During the last decade, a plethora of novel therapies containing live microorganisms as active substance(s) has emerged with the aim to treat, prevent, or cure diseases in human beings. Both the Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines and Health Care (EDQM) codified these biotherapies as Live Biotherapeutic Products (LBPs). While these innovative products offer healthcare opportunities, they also represent a challenge for developers who need to set the most suitable designs for non-clinical and clinical studies in order to demonstrate a positive benefit/risk ratio through relevant quality, safety, and efficacy data that are expected by the drug competent authorities. This article describes how YSOPIA Bioscience, supported by the Pharmabiotic Research Institute (PRI), addressed the regulatory challenges during the early development phase of their single-strain LBP, Xla1, in order to obtain the necessary authorizations to bring this drug to the clinical stage. Effects of the microbiome on human health were described for the first time at the beginning of the 1900's by Elie Metchnikoff , 3. FromFirstly defined by the Food and Drug Administration (FDA), LBPs are biological medicinal products containing live microorganism(s) as active substance(s) , 7 (AS).Christensenella minuta DSM 33407 with its Drug Product (DP), Xla1, as a novel biotherapy to treat obesity and associated metabolic disorders.YSOPIA Bioscience is a French pharmaceutical biotechnology company developing microbiome-based therapies focused on keystone bacteria. YSOPIA's first drug development program aims to exploit the potential of As drug development is aiming at global markets, and in absence of international harmonization of the regulatory expectations for LBPs, YSOPIA, supported by the PRI, engaged in discussions with the EMA and the FDA to adapt its development strategy to their evaluation and comments. YSOPIA submitted a pre-Investigational New Drug (IND) package to the FDA (in 2019) and requested a scientific advice to the EMA (in 2020) based on two briefing packages containing the same level of information. Knowing this, the EMA requested the minutes of the pre-IND meeting with the FDA. The company's strategy to provide evidence of quality, safety and efficacy of its LBP candidate has therefore been fostered by feedbacks from both the EMA and the FDA, shedding further light on an area where the regulatory agencies are in need of relevant data and scientific rationale.In the present article, the authors aimed at highlighting key regulatory concepts specific to LBPs that were raised by both competent authorities to support strategic decisions that must be made when designing comprehensive development plans for LBPs. Since the two competent authorities offer distinct procedures  nuances have to be expected and will be highlighted. Moreover, for the sake of clarity, the article will be presented based on the Common Technical Document structure  relevantLBP development begins with bacterial strain isolation, banking, and characterization. This step often involves several developmental steps of manipulation and culturing before the initial cell bank, the Research Cell Bank (RCB), can be finalized. Both in the EU and in the United States (U.S.), quality documentation must include the description of the strain's origin  and strain's culture/passage history before finalization of the bank , 7. FurtIn the case of LBPs, the management of the cell banking system is key as it contains the AS of the product itself and, it may therefore directly influence the quality of the final product, as well as its safety and efficacy , 11. AftDuring our interactions with the EMA, their representatives pointed out that the rationale of the selection of the desired strain and its purity should also be confirmed with relevant data. Indeed, we noted that it was highly important that LBP developers provide a rationale for the isolation and selection of the strain to be banked. This means that integration of quality aspects as well as potential safety and efficacy features of the AS must be considered early on in the development plan.Characterization of the microbial cells used to establish cell banks is an essential part of LBP quality documentation as it describes the identity, potency, quality, and purity of the AS. Both the FDA and the European Directorate on Quality of Medicines and Health Care (EDQM) have published their expectations regarding the characterization of the microorganism used as AS in LBPs , 7. For Developers must provide identification of the microorganism at both species and strain levels and the FDA especially recommends using at least two complementary methods for this identification . FurtherMicroorganism characterization must include an assessment of antibiotic resistance through genotypic and phenotypic assessments . Developers should determine minimum inhibitory or minimum bactericidal concentrations to a selected panel of antibiotics identified beforehand based on a justified scientific rationale considering the nature of the strain  and the targeted population –15. ThenTo rule out the risk of infection, it is also necessary to evaluate the translocation potential of the strain. With respect to the relationship between translocation potential and pathogenicity two aspects should be addressed: (1) the ability of the strain to cross the mucosal barrier, and, (2) the potential to induce a pathogenic reaction upon passage to the systemic circulation  . TherefoC. minuta DSM 33407) in line with the aforementioned guidelines   .The large-scale production of microorganisms which are intended to be kept alive in the final product raises additional challenges related to the reduction of risk of accidental cross-contamination. Microbiological examination and strain identification are therefore a critical part of the control strategy in order to ensure the quality and safety of LBPs. Microbiological quality examination includes aerobic microbial contamination count (AMCC), combined yeasts/molds contamination count (YMCC) and tests for specified micro-organisms such as 16S rDNA genotyping. Both the European and American pharmacopeia have described limits and methods specific to LBPs , 18, 19,The novelty and complexity of the biological analytical techniques involved in the characterization and manufacturing control strategy of LBPs also represent a challenging aspect of quality documentation for developers.Additional issues for LBP characterization, manufacturing process, and their compliance with global drug regulatory requirements are related to the analytical methods employed for these products. As for any other drug, regulatory agencies require the accurate description of analytical methods used during the drug manufacturing process, especially those deployed for the drug characterization and establishment of specifications, as they will consequently be applied to in-process controls and release tests. Furthermore, the EMA reminded us that suitability for use and validation of these analytical methods needs to be demonstrated and supported by data in accordance with international and regional guidance , 24.official passport” and will be the basis of genotypic controls for identity all along the drug quality control process. While plate count and cell count methods are generally exploited for purity and potency determination, several challenges reside in the robust execution and establishment of these methods including the execution of such methods under GMP conditions and in routine production. Furthermore, establishing a potency assay for a LBP may be challenging since the exact MoA is not always completely deciphered, rendering difficult the identification and validation of suitable tests for potency control. Finally, in the case of anaerobic strains such as C. minuta, an additional challenge resides in the execution and establishment of such assays under anaerobic conditions.Analytical methods used for LBPs principally include sequencing, plate count and cell count. For LBPs, the strains' genotypes often guide lead candidate selection and, when a specific strain is selected as a drug candidate, its genome acts as its “The final major industrial challenge of live ASs resides in ensuring batch-to-batch consistency of the Drug Substance (DS) and DP. Indeed, variations in the quantity of live microorganisms between batches is greater than what would be expected for other types of drugs. This is addressed by broadening product specifications (for both DS and DP) in terms of viable cell levels and/or Colony Forming Units (CFU) per grams/liters.Furthermore, the amount of AS within the final products is subject to higher instability than other types of drugs. This can lead to a large variance in viable cell levels and CFUs between batch release, which impacts on the end of shelf life. Neither of the agencies had issues with this principle, as long as appropriate stability data were provided.In summary, quality risk management principles are crucial considering the inherent variability of biological materials and should be respected or adapted to develop the control strategy of the manufacturing process in order to optimize, as much as possible, the consistency of LBP production .The objectives of the non-clinical safety studies are to assess pharmacological and toxicological effects prior to initiation of human studies and throughout clinical development . Before The following section will present the non-clinical program developed by YSOPIA and presented to the EMA and the FDA. The non-clinical plan  is simplC. minuta DSM 33407) is a commensal bacterium isolated from a healthy human and has already been reported to be linked to a positive clinical outcome  tract cannot be accurately mimicked in any animal model currently available , 29C. minuta DSM 33407) was conducted using the ex vivo GI SHIME® model , defining a clear MoA is not simple for LBPs as they usually act via multiple simultaneous pathways which can be directly mediated by interactions with the immune system, or indirect through gut microbiome modulation and production of active metabolites , 34. Oncin vitro biodistribution and host-microbiome interaction studies. Traditional dose ranging studies were performed in order to determine whether there was a dose-dependent relationship with the product efficacy. However, we did not observe any dose-effect relationship for our strain . As a consequence, both the EMA and the FDA acknowledged that traditional PK and toxicokinetic (TK) studies were not relevant for LBPs; however, it is recommended that developers should demonstrate through relevant studies  that the strain does not become systemically available.As stated in the ICH S6(R1) guideline , it is dEstimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers”  may also be associated with other risks specific to the species, to the strains and to the patient who will receive the treatment. In order to carry on a risk analysis, it is important to document any beneficial and/or adverse effect ever documented for the species and if available, for the strain to be used as AS. Then, assessment and documentation of all identified risks must be considered to design a relevant preclinical program that will allow to prepare an appropriate risk management plan for further clinical trials.As the DS of LBPs contains live bacteria, as mentioned above, a translocation assessment study is essential to demonstrate the absence of bacteria transfer into the systemic circulation in order to exclude any risk of treatment-induced bacterial infection for patients. To do so, relevant tissues must be analyzed using targeted qPCR along bacterial culture to detect potential live bacteria and prove that bacteria do not translocate. Bacterial translocation can be exacerbated by at least 3 mechanisms: altered intestinal barrier function, dysbiosis, and impaired host defense . Thus, tThe understanding of the complex molecular pathways involved in the interaction between the microbiota and its host  is only in its infancy. In accordance with recent guidelines applicable to biotechnological medicinal products , 36, a lThe FDA has considered that this package is appropriate to support the safety of Xla1 for a FIH study and that no further toxicity studies were needed at this stage of development. However, they specify that, if a safety signal arose during clinical development, the regulatory authority may request additional toxicity studies to address them.It is more difficult to draw such definite conclusions from the feedback received from the EMA. The EMA anticipated that for a marketing authorization, the need for additional toxicity studies would depend on several factors. For example, if the AS is derived from healthy human commensal bacteria that are ingested in amounts within physiological range, and if it does not become systemically available, no additional traditional toxicity studied may be necessary. Otherwise, the safety of the bacteria will have to be substantiated. The EMA did not rule out that this could be done based on existing literature.C. minuta, requires specific study conditions, which is an important limitation for many specialized CROs that are unable to perform anaerobic GLP microbiology in their facilities. With this in mind, regulatory authorities were receptive to these difficulties and accepted that non-clinical programs may be performed in non-GLP facilities that can demonstrate an adequate level of quality. Yet, the EMA highlighted that potential aspects of the non-clinical studies that would deviate from standard GLP conditions should be discussed.Most non-clinical studies are generally conducted in agreement with the Good Laboratory Practice (GLP) certification. As a result, this usually leads developers to subcontract their studies to GLP-certified Contract Research Organizations (CROs). However, handling strictly anaerobic bacteria, like Besides the usual clinical challenges posed by every targeted indication and associated pathophysiological mechanisms, LBP development has its own specific set of challenges to enter FIH clinical trial. Indeed, as mentioned above, because of poor translation from animal models to humans, non-clinical studies for LBPs provide limited information in comparison to the level of predictability obtained from non-clinical programs designed for other types of drugs. Consequently, LBP developers need to take into account this high level of uncertainty when designing their FIH clinical trials.For Xla1 FIH   receiving Xla1,Part 2: A randomized, parallel, double-blind, placebo-controlled phase in overweight or obese adult patients (Stage 1) receiving either Xla1 or placebo.Like every DP, the development of an LBP presents challenges regarding the design of clinical trials that need to conform to current guidelines or scientific recommendations adapted to the assessment of safety and efficacy in the target population , 40. HowBoth the FDA and the EMA were concerned about the risk of causing a systemic infection through administration of live bacteria. Therefore, a detailed management procedure had to be provided , includiThe purpose of the FIH clinical study is to assess the product's tolerability. In general, for products where toxicity is directly related to the dose, the dose range covered in Phase 1 should be larger than the dose range applied in later trials. However, for Xla1 a dose-effect relationship was not observed in non-clinical studies , the risks identified were consequently not considered as related to the dose and a dose-escalation scheme in Xla1 Phase 1 study design was not considered as relevant.The choice of testing solely a single dose was not challenged by the FDA, but the EMA did raise some questions. The EMA considered that the risk of infections may be higher when using a high dose of microorganisms, and therefore would recommend evaluating a lower dose to minimize the risk of translocation. The EMA recommended that the trial should ideally include a wide range of doses, starting with the minimal dose without any effect and ending with the highest possible dose, considering safety, efficacy and practical considerations . It seems that EMA would consider insufficient to only assess the dosing schedule . The FDA indicated the need for multiple dose assessment during later phases of the drug development program.C. minuta. Thus, healthy volunteers might be exposed to an unusual high dose of C. minuta after the administration of Xla1 and such overdosage may potentially lead to unexpected adverse events. In order to evaluate and address such risk, thoroughly monitoring of the microbiome of all participants in order to collect enough longitudinal data was proposed. Analysis of these data will enable to accurately evaluate modifications of the microbiome composition over the course of the study. In addition, 4-week wash-out period to monitor and assess the engraftment of the strain was included. No follow-up long-term assessment was proposed. Neither the EMA nor the FDA did require a long-term evaluation of the study and both accepted this proposal.The EMA also pointed out the fact that sponsors must consider that if some of the participants of the clinical trial are healthy, they might already be carriers of the commensal bacteria and then could react differently to the administration in comparison to diseased patients who are assumed to be low carriers. Indeed, this is particularly relevant to our LBP that is based on a low abundant strain of Submitting the same briefing package through the EMA and the FDA regulatory process has given us some insights into the mindset and perspective of both regulatory agencies. Although the EMA had knowledge of the feedback received from the FDA, their response to the approach in addressing regulatory challenges for LBPs was different. It is important to point out that while the responses provided by the FDA are decisive and binding for entry into the Phase 1 clinical trial, this is not within the remit of the EMA at this stage. Indeed, while the pre-IND procedure allows the FDA to authorize clinical trials for drug products, scientific advices from the EMA are offered with the objective of de-risking development and exchanging on key issues before clinical trial authorizations are submitted nationally. Such procedural difference may explain the differing responses from the two agencies, which were, nevertheless, aligned on many aspects and rather complementary on others. A clear distinction in the philosophy of the two agencies regarding LBPs may however be pointed out.The FDA provided with straight answers on the early development of the biotherapy, while the feedback received from consultation at the EMA covered the long-term vision of the drug development. In both situations, the authorities were highly concerned about patient safety, but both were supportive and open to the proposal of an innovative non-clinical package that they considered appropriate to the specific nature of LBPs. To this regard, the two authorities were true to their longstanding goal of supporting innovative medical care even if they have to juggle between benefits and risks that unconventional medicinal products may represent without one being at the expense of the other.In August 2020, IND authorization was granted to Xla1 allowing Phase 1 clinical trial to begin. The strategy developed to address the regulatory challenges of a single-strain LBP may therefore be considered as successful, or at least, as relevant for the FDA.This experience demonstrates that when guidelines do not exist for a specific type of product, interactions with competent authorities through scientific advice or pre-IND meetings are key to resolve uncertainties and de-risk developments of innovative products. Furthermore, this approach enables regulators to better understand innovative biotherapies and their associated challenges, allowing them to better define areas where specific guidances are needed. For all these reasons, it is important to engage with competent regulatory authorities at an early stage in order to drive a comprehensive and successful development when dealing with an innovative therapy.JCP, FE, and AR planned, outlined and coordinated the work of co-authors, and they drafted and edited the manuscript. JCP, WM, LR, and FE proceeded to the implementation of the CMC and non-clinical and clinical strategy of Yso1 described in this article. JCP submitted the manuscript. SC, MC-S, WM, GR, and LR edited and proceed to critical revision of the manuscript. All authors contributed to the article and approved the submitted version.JCP, SC, WM, GR, LR, and FE are employees of YSOPIA Bioscience. MC-S and AR are employees of the Pharmabiotic Research Institute.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Purpose: This study is a qualitative inquiry into meaning making during retirement transition.The study focuses on how Slovak retirees reconstruct meanings during thetransition and the factors which both help and hinder this process.Methods: Forty individuals  who had recently transitioned intoretirement were interviewed and data were analysed using the ConsensualQualitative Research-Modified approach.Results: The analysis generated five basic domains with categories and subcategories of theparticipants’ responses. The analysis showed that once retired, theparticipants generally continued to rely on previous meaning sources such aswork and family; however, there were changes such as switching from job-relatedwork to work related to hobbies and housekeeping, or from financially providingfor the family to maintaining family relationships and grandparenting. The mainfactors facilitating the meaning making process were positive attitudes andsocial support for meaning. The risk factors included lack of finances, poorhealth of retiree or a close person, and the loss of a spouse.Conclusions: In general, the research showed that the main features of the retirees’ meaningmaking processes were maintaining accessible sources, compensating for sourceslost during the transition, and managing beneficial and risk factors. Retirement belongs to the most important life transitions that can affect personal resources and well-being  participated in the study. They were retired from six months to four years (M = 2.8). They reported level of completed education: the majority had upper secondary education , followed by a university education ; and lower secondary schooling . Most were married , or widowed , single , or divorced . Twenty-one participants lived in villages and 19 participants lived in a town/city.Forty persons (75.5% of women) aged from 57 to 69 years n = 37) choose their homes, some of them (n = 3) a quiet café.To be eligible for this study, participants had to be retired and not working permanently, and to have been retired for a minimum of six months and a maximum of four years. The research was conducted in Slovakia and participants were recruited through institutes and associations for seniors and through the researchers’ personal networks. We used a snowball sampling technique. Before starting the interviews, participants read and agreed with the consent statement to participate in the research. Participants were fully informed about recording the interview, research aims, and conditions. They could terminate their participation at any time of the interview. The confidentiality of the participants was guaranteed, participants were informed that the data would be analysed together for the whole group, no names or other personal data would be collected, disclosed or published. All procedures performed in this study were in accordance with the ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Participants could choose the location of the interviews, most of them , the interviews were divided into four parts and analysed separately. Members of the research team separately analysed the transcriptions of the first ten interviews and sorted the data into categories and subcategories. Then, the team joined together and discussed the domain names, categories, and representative examples of the categories until a consensus was reached. Subsequently, the next tensomes of interviews were analysed one by one, and the coders evaluated how the new interviews saturated the categories. The saturation was attained after 30 interviews, as adding the last ten interviews did not bring any substantial changes in categories structure. In order to avoid the influence of groupthink of primary researchers, an external auditor (with the experience in CQR method) went through categories and subcategories and offered comments and suggestions  was a source of meaning before but not after retirement. Previous studies showed that the family remains an important source of meaning throughout life, but the conception of meaning in life depends on their personal role in the family  is needed in order to understand in a greater detail how retirees make their meaning in such difficult situations.


Sustainable mobility is becoming a key factor in improving the quality of life of the residents and increasing physical activity (PA) levels. The current situation of sustainable mobility and its analysis is a first step in understanding the factors that would encourage residents to discover and choose alternative modes of travel. The present study examined the factors that encourage the choice of active modes of travel among urban adult population. Walking and cycling were analyzed as the most sustainable forms of urban mobility from the perspective of car and public transport (PT) users. Total of 902 subjects aged 18 years or older were analyzed in the study to assess commuting habits in Kaunas city, Lithuania. The majority (61.1%) of the respondents used a passenger vehicle, 28.2% used PT, and only 13.5% used active modes of travel. The results showed that safer pedestrian crossings, and comfortable paths were the most significant factors that encourage walking. A wider cycling network, and bicycle safety were the most important incentives for the promotion of cycling. Our findings show that the main factors encouraging walking and cycling among car and PT users are similar, however, the individual characteristics that determine the choice of these factors vary significantly. Sustainable or active travel modes have gained interest by researchers, general public, decision-makers, and planners as a potential solution to challenges facing in transportation, environmental, social, economic, and public health issues . Active 2, PM). SUMP of Kaunas city has been recognized by the EC and received a special evaluation as one of the top three in the awards of sustainable urban mobility planning [In recent years, there has been an increased focus on the development of sustainable urban transport in European Union (EU) and because of this growing interest many strategic documents, projects, and initiatives were created at the EU level. One of the strategic documents is the sustainable urban mobility plan (SUMP) proposed by the European Commission (EC) as a policy tool that should contain a long-term and sustainable vision for cities in Europe to improve the overall quality of life for residents by addressing major challenges such as congestion, air and noise pollution, climate change, road accidents, unsightly on-street parking, and the integration of new mobility services . The EC planning .Previous studies have shown that individuals who walk or bike for commuting are more physically active and are more likely to meet public health recommendations . The stuHowever, planning and development of active travel infrastructures in cities faces numerous challenges and requires better understanding of both factors promoting active modes of travel as well as barriers to it. First, it is necessary to find out societal behavior and public attitudes toward sustainable modes of travel and factors that would encourage to use them. This study aimed to identify the main factors that would encourage car and public transport (PT) users to choose sustainable modes of travel more often. The main objective of this study was to identify active  and passive (car and PT) travel mode users and to investigate factors that would encourage more frequent choice of walking and cycling from the perspective of car and PT users. The secondary objective was to determine how the choice of certain incentives depended on demographic and socioeconomic factors. It is hypothesized that individuals will choose different factors that promote walking and cycling depending on the use of a certain transport mode. Second, the study hypothesized that demographic and socioeconomic characteristics of car and PT users directly influence the choice of factors encouraging walking and cycling.There is evidence that travel policies and interventions, transportation infrastructure, neighborhood patterns, social and psychological factors are associated with active travel modes. Findings from different studies confirm that quality of walking and cycling infrastructure as well as safety is one of the most important targets of active travel promotion policy and has a direct effect on the intention to use active modes of travel more ,13,14. APrevious studies have shown that comprehensive multi-level policies and strategies, new bike lanes may be effective in promoting active travel behavior changes ,17. EnviPrevious studies examining the main barriers to active commuting have shown that distance, comfort, safety, time spent on commuting, weather, cost, effort, and presence of bicycle parking are the most relevant discouraging factors ,22. The Previous research on the association between active commuting and age are inconsistent. Some studies report that active travel declines with age and older adults are less likely to be active commuters ,28. HoweOur previous study on determinants of travel mode choice showed that the use of cycling was associated with gender, body mass index (BMI), travel distance, and travel cost. Age, BMI, and travel distance was the most significant factors for walking . PreviouThe present study examined the factors that would encourage the use of active modes of travel among urban adult population in the city of Kaunas, Lithuania. This study contributes to the existing body of knowledge on the factors that promote sustainable mobility by analyzing walking and cycling separately from the perspective of car and PT users.Travel behavior studies suggest that walking and cycling should be analyzed separately, because they are seen differently by people and policies to encourage these active travel modes should be different . We inveA cross-sectional study on commuting habits of Kaunas residents was conducted in Kaunas city, Lithuania. Respondents were selected using the random sampling method based on gender and age in proportion to the size of the Kaunas population. The survey included permanent residents of Kaunas city who were 18 years of age or older. The participants were recruited and interviewed by telephone from September to November 2017. The survey was completely anonymous, and no identifiable personal details were collected from the respondents. The study received an approval from Kaunas Regional Biomedical Research Ethics Committee . Main outcome measure was active  and motorized (car and PT) modes of travel and factors that encourage the use of active modes of travel. In total, 1111 participants completed the questionnaire. Among these participants, only those who indicated that they regularly use at least one of the analyzed modes of travel more than once a week were included in the present study. Individuals who choose a different mode of travel depending on the season were assigned to both groups. Thus, the data of 902 participants were analyzed in this study to identify the demographic, socioeconomic, and other characteristics of active travel users and to investigate the factors that would encourage walking and cycling among car and PT users.2.The city of Kaunas  is the second-largest city of Lithuania with a population of 292,691 in 2017 and distributed over a land area of 157 kmKaunas is situated at strategically convenient position in terms of intersection of the main Lithuanian roads and the national and international integration axes and railways. Kaunas is well integrated not only into the general Lithuanian transport system, but also into the international transport corridor network. The city of Kaunas has a well-developed air transport infrastructure and is one of the largest air freight hubs in the Baltic States. An international airport is situated in close vicinity (the distance between the airport and the city center is 14 km) .2 in 2017. Almost half of the city′s territory is built up and the density of the street network is 6.48 km/km2 [The population density of Kaunas city reached 1864 inhabitants/km8 km/km2 . Accordi8 km/km2 .According to the database of enterprises of Kaunas, workplaces, schools, kindergartens, and shopping centers are distributed proportionally in the city.PT network is characterized by a high frequency of services and a concentrated network of routes so that it can meet the needs of passengers. In recent years, Kaunas PT park has been renovated, more convenient payment for travel has been introduced and the quality of services has increased. The priority is to ensure a shorter journey time so that public transport in Kaunas is faster, priority public transport lanes and a more attractive and simpler new ticketing system are provided . The citKaunas is actively expanding its infrastructure by building new bicycle paths and renovating old ones. The city is implementing projects aimed at expanding the bicycle transport infrastructure in order to create an integrated bicycle network system and promote the mobility of the population by non-motorized vehicles ,40. AccoThe city is constantly investing in the reconstruction and the development of the road and cycling networks as well as in the renewal of the urban public transport infrastructure ,42.The survey included questions about demographic , socioeconomic , health-related ) factors, travel behavior and the use of active and motorized modes of travel. Adults with one or more child under the age of 18 years (<18 y) were coded as yes and those adults who reported that they do not have a child or have one or more child over the age of 18 were coded as no. Education level was classified as low education (12 or fewer years), medium (non-university), and high education (university degree) level. According to the employment status, participants were classified into four groups: employed, students, retired, and unemployed individuals. Occupations were classified according to the International Standard Classification of Occupations (ISCO) and grouped into white-collar  and blue-collar  workers . Accordi2). Participants were classified into two smoking categories: current smokers and non-smokers. The chronic disease variable was measured using the question that asked the respondents whether a doctor had ever diagnosed them with one or more chronic diseases. Level of PA (min/week) was assessed based on the Global Physical Activity Questionnaire developed by World Health Organization (WHO) and was divided into two groups according to the WHO physical activity recommendations: (1) less than 150 min/week and (2) equal to or more than 150 min/week. In the study, the participants were asked “How many hours per day on average did you spend sitting outside of work?” They were asked to estimate in total the number of hours per day they spent sitting on a weekday and a weekend day, not including the time spent sitting at work. The participants indicated whether the mode of travel they used was a work commute or a non-work travel and a categorical variable commute type was used for the analysis.Body mass index (BMI) was calculated as the ratio of weight (kg) to height squared , the length of the shortest route on the road and pedestrian/cyclist networks between two locations  was calculated. The shortest route was assessed for different modes of travel. To determine the optimal path along a linear network road and path networks of Kaunas city were used. Routes of cyclists were based on the combination of path and road networks. To find the shortest path from a starting location to a destination location , the RouAccording to the use of the travel mode, the participants were divided into active  and motorized (car and PT users) modes users. The participants were asked whether they walked, rode a bicycle, or used motorized transport (a car or PT) for daily commute to work or to some other frequently visited location. To identify factors that encourage more walking and cycling for daily travel, two questions were asked: “What would encourage you to walk more?” and “What would encourage you to cycle more?” The outcome variables were coded as dichotomous variables (1) if the travel mode and factor that encourages walking and cycling was chosen, and 0 if not.p-value was calculated for categorical variables to determine the associations between the use of active and motorized travel modes and individual characteristics of the study participants and factors that encourage walking and cycling among car and PT users separately. Multiple responses analysis was performed using the SPSS Multiple Response Sets function. The participants who selected more than one option for the following questions: “What would encourage you to walk more?” and “What would encourage you to cycle more?” were included in this analysis. Logistic regression analysis was used and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the determinants of the choice of factors encouraging walking and cycling. We used binary logistic regression models to find associations between the choice of factors that encourage walking and cycling and individual characteristics of the study participants. In the multivariable logistic regression model, we adjusted for age, gender, marital status, health-related behaviors, and cardiometabolic risk factors. The p-value < 0.05 was used as the threshold of statistical significance. All statistical analyses were performed using SPSS version 25.0 . Data on travel distance were analyzed using ArcMap 10.4.1 .The descriptive statistics of the study population is expressed as the mean and standard deviation (SD) for continuous variables and frequencies and percentages for categorical variables. The independent t-test was used to compare the means of continuous variables by different travel modes. The chi-square test or Fisher’s exact test with less than 5 groups and its 2, and only 12.6% of the study population achieved recommended levels of physical activity. The majority (61.1%) of the respondents indicated using a car, 28.2% used PT, and 13.5% used active travel modes.The demographic and socioeconomic characteristics of the study population are presented in In order to investigate the factors that promote sustainable mobility, it is first important to understand the characteristics of people who walk or cycle or use motorized transport . The resp < 0.05). Meanwhile, a shorter distance, and having more time would encourage more car users to walk. However, we did not find a statistically significant difference in a shorter distance between car and PT users. A higher percentage of PT users indicated that they walk enough compared to car users. Considering the determinants that would promote cycling, the results showed that a wider cycling network (40.5% and 34.6%), and bicycle safety (39.9% and 37.0%) would be the most important incentives for car and PT users to cycle more. Analyzing multiple responses, the results showed that a combination of factors such as comfortable and high-quality paths, safer pedestrian crossings and crime prevention would encourage to walk 11.6% and 16.1% of car and PT users, respectively, (p = 0.050). Meanwhile, comfortable, and high-quality paths, and safer pedestrian crossings would encourage to walk 22.7% and 35.0% of car and PT users, respectively. There was a statistically significant association between variables (p < 0.001). The results for cycling promotion showed that a set of factors such as a wider cycling network, more bike storage, bicycle safety, and theft prevention would encourage to cycle 12.5% of car and 8.7% of PT users (p = 0.066).Factors encouraging people to choose the active mode of travel were analyzed for walking and cycling separately, from the perspective of car and PT users . The resDemographic, socioeconomic, and other characteristics of the study participants have a significant impact on the choice of the factors that promote active travel modes. For multivariable logistic regression analysis, we selected the most influential factors that encouraged walking and cycling among car and PT users. The main factors that encouraged walking were chosen as follows: comfortable and high-quality paths, safer pedestrian crossings, crime prevention, a shorter distance, and having more time. The main factors that encouraged cycling were chosen as follows: a wider cycling network, more bike storage, bicycle safety, and theft prevention. After adjusting for potential confounding factors, the results showed that car users who chose comfortable and high-quality paths as a factor encouraging walking were more likely to be without minor children, unemployed, spend more time in sedentary behavior (SB) during weekday, and non-smokers . Being oPT users, who would be encouraged to walk by comfortable and high-quality paths, tend to spend more time sitting on weekdays. Safer pedestrian crossings would encourage more unemployed people to walk. Crime prevention as a factor encouraging walking was more important for unemployed people, and those, who spend more time in SB on weekends. A shorter distance and having more time would encourage to walk those PT users who are employed and spend less time sitting on weekends.Analysis of cycling promotion among car users showed that a wider cycling network would encourage younger people, those who spend more time in SB on weekends and have lower BMI to cycle more. These results were similar for PT users except that they tend to spend more time in SB on weekdays and there was no significant association with BMI . More biTo promote sustainable mobility and to encourage people to cycle and walk more, it is important to increase the level of knowledge about the factors that would promote these modes of travel and identify the barriers that stop people from walking and cycling to their destinations. The principal aim of the present study was to identify the most important factors encouraging walking and cycling from the perspective of car and PT users and to determine the influence of individual characteristics on the choice of these encouraging factors.Our research showed that safer pedestrian crossings was the most important factor that would promote walking both for car and PT users. Similar results in terms of road safety and active travel were found in previous studies. Panter and colleagues  in a stuThe findings showed that factors associated with distance and time were important for car users to encourage walking. Previous studies have shown that one of the most important factors preventing people from choosing active modes of travel are distance, which is associated with increased travel time, and a lack of convenient infrastructure ,46. In aThe results of the study demonstrated that factors encouraging cycling differed between car and PT users. The most significant factor for car and PT users was the wider cycling network and bicycle safety, respectively. There are greater safety and security concerns among PT users ,49 and tOur findings revealed that demographic and socioeconomic characteristics of car and PT users influenced their attitude toward factors encouraging walking and cycling. Having minor children, education level, SB, BMI, and smoking were the most significant factors influencing the choice of factors that would encourage walking among car users. Employment status, and SB were the most significant factors affecting the choice of factors that would encourage walking among PT users. Comfortable and high-quality paths would encourage to walk more unemployed people, travelling for non-work purposes, and those who spend more time in SB on weekdays and weekends. These results may be due to the fact that unemployed people have more free time and as our previous study has shown they are more physically active compared to employed individuals . HoweverAmong car users, safer pedestrian crossings and crime prevention as factors to encourage walking were more often chosen among highly educated people. Educational attainment is linked to lower crime rates . TherefoAmong car users, younger people, those who have minor children, and spend less time in SB indicated that a shorter distance and having more time would encourage to walk more. Meanwhile among PT users, employed adults, those who commute to work, and spend less time in SB indicated that a shorter distance and having more time would encourage walking. These findings indicate that employed people and those who have minor children might have greater demands on their time and thus, prefer faster and more convenient modes of motorized transport ,47.The results of cycling promotion showed that the most significant individual characteristics influencing the choice of factors encouraging cycling were education level, SB, and BMI among car users and age, education level, and SB among PT users. Among car users, younger adults, those who spend more time in SB on weekends, and have lower BMI would be more encouraged to cycle by wider cycling network. Car users who have higher education, do not have minor children, spend more time sitting on weekdays, have higher BMI, and non-smokers indicated that the main factors encouraging cycling are more bike storage and bicycle safety. Theft prevention to encourage cycling was mostly chosen by highly educated people, those who tend to spend more time in SB on weekends and have higher BMI. Our findings show that highly educated people are more concerned about transport safety and thief prevention. Among PT users, younger people, those who have lower education, and spend less time in SB on weekdays would be encouraged to cycle more by analyzed factors. The findings of this study suggest that younger adults are more likely to cycle. Similar results were obtained in a study in the UK, which showed that cycling dominated among younger adults . DemograCity government faces the challenge of encouraging residents to discover sustainable modes of travel such as walking and cycling. To encourage residents to choose active modes of travel, it is important to expand and improve infrastructure of cycling and walking routes that is adapted for more convenient and safer sustainable mobility of people in the city. It is important to build bicycle storage facilities in public spaces and near apartment buildings, to install electronic passenger information systems at bus stops and PT, because without the right network it is very difficult to achieve a positive impact in sustainable mobility of people. The solutions of Kaunas General Plan and Kaunas Sustainable Urban Mobility Plan should ensure the development of infrastructure. It is important that the planned development is integrated and sustainable.This study contains few limitations that could be enhanced in future studies. Although questionnaires are widely used in these types of studies ,27 as thAlthough the sample size of our study was not small, having a larger sample size would have allowed a more detailed assessment of those encouraging factors that were less chosen. However, the sample size did not negate significance of our findings as the study population was representative to the entire population of Kaunas city.The study used a cross-sectional design and, therefore, cannot be used to infer causality.Our questionnaire did not include some other important barriers to active travel related to topography, weather, green spaces, and convenience. Future enhancements of these study components could be performed to strengthen the findings of the study.The most important factors encouraging sustainable modes of travel were examined from the perspective of car and PT users. The findings showed that safer pedestrian crossing was the most important factor encouraging walking both for car and PT users. However, there were differences in car and PT users’ attitudes toward factors encouraging cycling. Our findings indicated that a wider cycling network is of primary importance to car users, while public transport users identified bicycle safety as the key factor.The study showed that the main factors encouraging walking and cycling among car and PT users were similar, however, demographic, and socioeconomic characteristics that determine the choice of these factors vary significantly between car and PT users.The study also suggests that future research could involve individuals who have already changed their mobility behavior toward more active travel and investigate the causes and factors that influenced these changes.


The fast-growing world population places food production under enormous pressure to ensure food security. One of the most common methods to increase food production is the use of pesticides, but the continuous use thereof has numerous detrimental effects on the environment. The interest in biopesticides for a possible substitute has grown over the past two decades. To determine the research evolution of biopesticides (green pesticides), a bibliometric analysis from 1994 to 2019 was carried out. A total of 580 documents were found eligible in the Scopus database for this analysis. Parameters such as the number of articles, article citations, keywords, source impact, and countries of publication were used to analyse the documents and rank countries based on authors, productivity, article citations, and co-authorship. The analysis reveals production increased significantly from 2009 and has the most published documents in 2019 with a total of 74 articles. Asia's most populous countries, India and China, were ranked first and second, respectively, and the USA third in terms of the most productive countries in the field of plant biopesticides. Countries in Europe and Africa however have fewer publications than expected in this field, given the fact that they are high consumers of pesticides. India, China, and the USA have 4.08%, 2.94%, and 12.5% multiple country publications (MCPs), respectively, with the USA having a stronger collaboration. Finally, there is a clear indication in this study that India and China are taking the lead in substituting synthetic pesticides with the alternative natural plant biopesticide. The detrimental effects of synthetic pesticides on the environment are well established as it affects animal and plant biodiversity as well as terrestrial and aquatic ecosystems . Other eWith the continuously growing interest in botanical pesticides, it is necessary to carry out a bibliometric compilation to better understand the research trend. The fast-growing number of academic publications makes it extremely difficult to stay up to date with everything being published . To helpDuring this study, the objective was to analyse the global research activities on botanical pesticides from 1994 to 2019, in the Scopus database. The data obtained was then used to study the research progression using bibliometric parameters and indicators such as most productive authors, most productive countries, annual scientific production, country collaboration, average article citations per year, average total citations per year, most relevant keywords, bibliographic coupling, and documents production source impact. The Scopus database was chosen as it includes a wider spectrum of journals in citation analysis and keyword searching than PubMed and Web of Science . It alsoDue to the detrimental effects of synthetic pesticides on both the environment and human population, this study aims to carry out a descriptive bibliometric analysis on green pesticide research from 1994 to 2019, in order to present a general overview of global research trends towards finding an alternative for synthetic pesticides.The published research outputs on botanical pesticides were retrieved from the Scopus database on 7 August 2020. The Scopus database provides access to 27 million abstracts with citations dating back to 1966 . The keyTo determine the progression of research on green pesticides in this study, a wide spectrum of biopesticide keywords were used to query the database. A total of 540 published documents, from 332 sources, were recorded on green pesticides. These documents include articles, books, book chapters, conference papers, conference reviews, editorials, erratum, notes, reviews, and short surveys. An average citation of 12.63 per document makes them relevant in the scientific community . The annMost published documents contain a number of keywords to assist with online searches and identify certain editors to a document . To studIndia is ranked first in the most productive countries with a total of 98 publications, among which 4.08% are published out of collaboration. China and USA are ranked second and third with 68 and 32 publications, respectively. China has 2.94% and USA has 12.5% multiple country publications (MCP) which indicate the USA collaborates more while China relies more on local research. It is quite interesting to know that Italy and South Africa have fewer single country publications (SCP) compared to their MCP; hence they have a higher MCP: SCP ratio. The collaboration on publications of Italy, Netherlands, and South Africa is 60.86%, 75.0%, and 80.0%, respectively, making these the countries with the most collaboration network .According to Lee and Bozeman , scientiIn The increase in publications from 2009 could be due to the increasing realization of the detrimental effects of synthetic pesticides on the environment , the groTo determine the productivity of a research field based on a bibliometric study, the number of scientific publications is investigated . GloballConsidering the data collected in this study as shown in In The limitations that arose during this study were language, the fact that the quality of published documents could not be ascertained, and the research not available on Scopus being missed out. The documents retrieved from the Scopus database were limited to “English written documents.” Documents published in other languages also contribute to research productivity but were unfortunately eliminated in this study. The quality of published documents cannot be measured by total citations alone while the annual scientific production of an author or a country is also not a measure of research quality . It is wThis bibliometric study discussed the global trend of green pesticide research from 1994 to 2019 based on documents retrieved from Scopus. Despite the increasing research on green pesticides, commercial applications remain limited. Trends in the annual scientific production suggest that research on green pesticides will continue to increase. The detrimental effects of synthetic pesticides on the environment and human health could be the possible drivers for research productivity in the alternative field of plant biopesticides. This study also found that India, China, and USA are the leading countries in the production of green biopesticide research documents articles and amass the highest total citations per country. Countries in Europe and Africa, although high consumers of pesticides, have significantly less published research documents compared to the earlier mentioned countries. Europe and Africa countries need to intensify their research on alternative pesticides through either government or privately funded programs to promote environmentally friendly pesticides, especially in Africa where pesticides with high toxicity are still being used.


Background: Bullying has been recognized as an important risk factor for personal development in adolescence. Although numerous studies report high prevalence of bullying in Russian schools, limited research was based on the large-scale, nationally representative analysis, which highlights the lack of findings applicable to the national context.Objective: This study aims to address the following research questions: (1) What is the bullying victimization prevalence in Russian secondary schools? (2) What is the socio-demographic profile of the bullying victims? (3) To what extent do learning outcomes in core subject domains predict bullying? (4) How does psychological climate at school affect the occurrence of bullying? (5) Which emotional states do bullying victims typically display? (6) Which psychosocial traits are the most common for bullying victims?Data and Methods: The study adopts the statistical analysis of the Programme for International Student Assessment (PISA) data in Russia. The final sample consists of 6,249 children aged 15 years who answered the bullying questions. K-means clustering approach was adopted to identify schoolchildren who should be classified as bullying victims amongst those who have reported bullying. Logistic regression was used to estimate the probability change of bullying under different psychosocial factors and examine the effect of bullying on the emotional states of the victims.Results: The results of the study reveal that 16% of children are victims of bullying in the Russian secondary school. Bullying is strongly associated with learning outcomes in reading, thus outlining that low performers are at risk of severe victimization. Bullying is also contingent on the psychological climate and tends to develop more frequently in a competitive environment. The findings outline that bullying increases negative feelings such as misery, sadness, and life dissatisfaction amongst its victims, making a substantial footprint on their lives. Logically, bullying victims are less likely to feel happy and joyful. Finally, it was revealed that bullying victims do not tend to share negative attitudes to the per se, which identifies directions for future research in this domain.Implications: Instead of dealing with the consequences of bullying, prevention strategies should aim at facilitating a positive environment at school, thus addressing the problem. In 2015, while approving Sustainable Development Goals , which measures the learning outcomes of the students in the last year of lower secondary school. This school-based survey program supplies researchers with a vast number of dimensions to test their hypotheses, including questions to monitor bullying frequency in schools amongst adolescents.The current study explores cognitive, emotional, and psychosocial factors associated with bullying amongst students in the Russian secondary school. Adopting nationally representative data from PISA-2018 in Russia, the findings of the present research contribute to the growing body of knowledge regarding bullying in the Russian secondary school. Being also first-of-its-kind in terms of geographical coverage, the analysis of bullying victimization carried out in this study generates data-driven proposals for efficient bullying prevention programs.The relevance of research on bullying is high because this destructive behavior is widely spread amongst children and adolescents all over the world . Proceeding from this, “positive values on the index indicate students who reported to be more frequently bullied than the average student in OECD countries, while negative values indicate students who reported less frequent exposure to bullying than the average student in OECD countries” OECD, , p. 135.With this regard, the second relevant issue refers to the aggregation of the index. As outlined by the PISA 2015 report OECD, , p. 135,Analogous to the index of exposure to bullying suggested by the OECD, we employed standardization procedures to compute the index, where 0 indicates the average exposure of a schoolchild in Russia to bullying, and the range of values potentially varies within plus/minus three standard deviations.Statistical analysis was carried out in three main stages. First, we wanted to understand the prevalence of bullying in Russian secondary schools. In other words, the purpose was to estimate the probability of a child becoming a victim of bullying at school. We did not want to produce arbitrary decisions upon selecting a random threshold to distinguish victims of bullying from other students that might experience it occasionally. With this in mind, we conducted cluster analysis that helped identify victims of bullying in the overall number of Russian schoolchildren. This resulted in a binary variable “Victim,” which assigned 1 to students who are victims of bullying and 0 to those who are not.Inferential analysis went in two main directions. The first one used bullying as a dependent variable and aimed to model factors that could predict it. On the other hand, it was also necessary to understand the scope of reactions that bullying causes in its victims. Therefore, in the second stage of the analysis, bullying served as a predictor, whereas different emotional states or psychosocial traits were considered response variables. This step allowed for a better understanding of the profile and typical characteristics of bullying victims. We chose logistic regression to statistically model these relationships, which allowed for fixing the effects of the predictors on the probabilistic scale. The calculated model has the equation below:Xn is a predictor, βn is a coefficient of change associated with it, and ε is an error-term of the model.where The first model aimed to estimate how the learning outcomes of students shape bullying. The second model assessed the effects of the psychological environment in schools. Then we used bullying as a predictor to assess its impact on the emotional states of victims. PISA collects data on the eight emotional states, namely: happiness, joy, cheerfulness, liveliness, pride, misery, sadness, and fearfulness of schoolchildren. Schoolchildren were asked how frequently they experience a specific emotional state with four answer options, such as never, rarely, sometimes, and often. Those who answered “often” while reporting a specific emotional state were coded as 1 in opposition to other schoolchildren coded as 0. The same approach was used to estimate the propensity to different psychosocial traits. However, the responses there were fixed on the 1–4 scale, and depending on the variable, top 20% or bottom 20% were taken as the groups for calculating the effects of bullying on them. These parts of the analysis present a series of models that consisted of only two variables, bullying as a predictor and emotional state or psychosocial trait as an outcome variable.For all logistic regression models, both dependent and independent variables were transformed into categorical ones, and the results were presented not as regression coefficients but as marginal effects. As logits or odds ratio scales are not informative in summarizing how changes in response variables are associated with changes in predictors, presenting results as differences in probabilities was more meaningful for interpretation. Marginal effects are non-linear and present the magnitude of change on the probability scale. Therefore, depending on the value of predictors, the effect is always bound between 0 and 1. Marginal effects are easy to calculate using the equation below:R, lingua franca of statistical computing.Data analysis was carried out in https://osf.io/vhjr3/).This project was registered in Open Science Framework . The PCA results confirm that the first component explains 64% of the total variance, which means that there is no need to divide the composite index into subdimensions following the bullying types. In other words, the items load well on the unidimensional concept with the eigenvalue equal to 3.8. However, while items two to six obtained Pearson correlation coefficients with the principal component above 0.6, the first item scored just below 0.3. Consequently, the reliability and validity of the bullying scale in the Russian language provide sufficient statistical reason to exclude the first item from the analysis. Taking the arithmetic mean of five items in this case would result in the higher weight of items related to the physical bullying in the final score. Nonetheless, as the remaining items establish a high correlation with the first principal component, as shown on On the other hand, negative values allowed for identifying schoolchildren who experience bullying more rarely than a schoolchild on average. The association of the index calculated for the Russian sample with the original bullying index of OECD showed a statistically significant correlation at the level of 0.81. However, this high value should not be misinterpreted as it primarily means that 34% of the variance remains unexplained in this bivariate association (as squared Pearson R gives us a coefficient of determination). This confirms that our choice of producing a separate index for the Russian data was justified.However, one question remained open: how to identify schoolchildren that are actual victims of bullying. The resulting index varied from −0.67 to 3.56, outlining a high heterogeneity in distributing the scores. As In many ways, the clustering results confirmed our assumptions: the multimodality of distribution explicitly demarcates the borders between two groups. The algorithm classified those who obtained an index score higher than 0.67 as bullying victims. It is worth mentioning that this cohort accounts for 16% of all schoolchildren, which means that every one out of six schoolchildren in Russia is a victim of bullying.Profiling of the bullied victims forms another critical pillar of the analysis. It is essential to understand the composition of the group that experiences a high risk of exclusion. Though bullied students have a very heterogeneous background, we can still identify a few distinct patterns while looking at cohorts that comprise bullying victims. First, bullying in school occurs more frequently with boys than with girls, every two out of three bullying victims being male schoolchildren. It is also clear that victims of bullying carry psychological stigmatization associated with their status in society. More than 43% of the schoolchildren bullied belong to low-status groups by the PISA index of economic, social, and cultural capital. Finally, in ~70% of all cases, bullying victims reside in villages or towns with a population below 100,000 inhabitants. However, these numbers should not be interpreted in the causal perspective. Profiling helps us draw a portrait of a particular group by key socio-demographic dimensions; however, it presents descriptive statistics that in many ways could be affected by population distribution.This study explores the relation of bullying with the number of characteristics that can be grouped into four categories. The first one refers to learning outcomes and is comprised of skills in readings, mathematics, and science. Disciplinary climate at school, perceived cooperativeness and competitiveness of the school environment, and school belonging form the second group of the variables and denote the psychological environment at school. The third pillar of the analysis explores the impact of bullying on the propensity of frequently experiencing emotional states such as happiness, joy, cheerfulness, liveliness, pride, misery, sadness, and fearfulness. Finally, the fourth category is represented by the impact of bullying on diverse psychosocial characteristics and traits, which are life satisfaction, eudaemonia, fear of failure, task mastery, personal competitiveness, goal orientation, and attitude to bullying. To estimate the effect of learning outcomes on the probability of becoming a victim of bullying, we built a logistic regression model with an equation presented below.The results of the model are presented in The logits calculated for all three groups across the three domains and presented in PISA provides some variables that could serve as useful proxies for the psychological environment in schools. These variables include disciplinary climate, cooperativeness, and competitiveness of the school environment, and the feeling of children of belonging to school. Using these predictors, we built the following logistic regression model:p < 0.01). A competitive school environment demonstrates the highest magnitude of the effect, increasing the probability of bullying by 11%. On the other hand, the likelihood of bullying in schools with a cooperative school environment is 6% lower. It is also clear that a positive disciplinary climate in schools decreases the probability of bullying by 9%. Finally, students who do not demonstrate a high degree of belonging are also 6% more likely to become bullying victims.Summary results of the model are presented at This part of the analysis looks at victims of bullying, thus aiming to reveal emotional states and psychosocial traits that are most typical for them. With this regard, bullying instead of being a response, became an independent variable of the logistic regression, and the model aimed to estimate the probability of a specific emotional state or psychosocial trait to be typical for bullying victims. We thus ended up running 15 models where bullying predicted the likelihood of a specific emotional states or psychosocial traits. The model thus obtained the following equation:P(Y) referred to a probability of a schoolchild to have a certain psychosocial trait or experience very frequently one of eight emotions reported in PISA, accounting for an effect of bullying. The results of these regressions are presented in where p < 0.001) of bullying on the occurrence of almost all of the outlined, except cheerfulness and liveliness. The most potent positive effect of bullying is observed in connection with fearfulness, misery, and sadness. Victims of bullying have a higher probability of experiencing these emotions than other students . Bullying is also negatively associated with joy and happiness, which means that bullying victims are 11% less likely to report joy and 9% less likely to report happiness.As was mentioned earlier, PISA asks students to assess how frequently they feel joyful, happy, cheerful, miserable, afraid, sad, lively, and proud. Logistic regression modeling identified statistically significant effects ” study in 2014, which was supported by the World Health Organization  prone to victim behavior and (2) prone to aggressor behavior. That conclusion is consistent with the view of Vorontsov  that notThe carried out statistical analysis has thus provided a means of identifying the “primary risk group” of bullying victims in the secondary schools of Russia. It should be stressed that the research presents statistically proven pioneer work as the reading test results of PISA assessment have been first applied to estimate the probability of becoming a bullying victim. Similar research-based data have not been found in a large body of published literature.Our research findings provide valuable information for bullying prevention programs. Programs oriented to creating a comfortable psychological climate at school present clear advantages over those oriented to reducing undesirable social behavior patterns. If antibullying programs aim to ensure the psychological well-being of adolescents, they can be more efficient in dealing with the problems that even go beyond bullying. Instead of focusing on specific negative aspects of school life, they provide ground for an inclusive and psychologically comfortable learning environment that rejects bullying. These areas of work should constitute primary preventive measures.In the secondary prevention phase, the work should focus on those students who are specifically prone to risks of becoming victims. In other words, it should look at the profile of that 16% of schoolchildren who were identified as bullying victims. With these regards, increasing the learning outcomes by improving the literacy skills of low achieving students should be one of the core areas of work. Low performance in reading that outlines a lack of literacy skills needed to succeed in contemporary society shapes life even beyond schools, and bullying is one of the dimensions where the harmful effects of low achievement become so explicit. Another set of measures should be directed at improving the acceptance of students from low-status groups in the classroom to eliminate the influence of status-related issues on bullying.Working with the behavior of male students is crucial to develop an appropriate and safe expression of anger, aggression, and other negative emotions as these students are especially prone to physical bullying. It is necessary to teach them to understand the psychological essence of aggression, its characteristics, optimize the interaction of the group, develop cooperation, increase school belonging, self-reflection, increase empathy, and create a healthy emotional space. Antibullying programs should facilitate communication skills crucial for better conflict resolution to mitigate verbal or relational bullying.Generally, prevention strategies and antibullying programs should emphasize the ways and methods of self-control among adolescents. Creating situations of success, setting an encouraging environment that provides ground for positive emotions, developing awareness, and accepting their feelings are core areas of work. Antibullying programs should also teach socially acceptable ways of expressing aggression, aiming to reduce the verbal, indirect aggression through aggressiveness recognition and its think-aloud protocol, and develop empathy and skills of constructive problem solving and fostering personal maturity.Our study suggests that, on an average, one out of six children attending secondary school in Russia becomes a bullying victim. This measure is different from simple descriptive statistics based on the prevalence of different bullying types. To identify amongst schoolchildren who reported bullying those who are victims, we looked at the bullying distribution scores and used k-means clustering to crossvalidate our assumptions. These procedures allowed for concluding that for 16% of all schoolchildren at the Russian secondary school, experienced bullying, with some frequency leading to victimization. The findings of our research also indicate the prevalence of verbal bullying over relational and physical ones.Decomposition analysis of bullying victims outlines that male schoolchildren experience bullying more often. Although not all bullying victims come from marginalized groups, there are clear status-related considerations. More than 40% of bullying victims belong to families with the lowest economic, social, and cultural standing. Furthermore, most of the bullying victims (70%) reside in villages or sparsely populated towns.Analysis of factors predicting bullying also presents reasons for concern. We identified the relationship between learning outcomes in reading and bullying victimization, which presents high risks for low achieving schoolchildren. Considering the PISA framework, those who do not possess the necessary literacy skills to succeed in life are also likelier to be socially excluded and victimized.The psychological environment at school forms another group of factors behind bullying. Victimization is more likely to occur in a competitive school environment and, logically, less likely to occur in the cooperative one. Therefore, schoolchildren without a strong feeling of school belonging are also likelier to be bullied. However, our findings highlight that a positive disciplinary climate mitigates victimization. These conclusions provide ground for prevention efforts, and school psychologists and social pedagogues obtain a specific role in monitoring the psychological environment of the classroom.Our study suggests that bullying substantially affects the psychological well-being of a schoolchild. Bullying provokes negative emotions like fearfulness, misery, and sadness amongst victims. Furthermore, it causes rarer experiences of positive emotions compared to other schoolchildren. These peculiarities are crucial in elaborating bullying prevention programs that should compensate for the deficit of positive emotions amongst the victims and eliminate the harmful effects of the negative ones. The adverse effects of bullying, however, go beyond the emotional states. The bullying victims tend to have lower eudaemonia levels, outlining that they avoid reflecting the sense of meaning in life. They also are more likely to have a low level of life satisfaction in comparison to other schoolchildren.Finally, one of the critical findings of this study suggests that bullying victims could become perpetrators in other contexts. The analysis pointed out that bullying victims are less likely to share negative attitudes toward bullying and empathize with other bullying victims. It allows for hypothesizing that one person could potentially switch or combine victim–bully roles, and future research on bullying in Russian schools should focus on this aspect more.Considering this, primary prevention measures should address issues related to the school environment creating a friendly and pleasant atmosphere. The measures aimed to create a positive learning environment would be more efficient by eliminating the conditions in which bullying occurs instead of dealing with its negative consequences and undesirable behaviors. The secondary phase of antibullying programs should take into account emotional states and psychosocial factors of bullying victims to help them overcome frustration and stigmatization caused by bullying, thus ensuring that they can fully participate in the social life of the school and beyond, without risks of being victimized again.https://www.oecd.org/pisa/data/.Publicly available datasets were analyzed in this study. This data can be found at: GA and LD are the major authors who developed the initial manuscript. AB reviewed the literature and together with VK drafted the practical implications and prevention strategies. SK and VE contributed to the data processing and analysis. IA revised the final manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Our study objective was to determine lung cancer chemotherapy attributes that are important to patients in Japan. A discrete choice experiment survey in an anonymous web-based questionnaire format with a reward was completed by 200 lung cancer patients in Japan from November 25, 2019, to November 27, 2019. The relative importance of patient preferences for each attribute was estimated using a conditional logit model. A hierarchical Bayesian logit model was also used to estimate the impact of each demographic characteristic on the relative importance of each attribute. Of the 200 respondents, 191 with consistent responses were included in the analysis. In their preference, overall survival was the most important, followed by diarrhea, nausea, rash, bone marrow suppression (BMS), progression-free survival, fatigue, interstitial lung disease, frequency of administration, and duration of administration. The preferences were influenced by demographic characteristics  and disease background . Interestingly, the experience of cancer drug therapies and adverse events had a substantial impact on the hypothetical drug preferences. For the Japanese lung cancer patients, improved survival was the most important attribute that influenced their preference for chemotherapy, followed by adverse events, including diarrhea, nausea, rash, and BMS. The preferences varied depending on the patient’s demographic and experience. As drug attributes can affect patient preferences, pharmaceutical companies should be aware of the patient preferences and develop drugs that respond to segmented market needs. With the growing number of available drug therapies, patients have more treatment choices. Healthcare providers should have an accurate and comprehensive understanding of patient preferences and needs as the treatment value should be derived from its significance to the patient. Regulatory agencies in the United States and European countries and some private organizations advocate for patient centricity, patient preferences, and dialog . TherefoPrevious studies have demonstrated that treatment selection based on patient preferences has a significant impact on adherence . The impOf all cancer types, lung cancer has the highest prevalence worldwide. Approximately 2.2 million new lung cancer cases and 1.8 million deaths were reported in 2020, accounting for 18% of all cancer-related deaths . In JapaDue to the poor prognosis of lung cancer, the choice of therapy is essential. The various lung cancer treatment options according to recent guidelines in the United States, EU, and Japan include cytotoxic anticancer drugs , molecularly targeted drugs , and immune checkpoint inhibitors  . For traPreference studies on treatment attributes and their impact on patients’ value are gaining prominence in many countries . A literQuantitative analysis of lung cancer patients to identify the demographic characteristics associated with their preferences is often conducted by latent class analysis or subgroup analysis . The hieAmong Japanese patients with lung cancer, only three preference studies have been conducted. We investigated patient preferences for the attributes reflecting the benefits, risks, and utility of cancer drug treatment. We conducted a conjoint analysis  as it has previously been used to study patient preference in the healthcare field  and is lThe level of each attribute was based on the best and worst levels of the drugs listed in the guidelines. The risk levels were described in terms of incidence rate, and the severity of each risk was assumed to be fixed, corresponding to the drug descriptions listed in the guidelines.After creating hypothetical drug profiles comprising the aforementioned attributes and levels, a 24-question discrete choice questionnaire was first piloted anonymously to pharmaceutical experts of the two institutions to which the authors belong. We reduced the number of discrete choice questions as some respondents felt burdened. The questionnaire was also reviewed by the Lung Cancer Patient Network ONE STEP, a Japanese patient organization, to ensure that the questions, including the inquiries of the patient’s background, met ethical requirements and were easy to understand and the selected drug profiles were appropriate. Based on the suggestions by the patients’ association, we simplified the explanations and provided examples of questions in the consent statement.To reduce the respondent burden, we used a two-choice format, with no option of choosing neither. The number of levels for each attribute was minimized, with three OS levels and two for the other characteristics .In order to consider the efficiency of the estimation, based on the D-optimal design, the number of profiles were 48. The less than 48 profiles dropped the D-efficiency significantly. We created a questionnaire in Japanese comprising comparative combinations of profiles with the same attribute levels. Two sets of 14 questions were prepared, including four questions with one attribute difference between two profiles, to check the respondent’s reliability. The respondents answered the 14 questions from a randomly assigned set. We did not evaluate the strength of the preference or the level of confidence in the response; we simply queried the preferred treatment. An example of the questionnaire is shown in Based on previous literature , we collAn anonymous web-based questionnaire with a reward was administered from November 25, 2019, to November 27, 2019. Out of the 448 lung cancer patients in the panel held by Rakuten Insight, Inc., 200 people were enrolled in our study.The minimum sample size as calculated by the Johnson and Orme method  for conjProspective participants were informed that they needed to be lung cancer patients to participate in the study. Lung cancer diagnosis was based on the participant’s self-report, and no medical diagnosis was made to confirm the condition.The relative importance of patient preferences for each attribute was estimated using a conditional logit model , and the study registration was published in the University Hospital Medical Information Network (UMIN) as study ID: UMIN000039087. We obtained prior written consent from the respondents for analysis and publication of the results.Of the total 200 respondents, 191 were included in the subsequent analysis, excluding the nine unreliable respondents who chose the same option for all questions. The patient background data is shown in The relative importance of patient preferences for each attribute as the main effects estimated by the conditional logit model is shown in For sensitivity analyses, we estimated the results by excluding nine unreliable respondents who chose the same option for all questions and who did not make the correct choice in the dominated pair questions. The results of the sensitivity analyses are shown in the Of the demographic characteristics added to the model as explanatory variables, only age was expressed on an ordinal scale for each decade, while the other items were expressed on a binary nominal scale. A chi-square test was performed to investigate the relationship between demographic characteristics . Based oThe associations between the patient demographic characteristics and the preferences for each treatment attribute are shown in There was no substantial difference between these results and those of the subpopulation analysis, thus confirming the robustness of the results.This is the first study to quantify preferences for the benefit and risk profile of anticancer drugs in Japanese lung cancer patients. Our results clarify that survival time is the most important attribute, followed by adverse events, PFS, and the frequency and duration of administration. Additionally, the results showed the benefit and risk attributes valued by Japanese patients in relation to demographic characteristics and experience with anticancer treatment.With respect to the treatment benefit, Japanese patients considered OS as the most important attribute and PFS as the less important one. These preferences were consistent with those in previous studies . AlthougRegarding risk characteristics, patients did not consider fatigue and interstitial pneumonia important compared to the other safety attributes. Although many previous studies on lung cancer  demonstrOur regression results showed that preferences for treatment attributes are influenced by patient demographic characteristics . CompareIn this study, we reported varied importance of nausea depending on where the respondents live. However, such findings are difficult to interpret considering the lack of previous reports showing such regional disparities in the preferences of lung cancer patients. The number of physicians per population is higher in western Japan than in eastern Japan , and theSCLC accounts for about 13–15% of lung cancers worldwide . Our samPatients with higher education and/or income regarded OS as more important. No previous studies have shown a similar relationship between OS and education or income. A study on lung cancer  that incPFS was more important in patients who had experience with anticancer drugs. This is possibly because most patients with no experience of anticancer drugs have experience of surgery; thus, they have little concern for tumor shrinkage or progression. In contrast, patients with experience of anticancer drugs focus on tumor shrinkage or progression as part of drug response. Patients with prior experience of adverse events of anticancer drugs understood the importance of the benefits and adverse events. Our results showed that the importance of long-term OS, rash, and ILD was lower in such patient groups. The low importance of these two side effects may be due to both their severity and frequency; the rash may be experienced by many respondents but is relatively less severe, while ILD, if it occurs, is severe but less frequent, and few respondents experienced it.Our results underscore the importance of considering several demographic characteristics in the models to better estimate patient preferences. Based on the results from the hierarchical Bayesian model and the subpopulation analysis, we believe that gender and cancer type and stage should be included in a preference model as they showed substantial differences in preferences for several attributes. Age should also be included in the preference model, given the large amount of prior literature on lung cancer . Cancer A large percentage of respondents had at least one or more “incorrect” choices for each of the four dominated pair questions; only 47.5% of respondents answered all of them correctly. The reliability of web-based conjoint analysis has been doubted . For exaThis study has several limitations. First, we could not assess the importance of attributes in different settings, such as thyroid dysfunction in immunotherapy or bleeding events in molecularly targeted drugs, or change attribute levels beyond our settings. Second, our respondent population may not be representative of the “average” patient. Compared to the most recent lung cancer statistics in Japan , the resThis is the first study to focus on discrete choice experiment to determine the preferences of Japanese patients with lung cancer. Survival time was the most important attribute, followed by adverse events, PFS, and frequency and duration of administration. The preferences were dependent on demographic characteristics  and disease background . Interestingly, the experience of cancer drug therapies and adverse events seems to have a substantial impact on the preferences of hypothetical drug treatment. These results suggest the importance of patient experience considering patient preference. Hereafter, it would be better to design a quantitative preference study and analysis model that also takes into account the patient’s demographic and experience. Understanding patient preferences in detail would help select drugs that satisfy their needs and inform decisions for the clinical development of drugs for future patient generations.