Food allergens: threshold levels and methodologies for risk management

Food allergies and allergen management are important problems of the public health and food industry. The idea of determining allergen concentrations in food ingredients and food products that are capable of causing severe allergic reactions is of great interest for regulatory bodies as well as consumer associations and the industry all over the world. In this connection, scientists proposed different approaches to determining the basis for assessment of severity of risks of food allergens for health of patients suffering from food allergy similar to methods of risk assessment for other hazards associated with food products (for example, chemical, microbiological). To assess risk of allergens, three different approaches were proposed: i) traditional risk assessment using the no observed adverse effect level (NOAEL)) and uncertainty factors; (ii) approach based on the benchmark dose (BMD)) and margin of exposure (MoE)); and (iii) probability models. These approaches can be used in risk management in food production and in the development of warning marking about the presence of allergens. The reliability of risk assessment will depend on a type, quality and quantity of data used for determining both population threshold levels (or threshold distributions) and an impact of an allergenic product/ingredient on a particular individual.

A Model for Evaluating HR Analytics Critical Success Factors in Industry 5.0

This study offers a methodology to evaluate HR analytics application critical factors that can aid HR managers in making proper strategic decisions. To help advance the study on the implementation of HR analytics, this research is based on the grey DEMATEL approach to envisage the formation of complex interrelation between the CSFs and find the effect level of these factors. Drawing conclusion from the above, the present study addresses certain key issues. Firstly, it aims to examine the challenges in implementing HR analytics techniques in Indian industry. Secondly it examines the causal relationship to analyses the tasks and their effect in detail. After analysing the available literature and creating the research problem based on the gaps observed, the chapter accentuates the necessity for studying and analysing the HR analytics challenges in Indian industries.

LOGISTICS FLEXIBILITY, RELATIONSHIP FLEXIBILITY, AND LOGISTICS SERVICE QUALITY: THE MODERATING ROLE OF ENVIRONMENTAL UNCERTAINTY

This study examined the moderating role of environmental uncertainty on the connection between logistics flexibility, relationship flexibility, and logistics service quality. This study covered large and medium- sized companies operating in the Gaziantep Organized Industrial Zone. Company lists were created based on records in the Gaziantep Chamber of Industry. A questionnaire was sent to a total of 1627 companies by e-mail and company managers were asked to fill in the online questionnaire. The managers of 356 companies fully completed the questionnaire. SPSS Process Macro V3.4 was used to calculate the moderator effects of environmental uncertainty. The macro also reported the effect level of independent variables on dependent variables. According to the results of the analysis, logistics flexibility and relationship flexibility affected logistics service quality, positively and significantly. Besides, environmental uncertainty had a moderator role in the relationship between logistics flexibility and logistics service quality. There were some limitations. A questionnaire was used as a data collection tool in the study. Thus, personal perceptions of the participants could be apparent in the information given about the company since questionnaire data was formed in accordance with statements given by the respondents. In future researches, it is recommended that measurement tools that can determine environmental uncertainty more objectively could be used on a sectoral basis to secure clearer results. It is recommended that companies take into account environmental uncertainty when determining a strategy(s) to enhance the quality of logistics services.

Using Metabolite Data to Develop Patient Centric Specification for Amide Impurity in Vildagliptin Tablets

Many specified impurities in vildagliptin's finished product have been disclosed in the literature that are above their qualification threshold. We used the impurity B (amide impurity) as a case example to explore whether existing literature can be leveraged to determine the safe level of impurity and thereby develop a patient-centric specification (PCS) for impurities. No-observed-adverse-effect level (NOAEL) was derived from rate metabolism information and converted to human equivalent dose (HED). The HED was estimated as 6.5 mg/day. The high qualification levels are supported by repeat dose toxicity studies performed in rats, mice and dogs. Maximum theoretical amount (MTA) was correlated with the maximum observed amount (MOA) to verify whether the exposure was due to impurity and/or metabolite. MOA/MTA was found ≥1 suggesting that metabolism contributed to the amount excreted in feces and therefore could be used to further justify a higher specification limit than the usual one of ≤0.5%. Quite often the drug metabolism and degradation pathways overlap, resulting in the formation of identical constituents. Therefore, metabolism data can be leveraged for deriving safe levels of degradation impurities and develop PCS for impurities.

Case study: risk associated to wearing silver or graphene nanoparticle-coated facemasks for protection against COVID-19

The world is living a pandemic situation derived from the worldwide spreading of SARS-CoV-2 virus causing COVID-19. Facemasks have proven to be one of the most effective prophylactic measures to avoid the infection that has made that wearing of facemasks has become mandatory in most of the developed countries. Silver and graphene nanoparticles have proven to have antimicrobial properties and are used as coating of these facemasks to increase the effectivity of the textile fibres. In the case of silver nanoparticles, we have estimated that in a real scenario the systemic (internal) exposure derived from wearing these silver nanoparticle facemasks would be between 7.0 × 10–5 and 2.8 × 10–4 mg/kg bw/day. In addition, we estimated conservative systemic no effect levels between 0.075 and 0.01 mg/kg bw/day. Therefore, we estimate that the chronic exposure to silver nanoparticles derived form facemasks wearing is safe. In the case of graphene, we detected important gaps in the database, especially regarding toxicokinetics, which prevents the derivation of a systemic no effect level. Nevertheless, the qualitative approach suggests that the risk of dermal repeated exposure to graphene is very low, or even negligible. We estimated that for both nanomaterials, the risk of skin sensitisation and genotoxicity is also negligible.

Safety Evaluation for Restorin® NMN, a NAD+ Precursor

NAD+ is an abundant molecule in the body and vital to all living cells. NAD+ levels decline with age, and this decline correlates with age-related diseases. Therefore, sustaining NAD+ levels offers potential benefits to healthspan and longevity. Here we conducted toxicity studies to evaluate the safety of Restorin® NMN, a high purity form of the direct NAD+ precursor, β-nicotinamide mononucleotide (NMN). Based on the preliminary toxicity study and a 14-days repeated dose toxicity study at a higher dose level exposure, Restorin® NMN was administered orally to Sprague-Dawley rats for 91 days followed by a 14-days recovery period. The oral doses of 500, 1,000, and 2000 mg/kg/day were compared. There were no test item-related findings that could be considered adverse events in animals dosed at 500 mg/kg/day. The findings in the Restorin® NMN high dose group (2000 mg/kg/day) were similar to the reference item (Nicotinamide Riboside Chloride) dosed at 1740 mg/kg/day: reduced body weight, reductions in body weight gains, and diminished food consumption. In conclusion, the No-Observed-Adverse-Effect-Level (NOAEL) for Restorin® NMN is 1,000 mg/kg/day in female rats and 500 mg/kg/day in male rats, and the Low-Observed-Adverse-Effect-Level (LOAEL) for Resotrin® NMN is 2000 mg/kg/day.

IND-Enabling Studies of a Switchable Chimeric Antigen Receptor-T Cell (CLBR001+SWI019) to Support First in Human Clinical Study

Despite the tremendous clinical benefits, adverse events associated with CAR-T cell therapy remain a challenge. Most frequent adverse events are cytokine release and immune effector cell-associated neurotoxicity syndromes due to the inability to modulate the level of activity of current CAR-T cell products after administration to patients. Additional challenges include on target, off tumor toxicities and antigen loss mediated relapse of disease. To address these challenges, we have developed a "switchable" CAR-T (sCAR-T) where the activity of the sCAR-T cells is controlled by an antibody-based switch. The switch targets the tumor antigen, and the sCAR recognizes a unique peptide engrafted on the switch. The switch creates a bridge between the sCAR-T cell and the tumor cell, activating the sCAR-T cells and inducing tumor cell killing. Combined, the switch and sCAR-T cells afford complete elimination of tumors in xenograft and syngeneic models, but individually, each is designed to be inactive. A short half-life of the switch allows for a rapid modulation of sCART-cell activity through the switch dosing. Moreover, by swapping different switches, sCAR-T cells can be modularly redirected against other tumor targets. Further, we have shown the cyclical on/off stimulation of the sCAR-T cells affords improved memory and persistence of the sCAR-T cells. Here, we report IND-enabling studies for an optimized CD19-targeted switch (SWI019) and sCAR-T cell (CLBR001) to support a first in human (FIH) clinical study of the combination. The preclinical development of a platform which includes a sCAR-T cell that lacks any endogenous antigen target, in combination with an antibody-based switch molecule that lacks intrinsic activity in the absence of the sCAR-T cell, necessitated development of novel approaches. Fidelity of such a system is essential to control, thus, to confirm CLBR001 cells did not activate in the presence of normal tissues, in vitro activity studies were performed by co-culturing CLBR001 cells, in the presence or absence of SWI019, and a panel of 14 primary cells. This panel represented a survey of vital tissues throughout the body. CLBR001 did not demonstrate activity in any of the 14 cell types tested, supporting a high fidelity of CLBR001 recognition for SWI019. Because SWI019 lacks activity in the absence of CLBR001 cells, traditional toxicology studies to identify the no adverse effect level (NOAEL) in support of the first in human starting dose were not applicable. In such cases, a minimal anticipated biological effect level (MABEL) is commonly used to support starting human dose based on the predicted Cmax; however, the femtomolar-level in vitro activity of SWI019 in combination with CLBR001 resulted in starting doses that were modeled to be far outside of the range of potential clinical activity. Therefore, an in vivo-based approach to determine MABEL was developed. CLBR001 cells were administered in NSG mice bearing CD19+ Nalm-6 cell tumors and a single dose titration of SWI019 was performed. Comparison of the SWI019 efficacious dose (ED 50) values for anti-tumor activity, peripheral cytokines, and CLBR001 cells in peripheral blood demonstrated that reduction in Nalm-6 tumor burden was the most sensitive marker of activity. Extravasation of CLBR001 cells from peripheral blood and all three cytokines (IFN-γ, IL-2, and TNF-α) exhibited weaker ED 50 values. Therefore, antitumor activity (Nalm-6 tumor burden reduction) was chosen as the parameter for which to determine in vivo MABEL. Allometric scaling, using mouse and NHP SWI019 PK data, was used to model a SWI019 recommended dose in humans corresponding to the ED 20 of the in vivo MABEL study. Compared to the dose modelled using the in vitro MABEL approach, the in vivo MABEL approach afforded a first in human starting point which was ~13000-fold higher. We expect this approach provides an excellent starting point for the first in human study which balances safety and the potential for patient benefit. In summary, the results presented in this abstract led to the initiation of clinical trial NCT04450069, the combination of CLBR001+SWI019 for the treatment of relapse/ refractory B cell malignancies. Disclosures Stone: Abbvie: Current Employment, Current equity holder in publicly-traded company. Trikha: Abbvie: Current Employment, Current equity holder in publicly-traded company. Young: Abbvie: Research Funding; Qihan Bio: Membership on an entity's Board of Directors or advisory committees; Shoreline Bio: Membership on an entity's Board of Directors or advisory committees.

Evaluation and empirical research on the operation effect of the risk precontrol management system of safety in coal mines based on OSWM-TOPSIS

BACKGROUND: Most studies have focused on the establishment and application of the risk precontrol management system for safety in coal mines and have seldom considered the evaluation of the system operation effect. OBJECTIVE: This study aimed to evaluate the operation effect of risk precontrol management system of safety in coal mines and propose policy suggestions to improve the risk precontrol management level of safety. METHODS: This study applied the Objective and Subjective Weighting Method (OSWM) combined with the Technique for Order Preference by Similarity to an Ideal Solution (TOPSIS) to conduct evaluation and empirical research on the operation effect of the risk precontrol management system of safety in coal mines. RESULTS: First, the evaluation index system is mainly composed of six first-level indicators and 30 subordinate secondary indicators. Second, the OSWM combined with TOPSIS is an effective method for operation effect evaluation, which yields accurate and undistorted evaluation results. Third, the calculation reference value of the operation effect in the Gengcun coal mine is 57.34, and its corresponding effect level is level III, which is basically effective. Moreover, the calculation reference values of production equipment management (P4) and inspection, audit and review (P6) are the lowest, while the calculation reference values of risk precontrol management (P1) and auxiliary management (P5) reach the critical value corresponding to effect level I, which indicates a good operation effect. CONCLUSIONS: Corresponding policy suggestions to improve the risk precontrol management level in the Gengcun coal mine are proposed based on the above evaluation results.