Extensional faults are key components of foreland basin systems. They form within the upper crust in response to flexure of the lithosphere and accommodate subsidence within the foredeep and ...forebulge depozones. Such faults are excellent proxies for orogenic system evolution and control the distribution of natural resources and hazards. However, the spatiotemporal evolution of flexural extension has not been documented previously at a regional scale, thereby limiting our understanding of underlying geodynamic controls. Here, we resolve late Paleozoic flexural extension in the northern Arkoma basin and southern Ozark dome, USA. We synthesize a large database of previous mapping, existing research, subsurface data, and geophysical data into 3D geologic and 2D kinematic models. Mesh surfaces representing several key horizons from the Carboniferous Period (ca. 335-306 Ma) were constructed. These surfaces were built from oil and gas well tops (n = ∼10,000) and surface geologic map contacts using an advanced kriging method. The mesh surfaces are offset by a complex 3D fault network, allowing detailed analysis of along-strike and down-dip variations in fault displacement. Analysis of the 3D model reveals a regular and repeated fault segmentation pattern wherein E-W striking, left- and foreland-stepping en échelon normal faults are segmented by inherited NE striking basement faults. Maximum vertical separation along the E-W normal faults is generally focused between the inherited NE-trending faults. This suggests that the inherited basement faults delocalized extensional strain during late Paleozoic normal faulting. Maximum vertical separation and fault localization may correlate to areas with high-amplitude positive magnetic anomalies interpreted as Mesoproterozoic granitic rocks. Speculative covariance of magnetic anomalies and fault displacements implies that the relatively strong basement granite concentrated stress, leading to localized faulting within the relatively thin sedimentary cover. Lastly, we show that flexural extension migrated southeast to northwest from the Chesterian-Morrowan (ca. 335-319 Ma) to the Desmoinesian (ca. 306 Ma). The migratory flexural extension may be explained by diachronous loading during Pangean assembly, or by synchronous loading but variable load compensation due to inherent factors.
Display omitted
•Faulted 3D structural model of key horizons.•Inherited basement faults segment flexural extensional faults.•Localization of faulting above Mesoproterozoic granite.•2D sequential flexural-kinematic reconstructions.•Southeast to northwest migration of flexural extension.
The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride ...concentration in patients with cystic fibrosis (CF) and one or two
alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied.
To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two
alleles aged 12 years and older.
This prospective, observational, multicenter study assessed clinical outcomes including FEV
% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA.
A total of 107 patients with CF including 55 patients with one
and a minimal function mutation and 52
homozygous patients were enrolled in this study. In patients with one
allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range IQR, 27.5-72.4;
< 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6;
< 0.001). In
homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl
secretion to a level of 47.4% of normal (IQR, 19.3-69.2;
< 0.001) in nasal and 45.9% (IQR, 19.7-66.6;
< 0.001) in intestinal epithelia.
Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two
alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).
Objectives To evaluate whether in children born extremely preterm, indicators of sustained systemic inflammation in the first month of life are associated with cognitive impairment at school age. ...Study design A total of 873 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborn Study from 2002 to 2004 were evaluated at age 10 years. We analyzed the relationship between elevated blood concentrations of inflammation-associated proteins in the first 2 weeks (“early elevations”; n = 812) and the third and fourth week (“late elevations”; n = 532) of life with neurocognition. Results Early elevations of C-reactive protein, tumor necrosis factor-α, interleukin (IL)-8, intercellular adhesion molecule (ICAM)-1, and erythropoietin were associated with IQ values >2 SD below the expected mean (ORs: 2.0-2.3) and with moderate to severe cognitive impairment on a composite measure of IQ and executive function (ORs: 2.1-3.6). Additionally, severe cognitive impairment was associated with late protein elevations of C-reactive protein (OR: 4.0; 95% CI 1.5, 10), IL-8 (OR: 5.0; 1.9, 13), ICAM-1 (OR: 6.5; 2.6, 16), vascular endothelial growth factor-receptor 2 (OR: 3.2; 1.2, 8.3), and thyroid-stimulating hormone (OR: 3.1; 1.3, 7.3). Moderate cognitive impairment was most strongly associated with elevations of IL-8, ICAM-1, and vascular endothelial growth factor-receptor 2. When 4 or more inflammatory proteins were elevated early, the risk of having an IQ <70 and having overall impaired cognitive ability was more than doubled (ORs: 2.1-2.4); the presence of 4 or more inflammatory protein elevated late was strongly linked to adverse cognitive outcomes (ORs: 2.9-4.8). Conclusions Extremely preterm children who had sustained elevations of inflammation-related proteins in the first postnatal month are more likely than extremely preterm peers without such elevations to have cognitive impairment at 10 years.
In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via IL-1R signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in ...neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis caused by airway mucus obstruction precedes neutrophilic inflammation in Scnn1b-transgenic (Scnn1b-Tg) mice with CF-like lung disease.
To determine the role of epithelial necrosis and IL-1R signaling in the development of neutrophilic airway inflammation, mucus obstruction, and structural lung damage in CF lung disease.
We used genetic deletion and pharmacologic inhibition of IL-1R in Scnn1b-Tg mice and determined effects on airway epithelial necrosis; levels of IL-1α, keratinocyte chemoattractant, and neutrophils in bronchoalveolar lavage; and mortality, mucus obstruction, and structural lung damage. Furthermore, we analyzed lung tissues from 21 patients with CF and chronic obstructive pulmonary disease and 19 control subjects for the presence of epithelial necrosis.
Lack of IL-1R had no effect on epithelial necrosis and elevated IL-1α, but abrogated airway neutrophilia and reduced mortality, mucus obstruction, and emphysema in Scnn1b-Tg mice. Treatment of adult Scnn1b-Tg mice with the IL-1R antagonist anakinra had protective effects on neutrophilic inflammation and emphysema. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and chronic obstructive pulmonary disease.
Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other mucoobstructive airway diseases.
Objectives To compare the prevalence of cognitive, neurologic, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm. Study design A total of 889 of 966 ...eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborns Study from 2002-2004 were evaluated at 10 years of age. Children underwent a neuropsychological battery and testing for autism spectrum disorder (ASD), and parents reported on their child's behavior, development, and seizures. Results Of the children, 28% of boys and 21% of girls exhibited moderate to severe impairment on summary measures of cognitive abilities. Boys had a higher prevalence of impairment than girls in nearly all measures of cognition, were more than twice as likely to have microcephaly (15% in boys, 8% in girls), and require more often assistive devices to ambulate (6% in boys, 4% in girls). In contrast, boys and girls had comparable risk for a history of seizure (identified in 10% of the cohort) or epilepsy (identified in 7% of the cohort). The boy-to-girl ratio of ASD (9% in boys, 5% in girls) was lower than expected compared with the overall US autism population. Conclusions In this contemporary cohort of children born extremely premature and evaluated at school age, boys had higher prevalence of cognitive, neurologic, and behavioral deficits than girls. The ratio of boys to girls among those with ASD deserves further study as does the perinatal environmental-genetic interactions that might contribute to male preponderance of deficits in this high-risk sample.
The authors hypothesized that among extremely preterm infants, elevated concentrations of inflammation-related proteins in neonatal blood are associated with cerebral palsy at 24 months. In 939 ...infants born before 28 weeks gestation, the authors measured blood concentrations of 25 proteins on postnatal days 1, 7, and 14 and evaluated associations between elevated protein concentrations and cerebral palsy diagnosis. Protein elevations within 3 days of birth were not associated with cerebral palsy. Elevations of tumor necrosis factor-α, tumor necrosis factor-α-receptor-1, interleukin-8, and intercellular adhesion molecule-1 on at least 2 days were associated with diparesis. Recurrent-persistent elevations of interleukin-6, E-selectin, or insulin-like growth factor binding protein-1 were associated with hemiparesis. Diparesis and hemiparesis were more likely among infants who had at least 4 of 9 protein elevations that previously have been associated with cognitive impairment and microcephaly. Repeated elevations of inflammation-related proteins during the first 2 postnatal weeks are associated with increased risk of cerebral palsy.
Objective To evaluate the hypothesis that elevated levels of inflammation-related proteins in early postnatal blood predict impaired mental and motor development in extremely preterm infants. Study ...design We measured concentrations of 25 inflammation-related proteins in blood collected on postnatal days 1, 7, and 14 from 939 infants born before 28 weeks gestation. An elevated level was defined as a concentration in the highest quartile for gestational age and day of blood collection. We identified impaired development at age 24 months using the Bayley Scales of Infant Development, Second Edition . The primary outcomes were scores on the Mental Scale or the Motor Scale of <55 (more than 3 SDs below the mean). Results For 17 of the 25 inflammation-related proteins, 1 or more statistically significant associations ( P < .01) was found between an elevated blood level of the protein and a developmental impairment. Elevations on multiple days were more often associated with developmental impairment than were elevations present for only 1 day. The highest number of predictive elevations was found in day-14 blood. Conclusion In extremely preterm infants, elevated levels of inflammation-related proteins in blood collected on postnatal days 7 and 14, especially when sustained, are associated with impaired mental and motor development at age 2 years.
No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately ...among those with and without cognitive impairment.
We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient <70) in children born extremely preterm.
This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks’ gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal “infection” refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms “fetal growth restriction” and “small for gestational age” interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery <–2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability–, autism spectrum disorder+/intellectual disability+, autism spectrum disorder–/intellectual disability+, and autism spectrum disorder–/intellectual disability–). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability–, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder–/intellectual disability+).
In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability– was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder–/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2–6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3–6.6) and autism spectrum disorder+/intellectual disability– (odds ratio, 4.4; 95% confidence interval, 1.7–11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability– (odds ratio, 9.9; 95% confidence interval, 3.3–30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder–/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2–6.7).
Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.
PDF
