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Prior genome-wide association studies for oral clefts have focused on clinic-based samples with unclear generalizability. Prior samples were also small for investigating effects by cleft type and exclusively studied isolated clefts (those occurring without other birth defects). We estimated the effects of 17 top loci on cleft types in both isolated and nonisolated cases in the largest consortium to date of European-descent population-based studies. Our analytic approach focused on a mother-child dyad case-control design, but it also allowed analyzing mother-only or child-only genotypes to maximize power. Our total sample included 1,875 cases with isolated clefts, 459 cases with nonisolated clefts, and 3,749 controls. After correcting for multiple testing, we observed significant associations between fetal single-nucleotide polymorphisms (SNPs) at IRF6, PAX7, 8q21.3, 8q24, KIAA1598-VAX1, and MAFB and isolated cleft lip only (CLO) and cleft lip and palate (CLP). Significant associations were observed between isolated CLO and fetal SNPs near TPM1 and NOG1 and between CLP and fetal SNPs at ABCA4-ARHGAP29, THADA, FOXE1, and SPRY2. Overall, effects were similar for isolated CLO and CLP, except for ABCA4-ARHGAP29. A protective effect was observed for the fetal NOG1 SNP on cleft palate only, opposite in direction to the effect on CLO. For most fetal SNPs, a dose-response allelic effect was observed. No evidence of parent-of-origin or maternal genome effects was observed. Overall, effect direction and magnitude were similar between isolated and nonisolated clefts, suggesting that several loci are modifiers of cleft risk in both isolated and nonisolated forms. Our results provide reliable estimates of the effects of top loci on risks of oral clefts in a population of European descent. [ABSTRACT FROM AUTHOR]

Although children with oral clefts have a higher risk for dental anomalies when compared with the general population, prior studies have shown conflicting results regarding their dental decay risk. Also, few studies have assessed dental decay risk in unaffected relatives of children with clefts. Thus, the question of increased risk of dental decay in individuals with oral clefts or their unaffected relatives is still open for empirical investigation. This study characterizes dental decay in the largest international cohort to date of children with nonsyndromic clefts and their relatives, as compared with controls, and it addresses whether families with oral clefts have a significantly increased risk for dental decay versus the general population. A total of 3,326 subjects were included: 639 case probands, 1,549 unaffected relatives, and 1,138 controls. Decay was identified from in-person dental examinations or intraoral photographs. Case-control differences were tested with regression analysis. No significant differences were shown in percentage decayed and filled teeth and decayed teeth in the primary dentition (dft, dt) and permanent dentition (DFT, DT) in cases versus controls. In the cleft region, no significant differences were seen in primary or permanent decay (dt, DT) when compared with controls. No difference was found with regard to cleft type and percentage dft, dt, DFT, and DT in case probands. Nonsignificant differences were found in unaffected siblings and parents versus controls (primary and permanent dentitions). Collectively, these findings indicate that individuals with nonsyndromic oral clefts and their families do not have a higher dental decay risk as compared with the general population. These results suggest that either genetic or environmental factors underlying a higher susceptibility for dental anomalies do not increase caries risk or that the seemingly higher risk for dental decay associated with increased dental anomalies in case probands may be superseded by possible greater access to dental care. [ABSTRACT FROM AUTHOR]

This study evaluated associations between craniofacial candidate genes and skeletal variation in patients with malocclusion. Lateral cephalometric radiographs of 269 untreated adults with skeletal classes I, II, and III malocclusion were digitized with 14 landmarks. Two-dimensional coordinates were analyzed using Procrustes fit and principal component (PC) analysis to generate continuous malocclusion phenotypes. Skeletal class classifications (I, II, or III) were used as a categorical phenotype. Individuals were genotyped for 198 singlenucleotide polymorphisms (SNPs) in 71 craniofacial genes and loci. Phenotype-genotype associations were tested via multivariate linear regression for continuous phenotypes and multinomial logistic regression for skeletal malocclusion class. PC analysis resulted in 4 principal components (PCs) explaining 69% of the total skeletal facial variation. PC1 explained 32.7% of the variation and depicted vertical discrepancies ranging from skeletal deep to open bites. PC1 was associated with a SNP near PAX5 (P = 0.01). PC2 explained 21.7% and captured horizontal maxillomandibular discrepancies. PC2 was associated with SNPs upstream of SNAI3 (P = 0.0002) and MYO1H (P = 0.006). PC3 explained 8.2% and captured variation in ramus height, body length, and anterior cranial base orientation. PC3 was associated with TWIST1 (P = 0.000076). Finally, PC4 explained 6.6% and detected variation in condylar inclination as well as symphysis projection. PC4 was associated with PAX7 (P = 0.007). Furthermore, skeletal class II risk increased relative to class I with the minor alleles of SNPs in FGFR2 (odds ratio [OR] = 2.1, P = 0.004) and declined with SNPs in EDN1 (OR = 0.5, P = 0.007). Conversely, skeletal class III risk increased versus class I with SNPs in FGFR2 (OR 2.2, P = 0.005) and COL1A1 (OR = 2.1, P = 0.008) and declined with SNPs in TBX5 (OR = 0.5, P = 0.014). PAX5, SNAI3, MYO1H, TWIST1, and PAX7 are associated with craniofacial skeletal variation among patients with malocclusion, while FGFR2, EDN1, TBX5, and COL1A1 are associated with type of skeletal malocclusion. [ABSTRACT FROM AUTHOR]

Children with oral clefts show a wide range of dental anomalies, adding complexity to understanding the phenotypic spectrum of orofacial clefting. The evidence is mixed, however, on whether the prevalence of dental anomalies is elevated in unaffected relatives and is mostly based on small samples. In the largest international cohort to date of children with nonsyndromic clefts, their relatives, and controls, this study characterizes the spectrum of cleft-related dental anomalies and evaluates whether families with clefting have a significantly higher risk for such anomalies compared with the general population. A total of 3,811 individuals were included: 660 cases with clefts, 1,922 unaffected relatives, and 1,229 controls. Dental anomalies were identified from in-person dental exams or intraoral photographs, and case-control differences were tested using X2 statistics. Cases had higher rates of dental anomalies in the maxillary arch than did controls for primary (21% vs. 4%, P = 3 × 10-8) and permanent dentitions (51% vs. 8%, P = 4 × 10-62) but not in the mandible. Dental anomalies were more prevalent in cleft lip with cleft palate than other cleft types. More anomalies were seen in the ipsilateral side of the cleft. Agenesis and tooth displacements were the most common dental anomalies found in case probands for primary and permanent dentitions. Compared with controls, unaffected siblings (10% vs. 2%, P = 0.003) and parents (13% vs. 7%, P = 0.001) showed a trend for increased anomalies of the maxillary permanent dentition. Yet, these differences were nonsignificant after multiple-testing correction, suggesting genetic heterogeneity in some families carrying susceptibility to both overt clefts and dental anomalies. Collectively, the findings suggest that most affected families do not have higher genetic risk for dental anomalies than the general population and that the higher prevalence of anomalies in cases is primarily a physical consequence of the cleft and surgical interventions. [ABSTRACT FROM AUTHOR]

Abstract Background Oral clefts are one of the most common birth defects with significant medical, psychosocial, and economic ramifications. Oral clefts have a complex etiology with genetic and environmental risk factors. There are suggestive results for decreased risks of cleft occurrence and recurrence with folic acid supplements taken at preconception and during pregnancy with a stronger evidence for higher than lower doses in preventing recurrence. Yet previous studies have suffered from considerable design limitations particularly non-randomization into treatment. There is also well-documented effectiveness for folic acid in preventing neural tube defect occurrence at 0.4 mg and recurrence with 4 mg. Given the substantial burden of clefting on the individual and the family and the supportive data for the effectiveness of folic acid supplementation as well as its low cost, a randomized clinical trial of the effectiveness of high versus low dose folic acid for prevention of cleft recurrence is warranted. Methods/design This study will assess the effect of 4 mg and 0.4 mg doses of folic acid, taken on a daily basis during preconception and up to 3 months of pregnancy by women who are at risk of having a child with nonsyndromic cleft lip with/without palate (NSCL/P), on the recurrence of NSCL/P. The total sample will include about 6,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg and the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects, as well as the two study groups (4mg, 0.4 mg) to that of a historical control group. The study has been approved by IRBs (ethics committees) of all involved sites. Results will be disseminated through publications and presentations at scientific meetings. Discussion The costs related to oral clefts are high, including long term psychological and socio-economic effects. This study provides an opportunity for huge savings in not only money but the overall quality of life. This may help establish more specific clinical guidelines for oral cleft prevention so that the intervention can be better tailored for at-risk women. ClinicalTrials.gov Identifier NCT00397917

Abstract Background Oral clefts are one of the most common birth defects worldwide. They require multiple healthcare interventions and add significant burden on the health and quality of life of affected individuals. However, not much is known about the long term effects of oral clefts on health and healthcare use of affected individuals. In this study, we evaluate the effects of oral clefts on hospital use throughout the lifespan. Methods We estimate two-part regression models for hospital admission and length of stay for several age groups up to 68 years of age. The study employs unique secondary population-based data from several administrative inpatient, civil registration, demographic and labor market databases for 7,670 individuals born with oral clefts between 1936 and 2002 in Denmark, and 220,113 individuals without oral clefts from a 5% random sample of the total birth population from 1936 to 2002. Results Oral clefts significantly increase hospital use for most ages below 60 years by up to 233% for children ages 0-10 years and 16% for middle age adults. The more severe cleft forms (cleft lip with palate) have significantly larger effects on hospitalizations than less severe forms. Conclusions The results suggest that individuals with oral clefts have higher hospitalization risks than the general population throughout most of the lifespan.

Abstract Background Cleft lip and/or palate (CL/P) increase mortality and morbidity risks for affected infants especially in less developed countries. This study aimed at assessing the effects of systematic pediatric care on neonatal mortality and hospitalizations of infants with cleft lip and/or palate (CL/P) in South America. Methods The intervention group included live-born infants with isolated or associated CL/P in 47 hospitals between 2003 and 2005. The control group included live-born infants with CL/P between 2001 and 2002 in the same hospitals. The intervention group received systematic pediatric care between the 7th and 28th day of life. The primary outcomes were mortality between the 7th and 28th day of life and hospitalization days in this period among survivors adjusted for relevant baseline covariates. Results There were no significant mortality differences between the intervention and control groups. However, surviving infants with associated CL/P in the intervention group had fewer hospitalization days by about six days compared to the associated control group. Conclusions Early systematic pediatric care may significantly reduce neonatal hospitalizations of infants with CL/P and additional birth defects in South America. Given the large healthcare and financial burden of CL/P on affected families and the relatively low cost of systematic pediatric care, improving access to such care may be a cost-effective public policy intervention. Trial Registration ClinicalTrials.gov: NCT00097149

Abstract Background The contribution of birth defects, including cleft lip and palate, to neonatal and infant mortality and morbidity is substantial. As other mortality and morbidity causes including infections, hygiene, prematurity, and nutrition are eradicated in less developed countries, the burden of birth defects will increase proportionally. Methods/Design We are using cleft lip and palate as a sentinel birth defect to evaluate its burden on neonatal and infant health and to assess the effectiveness of systematic pediatric care during the first month and first two years of life in decreasing this burden. The neonatal intervention, consisting of weekly pediatric evaluation and referral to appropriate care, is delivered to about 696 infants born with cleft lip and/or palate in 47 hospitals in South America. Neonatal mortality in this group will be compared to that in a retrospective control group of about 464 infants born with cleft lip and/or palate in the same hospitals. The subgroup of infants with isolated clefts of both the lip and palate (about 264) is also randomized into two groups, intervened and non-intervened, and further followed up over 2 years. Intervened cases are evaluated by pediatricians every three months and referred for appropriate care. The intervened and non-intervened cases will be compared over study outcomes to evaluate the intervention effectiveness. Non-intervened cases are matched and compared to healthy controls to assess the burden of cleft lip and palate. Outcomes include child's neurological and physical development and family social and economic conditions. Discussion Large-scale clinical trials to improve infant health in developing countries are commonly suggested, making it important to share the methods used in ongoing studies with other investigators implementing similar research. We describe here the content of our ongoing pediatric care study in South America. We hope that this may help researchers targeting this area to plan their studies more effectively and encourage the development of similar research efforts to target other birth defects or infant outcomes such as prematurity and low birth weight.

Importance: The Veterans Health Administration (VHA) reports multiple indicators of hospital surgical performance, including hospital risk-standardized 30-day readmission rates (RSRRs). Currently, most routinely reported measures do not include readmissions that occur outside VHA hospitals. The impact of readmissions outside the VHA on hospital RSRR is not known., Objective: To measure the impact of including non-VHA readmissions on VHA hospital performance rankings for 30-day readmission., Design, Setting, and Participants: This retrospective cohort study included patients aged at least 65 years from 2013 to 2019 from the Veterans Affairs Surgical Quality Improvement Program linked to patient-level data from the VHA and Medicare. Data were limited to patients with VHA and Medicare enrollment during the year prior to surgery. Data were analyzed from November 2023 through July 2024., Main Outcomes and Measures: The main outcome was readmissions to acute care VHA or non-VHA hospitals within 30 days of discharge. VHA hospital-level RSRRs were estimated using separate generalized linear mixed-effects risk adjustment models that alternatively included VHA-only or VHA plus non-VHA readmissions. VHA hospitals were then stratified into quintiles based on RSRRs derived using VHA-only or VHA plus non-VHA readmissions. Changes in hospital performance quintiles with the addition of non-VHA readmissions were calculated, and characteristics of VHA hospitals most impacted by including non-VHA readmissions were evaluated., Results: The eligible cohort included 108 265 patients (mean [SD] age, 72.2 [6.5] years; 105 661 [97.6%] male) who underwent surgery in 104 VHA hospitals. The combined readmission rate was 14.0%. The proportion of readmissions occurring outside the VHA ranged from 0% to 55.3% across the 104 VHA hospitals (median, 20.9%). Using VHA and non-VHA readmissions, 24 VHA hospitals (23.1%) improved performance and 23 hospitals (22.1%) worsened performance, defined as a decrease or increase, respectively, of 1 or more RSRR quintiles. Improvements in hospital performance rank were associated with larger surgical volume (-7.48; 95% CI, -11.33 to 03.64; P < .001), urban location, greater surgical complexity (-9.86; 95% CI, -16.61 to -3.11; P = .005), and lower proportion of readmissions outside the VHA (-8.15; 95% CI, -12.75 to -3.55; P < .001)., Conclusions and Relevance: In this cohort study, VHA hospitals whose readmission performance metric improved by including non-VHA readmissions had higher patient volume, higher complexity, and lower proportion of care outside the VHA. Thus, improving continuity of care may have a paradoxical effect of worsening VHA performance metrics.

Objective: Mandatory enrollment into Medicaid-contracted health maintenance organizations (HMOs) is the most common form of Medicaid managed care (MMC), but the effects of this enrollment on children are unclear. We leveraged variation in MMC implementation within and across states over time to examine the effect of mandatory Medicaid HMO enrollment on children's access, utilization, and health outcomes., Methods: Using Medical Expenditure Panel Survey data from 2000 to 2018 and multivariable regression models, we estimated the effects of living in a county with mandatory Medicaid HMO enrollment only, compared to other MMC types and fee-for-service (FFS) combined in 1 comparison group, on outcomes for children under 18 years. We also evaluated potential effect heterogeneity across age, race and ethnicity, and for children with special health care needs (CSHCNs)., Results: There were small and nonsignificant associations between mandatory HMO enrollment and most outcome measures. However, mandatory HMO enrollment was associated with a 1.8%-point decline in the likelihood of having a usual source of care, 95% confidence interval (CI) [-0.035, -0.001], a 4.2%-point increase in the likelihood of delayed access to care, 95% CI [0.012, 0.072], and a 2.2%-point reduction in the likelihood of having any outpatient physician visits, 95% CI [-0.043, -0.0004], compared to other MMC and FFS combined in 1 group. Mandatory HMO enrollment was associated with more difficulty seeing a specialist for CSHCNs., Conclusions: Overall, there is little evidence that mandatory Medicaid HMO enrollment has discernable and consistent effects across a broad range of outcomes. Evaluating how mandatory Medicaid HMOs affect more nuanced health care measures, especially for children with greater health care needs, remains an important future research question., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Academic Pediatric Association. Published by Elsevier Inc. All rights reserved.)

Introduction: The 2021 American Association for the Study of Liver Disease (AASLD) Practice Guidance recommends albumin infusion when removing ≥5 L of ascites to prevent post-paracentesis circulatory dysfunction. However, the optimal criteria and scenarios for initiating albumin infusion subsequent to therapeutic paracentesis (TP) have been subject to limited scientific inquiry., Methods: We conducted a retrospective cohort study at a US academic healthcare center. Participants received elective, outpatient TP between July 2019 and December 2022. Patients with spontaneous bacterial peritonitis, post-TP clinical adjustments, and/or hospitalization were excluded. The institution strictly followed the AASLD Guidance. We used a sharp regression discontinuity (RD) design to estimate the effect of albumin infusion at the AASLD Guidance-recommended cutoff of 5 L on serum creatinine and sodium trajectory after TP., Results: Over the study period, 1,457 elective TPs were performed on 235 unique patients. Albumin infusion at the threshold of 5 L of ascites removal reduced serum creatinine levels by 0.046 mg/dL/d (95% confidence interval 0.003-0.116, P = 0.037) and increased serum sodium levels by 0.35 mEq/L/d (95% confidence interval 0.15-0.55, P = 0.001) compared with those who did not receive albumin infusion. The RD plots indicated worsened serum creatine/sodium levels after draining 3 L of fluid, approaching levels similar to or worse than with albumin infusion at 5 L or more., Discussion: Our RD models supported the 2021 AASLD Guidance with robust estimation of causal effect sizes at the cutoff level of 5 L. Nevertheless, the findings also highlight the need to further evaluate the efficacy of albumin infusion in patients who undergo elective TP and have 3-5 L of ascites removed., (Copyright © 2024 by The American College of Gastroenterology.)

Background: Despite the importance of regular dental visits for detecting oral cancer, millions of low-income adults lack access to dental services. In July 2009, California eliminated adult Medicaid dental benefits. We tested if this impacted oral cancer detection for Medicaid enrollees., Methods: We analyzed Surveillance, Epidemiology, and End Results-Medicaid data, which contains verified Medicaid enrollment status, to estimate a difference-in-differences model. Our design compares the change in early-stage (Stages 0-II) diagnoses before and after dropping dental benefits in California with the change in early-stage diagnoses among eight states that did not change Medicaid dental benefits. Patients were grouped by oropharyngeal cancer (OPC) and non-OPC (oral cavity cancer), type, and the length of Medicaid enrollment. We also assessed if the effect of dropping dental benefits varied by the number of dentists per capita., Results: Dropping Medicaid dental benefits was associated with a 6.5%-point decline in early-stage diagnoses of non-OPC (95% CI = -14.5, -3.2, p = 0.008). This represented a 20% relative reduction from baseline rates. The effect was highest among beneficiaries with 3 months of continuous Medicaid enrollment prior to diagnosis who resided in counties with more dentists per capita. Specifically, dropping dental coverage was associated with a 1.25%-point decline in the probability of early-stage non-OPC diagnoses for every additional dentist per 5000 population (p = 0.006)., Conclusions: Eliminating Medicaid dental benefits negatively impacted early detection of cancers of the oral cavity. Continued volatility of Medicaid dental coverage and provider shortages may be further delaying oral cancer diagnoses. Alternative approaches are needed to prevent advanced stage OPC., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Orofacial clefts (OFCs) are common birth defects including cleft lip, cleft lip and palate, and cleft palate. OFCs have heterogeneous etiologies, complicating clinical diagnostics because it is not always apparent if the cause is Mendelian, environmental, or multifactorial. Sequencing is not currently performed for isolated or sporadic OFCs; therefore, we estimated the diagnostic yield for 418 genes in 841 cases and 294 controls., Methods: We evaluated 418 genes using genome sequencing and curated variants to assess their pathogenicity using American College of Medical Genetics criteria., Results: 9.04% of cases and 1.02% of controls had "likely pathogenic" variants (P < .0001), which was almost exclusively driven by heterozygous variants in autosomal genes. Cleft palate (17.6%) and cleft lip and palate (9.09%) cases had the highest yield, whereas cleft lip cases had a 2.80% yield. Out of 39 genes with likely pathogenic variants, 9 genes, including CTNND1 and IRF6, accounted for more than half of the yield (4.64% of cases). Most variants (61.8%) were "variants of uncertain significance", occurring more frequently in cases (P = .004), but no individual gene showed a significant excess of variants of uncertain significance., Conclusion: These results underscore the etiological heterogeneity of OFCs and suggest sequencing could reduce the diagnostic gap in OFCs., Competing Interests: Conflict of Interest The authors declare no conflicts of interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Low-income children have higher rates of unmet oral health needs. Prior research suggests that poor oral health is associated with lower academic performance but uses cross-sectional and mostly parent-reported measures. This study examined the association between oral health during the first 5 y of life and subsequent academic achievement for low-income children. Birth certificates of children born in Iowa in 1999-2009 were linked to Medicaid enrollment and dental claims data in 1999-2014 and reading and math standardized school test scores for grades 2 through 11. The following oral health measures were examined: having minor dental treatments (mostly surface fillings), major dental treatments (mostly crowns and pulpotomy) or extractions, and comprehensive dental exams during the first 5 y of life. Regression models were estimated adjusting for sociodemographic factors, early infant health, and school district effects. The sample included 28,859 children and 127,464 child-grade observations. In total, 21%, 12%, and 62% of children had at least 1 minor dental treatment, 1 major treatment or extraction, and 1 comprehensive dental exam in the first 5 y of life, respectively. Children who received a minor dental treatment had higher reading and math scores by 1 percentile (95% CI, 0.09-1.9) and 0.9 percentiles (95% CI, 0.02-1.8), respectively. Children who had a major dental treatment or extraction had lower reading and math scores by 2.4 (95% CI, -3.5 to -1.4) and 1.8 (95% CI, -2.8 to -0.8) percentiles. Children who had a comprehensive oral exam had higher reading and math scores by 0.7 (95% CI, 0.06-1.4) and 1.2 (95% CI, 0.6-1.9) percentiles. The findings suggest that children's oral health before school age is associated with academic achievement later during school years.

Background: Low-income adults delay oral health care due to cost more than any other health care service. These delays lead to caries, periodontal disease, and tooth loss. Expanding Medicaid dental coverage has increased dental visits, but the potential impact on previously unmet oral health needs is not well understood., Methods: In this analysis, the authors estimated the association between Medicaid dental expansion and tooth loss. Data on self-reported tooth loss among adults below 138% federal poverty guideline were obtained from the Behavioral Risk Factor Surveillance System. A difference-in-differences regression was estimated. Additional analyses stratified according to age and separated extensive and limited dental benefits., Results: Expanding Medicaid dental coverage is associated with increased probability of total tooth loss of 1 percentage point in the total sample, representing a 20% relative increase from the pre-expansion rate. This increase was concentrated in states offering extensive dental benefits and was largest (2.5-percentage-point greater likelihood) among adults aged 55 through 64 years for whom both extensive and limited dental benefits were associated with total tooth loss., Conclusions: Medicaid expansion with extensive dental benefits was associated with increased total tooth loss among low-income adults. This finding suggests that greater access to oral health care addressed previously unmet oral health needs for this population., Practical Implications: As public dental coverage continues to expand, dental care professionals may find themselves treating a greater number of patients with substantial, previously unmet, oral health needs. Additional research to understand the long-term effects of Medicaid dental insurance for adults on their oral health is needed., (Copyright © 2022 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Nonsyndromic orofacial clefts (OFCs) are among the most common craniofacial birth defects worldwide, and known to exhibit phenotypic and genetic heterogeneity. Cleft lip plus cleft palate (CLP) and cleft lip only (CL) are commonly combined together as one phenotype (CL/P), separately from cleft palate alone. In comparison, our study analyzes CL and CLP separately. A sample of 2218 CL and CLP cases, 4537 unaffected relatives of cases, and 2673 pure controls with no family history of OFC were selected from the Pittsburgh Orofacial Cleft (Pitt-OFC) multiethnic study.genome-wide association studies were run for seven specific phenotypes created based on the cleft type(s) observed within these families, as well as the combined CL/P phenotype. Five novel genome-wide significant associations, 3q29 (rs62284390), 5p13.2 (rs609659), 7q22.1 (rs6465810), 19p13.3 (rs628271), and 20q13.33 (rs2427238), and nine associations (p ≤ 1.0E-05) within previously confirmed OFC loci-PAX7, IRF6, FAM49A, DCAF4L2, 8q24.21, ARID3B, NTN1, TANC2 and the WNT9B:WNT3 gene cluster-were observed. We also found that single nucleotide polymorphisms within a subset of the associated loci, both previously known and novel, differ substantially in terms of their effects across cleft- or family-specific phenotypes, indicating not only etiologic differences between CL and CLP, but also genetic heterogeneity within each of the two OFC subtypes., (© 2022 Wiley Periodicals LLC.)

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic and vary in prevalence by ethnicity. Africans have the lowest prevalence of OFCs (~ 1/2,500), Asians have the highest prevalence (~1/500), Europeans and Latin Americans lie somewhere in the middle (~1/800 and 1/900, respectively). Thus, ethnicity appears to be a major determinant of the risk of developing OFC. The Pittsburgh Orofacial Clefts Multiethnic study was designed to explore this ethnic variance, comprising a large number of families and individuals (~12,000 individuals) from multiple populations worldwide: US and Europe, Asians, mixed Native American/Caucasians, and Africans. In this current study, we analyzed 2,915 OFC cases, 6,044 unaffected individuals related to the OFC cases, and 2,685 controls with no personal or family history of OFC. Participants were grouped by their ancestry into African, Asian, European, and Central and South American subsets, and genome-wide association run on the combined sample as well as the four ancestry-based groups. We observed 22 associations to cleft lip with or without cleft palate at 18 distinct loci with p -values < 1e-06, including 10 with genome-wide significance (<5e-08), in the combined sample and within ancestry groups. Three loci - 2p12 (rs62164740, p = 6.27e-07), 10q22.2 (rs150952246, p = 3.14e-07), and 10q24.32 (rs118107597, p = 8.21e-07) are novel. Nine were in or near known OFC loci - PAX7, IRF6, FAM49A, DCAF4L2 , 8q24.21, NTN1, WNT3-WNT9B, TANC2 , and RHPN2 . The majority of the associations were observed only in the combined sample, European, and Central and South American groups. We investigated whether the observed differences in association strength were (a) purely due to sample sizes, (b) due to systematic allele frequency difference at the population level, or (c) due to the fact certain OFC-causing variants confer different amounts of risk depending on ancestral origin, by comparing effect sizes to observed allele frequencies of the effect allele in our ancestry-based groups. While some of the associations differ due to systematic differences in allele frequencies between groups, others show variation in effect size despite similar frequencies across ancestry groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mukhopadhyay, Feingold, Moreno-Uribe, Wehby, Valencia-Ramirez, Muñeton, Padilla, Deleyiannis, Christensen, Poletta, Orioli, Hecht, Buxó, Butali, Adeyemo, Vieira, Shaffer, Murray, Weinberg, Leslie and Marazita.)

Although de novo mutations (DNMs) are known to increase an individual's risk of congenital defects, DNMs have not been fully explored regarding orofacial clefts (OFCs), one of the most common human birth defects. Therefore, whole-genome sequencing of 756 child-parent trios of European, Colombian, and Taiwanese ancestry was performed to determine the contributions of coding DNMs to an individual's OFC risk. Overall, we identified a significant excess of loss-of-function DNMs in genes highly expressed in craniofacial tissues, as well as genes associated with known autosomal dominant OFC syndromes. This analysis also revealed roles for zinc-finger homeobox domain and SOX2-interacting genes in OFC etiology., (Copyright © 2020 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objective: We conducted a comprehensive review of state laws and regulations that require private health insurance plans to cover the services needed by children born with cleft lip and/or cleft palate (CL/P). The goal is to better understand how states are reducing the barriers children with CL/P face when seeking recommended health care services., Design: We identified all state laws and regulations mandating insurance coverage of services for children with CL/P by private insurance carriers from 1999 through 2017 using Westlaw legal database. We categorized laws and regulations into ten services: facial surgery (facial, corrective, reconstructive), oral surgery, orthodontics, dental care, habilitation/rehabilitation/speech therapy, prosthetic treatment, audiology, nutrition counseling, genetic testing, and psychological counseling. We also captured broad mandates indicating coverage for all necessary treatments., Results: There was a trend toward increased coverage of services for CL/P over time. In 1999, 27 states and Washington, DC did not have relevant laws or regulations. By 2017, there were 19 states without laws or regulations mandating services. The most common mandated service was facial surgery followed by habilitation/rehabilitation/speech therapy, orthodontics, dental care, and oral surgery. Nutrition, audiology, genetic testing and psychological counseling were rarely included in mandated services., Conclusions: States vary widely in their requirements for coverage of services needed by children with CL/P in private health insurance plans. There has been an increase in mandates over the past two decades to cover services, although significant variation continues to exist across states.

Objective: Rural populations may experience more frequent and intense risk factors for perinatal depression than their urban counterparts. However, research has yet to examine rural versus urban differences in a population-based study in the United States. Therefore, this study examined differences in risk of perinatal depression between women living in rural versus urban areas in the United States., Method: Using 2016 data from the Pregnancy Risk Assessment Monitoring System, we examined the association between rural-urban status and the risk of depression during the perinatal time period. The total analytical sample included 17,229 women from 14 states. The association between rural-urban status and risk of perinatal depression was estimated using logistic regression, adjusting for race/ethnicity, maternal age, and state of residence. A second model adjusted for maternal education, health insurance status, and Women, Infants, and Children Special Supplemental Nutrition Program (WIC)., Results: Odds of perinatal depression risk were higher by 21% among rural versus urban women (OR = 1.21, 95% CI: 1.05-1.41) adjusted for race, ethnicity, and maternal age. This risk difference became smaller and not significant when adding maternal education, health insurance coverage, and WIC participation., Conclusion: Findings suggest a rural-urban inequality in perinatal depression risk. Reducing this inequality may require improving socioeconomic conditions and reducing associated risk factors among rural women., (© 2019 National Rural Health Association.)

Objectives: To evaluate the Affordable Care Act's dependent coverage mandate impact on insurance take-up and health services use through the second full year of implementation., Data: Medical Expenditure Panel Survey from 2006 to 2012., Study Design: Difference-in-difference regressions comparing pre-/postpolicy-outcome changes between 19- to 25-year-olds and 27- to 34-year-olds., Principal Findings: Following significant increases in 2011, insurance take-up among 19- to 25-year-olds leveled off overall in 2012. However, increases in coverage for Black young adults were higher in 2012 compared to 2011. Despite increased coverage, there is little evidence of an overall effect on health services use postmandate. Evidence points to increased doctor visits and emergency department visits among Hispanics in the first year postmandate., Conclusions: The Affordable Care Act young adult mandate led to significant gains in insurance take-up, though evidence suggests that the bulk of the gains occurred in the first year after the mandate. Gains for Black young adults appear to have picked up in 2012., (© The Author(s) 2015.)

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10 -8 ), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10 -8 ). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10 -8 ) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Van der Woude syndrome (VWS) is an autosomal dominant malformation syndrome characterized by orofacial clefting (OFC) and lower lip pits. The clinical presentation of VWS is variable and can present as an isolated OFC, making it difficult to distinguish VWS cases from individuals with non-syndromic OFCs. About 70% of causal VWS mutations occur in IRF6, a gene that is also associated with non-syndromic OFCs. Screening for IRF6 mutations in apparently non-syndromic cases has been performed in several modestly sized cohorts with mixed results. In this study, we screened 1521 trios with presumed non-syndromic OFCs to determine the frequency of causal IRF6 mutations. We identified seven likely causal IRF6 mutations, although a posteriori review identified two misdiagnosed VWS families based on the presence of lip pits. We found no evidence for association between rare IRF6 polymorphisms and non-syndromic OFCs. We combined our results with other similar studies (totaling 2472 families) and conclude that causal IRF6 mutations are found in 0.24-0.44% of apparently non-syndromic OFC families. We suggest that clinical mutation screening for IRF6 be considered for certain family patterns such as families with mixed types of OFCs and/or autosomal dominant transmission., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis., (Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Objectives: The study assessed the time until first dental caries for young children seen at five Federally Qualified Health Centers (FQHC) in Iowa and the relationship with the frequency and gaps (in months) of dental episodes, the number of topical fluoride treatments, and the number of dentists caring for the subject., Methods: Forty children were randomly selected at each FQHC (n = 200). All children were continuously enrolled in the Medicaid program and had their first dental visit prior to age 6. Dental chart findings, claims data for the child and family, and birth certificate information were merged into one dataset. Dental visits were followed for a minimum of 36 months, including dental visits external to the FQHCs. Using time until first caries as the dependent variable, the data were subject to left, interval, and right censoring and were analyzed via Weibull regression., Results: Slightly more than half of the 200 children experienced caries. Regression analysis indicated that the hazard of first dental caries increased by approximately 2% with each additional month that transpired between preventive recall examinations. In addition, children with older siblings who had a dental visit at the same center during the previous year prior to the subject's first visit were more likely to have a longer time until first dental caries., Conclusions: Timing of dental care episodes was associated with caries experience in young children from low income families. Dental professionals should focus on regularity of dental care to prevent or delay caries experience in young children., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objectives: We sought to quantify how socioeconomic, health care, demographic, and geographic effects explain racial disparities in low birth weight (LBW) and preterm birth (PTB) rates in Brazil., Methods: We employed a sample of 8 949 infants born between 1995 and 2009 in 15 cities and 7 provinces in Brazil. We focused on disparities in LBW (< 2 500 g) and PTB (< 37 gestational weeks) prevalence between infants of African ancestry alone or African mixed with other ancestries, and European ancestry alone. We used a decomposition model to quantify the contributions of conceptually relevant factors to these disparities., Results: The model explained 45% to 94% of LBW and 64% to 94% of PTB disparities between the African ancestry groups and European ancestry. Differences in prenatal care use and geographic location were the most important contributors, followed by socioeconomic differences. The model explained the majority of the disparities for mixed African ancestry and part of the disparity for African ancestry alone., Conclusions: Public policies to improve children's health should target prenatal care and geographic location differences to reduce health disparities between infants of African and European ancestries in Brazil.

Reports of birth defects rates may focus on defects observed in the newborn period or include defects diagnosed at older ages. However, little information is available on the rates of additional anomalies detected after birth or on the ages at which such anomalies are diagnosed. The aims of this work were to describe the initial diagnoses of oral clefts, isolated or associated with other defects, in newborn infants ascertained in hospitals of the ECLAMC network, and diagnostic changes that occurred due to detection of additional defects during a 1-year follow-up period. Seven hundred ten liveborn infants with cleft lip only (CLO), cleft lip with cleft palate (CLP), or cleft palate (CP) were ascertained between 2003 and 2005. Prevalence estimates of isolated and associated (ASO) clefts, diagnoses in infants with associated clefts, and the percentage of isolated clefts that were reclassified as associated were established. Birth prevalence estimates (per 1,000) were as follows: Total: 1.7; CLP: 0.94 (ASO = 23.5%); CP: 0.46 (ASO = 42.3%); CLO: 0.28 (ASO = 7.6%). Initial diagnoses in infants with associated clefts included 38 infants with chromosomal abnormalities, 33 with non-chromosomal syndromes, 16 with malformation sequences, and 98 with multiple anomalies of unknown etiology. Seven percent of newborns initially classified as isolated were later reclassified as associated. Ten infants without associated defects or clinically suspected syndromes were diagnosed as syndromic only through laboratory findings or family history, illustrating the difference between the terms associated versus isolated, which refers to presence or absence of associated anomalies, and syndromic versus non-syndromic, which refers to etiology., (Copyright © 2011 Wiley-Liss, Inc.)

This study uses instrumental variable (IV) models with genetic instruments to assess the effects of maternal smoking on the child's risk of orofacial clefts (OFC), a common birth defect. The study uses genotypic variants in neurotransmitter and detoxification genes relateded to smoking as instruments for cigarette smoking before and during pregnancy. Conditional maximum likelihood and two-stage IV probit models are used to estimate the IV model. The data are from a population-level sample of affected and unaffected children in Norway. The selected genetic instruments generally fit the IV assumptions but may be considered "weak" in predicting cigarette smoking. We find that smoking before and during pregnancy increases OFC risk substantially under the IV model (by about 4-5 times at the sample average smoking rate). This effect is greater than that found with classical analytic models. This may be because the usual models are not able to consider self-selection into smoking based on unobserved confounders, or it may to some degree reflect limitations of the instruments. Inference based on weak-instrument robust confidence bounds is consistent with standard inference. Genetic instruments may provide a valuable approach to estimate the "causal" effects of risk behaviors with genetic-predisposing factors (such as smoking) on health and socioeconomic outcomes.