ANALYSIS OF THERMAL EFFECTS WITH MULTI-FOCI STRUCTURING

The possibility of a thermal imaging technique for studying the setting of composite materials in the light of the paradigm of multifocal structure formation is analyzed. Since thermal violated observations are characterized by a high thermal sensitivity to temperature gradients up to hundredths of degrees, they make it possible to distinguish the temperature differences arising in the adjacent sections of the hardening binding. A technique for obtaining thermal images (thermograms) of a hardening composite binder is implemented. A series of thermograms of setting processes was obtained, for two of them a quantitative study was carried out, including the temperature gauge and the construction of several types of graphic mappings of the obtained patterns ‒ the normalized frequency of the distribution of the area of the binder for those temperatures and two types of densitograms ‒ radial and circular, allowing to visualize the structure of thermal foci arising in a binder. The hardening of binding materials is considered as a multistage exothermic process, in which hydration processes is accompanied by heating. The speed of heterogeneous processes associated with hydration depends, in turn, on the characteristics of the forming structure of binding materials. The observed thermal processes are considered as an indirect response, "shadow" of structure formation processes. The information consisting in this indirect response, however, is enough to make a number of conclusions on the nature of the emerging structure. The study revealed a high probability of the formation of foci near the macroscopic boundaries of the section (walls and bottom of the form), inconsistency of the structural processes, the occurrence of diverse foci of structure formation corresponding to temperature foci. The interpretation of the data obtained is the conclusion about formation of the regions of high plastic deformations near the boundaries of the contact of the foci. This regions are considered as a cluster of microscopic boundaries of the section, cracks and pores, which give rise to the structure of the destruction of the hardened material. The emergence of such areas is associated with nonynchronouspassage of structuring in different parts of the binder.

Population pharmacokinetic-pharmacodynamic model of oxfendazole in healthy adults in a multiple ascending dose and food effect study and target attainment analysis

Oxfendazole is a potent veterinary antiparasitic drug undergoing development for human use to treat multiple parasitic infections. Results from two recently completed Phase I clinical trials conducted in healthy adults showed that the pharmacokinetics of oxfendazole is nonlinear, affected by food, and, after the administration of repeated doses, appeared to mildly affect hemoglobin concentrations. To facilitate oxfendazole dose optimization for its use in patient populations, the relationship among oxfendazole dose, pharmacokinetics and hemoglobin concentration was quantitatively characterized using population pharmacokinetic-pharmacodynamic modeling. In fasting subjects, oxfendazole pharmacokinetics was well described by a one-compartment model with first-order absorption and elimination. The change in oxfendazole pharmacokinetics when administered following a fatty meal was captured by an absorption model with one transit compartment and increased bioavailability. The effect of oxfendazole exposure on hemoglobin concentration in healthy adults was characterized by a lifespan indirect response model in which oxfendazole has positive but minor inhibitory effect on red blood cell synthesis. Further simulation indicated that oxfendazole has a low risk of posing a safety concern regarding hemoglobin concentration, even at a high oxfendazole dose of 60 mg/kg once daily. The final model was further used to perform comprehensive target attainment simulations for whipworm infection and filariasis at various dose regimens and target attainment criteria. The results of our modeling work, when adopted appropriately, have the potential to greatly facilitate oxfendazole dose regimen optimization in patient populations with different types of parasitic infections.

Ustekinumab Dosing Individualization in Crohn’s Disease Guided by a Population Pharmacokinetic–Pharmacodynamic Model

Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.

Indirect response of the temperature, humidity, and rainfall on the spread of the COVID-19 over the Indian monsoon region

This paper examines the role of the meteorological variable on the spread of the ongoing pandemic coronavirus disease 2019 (COVID-19) across India. COVID-19 has created an unprecedented situation for public health and brought the world to a standstill. The COVID-19 has caused more than 1,523,242 deaths out of 66,183,029 confirmed cases and around the world till the first week of December 2020. We have examined the surface temperature, relative humidity, and rainfall over five cities namely Delhi, Mumbai, Kolkata, Bengaluru, and Chennai severely affected by COVID-19. It is found that the prevailing southwest (SW) monsoon during the pandemic has acted as a natural sanitizer in limiting the spread of the virus. The day-to-day variation of the meteorological parameters and COVID-19 cases clearly demonstrate both surface temperature and relative humidity play a vital role in the indirect transport of the virus. Our analysis reveals that the majority of the COVID-19 cases fall within the surface temperature ranging from 24oC to 30oC and relative humidity ranging from 50–80%. At a given temperature, COVID-19 cases show a large dependency on the relative humidity which attributes those coastal environments were more prone to infections. Wavelet transforms coherence analysis of the daily COVID-19 cases with temperature and relative humidity reveal a significant coherence within 8 days.

P307 Modelling of the relationship between ustekinumab exposure, faecal calprotectin and endoscopic outcomes in patients with Crohn’s disease

Background In the UNITI endoscopy sub-study, only 17.4% of patients with Crohn’s disease (CD) on ustekinumab achieved endoscopic response and 10.9% achieved endoscopic remission at week (w)44. We aimed to investigate if improved endoscopic outcomes can be achieved through dose optimisation based on a population pharmacokinetic-pharmacodynamic (popPK-PD) modelling and simulation analysis. Methods Real-world data were obtained from 83 patients with moderate-to-severe CD (94% multi-refractory) enrolled in a prospective cohort study receiving ustekinumab 6 mg/kg induction and every eight-week (q8w) 90 mg maintenance therapy. Ustekinumab serum concentrations were measured at mid-dose (w4) and trough (w8, w16, w24). Faecal calprotectin (fCal) was measured at baseline and at w4, w8, w16, w24. Endoscopic response (≥50% decrease in simple endoscopic score for CD [SES-CD]) and endoscopic remission (SES-CD ≤2) were assessed at w24. Modelling and simulation were performed using NONMEM 7.4. Results Three sequential models were developed: a two-compartment popPK model linking ustekinumab dose to ustekinumab exposure, an indirect response popPK-PD model describing the effect of ustekinumab exposure on fCal, and a logistic regression popPD model linking fCal at w8 to endoscopic outcomes at w24 (Figure 1). Ustekinumab clearance increased with decreasing serum albumin and increasing bodyweight. The terminal half-life of ustekinumab in a median patient (bodyweight 65 kg, serum albumin 42.7 g/L) was 20.4 days. fCal decreased with increasing ustekinumab exposure. The probability of endoscopic response at w24 increased from 10.0% to 17.9% with fCal at w8 decreasing from 1,800 μg/g to 694 μg/g (Figure 2a) The probability of endoscopic remission at w24 increased from 2.1% to 10.0% with fCal at w8 decreasing from 1,800 μg/g to 214 μg/g (Figure 2b).The results from the simulation-based comparison of q8w and q4w maintenance dosing are shown in Table 1. Dose doubling (180 mg q8w), as opposed to interval halving (90 mg q4w), was predicted to result in a ustekinumab trough concentration of 2.4 μg/mL instead of 4.8 μg/mL. Conclusion The developed model can guide clinical trial design and support model-informed dose optimisation to improve endoscopic outcome rates. Although our analyses showed that q4w dosing resulted in higher ustekinumab and lower fCal concentrations, the proportion of patients achieving endoscopic remission was limited.

Pharmacokinetic-Pharmacodynamic Modelling of Systemic IL13 Blockade by Monoclonal Antibody Therapy: A Free Assay Disguised as Total

A sequential pharmacokinetic (PK) and pharmacodynamic (PD) model was built with Nonlinear Mixed Effects Modelling based on data from a first-in-human trial of a novel biologic, MEDI7836. MEDI7836 is a human immunoglobulin G1 lambda (IgG1λ-YTE) monoclonal antibody, with an Fc modification to reduce metabolic clearance. MEDI7836 specifically binds to, and functionally neutralizes interleukin-13. Thirty-two healthy male adults were enrolled into a dose-escalation clinical trial. Four active doses were tested (30, 105, 300, and 600 mg) with 6 volunteers enrolled per cohort. Eight volunteers received placebo as control. Following single subcutaneous administration (SC), individual time courses of serum MEDI7836 concentrations, and the resulting serum IL13 modulation in vivo, were quantified. A binding pharmacokinetic-pharmacodynamic (PK-PD) indirect response model was built to characterize the exposure-driven modulation of the target over time by MEDI7836. While the validated bioanalytical assay specification quantified the level of free target (i.e., a free IL13 assay), emerging clinical data suggested dose-dependent increase in systemic IL13 concentration over time, indicative of a total IL13 assay. The target time course was modelled as a linear combination of free target and a percentage of the drug-target complex to fit the clinical data. This novel PK-PD modelling approach integrates independent knowledge about the assay characteristics to successfully elucidate apparently complex observations.

Direct and Indirect Compliment Responses: A Descriptive Qualitative Study among Indonesians and Americans

Indonesians and Americans have the strategies to respond the compliment which came from different culture. The aims of this research were addressing types of strategies and disclosing the direct and indirect response used by the Indonesians and Americans to respond the compliments. The research data consist of English and Indonesian. The data was analyzed by using qualitative method. The Discourse Completion Test (DCT) questionnaire was used to know the differences between compliment response given to Indonesians and Americans. The result of the research showed that the (1) responded category of Holmes (1986) classification of compliment responses strategies (CRs) are using three strategies (accept, reject and evade) among Indonesians and Americans. Indonesians tended to accept, reject and evade compliment by giving some reasons. While Americans tended using three categories by saying, "thank you" due to express of openness and receiving appreciation from the interlocutor. (2) The existence of culture plays an important role in responding compliment towards Indonesians and Americans. The Americans respond to compliments direct response and simple answers to compliments. Meanwhile, Indonesians prefer to respond compliment with indirect responses because they were leaning on the principle known as saving face politeness.

Modeling and Simulation to Support Phase Ib/IIa Dose Selection for WBP216, A Long Half-Life Fully Human Monoclonal Antibody Against Interleukin-6

WBP216 is an innovative IL-6 antibody, presenting high affinity to IL-6 and a long half-life (40–60 days). To optimize the dosage regimen for future clinical trials, pharmacokinetics (PK) and pharmacodynamics (PD) of WBP216 would be firstly characterized in Chinese rheumatoid arthritis (RA) patients. PK, CRP and DAS28 data of WBP216 were collected from 26 RA patients in a single ascending dose study. Non-linear mixed effects modeling was used for a population PK/PD analysis. A two-compartment model with a sequential zero-first order absorption and a first order elimination best described PK behavior of WBP216. Apparent systemic clearance was 0.015 L/h, central volume was 8.04 L. CRP as the fast-decreasing endpoint and DAS28 as the slow-reacting endpoint were both fitted well through an indirect response model. The baseline of ALT and free IL-6 were found associated with PK/PD parameters during covariates exploration. Simulation results confirmed that a loading dose regimen either of administration at weeks 0, 2, and 6 or doubling the maintenance dose level, followed by maintenance dosing of 75–150 mg every 8 weeks, was expected to provide a best risk/benefit ratio in future clinical studies. We hope this first PK/PD study of WBP216 in Chinese RA patients will help in the clinical development of WBP216 in future and provide a reference to the dosage optimization of similar antibodies with long half-life.Clinical Trial Registration:CTR20170306

Predicting the evolution of sexual dimorphism in gene expression

Sexual dimorphism in gene expression is likely to be the underlying source of dimorphism in a variety of traits. Many analyses implicitly make the assumption that dimorphism only evolves when selection favors different phenotypes in the two sexes, although theory makes clear that it can also evolve as an indirect response to other kinds of selection. Furthermore, previous analyses consider the evolution of a single transcript or trait at a time, ignoring the genetic covariance with other transcripts and traits. We first show which aspects of the genetic-variance covariance matrix, G, affect dimorphism when these assumptions about selection are relaxed. We then reanalyze gene expression data from Drosophila melanogaster with these predictions in mind. Dimorphism of gene expression for individual transcripts shows the signature of both direct selection for dimorphism and indirect responses to selection. To account for the effect of measurement error on evolutionary predictions, we estimated a G matrix for eight linear combinations of expression traits. Sex-specific genetic variances in female- and male-biased transcription, as well as one relatively unbiased combination, were quite unequal, ensuring that most forms of selection on these traits will have large effects on dimorphism. Predictions of response to selection based on the whole G matrix showed that sexually concordant and antagonistic selection are equally capable of changing sexual dimorphism. In addition, the indirect responses of dimorphism due to cross-trait covariances were quite substantial. The assumption that sexual dimorphism in transcription is an adaptation could be incorrect in many specific cases.

The Influence of Coronavirus Disease-2019 (COVID-19) On Parkinson’s Disease: An Updated Systematic Review

Background COVID-19 has affected global communities with multiple neurological complications in addition to other critical medical issues. COVID-19 binds to the host’s angiotensin-converting enzyme 2 (ACE2) receptors, which are expressed in the neurons and glial cells, acting as an entry port to the central nervous system (CNS). ACE2 receptors are abundantly expressed on dopamine neurons, which may worsen the prognosis of motor symptoms in Parkinson’s disease (PD). SARS-CoV-2 may lead to an indirect response via immune-mediated cytokine storms and propagate through the CNS leading to damage. In this systematic review, we aim to provide thorough analyses of associations between COVID-19 and neurological outcomes for patients with PD. Methods Using PRISMA statement 2020, a systematic review was conducted to isolate confirmed COVID-19 patients and analyze the PD-associated neurological outcomes using the following databases: PubMed, Science Direct, Google Scholar, and Cochrane databases. The following keywords were used “COVID19, SARS-CoV-2, Parkinson’s disease, Pandemic, Mortality.” A modified Delphi process was employed. Results Of the 355 studies located during the initial round of screening, 16 were included in the final synthesis. Of PD patients who tested positive for SARS-CoV-2, worsening motor symptoms and other viral-associated symptoms were reported. These symptoms included bradykinesia, tremors, gait disturbances, delirium and dementia, and severe spasms of arms and legs. Encephalopathy was presented in 2 of the included studies. Increased mortality rates were identified for hospitalized patients due to COVID-19 and PD as compared to other patient groups. Conclusion Patients with PD may experience substantial worsening of symptoms due to COVID 19. Given the novelty of neurological-viral associations, clinical studies in the future ought to explore the disease severity and neurological outcomes in COVID-19 positive patients with PD as compared to non-PD patients, in addition to understanding the role of ACE2 in increased vulnerability to contracting the infection and as a treatment modality.