Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Who makes in-play bets? Investigating the demographics, psychological characteristics, and gambling-related harms of in-play sports bettors

Background and aims: Sports betting has increased markedly in recent years, in part due to legislative changes and the introduction of novel forms of sports betting (e.g., in-play betting). Some evidence suggests that in-play betting is more harmful than other types of sports betting (i.e., traditional and single-event). However, existing research on in-play sports betting has been limited in scope. To address this gap, the present study examined the extent to which demographic, psychological, and gambling- related constructs (e.g., harms) are endorsed by in-play sports bettors relative to single-event and traditional sports bettors. Methods: Sports bettors (N 5 920) aged 18þ from Ontario, Canada completed an online survey containing self-report measures of demographic, psychological, and gambling-related variables. Participants were classified as either in-play (n 5 223), single-event (n 5 533), or traditional bettors (n 5 164) based on their sports betting engagement. Results: In-play sports bettors reported higher problem gambling severity, endorsed greater gambling-related harms across several domains, and reported greater mental health and substance use difficulties compared to single- event and traditional sports bettors. There were generally no differences between single-event and traditional sports bettors. Discussion: Results provide empirical support for the potential harms asso- ciated with in-play sports betting and inform our understanding of who may be at risk for increased harms associated with in-play betting. Conclusions: Findings may be important for the development of public health and responsible gambling initiatives to reduce the potential harms of in-play betting, particularly as many jurisdictions globally move towards legalization of sports betting

Identification of 16q21 as a modifier of nonsyndromic orofacial cleft phenotypes

Orofacial clefts (OFCs) are common, complex birth defects with extremely heterogeneous phenotypic presentations. Two common subtypes—cleft lip alone (CL) and CL plus cleft palate (CLP)—are typically grouped into a single phenotype for genetic analysis (i.e., CL with or without cleft palate, CL/P). However, mounting evidence suggests there may be unique underlying pathophysiology and/or genetic modifiers influencing expression of these two phenotypes. To this end, we performed a genome-wide scan for genetic modifiers by directly comparing 450 CL cases with 1,692 CLP cases from 18 recruitment sites across 13 countries from North America, Central or South America, Asia, Europe, and Africa. We identified a region on 16q21 that is strongly associated with different cleft type (P = 5.611 × 10−8). We also identified significant evidence of gene–gene interactions between this modifier locus and two recognized CL/P risk loci: 8q21 and 9q22 (FOXE1) (P = 0.012 and 0.023, respectively). Single nucleotide polymorphism (SNPs) in the 16q21 modifier locus demonstrated significant association with CL over CLP. The marker alleles on 16q21 that increased risk for CL were found at highest frequencies among individuals with a family history of CL (P = 0.003). Our results demonstrate the existence of modifiers for which type of OFC develops and suggest plausible elements responsible for phenotypic heterogeneity, further elucidating the complex genetic architecture of OFCs.Fil: Carlson, Jenna C.. University of Pittsburgh; Estados UnidosFil: Standley, Jennifer. University of Iowa; Estados UnidosFil: Petrin, Aline. University of Iowa; Estados UnidosFil: Shaffer, John R.. University of Pittsburgh; Estados UnidosFil: Butali, Azeez. University of Iowa; Estados UnidosFil: Buxó, Carmen J.. Universidad de Puerto Rico; Puerto RicoFil: Castilla, Eduardo Enrique. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; ArgentinaFil: Christensen, Kaare. University of Southern Denmark; DinamarcaFil: Deleyiannis, Frederic W.-D.. State University of Colorado Boulder; Estados UnidosFil: Hecht, Jacqueline T.. University of Texas; Estados UnidosFil: Field, L. Leigh. University of British Columbia; CanadáFil: Garidkhuu, Ariuntuul. Tohoku University; Japón. Mongolian National University Of Medical Sciences; MongoliaFil: Moreno Uribe, Lina M.. University of Iowa; Estados UnidosFil: Nagato, Natsume. Aichi Gakuin University; JapónFil: Orioli, Ieda M.. Instituto Nacional de Genética Médica Populacional; Brasil. Universidade Federal do Rio de Janeiro; BrasilFil: Padilla, Carmencita. University Of The Philippines Manila; FilipinasFil: Poletta, Fernando Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; ArgentinaFil: Suzuki, Satoshi. Aichi Gakuin University; JapónFil: Vieira, Alexandre R.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Wehby, George. University of Iowa; Estados UnidosFil: Weinberg, Seth M.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Beaty, Terri H.. University Johns Hopkins; Estados UnidosFil: Feingold, Eleanor. University of Pittsburgh; Estados UnidosFil: Murray, Jeffrey C.. University of Iowa; Estados UnidosFil: Marazita, Mary L.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Leslie, Elizabeth J.. University of Emory; Estados Unido

A multi-ethnic genome-wide association study identifies novel loci for non-syndromic cleft lip with or without cleft palate on 2p24.2, 17q23 and 19q13

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 am ultiethnic 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 x 10(-8)), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 x 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 x 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.National Institutes of Health [X01-HG007485, R01-DE016148, U01-DE024425, R37-DE008559, R01-DE009886, R01-DE014667, R21-DE016930, R01-DE012472, R01-DE011931, R01-DE011948, R01-DD000295, U54-MD007587]; Robert Wood Johnson Foundation, AMFDP [72429]; Research Institute of the Children&apos;s Hospital of Colorado (FWD); Institute of Human Genetics, National Institutes of Health, University of the Philippines, Manila; Fundacao de Amparo a Pesquisa do Estado do Rio de Janeiro, Brazil [E-26/102.797/2012, E-26/110.140/2013]; CNPq, Brazil [481069/2012-7, 306396/2013-0, 400427/2013-3]; Danish National Research Foundation; Pharmacy Foundation; Egmont Foundation; March of Dimes Birth Defects Foundation; Augustinus Foundation; Health Foundation; National Institute of Environmental Health Sciences/National Institutes of Health Intramural Research Program; Norwegian Research Council; The National Institutes of Health [R25-MD007607, K99-DE024571, K99/R00-DE022378, K99-DE025060, R01-DE020895, HHSN268201200008I]SCI(E)[email protected]

A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in <i>GRHL3</i>

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

Umbilical Cord Milking vs Delayed Cord Clamping and Associations with In-Hospital Outcomes among Extremely Premature&nbsp;Infants

ObjectiveTo compare in-hospital outcomes after umbilical cord milking vs delayed cord clamping among infants &lt;29&nbsp;weeks of gestation.Study designMulticenter retrospective study of infants born &lt;29&nbsp;weeks of gestation from 2016 to 2018 without congenital anomalies who received active treatment at delivery and were exposed to umbilical cord milking or delayed cord clamping. The primary outcome was mortality or severe (grade III or IV) intraventricular hemorrhage (IVH) by 36&nbsp;weeks of postmenstrual age (PMA). Secondary outcomes assessed at 36&nbsp;weeks of PMA were mortality, severe IVH, any IVH or mortality, and a composite of mortality or major morbidity. Outcomes were assessed using multivariable regression, incorporating mortality risk factors identified a priori, confounders, and center. A prespecified, exploratory analysis evaluated severe IVH in 2 gestational age strata, 22-246/7 and 25-286/7&nbsp;weeks.ResultsAmong 1834 infants, 23.6% were exposed to umbilical cord milking and 76.4% to delayed cord clamping. The primary outcome, mortality or severe IVH, occurred in 21.1% of infants: 28.3% exposed to umbilical cord milking and 19.1% exposed to delayed cord clamping, with an aOR that was similar between groups (aOR 1.45, 95% CI 0.93, 2.26). Infants exposed to umbilical cord milking had higher odds of severe IVH (19.8% umbilical cord milking vs 11.8% delayed cord clamping, aOR 1.70 95% CI 1.20, 2.43), as did the 25-286/7&nbsp;week stratum (14.8% umbilical cord milking vs 7.4% delayed cord clamping, aOR 1.89 95% CI 1.22, 2.95). Other secondary outcomes were similar between groups.ConclusionsThis analysis of extremely preterm infants suggests that delayed cord clamping is the preferred practice for placental transfusion, as umbilical cord milking exposure was associated with an increase in the adverse outcome of severe IVH.Trial registrationClinicalTrials.gov: NCT00063063

Admission Temperature and Associated Mortality and Morbidity among Moderately and Extremely Preterm Infants

ObjectiveTo evaluate the temperature distribution among moderately preterm (MPT, 29-33 weeks) and extremely preterm (EPT, &lt;29 weeks) infants upon neonatal intensive care unit (NICU) admission in 2012-2013, the change in admission temperature distribution for EPT infants between 2002-2003 and 2012-2013, and associations between admission temperature and mortality and morbidity for both MPT and EPT infants.Study designProspectively collected data from 18 centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network were used to examine NICU admission temperature of inborn MPT and EPT infants. Associations between admission temperature and mortality and morbidity were determined by multivariable logistic regression. EPT infants from 2002-2003 and 2012-2013 were compared.ResultsMPT and EPT cohorts consisted of 5818 and 3213 infants, respectively. The distribution of admission temperatures differed between the MPT vs EPT (P &lt; .01), including the percentage &lt;36.5°C (38.6% vs 40.9%), 36.5°C-37.5°C (57.3% vs 52.9%), and &gt;37.5°C (4.2% vs 6.2%). For EPT infants in 2012-2013 compared with 2002-2003, the percentage of temperatures between 36.5°C and 37.5°C more than doubled and the percentage of temperatures &gt;37.5°C more than tripled. Admission temperature was inversely associated with in-hospital mortality.ConclusionsLow and high admission temperatures are more frequent among EPT than MPT infants. Compared with a decade earlier, fewer EPT infants experience low admission temperatures but more have elevated temperatures. In spite of a change in distribution of NICU admission temperature, an inverse association between temperature and mortality risk persists