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BACKGROUND: The health visiting service in UK promotes the health and wellbeing of families with young children and comprises a universal offer (three mandated contacts between birth and 12 months) and additional contacts based on need. We aimed to understand how the level of health visiting support received varies by family characteristics. METHODS: Using the Community Services Data Set linked to Hospital Episode Statistics, we identified 52 555 children in 10 local authorities with complete health visiting data for 12 months between April 2016 and March 2020. We analysed variation in health visiting contacts by deprivation, child ethnicity, maternal age, adversity and previous live births. RESULTS: 41 340/52 555 children (79%) received the universal service; 63% received ≥1 additional contact and 25% received ≥3 additional contacts. The likelihood of receiving ≥3 additional contacts was greatest for children whose mothers had a history of hospital admissions relating to mental health, violence, self-harm or substance misuse (adjusted relative risk = 1.55, 95% confidence interval 1.26-1.92). CONCLUSIONS: Most families received health visiting support in addition to the universal service. Policymakers and commissioners should consider how health visiting services can be expanded or targeted more effectively to ensure all families receive the support they need.

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The biological pump supplies carbon to the oceans' interior, driving long-term carbon sequestration and providing energy for deep-sea ecosystems1,2. Its efficiency is set by transformations of newly formed particles in the euphotic zone, followed by vertical flux attenuation via mesopelagic processes3. Depth attenuation of the particulate organic carbon (POC) flux is modulated by multiple processes involving zooplankton and/or microbes4,5. Nevertheless, it continues to be mainly parameterized using an empirically derived relationship, the 'Martin curve'6. The derived power-law exponent is the standard metric used to compare flux attenuation patterns across oceanic provinces7,8. Here we present in situ experimental findings from C-RESPIRE9, a dual particle interceptor and incubator deployed at multiple mesopelagic depths, measuring microbially mediated POC flux attenuation. We find that across six contrasting oceanic regimes, representing a 30-fold range in POC flux, degradation by particle-attached microbes comprised 7-29 per cent of flux attenuation, implying a more influential role for zooplankton in flux attenuation. Microbial remineralization, normalized to POC flux, ranged by 20-fold across sites and depths, with the lowest rates at high POC fluxes. Vertical trends, of up to threefold changes, were linked to strong temperature gradients at low-latitude sites. In contrast, temperature played a lesser role at mid- and high-latitude sites, where vertical trends may be set jointly by particle biochemistry, fragmentation and microbial ecophysiology. This deconstruction of the Martin curve reveals the underpinning mechanisms that drive microbially mediated POC flux attenuation across oceanic provinces.

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BACKGROUND: Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. METHODS AND RESULTS: In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. CONCLUSIONS: Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. REGISTRATION: https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

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The continued emergence of antimalarial drug resistance highlights the need to develop new antimalarial therapies. Unfortunately, new drug development is often hampered by poor drug-like properties of lead compounds. Prodrugging temporarily masks undesirable compound features, improving bioavailability and target penetration. We have found that lipophilic diester prodrugs of phosphonic acid antibiotics, such as fosmidomycin, exhibit significantly higher antimalarial potency than their parent compounds (1). However, the activating enzymes for these prodrugs were unknown. Here, we show that an erythrocyte enzyme, acylpeptide hydrolase (APEH) is the major activating enzyme of multiple lipophilic ester prodrugs. Surprisingly, this enzyme is taken up by the malaria parasite, Plasmodium falciparum, where it localizes to the parasite cytoplasm and retains enzymatic activity. Using a novel fluorogenic ester library, we characterize the structure activity relationship of APEH, and compare it to that of P. falciparum esterases. We show that parasite-internalized APEH plays an important role in the activation of substrates with branching at the alpha carbon, in keeping with its exopeptidase activity. Our findings highlight a novel mechanism for antimicrobial prodrug activation, relying on a host-derived enzyme to yield activation at a microbial target. Mutations in prodrug activating enzymes are a common mechanism for antimicrobial drug resistance (2-4). Leveraging an internalized host enzyme would circumvent this, enabling the design of prodrugs with higher barriers to drug resistance.

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BACKGROUND: Patients with rectal cancer are often treated with neoadjuvant chemoradiotherapy, followed by a waiting period and surgical resection. Good or complete response to neoadjuvant chemoradiotherapy might enable organ preservation, which highlights the need to increase response rates. Pre-clinical studies suggest that physical activity during neoadjuvant chemoradiotherapy may improve tumor downstaging. PURPOSE: To investigate whether physical activity and physical functioning of patients with rectal cancer at diagnosis are associated with tumor downstaging after neoadjuvant chemoradiotherapy. MATERIALS AND METHODS: Patients were included if they participated in the Dutch Prospective ColoRectal Cancer Cohort, a nationwide cohort providing an infrastructure for scientific research, and received neoadjuvant chemoradiotherapy for rectal cancer. Tumor downstaging was dichotomized into good/complete or moderate/poor downstaging. Physical activity (total physical activity, moderate-to-vigorous physical activity (MVPA), and Dutch physical activity guideline adherence) and physical functioning were assessed using questionnaires. Logistic regression analyses were performed to examine associations of physical activity and physical functioning with tumor downstaging, adjusted for relevant confounders. RESULTS: 268 patients (aged 62 ± 11 years, 33 % female) with rectal cancer were included. Patients with moderate (OR = 2.07; 95%CI = 1.07 - 4.07; p = 0.03) or high (OR = 2.05; 95%CI = 1.05 - 4.07; p = 0.04) levels of MVPA were more likely to have good/complete tumor downstaging than patients with low levels. No significant associations with tumor downstaging were found for total physical activity, Dutch physical activity guideline adherence, and physical functioning. CONCLUSIONS: We found augmented tumor downstaging in patients with rectal cancer with moderate or high levels of self-reported MVPA before the start of neoadjuvant chemoradiotherapy compared to patients with low levels.

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In palliative care patient problems often are complex and have elements that relate to more than one dimension and therefore require a multidisciplinary approach.In this article the methodical approach of "palliative reasoning" is described, which helps to analyse, treat and follow up complex patient problems in the palliative phase. Furthermore, tips, general recommendations and treatment options are described based on existing Dutch clinical practice palliative care guidelines, literature and expert opinion.

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INTRODUCTION: Machine learning models have shown promising potential in individual-level outcome prediction for patients with psychosis, but also have several limitations. To address some of these limitations, we present a model that predicts multiple outcomes, based on longitudinal patient data, while integrating prediction uncertainty to facilitate more reliable clinical decision-making. MATERIAL AND METHODS: We devised a recurrent neural network architecture incorporating long short-term memory (LSTM) units to facilitate outcome prediction by leveraging multimodal baseline variables and clinical data collected at multiple time points. To account for model uncertainty, we employed a novel fuzzy logic approach to integrate the level of uncertainty into individual predictions. We predicted antipsychotic treatment outcomes in 446 first-episode psychosis patients in the OPTiMiSE study, for six different clinical scenarios. The treatment outcome measures assessed at both week 4 and week 10 encompassed symptomatic remission, clinical global remission, and functional remission. RESULTS: Using only baseline predictors to predict different outcomes at week 4, leave-one-site-out validation AUC ranged from 0.62 to 0.66; performance improved when clinical data from week 1 was added (AUC = 0.66-0.71). For outcome at week 10, using only baseline variables, the models achieved AUC = 0.56-0.64; using data from more time points (weeks 1, 4, and 6) improved the performance to AUC = 0.72-0.74. After incorporating prediction uncertainties and stratifying the model decisions based on model confidence, we could achieve accuracies above 0.8 for ~50% of patients in five out of the six clinical scenarios. CONCLUSION: We constructed prediction models utilizing a recurrent neural network architecture tailored to clinical scenarios derived from a time series dataset. One crucial aspect we incorporated was the consideration of uncertainty in individual predictions, which enhances the reliability of decision-making based on the model's output. We provided evidence showcasing the significance of leveraging time series data for achieving more accurate treatment outcome prediction in the field of psychiatry.

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Odontogenic myxoma is a rare, benign, and locally aggressive tumor that develops in the tooth-bearing areas of the jaw. The molecular mechanisms underlying odontogenic myxomas are unknown and no diagnostic markers are available to date. The aim of this study was to analyze DNA methylation and copy number variations in odontogenic myxomas to identify new molecular signatures for diagnostic decision-making. We collected a cohort of 16 odontogenic myxomas from 2006 to 2021 located in the mandible (n = 10) and maxilla (n = 6) with available formalin-fixed paraffin-embedded or fresh frozen tumor tissue from a biopsy or resection material. Genome-wide DNA methylation and copy number variation data were generated from 12 odontogenic myxomas using the Illumina Infinium Methylation EPIC array, interrogating >850,000 CpG sites. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that odontogenic myxomas formed a distinct DNA methylation class. Copy number profiling showed recurrent whole-chromosome gains (trisomies) of chromosomes 5, 8, and 20 in all cases, and of chromosomes 10, 12, and 17 in all except one case. In conclusion, odontogenic myxomas harbor recurrent copy number patterns and a distinct DNA methylation profile, which can be used as an additional diagnostic tool in the appropriate clinical and radiologic context. Further research is needed to explain the genetic mechanisms caused by these alterations that drive these locally aggressive neoplasms.

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BACKGROUND: Robin sequence (RS) is characterized by micrognathia, glossoptosis, and upper airway obstruction, and is often combined with a cleft palate. It is unclear whether RS negatively impacts the development of velopharyngeal incompetence (VPI) and attainable speech outcomes. This study systematically reviewed speech outcomes in patients with cleft and isolated RS (IRS) compared with only isolated cleft palate (ICP). METHODS: A literature search following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines was performed using the PubMed and EMBASE databases. Articles reporting speech outcomes following primary palatoplasty in patients with IRS only or IRS versus ICP were identified. Study characteristics and methods, primary- and VPI palatoplasty, speech measurements, and post-operative complications were collected. Primary outcomes included VPI and need for speech correcting surgery (SCS). Methodological quality was appraised using the methodological index for non-randomized studies (MINORS) criteria (range: 0-16 and 0-24). RESULTS: Nineteen studies reported VPI event rates that varied between 14% and 88% for IRS and 0% and 62% for ICP. Five out of 8 studies (67%) comparing VPI event rates between IRS and ICP found no significant difference. SCS rates varied between 0% and 48% for IRS and 0% and 24% for ICP. Six out of 9 studies (67%) comparing SCS rates between IRS and ICP, found no significant difference. Combined VPI event rates were 36.1% for the IRS group and 26% for the ICP group, for SCS rates this was 20% for IRS and 13% for ICP. CONCLUSION: Most articles found no significant difference between the VPI and SCS rates indicating that speech outcomes might be similar in patients with IRS and ICP. To better compare these groups a standardized international protocol is needed.

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In the global efforts to combat antimicrobial resistance and reduce antimicrobial use in pig production, there is a continuous search for methods to prevent and/or treat infections. Within this scope, we explored the relationship between the developing piglet nasal microbiome and (zoonotic) bacterial pathogens from birth until 10 weeks of life. The nasal microbiome of 54 pigs was longitudinally studied over 16 timepoints on 9 farms in 3 European countries (Germany, Ireland, and the Netherlands) using amplicon sequencing targeting the V3-V4 16S rRNA region as well as the tuf gene for its staphylococcal discrimination power. The piglets' age, the farm, and the litter affected the nasal microbiome, with piglets' age explaining 19% of the variation in microbial composition between samples. Stabilization of the microbiome occurred around 2 weeks post-weaning. Notably, while opportunistic pathogens were ubiquitously present, they did not cause disease. The piglet nasal microbiome often carried species associated with gut, skin, or vagina, which suggests that contact with the vaginal and fecal microbiomes shapes the piglet nasal microbiome. We identified bacterial co-abundance groups of species that were present in the nasal microbiomes in all three countries over time. Anti-correlation between these species and known bacterial pathogens identified species that might be exploited for pathogen reduction. Further experimental evidence is required to confirm these findings. Overall, this study advances our understanding of the piglet nasal microbiome, the factors influencing it, and its longitudinal development, providing insights into its role in health and disease. IMPORTANCE: Our study on the nasal microbiota development in piglets across farms in three European countries found that the microbiomes developed similarly in all locations. Additionally, we observed that the colonization of porcine pathogens was either positively or negatively associated with the presence of other bacterial species. These findings enhance our knowledge of co-colonizing species in the nasal cavity and the identified microbial interactions that can be explored for the development of interventions to control pathogens in porcine husbandry.

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In this study, passive acoustic monitoring was used to assess the impact of investigator disturbance on the acoustic behavior of a colony of common terns. A graded antipredator response in the colony was hypothesized, which would result in an increase in acoustic energy with increased proximity to investigator disturbance. Human disturbance was found to result in a significant increase in acoustic energy within 20 meters of recorders, though not from farther distances. Our findings provide a framework for assessing the behavioral impact of disturbance on colonies and support the existence of a graded alarm call system in common terns.

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Motivated by the cellular heterogeneity in complex tissues, particularly in brain and induced pluripotent stem cell (iPSC)-derived brain models, we developed a complete workflow to reproducibly characterize cell types in complex tissues. Our approach combines a flow cytometry (FC) antibody panel with our computational pipeline CelltypeR, enabling dataset aligning, unsupervised clustering optimization, cell type annotating, and statistical comparisons. Applied to human iPSC derived midbrain organoids, it successfully identified the major brain cell types. We performed fluorescence-activated cell sorting of CelltypeR-defined astrocytes, radial glia, and neurons, exploring transcriptional states by single-cell RNA sequencing. Among the sorted neurons, we identified subgroups of dopamine neurons: one reminiscent of substantia nigra cells most vulnerable in Parkinson's disease. Finally, we used our workflow to track cell types across a time course of organoid differentiation. Overall, our adaptable analysis framework provides a generalizable method for reproducibly identifying cell types across FC datasets in complex tissues.

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Pushing selected information to clinicians, as opposed to the traditional method of clinicians pulling information from an electronic medical record, has the potential to improve care. A digital notification platform was designed by clinicians and implemented in a tertiary hospital to flag dysglycaemia. There were 112 patients included in the study, and the post-implementation group demonstrated lower rates of dysglycaemia (2.5% vs 1.1%, P = 0.038). These findings raise considerations for information delivery methods for multiple domains in contemporary healthcare.

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Seed priming with biostimulant for soybean is a promising practice contributing positively to the physiological quality and vigor of seedlings, but there are little studies regarding protocols of bioinputs, such as Ascophyllum nodosum L. seaweed extract. We aimed to evaluate the effect of doses of A. nodosum macroalgae in seed priming and its impact on germination and seedling vigor of soybean. Seeds were subjected to priming with A. nodosum extract (ANE) at doses of 0, 1, 2, 3, 4, and 5 mL kg seed-1 during 15 min. Priming with ANE did not influence the first count and seed germination. Soybean seedlings from priming with 5 mL kg-1 ANE showed higher growth and shoot and root dry biomass. We observed increase 18% for shoot dry matter with priming of 5 mL kg-1 ANE compared to untreated seeds. The responses were variable for the emergence speed index in function ANE and did not influence the photochemical processes in photosystem II. Seed priming with ANE contributed in higher chlorophyll index. ANE showed a biostimulant effect on soybean seedlings, providing better growth and biomass characteristics, being promising in seed priming, but further studies are suggested in order to increase information regarding its use protocol for soybean.

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OBJECTIVES: To determine the presence and categorise the severity of enteritis in dogs with gallbladder mucoceles, and evaluate for any associations with enteritis. This study also aimed to report clinical outcome following cholecystectomy and evaluate for associations with survival. MATERIALS AND METHODS: Medical records were retrospectively reviewed (2014 to 2021) for dogs undergoing cholecystectomy and duodenal biopsy procedures for gallbladder mucocele. Signalment, bloodwork, abdominal ultrasound findings, surgical details, histology results and outcomes were reported. Surgeries were considered elective or emergent based on each dog's clinical presentation. Enteritis was categorised based on cell type and severity. Inflammation and clinical outcome were statistically evaluated. RESULTS: Seventy-one dogs met the study criteria. Enteritis was present in 85.9% (61/71) of cases with the majority being lymphoplasmacytic (53.5%). Twelve dogs (16.9%) underwent gastrointestinal biopsies from multiple sites, which revealed the same enteritis type at each location. A total of 87.3% (n = 62) dogs survived, including 90.4% elective and 86% emergent cases. No significant differences in enteritis severity or patient survival were found between elective and emergent cases. Septic peritonitis was diagnosed in two dogs (2.82%). Mortality was significantly associated with leukocytosis, with nonsurviving dogs having a mean WBC count of 27.6 G/L (95% confidence interval: 10.6 to 21.5). CLINICAL SIGNIFICANCE: Enteritis is present in a majority of dogs with gallbladder mucocele, especially mild to moderate with lymphoplasmacytic cell type. Obtaining a duodenal biopsy had minimal impact on patient outcome. Compared to previous studies, improved survival in emergent cases was noted. Further studies with long-term follow-up are needed to determine if enteropathy-related signs persist after cholecystectomy.

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To date, published comprehensive pathology investigations documented in Steller sea lions (SSL; Eumetopias jubatus) are from free-ranging populations, whereas health data from those under professional care in aquariums are currently lacking. A retrospective review of gross and histopathologic reports of SSL under human care in North American aquariums from 1979 to 2021 (n = 20) was performed. Associations between age, sex, or birth origin (born in aquariums versus the wild) with cause of death (COD) and comorbidities were explored. Age was significantly associated with development of endocrine organ pathology (P = 0.011). A relationship between age and both cardiovascular and ocular disease was suggested by the data, but did not reach significance (P = 0.058). Ocular disease was significantly associated with being born in aquariums (P = 0.022). The most common COD was neoplasia (n = 10), which was significantly associated with aged animals (P = 0.038). Less frequent COD included sepsis (confirmed, n = 2; suspected, n = 3), cardiomyopathy (n = 1), clostridial enteritis (n = 1), Sarcocystis spp. (n = 1), complication secondary to sedation (n = 1), and unknown (n = 1). This is the first report documenting the high prevalence of neoplasia in SSL, with tumors found incidentally in three individuals, frequent metastasis (10/13, 77%), and many cases of multiple primary malignancies (6/13, 46%). These data expand upon the current understanding of disease in SSL, highlight this species' predisposition to neoplasia with increasing longevity, and underscore the need for heightened screening in aged animals, which may ultimately serve to elevate the care of SSL under professional care in aquariums.

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Grief is a normal reaction after the death of a loved one. Death rituals are an integral part of the mourning processes. Not being able to carry out death rituals can affect relatives' quality of life. The aim was to evaluate death rituals during COVID-19 and their association with relatives' quality of life. In a Swedish nation-wide study relatives to persons who died during the COVID-19-pandemic received questionnaires about their quality of life and how they could perform death rituals. Association between quality of life and death rituals was analyzed with linear regression. Of the 324 relatives, a minority indicated that their loved one's funeral (17%) met their wishes. Not being able to carry out the funeral as desired was significantly associated with a lower quality of life (p = 0.006). The experiences during the pandemic revealed that it is important for people to perform death rituals according to their wishes.

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OBJECTIVE: The proportion of long-term care (LTC) residents being treated with antipsychotic medication is high, and these medications may exacerbate behavioral symptoms. We used propensity scores to investigate the effect of antipsychotic use on the worsening of behavioral symptoms among residents in LTC facilities. DESIGN: A retrospective study. SETTING AND PARTICIPANTS: Residents in LTC in 8 provinces and 1 territory in Canada, without severe aggressive behavior at baseline and reassessed at follow-up, between March 2000 and March 2022. METHODS: We used propensity score matching and weighting to balance baseline covariates and logistic regression to estimate the effect of antipsychotics on the worsening of behavioral symptoms in the original, matched, and weighted cohorts. The treatment variable was use of antipsychotic medication at baseline and the outcome was worsening of behavior at follow-up. RESULTS: A total of 494,215 participants were included (318,234 women and 175,981 men; mean age 82.8 years [SD 10.1; range 18-112]).130 558 (26.4%) used antipsychotics at baseline and 88,632 (17.9%) had worsening behavior in follow-up. In the matched cohort, there were 249,698 participants, and 124,849 were matched (1:1) in each treatment group. There was a significant association between antipsychotic use at baseline and worsening in behavior at follow-up in the adjusted regression models (OR 1.27 [95% CI 1.25-1.29], <0.0001) as well as in matched (OR 1.20 [95% CI 1.17-1.21], <0.0001) and weighted (OR 1.26 [95% CI 1.24-1.28], <0.0001) cohorts. CONCLUSIONS AND IMPLICATIONS: This study further evidence to support the cautious use of antipsychotics in LTC facilities. Future research in LTC facilities could include a more granular analyses of behavior change, including bidirectional analyses between different symptom severity classifications.

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AIM: To investigate the association between presence of caries in anterior teeth and bullying victimization in schoolchildren. METHODS: A cross-sectional study was conducted in Brazil with a sample of 387 schoolchildren aged 6 to 10 years. The presence of moderate/extensive dental caries was assessed using the International System for the Evaluation and Detection of Dental Caries (ICDAS-II). The children answered the "Olweus Bullying" (QBO). Descriptive analyses were performed, and the associations between bullying victimization and independent variables collected were determined by univariate and multivariate Poisson regression. RESULTS: The prevalence of bullying victimization was 66.4%. Bullying victimization was higher among children who had moderate/extensive caries in some anterior teeth (p = 0.010). 8-year-old (p = 0.048), 9-year-old (p = 0.001), and 10-year-old (p = 0.002) children reported greater bullying victimization when compared to 6-year-olds. CONCLUSION: The presence of moderate/extensive dental caries in anterior teeth is associated with bullying victimization in schoolchildren.