amphibians focus on shape as a complex, multi-faceted trait made up of different variables. In this study, we analyse how multiple aspects of shape change in D. pulex along a gradient of predation risk from C. flavicans. These changes are dominated by the inducible morphological defence, but there are also changes in the size and shape of the head and the body. We detected change in specific modules of the body plan and a level of integration among modules. These results are indicative of a complex, multi-faceted response to predation and provide insight into how predation risk drives variation in shape and size at the level of the whole organism.

Short title Macroevolution and ecology drive multiple facets of tree diversityMartha Paola Barajas Barbosa*1,2(paolabarajas@gmail.com)Tiffany M. Knight1,3,4 Renske Onstein5,1 Jonathan Chase1,2 1 German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Leipzig, Germany2 Department of Computer Science, Martin Luther University Halle-Wittenberg, Germany3 Department for Community Ecology, Helmholtz Centre for Environmental Research–UFZ, Leipzig, Germany4 Institute of Biology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany5 Naturalis Biodiversity Center, Darwinweg 2, 2333CR Leiden, the Netherlands*Corresponding author

Freshwater ecosystems are increasingly affected by rising annual mean temperatures and extreme heatwaves. While heatwaves are expected to have more immediate effects than mean temperature increases on local communities, comparative experimental studies are largely lacking. We conducted a one-month mesocosm experiment to test the effect of different warming scenarios, constantly raised temperatures (+3°C), and recurring heatwaves (+6°C) on plankton communities. We specifically tested how shifts in zooplankton trait composition and functional groups are reflected in ecosystem functioning (top-down control on primary producers). We found that heatwaves had a stronger and more immediate effect on trait and functional group compositions. Heatwaves were associated with larger body sizes, and the decrease in micrograzers resulted in weaker top-down control, leading to elevated algal biomass. Altogether, our results highlight the importance of the indirect effects of heatwaves via inducing shifts in zooplankton functional groups and trait composition which may foster periodic algal blooms.

Ziping Zuoa, Jimmy C.H. Funga,b, Zhenning Lia,*, Yiyi Huangd, Mau Fung, Wonga, Alexis K.H. Laua,c, Xingcheng Luea Division of Environment and Sustainability, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Chinab Department of Mathematics, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Chinac Department of Civil and Environmental Engineering, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, Chinad Department of Hydrology and Atmospheric Sciences, University of Arizona, Tucson, AZ, USAe Department of Geography and Resource Management, The Chinese University of Hong Kong, Shatin, Hong Kong, ChinaCorresponding author: Zhenning Li,lzhenn@ust.hkABSTRACTRecent worldwide heatwaves have shattered temperature records in many regions. In this study, we applied a dynamical downscaling method on the high-resolution version of the Max Planck Institute Earth System Model (MPI-ESM-1-2-HR) to obtain projections of the summer thermal environments and heatwaves in the Pearl River Delta (PRD) considering three shared socioeconomic pathways (SSP1-2.6, SSP2-4.5, and SSP5-8.5) in the middle and late 21st century. Results indicated that relative to the temperatures in the 2010s, the mean increases in the summer (June–September) daytime and nighttime temperatures in the 2040s will be 0.7–0.8 °C and 0.9–1.1 °C, respectively. In the 2090s, the mean difference will be 0.5–3.1 °C and 0.7–3.4 °C, respectively. SSP1-2.6 is the only scenario in which the temperatures in the 2090s are expected to be lower than those in the 2040s. Compared with those in the 2010s, hot extremes are expected to be more frequent, intense, extensive, and longer-lasting in the future in the SSP2-4.5 and SSP5-8.5 scenarios. In the 2010s, a heatwave occurred in the PRD lasted for 6 days on average, with a mean daily maximum temperature of 34.4 °C. In the 2040s, the heatwave duration and intensity are expected to increase by 2–3 days and 0.2–0.4 °C in all three scenarios. In the 2090s, the increase in these values will be 23 days and 36.0 °C in SSP5-8.5. Moreover, a 10-year extreme high temperature in the 2010s is expected to occur at a monthly frequency from June to September in the 2090s.SIGNIFICANCE STATEMENTPearl River Delta (PRD) has been experiencing record-shattering heatwaves in recent years. This study aims to investigate the future trends of summer heatwaves in the PRD by modeling three future scenarios including a sustainable scenario, an intermediate scenario, and a worst-case scenario. Except the sustainable scenario, summer temperatures in the intermediate and worst-case scenarios will keep increasing, and heatwaves will become more frequent, intense, extensive, and longer-lasting. In the worst-case scenario, extreme heat events that occurred once in 10 years in the 2010s will shorten to once a month in the 2090s. A better understanding of heatwave trends will benefit implementing climate mitigation methods, urban planning, and improving social infrastructure.

Background: Rational design of synthetic phage-displayed libraries requires the identification of the most appropriate positions for randomization using the best-fitting amino acid set to recapitulate the natural occurrence. To this end, the present study uses position-specific scoring matrixes (PSSMs) for identifying and randomizing Camelidae nanobody (VHH) CDRs. The functionality of a synthetic VHH repertoire designed by this method was tested against recombinant coagulation factor VII (rfVII). This study investigates the applicability of anti-rfVII VHH binders isolated from a PSSM-based library as immunoaffinity purification ligands. Methods: Based on PSSM analysis, the CDR3 of cAbBCII10 VHH framework was identified, and a set of amino acids for the substitution of each PSSM-CDR position was defined. Using the Rosetta design SwiftLib tool, the final repertoire was back-translated to a degenerate nucleotide sequence. This library was screened against recombinant coagulation factor VII, and the isolated VHH binders being coupled with Sepharose CL-4B beads were tested for rfVII purification. Results: A synthetic phage-displayed VHH library with 108 variants was constructed. Three VHH binders were isolated from this library with affinity constants (KAff)) of 108, 1.7x107, and 3.8x106. We could develop an immunoaffinity chromatography resin from one of the isolated binders. This resin showed acceptable specificity and stability with a capacity of 2.3 mg rfVII per ml of the resin. Conclusion: PSSM analysis is a simple and efficient way to design synthetic phage-displayed libraries. VHH binders discovered through this method can be effectively exploited in developing immunoaffinity chromatography resins.

Autonomous cars are complex automotive systems with multiple subsystems working together in harmony to produce the desired result. The autopilot then works as the brain that governs the behavior of the car when the self-driving mode is switched on. In this work 1 , the design of a computer vision-based self-driving car autopilot was conducted in a simulation environment using an End-to-End approach, where a single neural network model maps the images from the environment directly to some sort of action. The NVIDIA End-to-End model was chosen, because it takes the input picture, does end-to-end processing, and gives an output of a steering angle. This is done without any human intervention. Two models influenced by NVIDIA's model were developed. The first one is based on VGG architecture while the second is based on the ResNet architecture. Unlike their baseline model, each of our models is supposed to not only determine the steering angle but also control the acceleration and the break. The two models were compared using different matrices.

Recently, the ever-increasing complexity of datasets has necessitated the development of sophisticated techniques to uncover meaningful patterns and interactions within the data. This paper investigates the synergy between Rough Set Theory and Association Rule Mining, which is a potent approach to detecting interactions and enhancing the prediction capabilities of machine learning models. The proposed framework leverages the Greedy Heuristic Method for reduct generation, an established technique in Rough Set Theory, to efficiently identify relevant features and reduce the dimensionality of the dataset. Furthermore, Association Rule Mining extracts association rules from the data, revealing interesting relationships and dependencies among the features. These association rules are transformed into binary values, representing the detected interactions, to create a concise yet informative representation of the data’s intrinsic relationships. This binary representation is ideal for integration into machine learning models, enabling them to exploit the discovered interactions and gain a more comprehensive understanding of the underlying patterns. To assess the effectiveness of our proposed framework, we propose a comprehensive experiment involving a weather dataset scraped from www.wunderground.com for Kariki farm in the Juja sub-county, Kiambu County, Kenya. Using detected interactions, we modelled them to base machine learning models, including Naive Bayes, Decision Trees, Support Vector Machines (SVM), and Logistic Regression models. We compared the performance of these models while using the detected interactions versus not using the detected interactions. Through extensive experimentation, we demonstrate that our proposed approach is more effective than traditional machine learning models without interaction detection. Our results indicate that our interaction detection method framework significantly improves the prediction accuracy of the tested models on the benchmark datasets. This enhancement in accuracy highlights the practical relevance and potential benefits of adopting our approach to uncover valuable insights from datasets.

Phylogenetic gaps of publicly-available reference sequences are a major obstacle for species identification and management, particularly in the Global South, where economically important fisheries and conservation flagship species often lack closely-related references. We applied target-enrichment to obtain complete mitochondrial genomes of marine ichthyofauna from the Brazilian coast lacking phylogenetically-close references. Species were selected based on economic significance, including three sardines (Dorosomatidae and Alosidae), three mackerels (Scombridae) and nine croakers (Sciaenidae), as well as conservation status, notably groupers and snappers of the Epinephelid family. Custom baits were designed to enrich mitochondrial DNA across a broad phylogenetic range of fishes. Sequencing generated approximately 100k reads per sample, which were assembled in a total of 70 complete mitochondrial genomes and include fifty-two new additions to databases, including five species with no previous mitochondrial data. Departures from the typical gene content and order occurred in only three taxa and mostly involved tRNA gene duplications. Start-codons for all genes, except Cytochrome c Oxidase Subunit I (COI), were consistently ATG, whilst a wide range of stop-codons deviated from the prevailing TAA. Phylogenetic analysis confirmed assembly accuracy and revealed signs of cryptic diversification within the Mullus genus. Lineage delimitation methods using Sardinella aurita and S. brasiliensis mitochondrial genomes support a single Operational Taxonomic Unit. Target enrichment was highly efficient, providing complete novel mitochondrial genomes with little sequencing effort. These sequences are deposited in public databases to enable conservation and management programs in Latin America that rely on molecular data for species and genus-level identification.

Background: The introduction of primary HPV cervical cancer screening requires the implementation of an appropriate triage strategy that will be effective in detecting high-grade cervical disease without losing diagnostic specificity. Methods: From the 30.066 screening tests results, a total of 1086 with available high-risk human papillomavirus (HRHPV) with limited genotyping, cytology and p16/Ki67 dual-stain were selected. Two triage strategies for primary HPV screening were analyzed retrospectively based on the study group. Performance characteristics for p16/Ki67 and cytology triage in detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+) and grade 3 or worse (CIN3+) were calculated, detected in colposcopic biopsy. Results: In HPV16/18-positive cases, primary HPV with p16/Ki67 triage was significantly more specific than cytology (53.1%/16.8% for CIN2+; p<0.0001; 45.9%/17.0% for CIN3+; p<0.0001), with yielded sensitivity (95.7%/84.8% for CIN2+; p=0.0955; 100.0%/87.5% for CIN3+; p=0.0832). In other HRHPV-positive cases (N16/N18), p16/Ki67 triage was also significantly higher specific (51.3%/15.3% for CIN2+; p<0.0001; 44.5%/16.5% for CIN3+; p<0.0001), with sensitivity (92.3%/74.4% for CIN2+; p=0.0522; 90.9%/81.8% for CIN3+; p=0.5637). Diagnostic predictive values were significantly higher for p16/Ki67 triage with the highest PPV in HPV16/18-positive cases for CIN2+ (45.4%; 95% CI: 35.2-55.8; p<0.0001) and very high NPV in all HPV-positive cases regardless of detected genotype (96.3%-100.0%). The risk (1-NPV) for CIN3+ in HRHPV16/18-positive/p16/Ki67-negative women was 0.0%. Conclusions: Superior diagnostic performance compared to cytology for detecting cervical cancer precursors indicates that p16/Ki67 dual-immunostain may be a highly effective tool of triage in primary HPV screening with limited HPV 16/18 genotyping in the secondary cervical cancer prevention.

The southeastern margin of the Tibetan Plateau has experienced complex deformation since the Cenozoic, resulting in a high level of seismicity and seismic hazard. Knowledge about the seismic anisotropy provides important insight into the deformation mechanism and the regional seismotectonics beneath this tectonically active region. In this study, we conduct a fullwave multi-scale tomography to investigate the seismic anisotropy in the southeastern margin of the Tibetan Plateau. Broadband records from 470 teleseismic events at 111 permanent stations in the region are used to obtain 5,216 high-quality SKS splitting intensity measurements, which are then inverted in conjunction with 3D sensitivity kernels to obtain the anisotropic model for the region with a multi-scale resolution. Resolution tests show that our dataset recovers anisotropy anomalies reasonably well on the scale of 1º x 1º horizontally and ~100 km vertically. Our result suggests that in the southeastern margin of the Tibetan Plateau the deformations in the lithosphere and asthenosphere are decoupled. The anisotropy in the lithosphere varies both laterally and vertically as a result of the dynamic interactions of neighboring blocks as well as lithospheric reactivation. The anisotropy in the asthenosphere largely follows the direction of regional absolute plate motion, i.e. southeastward under the Songpan-Ganzi Terrane and the Yangtze Craton and nearly east-west south of 26ºN latitude. The SKS splitting observed at the surface can be interpreted as the vertical integration of the contributions from lithosphere and asthenosphere.

In the context of textile manufacturing’s weaving section, efficient maintenance operations play a pivotal role in upholding critical equipment’s peak performance and longevity. However, inconsistencies in data utilization during maintenance can lead to equipment failures, downtimes, and decreased efficiency. To address this, this study endeavors to scrutinize these data disparities, focusing on the weaving section’s essential machinery. The objective encompasses identifying failure patterns, gauging parameter impacts on system components, and proposing personalized maintenance strategies based on failure characteristics. The study employed the Weibull distribution plot to analyze data from 19 distinctive components, with shape (β) and scale (η) parameters elucidating failure trends, distinguishing early-life and wear-out failures. The Anderson-Darling (AD) statistic validated Weibull fitting. Visual aids and charts presented findings effectively. Analysis showcased distinct failure patterns across system components, where shape parameters exceeding 1 denoted wear-out failures, and scale parameters revealed equipment lifespans. The study emphasized the necessity of bespoke maintenance approaches in response to equipment failure traits. Tailoring strategies for early-life and wear-out failures is essential. The Weibull analysis aids in pinpointing crucial maintenance junctures, optimizing schedules, and enhancing equipment reliability. This study’s contribution lies in elevating equipment dependability, curbing downtimes, and augmenting operational efficiency in textile manufacturing processes. Recommendations encompass tailored maintenance strategies, prioritized preventive measures for wear-out-prone components, comprehensive craftsman training, and exploring predictive techniques leveraging sensor data and AI.

Purpose: The aim of this study was to construct a reference system for preclinical evidence and drug superiority characterization of the anti-inflammatory effects of icariin glycosides and their derivatives through meta-analysis combined with machine learning, and to excavate the biological mechanisms behind them. Methods: The data were obtained from databases of PubMed, Embase, Cochrane Library, and Web of Science. STATA software was used for meta-analysis of indicators, and subgroup analysis was conducted based on animal species, gender, type of disease, drug dosage, and course to obtain more particulars. Furthermore, model construction were performed using R software to explore influential features on drug efficacy. In addition, the pharmacological mechanisms of icariin and its derivatives in anti-inflammation were summarized based on a comprehensive understanding of relevant literature. Results: After searching and screeningThe results showed that icariin and its derivatives significantly inhibit inflammation indicators such as TNF-α and IL-1β. Besides, machine learning with TNF-α as the output variable showed that icariin and its derivatives had stronger anti-inflammatory effects when the type of disease was respiratory, urological, neurological, and digestive, and when the dose and duration of Icariin were greater than 27.52 mg/kg/day and 31.22 days, respectively. Conclusion: Icariin and its derivatives demonstrate strong anti-inflammatory effects, particularly for respiratory, urinary, neurological, and digestive disorders. When given at doses of 27.52 mg/kg/day or more, with treatment lasting 31.22 days or beyond, these compounds hold significant potential as drugs for inflammation inhibition across multiple dis

IFR forecasts and the conducted literature analysis prove that part of the research should be focused on adapting the companion robot to moving around in open space in external conditions. There is a visible interest in the use of robotic devices in the care and assistance of the elderly or disabled people. However, the external environment still contains many obstacles and barriers. According to the authors, the solution to some of the problems related to movement in outdoor conditions would be to communicate the companion robot with the road infrastructure, inter alia, via IoRT (Internet of Robotic Things). This is why the purpose of this article is to present the concept of communication of the companion robot with the road infrastructure.

In the last decade, recognizing and reducing uncertainties in hydrological forecasting has shown renewal interest. However, from a modeler’s perspective, a unified code of practice is always needed to handle the various facets of uncertainty in hydrological forecasting. Pappenberger and Beven, (2006) suggested nine codes of practice for handling uncertainties in hydrological modelling. In this paper, we have revisited those principles and added new insights to yield seven key principles for accounting and reducing uncertainties in catchment related hydrological forecasting tasks: (1) objectives define the need for uncertainty, (2) exploring the Catchment Puzzle, (3) selection of models is key, (4) choices of the method for quantifying uncertainties and calibration (5) finding the sources of uncertainties (6) advancements are a critical choice (7) prioritizing End User Needs for Reliable Forecasting Services. We derive these principles as a summary of understanding how modelers across the world have approached uncertainty handling from the analysis of recent literature on reducing uncertainties in hydrological forecasting. The triangulated interdependence and uncertainty contributions between the hydrological processes, epistemic uncertainties, and model development inevitably impact the forecast. Yet, the mapping of these principles provided in this study can assist the modelers in developing an improved framework for hydrological forecasting. Further, this work calls for discussions among the hydrological science community to establish these principles.

Sputum cytokines associated with raised FeNO after anti-IL5 biologic therapy in severe asthma.To the Editor,Biomarkers such as circulating absolute eosinophil count, % of eosinophils in sputum, and fraction of exhaled nitric oxide (FeNO) are predictors of response to anti-inflammatory therapy for asthma. Failure to normalize FeNO with high doses of corticosteroids are likely to be related to cytokines and chemokines such as IL-5, IL-4, IL-13, eotaxin and TARC derived from eosinophils and other Th2 cells, and alarmins such as TSLP and IL-33 from sources such as the airway epithelium(1). All Anti-IL5 biologics suppress eosinophils in sputum. However benralizumab (anti-IL5RMab) has greater effect in the severe prednisone-dependent patients than mepolizumab/reslizumab (anti-IL5 neutralizing Mab)(2,3). While raised eosinophil count is a predictor of clinical response to anti-IL5 biologics, raised FeNO is often not(4). However, they reduce FeNO to variable levels(4,5) suggesting that FeNO is partly regulated by cytokines derived from eosinophils in the airway(1). The cytokines in sputum associated with raised FeNO in prednisone-dependent severe asthmatics treated with effective anti-eosinophil drugs are not known.In this retrospective observational study, we measured cytokines in sputum using an automated ELISA reader (EllaTM, Protein Simple, R&D Systems, BioTechne, Minneapolis) at baseline and after 4 months of treatment with either benralizumab or mepolizumab/reslizumab and compared the levels of cytokines in those whose FeNO remained high after treatment. Raised FeNO was defined by FeNO >40ppb and an increase of at least 16ppb from pre-treatment value. The study was approved by Hamilton Integrated Research Ethics Board (#11227, 5037), and all patients gave written informed consent. The cytokines assayed were IL-5, IL-4 and IL-13 (Th2 inflammation) and IL-1β, IL-6, IL-10, IL-12p70, IL-15 IL-17A, IL-18, IL-33, IFNγ and TNFα (Th1/Th17 inflammation, Table e3). Details of baseline demographics, methods and statistics are shown in the online supplement.Paired measurements were made in 30 patients who received benralizumab, and 10 each who received mepolizumab/reslizumab. Overall, as previously reported(5), FeNO levels were not significantly reduced by anti-IL5 treatment (median FeNO pre-treatment 29 [5-156] vs FeNO post treatment 37 [6-280]; p=0.25; Figure e1). This change in FeNO did not correlate with a reduction of sputum eosinophils (r=-0.24; p=0.16).Among 15 patients, FeNO remained raised after treatment (Table 1). On average, IL-4 and IL-13 were the only cytokines significantly higher in the sputum of these patients compared to those in whom the FeNO values normalized (Figure 1, Figure e2). Within this group, there were patients with raised IL-4 (31%) and IL-13 (15%) and those with normal IL-4/IL-13. A small proportion of those with normal IL4/13 had raised levels of IL-18 or IL-1β (20%). Residual eosinophilic airway inflammation was significantly more present in patients with raised FeNO (30.8% vs 8.1%; P=0.04; Table e2). Patients with raised FeNO remained to have poor asthma control with an ACQ>1.5, however this did not significantly differ from those with a normalized FeNO (ACQ 1.7±0.9 vs 1.4±1.1; P=0.36; Table 1).This study, despite its limitation of retrospective design and small numbers, provide novel information on the cytokine profile in the airways of severe prednisone-dependent eosinophilic asthma patients whose FeNO remain high after anti-IL5 treatment. This is a common clinically encountered situation. Our observations suggest that IL-4/IL-13 are the cytokines most associated with this phenomenon. This may be due to the airway eosinophilia being uncontrolled or due to a non-eosinophilic source of these cytokines. However, there could be non-IL-4/IL-13 related increase in FeNO that may be due to inflammasome activation and through non-Th2 cytokine pathways that may raise the possibility of airway infections or autoimmune activation(6). This has important clinical implication. These patients may not show adequate response to switching to anti-IL4R Mab if their asthma remains uncontrolled. This needs to be evaluated prospectively.References:Couillard S, Shrimanker R, Chaudhuri R, et al. Fractional Exhaled Nitric Oxide Nonsuppression Identifies Corticosteroid-Resistant Type 2 Signaling in Severe Asthma. Am J Respir Crit Care Med 2021; 204: 731-734.Mukherjee M, Forero DF, Tran S, Boulay ME, et al. Suboptimal treatment response to anti-IL-5 monoclonal antibodies in severe eosinophilic asthmatics with airway autoimmune phenomena. Eur Respir J 2020 Oct 8;56(4):2000117. doi: 10.1183/13993003.00117-2020.Mukherjee M, Bhalla A, Venegas-Garrido C, et al. Benralizumab attenuates blood and airway eosinophilia in severe asthmatics with inadequate response to anti-IL-5 neutralizing antibodies [abstract]. Eur Respir J 2022; 60 (suppl 66): 3994; DOI: 10.1183/13993003.Hearn AP, Kavanagh J, d’Ancona G, et al. The relationship between Feno and effectiveness of mepolizumab and benralizumab in severe eosinophilic asthma. J Allergy Clin Immunol Pract 2021; 9: 2093-2096.e1.Nair P, Kjarsgaard M, Armstrong S, Efthimiadis A, O’Byrne PM, Hargreave FE. Nitric oxide in exhaled breath is poorly correlated to sputum eosinophils in patients with prednisone-dependent asthma. J Allergy Clin Immunol 2010; 126: 404-6.Donnelly LE, Barnes PJ. Expression and regulation of inducible nitric oxide synthase from human primary airway epithelial cells. Am J Respir Cell Mol Biol 2002; 26: 144-51.AuthorsPieter-Paul Hekking 1,2, Kayla Zhang1, Carmen Paz Venegas Garrido 1, Raquel Lopez-Rodriguez 1,3, Melanie Kjarsgaard1, Manali Mukherjee 1, Parameswaran Nair 11. Division of Respirology, Department of Medicine, St. Joseph’s Healthcare Hamilton, McMaster University, Hamilton, Ontario, Canada.2. Department of Respiratory Diseases, STZ Centre of Excellence for Asthma & COPD, Franciscus Gasthuis & Vlietland Hospital, Rotterdam, the Netherlands.3. Department of Allergy, Lucus Augusti Hospital, Lugo, SpainCorrespondenceDr Parameswaran NairFirestone Institute for Respiratory HealthSt Joseph’s Healthcare Hamilton50 Charlton Avenue EastHamilton, Ontario, L8N4A6, CanadaTel: 905-522-1155 x 35044Fax: 905-521-6183E-mail: parames@mcmaster.ca

Competing Interests:  MK, CK, IRS, MTS, and JCJ  are compensated by NRx Pharmaceuticals, Inc. Lavin Statistical Associates is paid of independent statistical analysis by NRx Pharmaceuticals, Inc.IntroductionClinician-administered rating scales are a universal endpoint required by regulators around the world for ascertainment of primary endpoint in psychiatric clinical trials. Signal detection in multi-site trials requires strong inter-rater reliability on these instruments; poor inter-rater reliability is associated with increased error variance, reduced study power2 and, ultimately, failed trials. Poor inter-rater reliability, or unreliability, in psychometric rating scales has many sources, including a lack of adherence to structured and semi-structured interviews, rater scoring differences, and inconsistent interview duration.3 Williams & Koback correctly state “The importance of reliability of assessments in a clinical trial cannot be overestimated. Without good interrater agreement the chances of detecting a difference in effect between drug and placebo are significantly reduced.”4 Commonly used methods for establishing and maintaining strong inter-rater reliability include site-rater training, external evaluation and monitoring of site-raters, and centralized rating.Monitoring of endpoint ascertainment in clinical trials is routinely outsourced to Clinical Research Organizations (CROs) and to central laboratories. While psychometric assessments are often monitored by specialized CROs, this may not always be the best choice for a clinical trial. The unique rigor required to ensure valid and reliable clinical scale ratings means CROs must employ enough expert psychometricians who are familiar both with the rating instruments and the unique aspects of the disease and drug being studied. CRO raters must review site assessments within a day of completion to ensure rater quality and accuracy and provide remediation in a timely manner, if needed. Since personnel turnover at CROs may be as high as 20% per year5, outsourcing the day-to-day management of highly nuanced psychometric ratings becomes impractical when there is turnover and inter-rater variation among the “master raters.”The Sponsor Rating Monitoring System (SRMS) was developed as a pre-defined, protocol-specific, data-driven method to optimize psychometric training, data validity and reliability in the context of a clinical trial of a novel antidepressant targeting bipolar depression with suicidality. In this system, the Sponsor employs expert raters with extensive experience in conducting, analyzing, and training others in the rating scales used to ascertain primary and secondary endpoints. In SRMS, these master raters help the clinical operations team select suitable clinical trial sites, document site rater qualifications, oversee rater training and qualification, and confirm that all data management conforms to the Study Protocol and GDP & GCP guidelines. Most importantly, the Sponsor “master raters” review psychometric assessments within 24 to 48 hours and provide corrective feedback, as needed. This approach further allows for referral of an aberrant rating to an adjudicating rater in real time, prior to data unblinding. The centralized SRMS model does not transfer regulatory obligations to an outside CRO or engage multiple data quality systems, which minimizes oversight and subsequent audit responsibilities.We examined the Inter-rater Reliability (IRR), i.e., the concordance between site raters and Sponsor “master raters” on MADRS scores on patients participating in the Phase 2b/3 clinical trial “NRX101 for Suicidal Treatment Resistant Bipolar Depression” (ClinicalTrials.gov Identifier: NCT03395392) to assess the potential efficacy of the SRMS.

Michael T. Sapko1, Jonathan C. Javitt1,21NRx Pharmaceuticals2Johns Hopkins UniversityKeywords: D-cycloserine, lurasidone, NMDA receptor, chronic pain, chronic pain-induced depressionCompeting Interests: MTS and JCJ are consultants to NRx Pharmaceuticals, Inc. JCJ owns equity in NRx Pharmaceuticals, Inc.Funding: Preparation of this manuscript was funded by NRx Pharmaceuticals, Inc.

Light olefins, especially ethylene and propylene, are essential intermediates in the petrochemical industry, which are used to produce polyethylene, polypropylene, and other essential products. Olefins can be produced using different processes and raw materials. The method of converting methanol to olefins is one of the processes that has received much attention in recent years. The purpose of this research is to review the mathematical modeling of the reaction and regenerator sections, hydrodynamic simulation, heat transfer, and reaction in the fluidized bed reactor using computational fluid dynamics (CFD), large eddy simulation (LES), for methanol to olefin process (MTO). It is also an examination of effective parameters such as reactor length, reactor flow rate, product distribution, optimal product distribution scenario, and flow rates in a fluidized bed reactor.