Identification and estimation of causal peer effects using double negative controls for unmeasured network confounding.

Identification and estimation of causal peer effects are challenging in observational studies for two reasons. The first is the identification challenge due to unmeasured network confounding, for example, homophily bias and contextual confounding. The second is network dependence of observations. We establish a framework that leverages a pair of negative control outcome and exposure variables (double negative controls) to non-parametrically identify causal peer effects in the presence of unmeasured network confounding. We then propose a generalised method of moments estimator and establish its consistency and asymptotic normality under an assumption about ψ-network dependence. Finally, we provide a consistent variance estimator.

Vitamin K prophylaxis in neonates: comparing two different oral regimens.

OBJECTIVE: This prospective study compared PIVKA-II and PT-INR levels in infants who received two vitamin K (VK) prophylactic regimens. METHODS: A single institution administered 119 healthy newborns 2 mg of VK syrup. Infants were assigned to a 3-time regimen (n = 56) with VK at birth, five days (5D), and 1-month-old (1 M), or a 13-time regimen (n = 63) with VK at birth, 5D, and then weekly for 11 weeks. RESULTS: The 13-time regimen significantly lowered PIVKA-II and reduced PT-INR at 1 M in both breastfed (PIVKA-II: 18-16 mAU/mL, p = 0.02; PT-INR: 1.37-1.13, p < 0.01) and formula-fed infants (PIVKA-II: 18-15 mAU/mL, p = 0.01; PT-INR: 1.54-1.24, p < 0.01), compared to baseline measurements taken at 5D. The 3-time regimen did not significantly alter PIVKA-II levels and only improved PT-INR (2.00-1.50, p < 0.01) in formula-fed infants. CONCLUSION: The 13-time VK regimen significantly enhanced coagulation profiles more effectively than the 3-time regimen.

The clinical and genetic landscape of early-onset thrombophilia in Japan.

OBJECTIVES: To determine the optimal management for early-onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)-, protein S (PS)-, or antithrombin (AT)-deficient patients of ≤20 years of age were studied in Japan. METHODS/RESULTS: Clinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One-hundred-one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC- and PS-monoallelic variant. Fifty-five PC-deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS-deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT-biallelic variants. The frequent low-risk allele p.K193del (PC-Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low-risk allele p.K196E (PS-Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother-newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication-free survivors. Neurological complications were more frequently found in patients with PC-biallelic variants than those with PC-, PS-, or AT-monoallelic variants (73% vs. 24%, p = .019). CONCLUSIONS: We demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother-infant pairs may prevent perinatal thrombosis in them.

[Genetic predisposition to early-onset thrombophilia: a study on challenges in personalized medicine for mothers, infants, and children].

The number of reports on genetic predisposition to pediatric thrombosis is increasing. The risk of thrombosis in childhood varies according to patient age, and the contribution of genetic predisposition also differs. The term early-onset thrombophilia, which occurs until the age of 20 years in patients with genetic diagnosis, was defined. Then, the registry in Japan was established. Further, publications were reviewed comprehensively, and results revealed the genetic and clinical characteristics of patients. Less than 60% of patients presented with protein C (PC) deficiency, and over half of them had PC-gene monoallelic variants. The number of patients with protein S or antithrombin deficiency increased with age. None of them were aged between 6 and 8 years. PC-Tottori and protein S-Tokushima, which are high-frequency and low-risk variants in Japanese, contributed to the development of thrombosis. However, PC-Tottori did not affect the development of severe PC deficiency. One exceptional de novo PC-deficient variant was identified in 32 EOT families, and thrombosis developed concurrently in three pairs of mothers-newborns. Appropriate EOT screening tests targeting PC deficiency are required to prevent maternal and neonatal thromboses.

Ductus Arteriosus Aneurysm and Pulmonary Artery Thromboses in a Protein S-Deficient Newborn.

Ductus arteriosus aneurysm (DAA) asymptomatically occurs in newborn infants and resolves spontaneously. High-risk DAA with compression, rupture, and thrombosis requires early surgical intervention. Newborn infants have the highest risk of thrombosis among pediatric patients, but the genetic predisposition is difficult to determine in infancy. We herein report a neonatal case of massive thromboses in DAA and pulmonary artery. Desaturation occurred in an active full-term infant 2 days after birth. Echocardiography and contrast-enhanced computed tomography indicated thrombotic occlusion of the DAA and pulmonary artery thrombus. Urgent thrombectomy and ductus resection were successfully performed. After 6 months of anticoagulant therapy, the dissociated low plasma activity levels of protein S from protein C suggested protein S deficiency. A genetic study of PROS1 identified a heterozygous variant of protein S K196E, a low-risk variant of thrombophilia in Japanese populations. There have been seven reported cases with neonatal-onset symptomatic thromboses of DAA involving the pulmonary artery. All survived without recurrence after surgical intervention in five and anticoagulant therapy alone in two. Two newborns had a heterozygous methylenetetrahydrofolate reductase ( MTHFR ) variant, but information on thrombophilia was not available for any other cases. A genetic predisposition may raise the risk of DAA thrombosis, leading to rapid progression.

How to make causal inferences using texts.

Text as data techniques offer a great promise: the ability to inductively discover measures that are useful for testing social science theories with large collections of text. Nearly all text-based causal inferences depend on a latent representation of the text, but we show that estimating this latent representation from the data creates underacknowledged risks: we may introduce an identification problem or overfit. To address these risks, we introduce a split-sample workflow for making rigorous causal inferences with discovered measures as treatments or outcomes. We then apply it to estimate causal effects from an experiment on immigration attitudes and a study on bureaucratic responsiveness.

Pediatric pulmonary veno-occlusive disease associated with a novel BMPR2 variant.

Pulmonary veno-occlusive disease (PVOD) and idiopathic/heritable pulmonary arterial hypertension (I/HPAH) cause progressive PH on the distinct genetic impact. A 29-month-old boy presented with a loss of consciousness. He had severe PH refractory to pulmonary vasodilators. Hypoxemia and ground-glass opacity on the chest computed tomography were present, and significant pulmonary edema developed after the introduction of continuous intravenous prostaglandin I2 . Based on the clinical diagnosis of PVOD, he underwent a single living-donor lobar lung transplantation with the right lower lobe of his mother. The pathological findings of his explanted lung showed intimal thickening and luminal narrowing of the pulmonary vein. A genetic test revealed a novel heterozygous splice acceptor variant (c.77-2A>C) in BMPR2, which is typically associated with I/HPAH. This is the first pediatric case of PVOD with BMPR2 variant, supporting the concept that I/HPAH and PVOD are part of a spectrum of pulmonary vascular disease.

Synthesis and Properties of V-Shaped Xanthene Dyes with Tunable and Predictable Absorption and Emission Wavelengths.

V-shaped xanthene dyes capable of predicting absorption and emission wavelengths are described. These dyes were synthesized by bridging a xanthene ring and an aryl moiety of fluorescein through ether covalent bonds. These dyes showed longer absorption and emission wavelengths than those of the parent fluorescein. Furthermore, substituents introduced on the aryl moiety mainly affected the lowest unoccupied molecular orbital energy level of the molecule. Therefore, the Hammett substituent constants could be used to predict the absorption and emission wavelengths of the compound.

Mild neonatal complications following guideline-compliant vacuum-assisted delivery in Japan: improvements still needed.

INTRODUCTION: Neonatal cephalohematoma and hyperbilirubinemia are often encountered after vacuum-assisted delivery. For safe obstetric practice, guidelines for vacuum procedure were published in 2014 in Japan. We aimed to identify the risk of mild neonatal complications since guideline introduction. METHODS: This retrospective observational study included singleton deliveries at term gestation from 2015 to 2019 at a single perinatal center in Japan. Incidences of neonatal jaundice requiring phototherapy, cephalohematoma, and umbilical artery pH <7.10 were determined and risk factors relevant to the development of hyperbilirubinemia were evaluated. RESULTS: Of 1010 deliveries during the study period, vacuum procedures were attempted in 183 (18%). Guideline recommendations were fully adhered to in over 98% of vacuum procedures. Phototherapy for neonatal hyperbilirubinemia was performed in 75 (41%) of 183 deliveries with vacuum procedure, cephalohematoma occurred in 35 (19%), and umbilical artery pH <7.10 was observed in 10 (5.5%), all of which were significantly higher than without vacuum procedure, such as hyperbilirubinemia (11%, risk ratio [RR] = 3.8, 95% confidence interval [CI] = 2.9 - 4.9, p < .0001), cephalohematoma (1.0%, RR = 19.8, 95%CI = 9.3 - 41.9, p < .0001), and umbilical artery pH <7.10 (0.6%, RR = 9.0, 95%CI = 3.1 - 26.1, p < .0001). Multiple logistic regression analysis demonstrated that vacuum procedure was the factor most strongly associated with neonatal hyperbilirubinemia (odds ratio = 3.5, 95%CI = 2.2 - 5.5, p < .0001). DISCUSSION: Vacuum procedure is an important option for the safe vaginal delivery. However, neonates should be observed for development of jaundice to prevent kernicterus even after optimally performed vacuum-assisted delivery.

Synthesis of Bridged Indigos and Their Thermoisomerization and Photoisomerization Behaviors.

Bridged indigos were synthesized by bridging the two nitrogen atoms in the indigo structure with a carbon chain, and their properties were carefully examined. These bridged indigos have intrinsic planar chirality, and the enantiomers were separated using chiral high-performance liquid chromatography. When the chiral bridged indigos were subjected to thermo- and photoisomerization, the corresponding (Z)-indigo was not observed at all, and racemization was observed. This phenomenon is caused by the low activation energy of inversion due to the 1.5 bond order of the double bond of the indigo skeleton and the large energy difference between the ground states of (E)-indigo and (Z)-indigo.

Clinical Impact of Heritable Thrombophilia on Neonatal-Onset Thromboembolism: A Nationwide Study in Japan.

OBJECTIVE: To clarify the incidence and genetic risk of neonatal-thromboembolism, we conducted a nationwide study exploring the impact of thrombophilia on neonatal-thromboembolism in Japan. STUDY DESIGN: A questionnaire survey was conducted for perinatal centers in Japan, focusing on the clinical expression, genotype, treatment, and outcome of patients who developed thromboembolism within 28 days of birth from 2014 to 2018. RESULTS: The estimated incidence of neonatal-thromboembolism was 0.39 cases per 10 000 live births. Intracranial lesions and purpura fulminans occurred in 66 and 5 of 77 patients, respectively. Fifty-eight (75.3%) infants presented within 3 days after birth. Four (5.2%) died, and 14 (18.2%) survived with disability. At the diagnosis, <20% plasma activity of protein C was noted in 16 infants, protein S (in 2), and antithrombin (in 1). Thirteen genetic tests identified 4 biallelic and 5 monoallelic protein C-variants but no protein S- or antithrombin-variants. Protein C-variants had purpura fulminans (P < .01), ocular bleeding (P < .01), positive-family history (P = .01), and death or disability (P = .03) more frequently than others. Protein C-variants were independently associated with disability (OR 5.74, 95% CI 1.16-28.4, P = .03) but not death. Four biallelic variants had serious thrombotic complications of neurologic disability, blindness, and/or amputation. Three monoallelic variants survived without complications. The only protein C-variant death was an extremely preterm heterozygote infant. CONCLUSIONS: Monoallelic protein C-variants had a higher incidence of neonatal-thromboembolism than biallelic variants. Thrombophilia genetic testing should be performed in the setting of neonatal-thromboembolism and low protein C to identify the underlying genetic defect.

Impact of clinical practice guidelines for vacuum-assisted delivery on maternal and neonatal outcomes in Japan: A single-center observational study.

AIM: Practice guidelines for vacuum-assisted delivery in Japan were revised in 2014 to improve clinical safety. We aimed to determine the success rates of vacuum delivery before and after the release of the revised guidelines. METHODS: This retrospective observational study included singleton deliveries at term gestation. Success rate of vacuum delivery, duration of extraction, number of tractions and maternal and neonatal injuries were compared between 2011-2014 and 2015-2019. RESULTS: Vacuum extraction was attempted in 249 (15%) of 1657 deliveries. Duration of extraction was shorter in 2015-2019 (median, 3.0 min; interquartile range [IQR], 1.0-5.8 min) than in 2011-2014 (median, 4.0 min; IQR, 2.0-6.5 min; P = 0.0045). No significant differences were seen in success of vacuum extraction (98%), prolonged (>20 min) duration of extraction (1.5%) and repeated (>5 pulls) tractions (3.1%) in vacuum deliveries during 2011-2014, compared to success of vacuum extraction (94%), prolonged duration of extraction (1.6%) and repeated tractions (1.1%) in those during 2015-2019. Likewise, no significant differences were identified in maternal or neonatal injuries. CONCLUSION: Successful vacuum-assisted deliveries and shortened duration of extraction were still confirmed after guideline revision. However, because of consistent safe practice with vacuum delivery from before the revision, improvements in maternal and neonatal injuries were not observed.

[Diagnosis and management of early-onset thrombophilia/thrombosis: a review].

Evidence of the molecular epidemiology of thrombophilia is growing, and the clinical management of adult thromboembolism patients has recently made significant progress. On the other hand, there is little or no evidence concerning the genetic variation, treatment, and prophylaxis of thromboembolism development in the early life stage. The clinical presentation of early-onset thrombosis/thrombophilia, which mostly occurs in newborns and adolescents, differs from that in cases of adult-onset. Recurrent purpura fulminans and/or intracranial hemorrhage/infarction leads to dangerous lifelong complications. As in the setting of cancer genomic medicine, germline variants require determination for the individualized control of early-onset thrombophilia. The genetic predisposition to thrombosis varies among ethnicities. In the Japanese population, the protein S variant (PS-Tokushima, K196E) has attracted attention as the cause of a common and low-risk prothrombotic predisposition in adults, while protein C deficiency greatly impacts the onset of pediatric thrombosis. In 2020, 3 years after the registration of idiopathic thrombosis as a designated intractable disease, genetic tests have been promulgated for health insurance portability. Disease-specific therapy for early-onset thrombophilia is crucial. Here, we review the genetic heterogeneity, prophylaxis, and treatment strategy of the rare subgroups of severe heritable thrombosis conditions in Japan.

Weather condition, air pollutants, and epidemics as factors that potentially influence the development of Kawasaki disease.

Environmental factors have been suspected to have effects on the development of Kawasaki disease. However, the associations have been conflicting. The aim of this study was to investigate the effects of air pollution, weather conditions, and epidemic infections on the risks for Kawasaki disease in Japan. The concentrations of air pollutants (nitric oxide, nitrogen dioxide, and sulfur dioxide); ambient weather conditions (temperature, atmospheric pressure, relative air humidity, precipitation, sunshine duration, and wind velocity); and the epidemic conditions of 14 infectious diseases in hospitalized patients with Kawasaki disease were monitored from 2011 to 2018 in Beppu, Japan. The overdispersed generalized additive model was used to evaluate the effects, and a combination model with a distributed lag nonlinear model was used to estimate the cumulative effects. The incidence of Kawasaki disease had positive associations with preceding hot temperature and increased concentrations of nitric oxide and sulfur dioxide and a negative association with epidemic herpangina. The cumulative relative risk of Kawasaki disease at 5 lagged days of increased temperature was 1.76 (95% confidence interval: 1.01-3.07). This city-level observational study suggested that the incidence of Kawasaki disease was associated with air pollution and increased temperature and may be indirectly influenced by epidemic herpangina.

Late-Onset Circulatory Collapse and Risk of Cerebral Palsy in Extremely Preterm Infants.

OBJECTIVE: To investigate whether the development of postnatal, late-onset refractory hypotension, referred to as late-onset circulatory collapse, was associated with an increased risk of developing cerebral palsy (CP) at 3 years of age in extremely preterm infants. METHODS: In this historical cohort study, infants who were born at 22-27 weeks of gestation from 2008 to 2012 in the Neonatal Research Network of Japan were eligible. The study sample consisted of 3474 infants (45.6% of 7613 potentially eligible infants) who were evaluated at 36-42 months of age. Late-onset circulatory collapse was defined as a clinical diagnosis of late-onset circulatory collapse requiring treatment with corticosteroids. We compared the neurodevelopmental outcomes between infants with and without late-onset circulatory collapse. RESULTS: Late-onset circulatory collapse was diagnosed in 666 of the infants studied. Infants with late-onset circulatory collapse had a higher incidence of CP than those without late-onset circulatory collapse (18.0% vs 9.8%; P < .01). In multivariable logistic analysis, late-onset circulatory collapse was independently associated with CP (aOR, 1.52; 95% CI, 1.13-2.04) and developmental quotient score of <50 (OR, 1.83; 95% CI, 1.23-2.72). CONCLUSIONS: Late-onset circulatory collapse may be a relatively common event occurring in extremely preterm infants and an independent risk factor for CP at 3 years of age.