A large-scale CRISPR screen reveals context-specific genetic regulation of retinal ganglion cell regeneration.

Many genes are known to regulate retinal regeneration after widespread tissue damage. Conversely, genes controlling regeneration after limited cell loss, as per degenerative diseases, are undefined. As stem/progenitor cell responses scale to injury levels, understanding how the extent and specificity of cell loss impact regenerative processes is important. Here, transgenic zebrafish enabling selective retinal ganglion cell (RGC) ablation were used to identify genes that regulate RGC regeneration. A single cell multiomics-informed screen of 100 genes identified seven knockouts that inhibited and 11 that promoted RGC regeneration. Surprisingly, 35 out of 36 genes known and/or implicated as being required for regeneration after widespread retinal damage were not required for RGC regeneration. The loss of seven even enhanced regeneration kinetics, including the proneural factors neurog1, olig2 and ascl1a. Mechanistic analyses revealed that ascl1a disruption increased the propensity of progenitor cells to produce RGCs, i.e. increased 'fate bias'. These data demonstrate plasticity in the mechanism through which Müller glia convert to a stem-like state and context specificity in how genes function during regeneration. Increased understanding of how the regeneration of disease-relevant cell types is specifically controlled will support the development of disease-tailored regenerative therapeutics.

Fatty acid-binding proteins and fatty acid synthase influence glial reactivity and promote the formation of Müller glia-derived progenitor cells in the chick retina.

A recent comparative transcriptomic study of Müller glia (MG) in vertebrate retinas revealed that fatty acid binding proteins (FABPs) are among the most highly expressed genes in chick ( Hoang et al., 2020). Here, we investigate how FABPs and fatty acid synthase (FASN) influence glial cells in the chick retina. During development, FABP7 is highly expressed by retinal progenitor cells and maturing MG, whereas FABP5 is upregulated in maturing MG. PMP2 (FABP8) is expressed by oligodendrocytes and FABP5 is expressed by non-astrocytic inner retinal glial cells, and both of these FABPs are upregulated by activated MG. In addition to suppressing the formation of Müller glia-derived progenitor cells (MGPCs), we find that FABP-inhibition suppresses the proliferation of microglia. FABP-inhibition induces distinct changes in single cell transcriptomic profiles, indicating transitions of MG from resting to reactive states and suppressed MGPC formation, with upregulation of gene modules for gliogenesis and decreases in neurogenesis. FASN-inhibition increases the proliferation of microglia and suppresses the formation of MGPCs. We conclude that fatty acid metabolism and cell signaling involving fatty acids are important in regulating the reactivity and dedifferentiation of MG, and the proliferation of microglia and MGPCs.

The Ability of a 3-Gene Host Signature in Blood to Distinguish Tuberculous Meningitis From Other Brain Infections.

BACKGROUND: Tuberculous meningitis (TBM) is difficult to diagnose. We investigated whether a 3-gene host response signature in blood can distinguish TBM from other brain infections. METHODS: The expression of 3 genes (dual specificity phosphatase 3 [DUSP3], guanylate-binding protein [GBP5], krupple-like factor 2 [KLF2]) was analyzed by RNA sequencing of archived whole blood from 4 cohorts of Vietnamese adults: 281 with TBM, 279 with pulmonary tuberculosis, 50 with other brain infections, and 30 healthy controls. Tuberculosis scores (combined 3-gene expression) were calculated following published methodology and discriminatory performance compared using area under a receiver operator characteristic curve (AUC). RESULTS: GBP5 was upregulated in TBM compared to other brain infections (P < .001), with no difference in DUSP3 and KLF2 expression. The diagnostic performance of GBP5 alone (AUC, 0.74; 95% confidence interval [CI], .67-.81) was slightly better than the 3-gene tuberculosis score (AUC, 0.66; 95% CI, .58-.73) in TBM. Both GBP5 expression and tuberculosis score were higher in participants with human immunodeficiency virus (HIV; P < .001), with good diagnostic performance of GBP5 alone (AUC, 0.86; 95% CI, .80-.93). CONCLUSIONS: The 3-gene host signature in whole blood has the ability to discriminate TBM from other brain infections, including in individuals with HIV. Validation in large prospective diagnostic study is now required.

Residential proximity to oil and gas developments and childhood cancer survival.

BACKGROUND: Environmental toxicants may impact survival in children with cancer, but the literature investigating these associations remains limited. Because oil and gas developments emit several hazardous air pollutants, the authors evaluated the relationship between residential proximity to oil or gas development and survival across 21 different pediatric cancers. METHODS: The Texas Cancer Registry had 29,730 children (≤19 years old) diagnosed with a primary cancer between 1995 to 2017. Geocoded data were available for 285,266 active oil or gas wells and 109,965 horizontal wells. The authors calculated whether each case lived within 1000 m (yes/no) from each type of oil or gas development. Survival analyses were conducted using Cox regression, adjusting for potential confounders. RESULTS: A total of 14.2% of cases lived within 1000 m of an oil or gas well or horizontal well. Living within 1000 m of an oil or gas well was associated with risk of mortality in cases with acute myeloid leukemia (AML) (adjusted hazard ratio [aHR], 1.36; 95% confidence interval [CI], 1.01-1.84) and hepatoblastoma (aHR, 2.13; 95% CI, 1.03-4.39). An inverse association was observed with Ewing sarcoma (aHR, 0.35; 95% CI, 0.13-0.95). No associations were observed with horizontal well. There was evidence of a dose-response effect in children with AML or hepatoblastoma and residential proximity to oil or gas wells. In general, the magnitude of association increased with decreasing distance and with higher number of wells across the three distances. CONCLUSIONS: Residential proximity to oil or gas wells at diagnosis is associated with the risk of mortality in children with AML or hepatoblastoma.

Photonic Flatband Resonances in Multiple Light Scattering.

We introduce the concept of photonic flatband resonances and demonstrate it for an array of high-index dielectric particles. We employ the multiple Mie scattering theory and demonstrate that both short- and long-range interactions between the resonators are crucial for the emerging collective resonances and their associated photonic flatbands. By examining both near- and far-field characteristics, we uncover how the flatbands emerge due to a fine tuning of resonators' radiation fields, and predict that hybridization of a flatband resonance with an electric hot spot can lead to giant values of the Purcell factor for the electric dipolar emitters.

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.

Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Factors Influencing Tobacco Smoking and Cessation Among People Living with HIV: A Systematic Review and Meta-analysis.

Tobacco smoking is highly prevalent among people living with HIV (PLWH), yet there is a lack of data on smoking behaviours and effective treatments in this population. Understanding factors influencing tobacco smoking and cessation is crucial to guide the design of effective interventions. This systematic review and meta-analysis of studies conducted in both high-income (HICs) and low- and middle-income countries (LMICs) synthesised existing evidence on associated factors of smoking and cessation behaviour among PLWH. Male gender, substance use, and loneliness were positively associated with current smoking and negatively associated with smoking abstinence. The association of depression with current smoking and lower abstinence rates were observed only in HICs. The review did not identify randomised controlled trials conducted in LMICs. Findings indicate the need to integrate smoking cessation interventions with mental health and substance use services, provide greater social support, and address other comorbid conditions as part of a comprehensive approach to treating tobacco use in this population. Consistent support from health providers trained to provide advice and treatment options is also an important component of treatment for PLWH engaged in care, especially in LMICs.

Reaching High Accuracy for Energetic Properties at Second-Order Perturbation Cost by Merging Self-Consistency and Spin-Opposite Scaling.

Quantum chemical methods dealing with challenging systems while retaining low computational costs have attracted attention. In particular, many efforts have been devoted to developing new methods based on second-order perturbation that may be the simplest correlated method beyond Hartree-Fock. We have recently developed a self-consistent perturbation theory named one-body Møller-Plesset second-order perturbation theory (OBMP2) and shown that it can resolve issues caused by the noniterative nature of standard perturbation theory. In this work, we extend the method by introducing spin-opposite scaling to the double-excitation amplitudes, resulting in the O2BMP2 method. We assess the O2BMP2 performance on the triple-bond N2 dissociation, singlet-triplet gaps, and ionization potentials. O2BMP2 performs much better than standard MP2 and reaches the accuracy of coupled-cluster methods in all cases considered in this work.

Organochlorine pesticides and risk of papillary thyroid cancer in U.S. military personnel: a nested case-control study.

BACKGROUND: The effects of organochlorine pesticide (OCP) exposure on the development of human papillary thyroid cancer (PTC) are not well understood. A nested case-control study was conducted with data from the U.S. Department of Defense Serum Repository (DoDSR) cohort between 2000 and 2013 to assess associations of individual OCPs serum concentrations with PTC risk. METHODS: This study included 742 histologically confirmed PTC cases (341 females, 401 males) and 742 individually-matched controls with pre-diagnostic serum samples selected from the DoDSR. Associations between categories of lipid-corrected serum concentrations of seven OCPs and PTC risk were evaluated for classical PTC and follicular PTC using conditional logistic regression, adjusted for body mass index category and military branch to compute odds ratios (OR) and 95% confidence intervals (CIs). Effect modification by sex, birth cohort, and race was examined. RESULTS: There was no evidence of associations between most of the OCPs and PTC, overall or stratified by histological subtype. Overall, there was no evidence of an association between hexachlorobenzene (HCB) and PTC, but stratified by histological subtype HCB was associated with significantly increased risk of classical PTC (third tertile above the limit of detection (LOD) vs.

Pediatric Profound Dengue Shock Syndrome and Use of Point-of-Care Ultrasound During Mechanical Ventilation to Guide Treatment: Single-Center Retrospective Study, 2013-2021.

OBJECTIVES: Profound dengue shock syndrome (DSS) complicated by severe respiratory failure necessitating mechanical ventilation (MV) accounts for high case fatality rates among PICU-admitted patients. A major challenge to management is the assessment of intravascular volume, which can be hampered by severe plasma leakage and the use of MV. DESIGN: Retrospective cohort, from 2013 to 2021. PATIENTS: Sixty-seven children with profound DSS supported by MV, some of whom underwent bedside point-of-care ultrasound (POCUS) for assessment and monitoring of hemodynamics and fluid administration. SETTING: PICU of the tertiary Children's Hospital No. 2 in Vietnam. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed data clinical and laboratory data during PICU stay. In particular, during use of MV (i.e., at times 0-, 6-, and 24-hr after commencement) and fluid resuscitation. The primary study outcome was 28-day in-hospital mortality, and the secondary outcomes were associations with changes in hemodynamics, blood lactate, and vasoactive-inotrope score (VIS). Patients had a median age of 7 years (interquartile range, 4-9). Use of POCUS during fluid management (39/67), as opposed to not using (28/67), was associated with lower mortality (6/39 [15%] vs. 18/28 [64%]; difference 49 % [95% CI, 28-70%], p < 0.001). Use of POCUS was associated with lower odds of death (adjusted odds ratio 0.17 [95% CI, 0.04-0.76], p = 0.02). The utilization of POCUS, versus not, was associated with greater use of resuscitation fluid, and reductions in VIS and pediatric logistic organ dysfunction (PELOD-2) score at 24 hours after MV and PICU discharge. CONCLUSIONS: In our experience of pediatric patients with profound DSS and undergoing MV (2013-2021), POCUS use was associated with lower odds of death, a higher volume of resuscitation fluid, and improvements in the blood lactate levels, VIS, and PELOD-2 score.

A Simple Procedure of Fascia-Fat Grafting and Blepharoplasty as a Single-Stage Procedure for the Correction of Sunken Eyelids in Vietnamese Population.

PURPOSES: Upper sunken eyelids, which are characterized by the hollowness of the upper eyelids, often cause a poor aesthetic appearance. Herein, we present a simplified technique using fascia-fat grafts for volume augmentation combined with blepharoplasty as a single-stage procedure. METHODS: From January 2021 to December 2021, 30 patients with sunken eyelids visiting our clinic for hollow eyelid treatment underwent a fascia-fat grafting derived from the inguinal crease combined with simultaneous eyelid reconstruction. A modified classification of sunken eyelids that was more suitable for the Asian population was proposed. RESULTS: Postoperatively, edema and ptosis were transient and addressed thanks to proper massage and compresses. Two cases had scar fibers leading to a slight tension of upper eyelids at 6-month follow-up. This event was addressed by triamcinolone acetonide injections at 4-6-week intervals with satisfactory results. The orbital volume of all patients was satisfying and stable up to 12 months after the surgery. The satisfaction rate was 100% and 88.8% in group 1 and group 2, respectively, at 12-month follow-up. CONCLUSIONS: Fascia-fat grafting combined with blepharoplasty as a single-stage procedure was a simplified method that did not require varied types of surgical tools but brought satisfactory results. This method facilitated the routine procedure and eased surgeons in the clinical practices.

A pre-post evaluation of a digital intervention to improve psychosocial outcomes of caregivers of people living with cancer in Vietnam.

OBJECTIVES: To evaluate a co-designed intervention using digital resources "Vietnam Cancer Caring Coping" (V-CCC) on the health literacy, depression, and quality of life of caregivers supporting a cancer patient in oncology hospitals in Vietnam. METHODS: A pre-post quantitative evaluation with adult cancer caregivers across regional Oncology hospitals in Vietnam (Ho Chi Minh City, Da Nang, Can Tho, and Hue). Participants completed baseline and follow-up measures of health literacy (HLS-SF12) depression (PHQ-9) and Health-related Quality of Life (5Q-5D-5L). Participants accessed and reviewed V-CCC for a 2-week period. RESULTS: Two hundred and thirty-four caregivers completed pre and post-tests. Most participants were female (n = 143, 61%), married (n = 165, 70%), aged 18-44 (n = 155, 66%), lived rurally (n = 157, 67%). All health literacy scores of participants in post-intervention were significantly higher than that in pre-intervention across all domain's healthcare, disease prevention, and health promotion as well as the total score (p < 0.001). A significant reduction in the proportion of caregivers reporting PHQ-9 moderately severe/severe depression post-intervention was demonstrated (10.2 vs. 6.1%, respectively (p ≤ 0.001). No significant differences were observed pre and post-intervention across four 5Q-5D-5L health dimensions: mobility, self-care, usual activities, and pain/discomfort. Regarding anxiety/depression as measured by 5Q-5D-5L the proportion of participants who reported having moderate, severe, and extreme problems in pre- and post-intervention was statistically significant (32 vs. 24%), respectively (p = 0.0028). CONCLUSION: Co-designed digital resources can reduce health literacy inequities and improve psychological outcomes for cancer caregivers.

Expanded Polytetrafluoroethylene Combined with Human Acellular Dermis Matrix for the Nasal Reconstruction in Patients with Postoperative Deformities.

INTRODUCTION: Augmentation rhinoplasty is one of five aesthetic surgeries in the world. Expanded polytetrafluoroethylene (ePTFE) has been reported as a rational choice to augment the nasal dorsum and tip. However, its application for nasal tip augmentation has some debates. This study presented a technique using ePTFE grafts combined with human acellular dermis matrix (HADM) to reconstruct a deformed nose caused by previous rhinoplasties. METHODS: 50 female patients who came to the hospital from 08/2022 to 09/2022 for surgical revision of their nasal deformity. ePTFE was applied to reconstruct the nasal dorsum, tip, and columella strut. HADM grafts were utilized to reinforce the reconstructed framework. Patients were evaluated for at least 12 months for both aesthetic and functional results. RESULTS: Postoperatively, the nasal dorsal length increased from 38.9 ± 1.32 to 43.4 ± 1.22 mm; while, the projection of the nasal tip also raised from 19.8 ± 1.16 to 23.9 ± 1.05 mm. 38 patients (76%) reported that their breathing and smelling were improved compared to preoperatively. No cases had implant reactions, extrusion, or warping columella strut. Most of the patients (84%) were satisfied with the surgical outcomes. Three patients (6%) had redness at the nasal tip. The nasal tip of ten patients (20%) was hardened for 3 months postoperatively. There were 6% of patients who developed an infection and 2% of patients had asymmetric soft tissues of the tip 3 postoperative months. CONCLUSION: This technique brought satisfactory aesthetic and functional results to patients, with no extrusion or rejection observed 12 months postoperatively. Infection was a prominent complication that should be considered and strictly monitored. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Notch Inhibition Promotes Regeneration and Immunosuppression Supports Cone Survival in a Zebrafish Model of Inherited Retinal Dystrophy.

Photoreceptor degeneration leads to irreversible vision loss in humans with retinal dystrophies such as retinitis pigmentosa. Whereas photoreceptor loss is permanent in mammals, zebrafish possesses the ability to regenerate retinal neurons and restore visual function. Following acute damage, Müller glia (MG) re-enter the cell cycle and produce multipotent progenitors whose progeny differentiate into mature neurons. Both MG reprogramming and proliferation of retinal progenitor cells require reactive microglia and associated inflammatory signaling. Paradoxically, in zebrafish models of retinal degeneration, photoreceptor death does not induce the MG to reprogram and regenerate lost cells. Here, we used male and female zebrafish cep290 mutants to demonstrate that progressive cone degeneration generates an immune response but does not stimulate MG proliferation. Acute light damage triggered photoreceptor regeneration in cep290 mutants but cones were only restored to prelesion densities. Using irf8 mutant zebrafish, we found that the chronic absence of microglia reduced inflammation and rescued cone degeneration in cep290 mutants. Finally, single-cell RNA-sequencing revealed sustained expression of notch3 in MG of cep290 mutants and inhibition of Notch signaling induced MG to re-enter the cell cycle. Our findings provide new insights on the requirements for MG to proliferate and the potential for immunosuppression to prolong photoreceptor survival.SIGNIFICANCE STATEMENT Inherited retinal degenerations (IRDs) are genetic diseases that lead to the progressive loss of photoreceptors and the permanent loss of vision. Zebrafish can regenerate photoreceptors after acute injury by reprogramming Müller glia (MG) into stem-like cells that produce retinal progenitors, but this regenerative process fails to occur in zebrafish models of IRDs. Here, we show that Notch pathway inhibition can promote photoreceptor regeneration in models of progressive degeneration and that immunosuppression can prevent photoreceptor loss. These results offer insight into the pathways that promote MG-dependent regeneration and the role of inflammation in photoreceptor degeneration.

NF-κB signaling regulates the formation of proliferating Müller glia-derived progenitor cells in the avian retina.

Retinal regeneration is robust in some cold-blooded vertebrates, but this process is ineffective in warm-blooded vertebrates. Understanding the mechanisms that suppress the reprogramming of Müller glia into neurogenic progenitors is key to harnessing the regenerative potential of the retina. Inflammation and reactive microglia are known to influence the formation of Müller glia-derived progenitor cells (MGPCs), but the mechanisms underlying this interaction are unknown. We used a chick in vivo model to investigate nuclear factor kappa B (NF-κB) signaling, a critical regulator of inflammation, during the reprogramming of Müller glia into proliferating progenitors. We find that components of the NF-κB pathway are dynamically regulated by Müller glia after neuronal damage or treatment with growth factors. Inhibition of NF-κB enhances, whereas activation suppresses, the formation of proliferating MGPCs. Following microglia ablation, the effects of NF-κB-agonists on MGPC-formation are reversed, suggesting that signals provided by reactive microglia influence how NF-κB impacts Müller glia reprogramming. We propose that NF-κB is an important signaling 'hub' that suppresses the reprogramming of Müller glia into proliferating MGPCs and this 'hub' coordinates signals provided by reactive microglia.

Effective aqueous chromate treatment using triethanolamine anacardate coated magnetic nanoparticles.

Low-cost adsorbents derived from agricultural by-products incorporated magnetic nanoparticles (NPs) are promising for wastewater treatment. They are always preferred due to their great performance and easy separation. This study reports cobalt superparamagnetic (CoFe2O4) nanoparticles (NPs) incorporated with triethanolamine (TEA) based surfactants from cashew nut shell liquid, namely TEA-CoFe2O4, for the removal of chromium (VI) ions from aqueous solutions. To have detailed characteristics of the morphology and structural properties, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and vibrating sample magnetometry (VSM) were employed. The fabricated TEA-CoFe2O4 particles exhibit soft and superparamagnetic properties, which make the nanoparticles easily recycled by using a magnet. Chromate adsorption on the TEA-CoFe2O4 nanomaterials reached an optimal efficiency of 84.3% at pH = 3 with the initial adsorbent dose of 10 g/L and chromium (VI) concentration of 40 mg/L. The TEA-CoFe2O4 nanoparticles can maintain the effective adsorption of chromium (VI) ion (by 29% of efficiency loss) and retain the magnetic separation using a magnet up to three cycles of the regeneration, which promise a high potential of this low-cost adsorbent for long-term treatment of heavy metal ions from polluted waters.

Protocol for Development of American Association of Clinical Endocrinology Clinical Practice Guidelines and Consensus Statements: Summary of Methodology, Process, and Policy - 2023 Update.

OBJECTIVE: This 2023 updated protocol summarizes the American Association of Clinical Endocrinology's (AACE's) new framework for the development of clinical practice guidelines and other guidance documents that includes changes to methodology, processes, and policies. METHODS: AACE has critically reviewed its development processes for guidance documents over the last several years against the National Academy of Medicine Standards for Developing Trustworthy Clinical Practice Guidelines and the Council of Medical Specialty Societies Principles for Development of Specialty Society Clinical Guidelines to determine areas for improvement. RESULTS: The new AACE framework for development of guidance documents incorporates many changes, including a revised conflicts of interest (COI) policy; strengthened commitment to collection of disclosures and management of relevant COI during development; open calls to membership for authors; new requirements for authors; new diversity, equity, and inclusion (DEI) policy; new empanelment process that incorporates consideration of DEI; and adoption of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to increase the quality of evidence assessment and standardize recommendation grades and statements, among other improvements. CONCLUSIONS: AACE has revised its policies and adopted a completely new methodology for guideline development in support of the mission to elevate the practice of clinical endocrinology to improve patient care. With the use of an evidence-based medicine framework and by continually assessing and improving its processes for development of guidance, AACE strives to deliver trustworthy, unbiased, and up-to-date information that ensures clinician and patient confidence in AACE content. Further, AACE hopes that these enhancements foster a more collaborative approach to development and increase engagement with the worldwide medical community to improve global health.

Using primary teeth and archived dried spots for exposomic studies in children: Exploring new paths in the environmental epidemiology of pediatric cancer.

It is estimated that 300,000 children 0-14 years of age are diagnosed with cancer worldwide each year. While the absolute risk of cancer in children is low, it is the leading cause of death due to disease in children in high-income countries. In spite of this, the etiologies of pediatric cancer are largely unknown. Environmental exposures have long been thought to play an etiologic role. However, to date, there are few well-established environmental risk factors for pediatric malignancies, likely due to technical barriers in collecting biological samples prospectively in pediatric populations for direct measurements. In this review, we propose the use of novel or underutilized biospecimens (dried blood spots and teeth) and molecular approaches for exposure assessment (epigenetics, metabolomics, and somatic mutational profiles). Future epidemiologic studies of pediatric cancer should incorporate novel exposure assessment methodologies, data on molecular features of tumors, and a more complete assessment of gene-environment interactions.