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Abstract Given the substantial body of educational research highlighting the significant influence of student attitudes on academic performance, particularly in disciplines like statistics where anxiety is prevalent, there is a need to investigate how innovative methodologies could reshape these attitudes. This paper will capitalize on the advancements from previously uncombined innovative methodologies of teaching statistics, such as project-based learning, data analytics, collaborative work, or the use of technology. Specifically, this paper reports on the design, implementation, and evaluation of innovative technology-enhanced, collaborative, and data-driven project-based learning, aiming to positively impact students’ attitudes towards statistics as a cornerstone to improve statistical knowledge. To achieve this, a quasi-experimental research study involving 174 secondary students was undertaken, with participants divided into an experimental group (EG) and a control group (CG). Results indicate a notable positive shift in attitudes among EG students following the intervention. The EG students decreased their anxiety after the intervention and, increased their affect and positive attitude toward using technology for learning statistics. By contrast, the CG students do not show any positive effect on their attitudes. These findings underscore the potential of the innovative instructional design implemented in this project to not only foster practical statistical problem-solving skills but also cultivate positive attitudes crucial for statistical competence. Educational implications are discussed.

The growing body of creativity research involves Artificial Intelligence (AI) and Machine learning (ML) approaches to automatically evaluating creative solutions. However, numerous challenges persist in evaluating the creativity dimensions and the methodologies employed for automatic evaluation. This paper contributes to this research gap with a scoping review that maps the Natural Language Processing (NLP) approaches to computations of different creativity dimensions. The review has two research objectives to cover the scope of automatic creativity evaluation: to identify different computational approaches and techniques in creativity evaluation and, to analyze the automatic evaluation of different creativity dimensions. As a first result, the scoping review provides a categorization of the automatic creativity research in the reviewed papers into three NLP approaches, namely: text similarity, text classification, and text mining. This categorization and further compilation of computational techniques used in these NLP approaches help ameliorate their application scenarios, research gaps, research limitations, and alternative solutions. As a second result, the thorough analysis of the automatic evaluation of different creativity dimensions differentiated the evaluation of 25 different creativity dimensions. Attending similarities in definitions and computations, we characterized seven core creativity dimensions, namely: novelty, value, flexibility, elaboration, fluency, feasibility, and others related to playful aspects of creativity. We hope this scoping review could provide valuable insights for researchers from psychology, education, AI, and others to make evidence-based decisions when developing automated creativity evaluation.

Species traits often vary in a coordinated manner, making up an ecological strategy comprised of suites of interrelated traits. Environmental gradients, such as those along elevational gradients, provide an ideal venue in which to examine variation in ecological strategies with the environment. We examined variation in the morphological strategies of ants along elevational gradients on thirteen mountains across three mountain ranges in central and south-eastern Australia. We pitfall-trapped ants, counted and identified workers and measured morphological traits. Most species showed a hump-shaped relationship between occurrence and elevation, and several responded to microhabitat variables. Morphological traits varied along two key axes: “gracility”, where high values indicated longer-legged species with dorsally positioned eyes and smooth, bare cuticles; and “size and darkness”, where species with high values were larger and darker. Analysis of assemblage-weighted means revealed that gracility decreased with temperature and increased with precipitation, suggesting links with desiccation tolerance. Size and darkness increased with UV-B, declined with increasing canopy cover and peaked at mid-temperatures. We thus detected strong shifts in dominant morphological strategies along our elevational gradients. However, the multifunctionality and interrelatedness of traits and the covariance of climatic factors may make isolation of the function of individual traits difficult. Further, the predictive power of our models may be limited in the context of novel environments predicted under global change.

The importance of cultivating creativity in language education has been widely acknowledged in the academic literature. In this respect, digital technologies can play a key role in achieving this endeavour. The socio-cultural conceptualization of creativity stresses the role of communication, collaboration and dialogical interaction of creative expression in language education. The objective of this paper is to study the literature focusing on cases of collaborative creativity and technology embedded in language education. To this end, we carry out a systematic revision of state-of-the-art literature consisting of 26 blind peer-reviewed empirical studies selected from several databases that address our main research question, namely, which specific roles and forms of digital technology can be identified in the existing literature that support collaborative creativity in language education. Results show that the features of digital technology unfold a range of learning opportunities in language education and can play three different roles in promoting collaborative creativity: (1) as a tutoring device that guides the implementation of key co-creation skills; (2) as a tool that enables and shapes the development of co-creative thinking skills; and (3) as a medium that creates rich and resourceful environments to stimulate the emergence of collective creative processes. The paper also reveals that these three roles can be performed using a wide range of interactive technologies that encourage students to participate in a rich, co-creative language learning experience and equip learners with key competences to approach complex problems in a globalised and hyper-connected world. Finally, this paper may contribute to developing future language technology-enhanced learning projects capable of promoting key collaborative and creative processes.

PURPOSE: Gastric cancer (GC) is among the leading causes of cancer mortality worldwide. The objective of this study was to investigate the association between dietary fiber intake and GC. METHODS: We pooled data from 11 population or hospital-based case-control studies included in the Stomach Cancer Pooling (StoP) Project, for a total of 4865 histologically confirmed cases and 10,626 controls. Intake of dietary fibers and other dietary factors was collected using food frequency questionnaires. We calculated the odds ratios (OR) and 95% confidence intervals (CI) of the association between dietary fiber intake and GC by using a multivariable logistic regression model adjusted for study site, sex, age, caloric intake, smoking, fruit and vegetable intake, and socioeconomic status. We conducted stratified analyses by these factors, as well as GC anatomical site and histological type. RESULTS: The OR of GC for an increase of one quartile of fiber intake was 0.91 (95% CI: 0.85, 0.97), that for the highest compared to the lowest quartile of dietary fiber intake was 0.72 (95% CI: 0.59, 0.88). Results were similar irrespective of anatomical site and histological type. CONCLUSION: Our analysis supports the hypothesis that dietary fiber intake may exert a protective effect on GC.

The purpose of this paper is to examine the relationship between happiness at work and cross-selling performance in the banking sector. In addition, the mediating effect of service-skill use is analyzed in the relationship between happiness at work and performance. Confirmatory factor analysis is used by means of structural equation models to assess the relationship between happiness at work, service-skill use, and cross-selling performance. A sample of 492 financial service employees is examined. Results reveal that happiness at work positively and directly affects cross-selling performance. The study also shows that service-skill use plays a partial mediating role in the relationship between happiness at work and cross-selling performance. This research expands the theory of the happy productive worker perspective based on the job demands-resources model and defines and conceptualizes service-skill use. Employees who are happier at work cross-sell better, but their service-skill use mediates the effect of happiness at work on cross-selling performance.

Enhancing creativity and developing technology skills in the classroom are the future of education and can turn out to be powerful tools to smooth out inequalities in class. This paper presents a systematic scoping review study of the literature focusing on cases of social creativity and digital technology embedded in science education. To this end, 23 empirical studies were selected from several databases—all in English and subjected to a blind peer-review process—to address the interconnectedness of key themes encapsulated in the following three research questions: (i) which digital technology roles support collaborative and creative processes in science education? (ii) which forms of technology and technological features support and organize the aforementioned creative processes? and (iii) what pedagogical principles guide the promotion of social creativity using technology in science education and involve all the students? Results show that technology can play different roles in promoting social creativity: (1) as a tutoring device that nurtures some key science creative processes; (2) as a tool that shapes students' creative thinking; and (3) as a medium that builds the supportive environment to perform collective creativity processes. In our project, these three roles were performed using a wide range of web 2.0 technologies (e.g., web-based environments, digital platforms, mobile technology) that both engaged all students in active and rich user experience for collective knowledge creation and equipped all learners with the necessary skills that would turn them into active, i.e., dynamic and resourceful, citizens in a swiftly changing world.

Abstract The circadian clock and its output pathways play a pivotal role in optimizing daily processes. To obtain insights into how diverse rhythmic physiology and behaviors are orchestrated, we have generated a comprehensive connectivity map of an animal circadian clock using the Drosophila FlyWire brain connectome. Intriguingly, we identified additional dorsal clock neurons, thus showing that the Drosophila circadian network contains ~240 instead of 150 neurons. We revealed extensive contralateral synaptic connectivity within the network and discovered novel indirect light input pathways to the clock neurons. We also elucidated pathways via which the clock modulates descending neurons that are known to regulate feeding and reproductive behaviors. Interestingly, we observed sparse monosynaptic connectivity between clock neurons and downstream higher-order brain centers and neurosecretory cells known to regulate behavior and physiology. Therefore, we integrated single-cell transcriptomics and receptor mapping to decipher putative paracrine peptidergic signaling by clock neurons. Our analyses identified additional novel neuropeptides expressed in clock neurons and suggest that peptidergic signaling significantly enriches interconnectivity within the clock network.

Scarcity of freshwater for agriculture has led to increased utilization of treated wastewater (TWW), establishing it as a significant and reliable source of irrigation water. However, years of research indicate that if not managed adequately, TWW may deleteriously affect soil functioning and plant productivity, and pose a hazard to human and environmental health. This review leverages the experience of researchers, stakeholders, and policymakers from Israel, the United-States, and Europe to present a holistic, multidisciplinary perspective on maximizing the benefits from municipal TWW use for irrigation. We specifically draw on the extensive knowledge gained in Israel, a world leader in agricultural TWW implementation. The first two sections of the work set the foundation for understanding current challenges involved with the use of TWW, detailing known and emerging agronomic and environmental issues (such as salinity and phytotoxicity) and public health risks (such as contaminants of emerging concern and pathogens). The work then presents solutions to address these challenges, including technological and agronomic management-based solutions as well as source control policies. The concluding section presents suggestions for the path forward, emphasizing the importance of improving links between research and policy, and better outreach to the public and agricultural practitioners. We use this platform as a call for action, to form a global harmonized data system that will centralize scientific findings on agronomic, environmental and public health effects of TWW irrigation. Insights from such global collaboration will help to mitigate risks, and facilitate more sustainable use of TWW for food production in the future.

Increasing evidence suggests that intact social bonds are protective against age-related morbidity, while bond disruption and social isolation increase the risk for multiple age-related diseases. Social attachments, the enduring, selective bonds formed between individuals, are thus essential to human health. Socially monogamous species like the prairie vole (M. ochrogaster) form long-term pair bonds, allowing us to investigate the mechanisms underlying attachment and the poorly understood connection between social bonds and health. In this review, we explore several potential areas of focus emerging from data in humans and other species associating attachment and healthy aging, and evidence from prairie voles that may clarify this link. We examine gaps in our understanding of social cognition and pair bond behavior. Finally, we discuss physiologic pathways related to pair bonding that promote resilience to the processes of aging and age-related disease. Advances in the development of molecular genetic tools in monogamous species will allow us to bridge the mechanistic gaps presented and identify conserved research and therapeutic targets relevant to human health and aging.

The association between sleep and stress and cancer is underinvestigated. We evaluated these factors in association with gastric cancer (GC). Five case-control studies from the Stomach Cancer Pooling (StoP) Project were included. We calculated the odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for sleep duration and stress level in association with GC through multiple logistic regression models adjusted for several lifestyle factors. The analysis included 1293 cases and 4439 controls, 215 cardia and 919 noncardia GC, and 353 diffuse and 619 intestinal types. Sleep duration of ≥9 h was associated with GC (OR =1.57, 95% CI = 1.23-2.00) compared to 8 h. This was confirmed when stratifying by subsite (noncardia OR = 1.59, 95% CI = 1.22-2.08, and cardia OR = 1.63, 95% CI = 0.97-2.72) and histological type (diffuse OR = 1.65, 95% CI = 1.14-2.40 and intestinal OR = 1.24, 95% CI = 0.91-1.67). Stress was associated with GC (OR = 1.33, 95% CI = 1.18-1.50, continuous). This relationship was selectively related to noncardia GC (OR = 1.28, 95% 1.12-1.46, continuous). The risk of diffuse (OR = 1.32, 95% CI = 1.11-1.58) and intestinal type (OR = 1.23, 95% CI = 1.07-1.42) were higher when stress was reported. Results for the association between increasing level of stress and GC were heterogeneous by smoking and socioeconomic status (p for heterogeneity = 0.02 and

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Edible mushrooms have high concentrations of vitamins and minerals. They are considered functional foods for their disease-prevention properties. Mushroom consumption may reduce the risk of gastric cancer, the fifth most common cancer worldwide. We investigated the association between mushroom consumption and gastric cancer risk in a pooled analysis within the Stomach Cancer Pooling (StoP) Project and in a meta-analysis that also included previously published studies. A total of 3900 gastric cancer cases and 7792 controls from 11 studies were included in the StoP analysis. Mushroom consumption was measured using food frequency questionnaires. Higher mushroom consumption was associated with a lower risk of gastric cancer [relative risk (RR) for the highest vs. lowest consumption categories, 0.82; 95% confidence interval (CI), 0.71-0.95]. The corresponding RRs were 0.59 (95% CI, 0.26-1.33) in a meta-analysis of four previously published studies and 0.77 for all studies combined (95% CI, 0.63-0.95; n = 15 studies). In geographic subgroup analysis, the pooled risk in Western Pacific countries was (RR, 0.59; 95% CI, 0.40-0.87; n = 6). The stronger effect in Asian countries may reflect high level of antioxidants in mushroom species consumed in Asia.

Prairie voles are among a small group of mammals that display long-term social attachment between mating partners. Many pharmacological studies show that signaling via the oxytocin receptor (Oxtr) is critical for the display of social monogamy in these animals. We used CRISPR mutagenesis to generate three different Oxtr-null mutant prairie vole lines. Oxtr mutants displayed social attachment such that males and females showed a behavioral preference for their mating partners over a stranger of the opposite sex, even when assayed using different experimental setups. Mothers lacking Oxtr delivered viable pups, and parents displayed care for their young and raised them to the weanling stage. Together, our studies unexpectedly reveal that social attachment, parturition, and parental behavior can occur in the absence of Oxtr signaling in prairie voles.

BackgroundYoghurt can modify gastrointestinal disease risk, possibly acting on gut microbiota. Our study aimed at exploring the under-investigated association between yoghurt and gastric cancer (GC).MethodsWe pooled data from 16 studies from the Stomach Cancer Pooling (StoP) Project. Total yoghurt intake was derived from food frequency questionnaires. We calculated study-specific odds ratios (ORs) of GC and the corresponding 95% confidence intervals (CIs) for increasing categories of yoghurt consumption using univariate and multivariable unconditional logistic regression models. A two-stage analysis, with a meta-analysis of the pooled adjusted data, was conducted.ResultsThe analysis included 6278 GC cases and 14,181 controls, including 1179 cardia and 3463 non-cardia, 1191 diffuse and 1717 intestinal cases. The overall meta-analysis revealed no association between increasing portions of yoghurt intake (continuous) and GC (OR = 0.98, 95% CI = 0.94-1.02). When restricting to cohort studies, a borderline inverse relationship was found (OR = 0.93, 95% CI = 0.88-0.99). The adjusted and unadjusted OR were 0.92 (95% CI = 0.85-0.99) and 0.78 (95% CI = 0.73-0.84) for any vs. no yoghurt consumption and GC risk. The OR for 1 category of increase in yoghurt intake was 0.96 (95% CI = 0.91-1.02) for cardia, 1.03 (95% CI = 1.00-1.07) for non-cardia, 1.12 (95% CI = 1.07-1.19) for diffuse and 1.02 (95% CI = 0.97-1.06) for intestinal GC. No effect was seen within hospital-based and population-based studies, nor in men or women.ConclusionsWe found no association between yoghurt and GC in the main adjusted models, despite sensitivity analyses suggesting a protective effect. Additional studies should further address this association.

The goal of the present research was to assess the environmental worldviews and concerns of students from the fourth to the seventh grade in Slovenia. The New Ecological Paradigm Scale for Children was translated and validated for use with Slovenian primary school students (N = 310). The students were also asked about their environmental concerns (using statements from the Environmental Motives Scale) and demographic questions. A confirmatory factor analysis was conducted for the New Ecological Paradigm scale using AMOS software, confirming a three-dimensional model with ten items. The students showed the highest agreement with the items in the factor Rights of Nature, and the lowest agreement with Human Exemptionalism. The environmental attitudes of the students decreased from the fourth to the seventh grade, while altruistic environmental concerns significantly increased with higher grades. Gender differences were not statistically significant for environmental worldviews and concerns. The reported results show that biospheric environmental concern positively correlates with the factors Rights of Nature and belief in Eco-Crisis, and negatively correlates with Human Exemptionalism. The New Ecological Paradigm tool will enable the evaluation of education programmes for children in Slovenia.

BackgroundTreatment and prophylaxis options for neonatal HIV are limited. This study aimed to develop a population pharmacokinetic model to characterize the disposition of maraviroc in neonates to inform dosing regimens and expand available options.MethodsUsing maraviroc concentrations from neonates who received either a single dose or multiple doses of 8 mg/kg of maraviroc in the first 6 weeks of life, a population pharmacokinetic model was developed to determine the effects of age, sex, maternal efavirenz exposure and concomitant ARV therapy on maraviroc disposition. The final model was used in Monte Carlo simulations to generate expected exposures with recommended dosing regimens.ResultsA total of 396 maraviroc concentrations, collected in the first 4 days of life, at 1 week, at 4 weeks and at 6 weeks, from 44 neonates were included in the analysis. After allometrically scaling for weight, age less than 4 days was associated with a 44% decreased apparent clearance compared with participants 7 days to 6 weeks of life. There were no differences identified in apparent clearance or volume of distribution from ages 7 days to 6 weeks, sex, maternal efavirenz exposure or concomitant nevirapine therapy. Monte Carlo simulations with FDA-approved weight band dosing resulted in the majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL.ConclusionsWhile maraviroc apparent clearance is decreased in the first few days of life, the current FDA-approved maraviroc weight band dosing provides maraviroc exposures for neonates in the first 6 weeks of life, which were consistent with adult maraviroc exposure range. Maraviroc provides another antiretroviral treatment option for very young infants.

BackgroundEvidence from epidemiological studies on the role of tea drinking in gastric cancer risk remains inconsistent. We aimed to investigate and quantify the relationship between tea consumption and gastric cancer in the Stomach cancer Pooling (StoP) Project consortium.MethodsA total of 9438 cases and 20,451 controls from 22 studies worldwide were included. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of gastric cancer for regular versus non-regular tea drinkers were estimated by one and two-stage modelling analyses, including terms for sex, age and the main recognised risk factors for gastric cancer.ResultsCompared to non-regular drinkers, the estimated adjusted pooled OR for regular tea drinkers was 0.91 (95% CI: 0.85-0.97). When the amount of tea consumed was considered, the OR for consumption of 1-2 cups/day was 1.01 (95% CI: 0.94-1.09) and for >3 cups/day was 0.91 (95% CI: 0.80-1.03). Stronger inverse associations emerged among regular drinkers in China and Japan (OR: 0.67, 95% CI: 0.49-0.91) where green tea is consumed, in subjects with H. pylori infection (OR: 0.68, 95% CI: 0.58-0.80), and for gastric cardia cancer (OR: 0.64, 95% CI: 0.49-0.84).ConclusionOur results indicate a weak inverse association between tea consumption and gastric cancer.

BackgroundThe causal pathway between high education and reduced risk of gastric cancer (GC) has not been explained. The study aimed at evaluating the mediating role of lifestyle factors on the relationship between education and GC METHODS: Ten studies with complete data on education and five lifestyle factors (smoking, alcohol drinking, fruit and vegetable intake, processed meat intake and salt consumption) were selected from a consortium of studies on GC including 4349 GC cases and 8441 controls. We created an a priori score based on the five lifestyle factors, and we carried out a counterfactual-based mediation analysis to decompose the total effect of education on GC into natural direct effect and natural indirect effect mediated by the combined lifestyle factors. Effects were expressed as odds ratios (ORs) with a low level of education as the reference category.ResultsThe natural direct and indirect effects of high versus low education were 0.69 (95% CI: 0.62-0.77) and 0.96 (95% CI: 0.95-0.97), respectively, corresponding to a mediated percentage of 10.1% (95% CI: 7.1-15.4%). The mediation effect was limited to men.ConclusionsThe mediation effect of the combined lifestyle factors on the relationship between education and GC is modest. Other potential pathways explaining that relationship warrants further investigation.

In today's age of information, the use of data is very powerful in making informed decisions. Data analytics is a field that is interested in identifying and interpreting trends and patterns within big data to make data-driven decisions. We focus on informal statistical inference and data modeling as a means of developing students' data analytics skills in school. In this study, we examine how students apply the data modeling process to draw informal inferences when exploring trends, patterns and relationships in a real dataset using technological tools, such as CODAP and Excel. We analyzed 17-18-year-old students' written reports on their explorations of data supplied by third parties. Students used a variety of statistical measures and visualizations to account for variability in analyzing data. They tended to make statements with certainty in their inferences and predictions beyond the data. When the pattern in the data was uncertain, they were inclined to use contextual knowledge to remain certain in their claims.

This article reports on the main experiences gained from a teaching intervention which utilised the alternate reality game 'Helping Nemo' in an augmented reality environment for formative assessment. The purpose of the study was to explore the ways in which the affordances arising from the combination of alternate reality games and augmented reality, situated in the context of Universal Design for Learning, might facilitate students' learning amongst the aspects of engagement, participation, and response to students' variability. The study took place in a public primary school located in a rural area of Cyprus. A second-grade class consisting of 24 students aged 7-8 years old was selected to comprise the sample. A qualitative research approach was adopted. The data collection methods included classroom observations and focus groups with the students. Findings gained from the teaching intervention suggest that the creation of a multimodal environment that draws on the principles of Universal Design for Learning and combines the affordances of alternate reality games and augmented reality for formative assessment contributes towards higher levels of engagement and participation in learning of all students, including bilingual students, students with learning disabilities, and students who are currently disengaged.

The purpose of this study is to explore the challenges and needs of teachers' who offer language support to young refugees within the framework of formal education in Greece. In a field where research is limited and at an initial stage, a qualitative inquiry was conducted in a public school, which host classes of reception for refugee students, in the region of Fthiotida, in Greece. In particular, an exploratory case study was conducted through semi-structured interviews and observations in formal educational environments. Five participants were engaged in semi-structured interviews while observations occurred in two of their classrooms. The findings of the inquiry demonstrated that within the framework of refugee teaching environments in Greece teachers faced several challenges regarding practical, sociocultural, religious, ethical and emotional issues. The findings of the study highlight the need for teacher education to help them cope with diversity issues in their classrooms.

BackgroundThe role of allium vegetables on gastric cancer (GC) risk remains unclear.MethodsWe evaluated whether higher intakes of allium vegetables reduce GC risk using individual participant data from 17 studies participating in the "Stomach cancer Pooling (StoP) Project", including 6097 GC cases and 13,017 controls. Study-specific odds ratios (ORs) were pooled using a two-stage modelling approach.ResultsTotal allium vegetables intake was inversely associated with GC risk. The pooled OR for the highest versus the lowest study-specific tertile of consumption was 0.71 (95% confidence interval, CI, 0.56-0.90), with substantial heterogeneity across studies (I2 > 50%). Pooled ORs for high versus low consumption were 0.69 (95% CI, 0.55-0.86) for onions and 0.83 (95% CI, 0.75-0.93) for garlic. The inverse association with allium vegetables was evident in Asian (OR 0.50, 95% CI, 0.29-0.86) but not European (OR 0.96, 95% CI, 0.81-1.13) and American (OR 0.66, 95% CI, 0.39-1.11) studies. Results were consistent across all other strata.ConclusionsIn a worldwide consortium of epidemiological studies, we found an inverse association between allium vegetables and GC, with a stronger association seen in Asian studies. The heterogeneity of results across geographic regions and possible residual confounding suggest caution in results interpretation.

Increasing prevalence of infections caused by antimicrobial-resistant gram-negative bacteria represents a global health crisis, and while several novel therapies that target various aspects of antimicrobial resistance have been introduced in recent years, few are currently approved for children. Ceftazidime-avibactam is a novel β-lactam β-lactamase inhibitor combination approved for adults and children 3 months and older with complicated intra-abdominal infection, and complicated urinary tract infection or hospital-acquired ventilator-associated pneumonia (adults only in the United States) caused by susceptible gram-negative bacteria. Extensive population pharmacokinetic (PK) data sets for ceftazidime and avibactam obtained during the adult clinical development program were used to iteratively select, modify, and validate the approved adult dosage regimen (2,000-500 mg by 2-hour intravenous (IV) infusion every 8 hours (q8h), with adjustments for renal function). Following the completion of one phase I (NCT01893346) and two phase II ceftazidime-avibactam studies (NCT02475733 and NCT02497781) in children, adult PK data sets were updated with pediatric PK data. This paper describes the development of updated combined adult and pediatric population PK models and their application in characterizing the population PK of ceftazidime and avibactam in children, and in dose selection for further pediatric evaluation. The updated models supported the approval of ceftazidime-avibactam pediatric dosage regimens (all by 2-hour IV infusion) of 50-12.5 mg/kg (maximum 2,000-500 mg) q8h for those ≥6 months to 18 years old, and 40-10 mg/kg q8h for those ≥3 to 6 months old with creatinine clearance > 50 mL/min/1.73 m2 .

Background: Inconsistent findings have been reported regarding the relationship between dietary iron intake and the risk of gastric cancer (GC). Methods: We pooled data from 11 case-control studies from the Stomach Cancer Pooling (StoP) Project. Total dietary iron intake was derived from food frequency questionnaires combined with national nutritional tables. We derived the odds ratios (ORs) and 95% confidence intervals (CIs) for quartiles of dietary iron through multivariable unconditional logistic regression models. Secondary analyses stratified by sex, smoking status, caloric intake, anatomical subsite and histological type were performed. Results: Among 4658 cases and 12247 controls, dietary iron intake was inversely associated with GC (per quartile OR 0.88; 95% CI: 0.83-0.93). Results were similar between cardia (OR = 0.85, 95% CI = 0.77-0.94) and non-cardia GC (OR = 0.87, 95% CI = 0.81-0.94), and for diffuse (OR = 0.79, 95% CI = 0.69-0.89) and intestinal type (OR = 0.88, 95% CI = 0.79-0.98). Iron intake exerted an independent effect from that of smoking and salt intake. Additional adjustment by meat and fruit/vegetable intake did not alter the results. Conclusions: Dietary iron is inversely related to GC, with no difference by subsite or histological type. While the results should be interpreted with caution, they provide evidence against a direct effect of iron in gastric carcinogenesis.