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Phase stability predictions are central to computational materials discovery efforts and have been made possible by large databases of computed properties from high-throughput density functional theory (DFT) calculations. Such databases now contain millions of calculations at the generalized gradient approximation (GGA) level of theory, representing an enormous investment of computational resources. Although it is now feasible to carry out large numbers of calculations using more accurate methods, such as meta-GGA functionals, recomputing the entirety of a database with a higher-fidelity method is impractical and would not effectively leverage the value embodied in existing calculations. Instead, we propose in this work a general procedure by which higher-fidelity, low-coverage calculations (e.g., meta-GGA calculations for selected chemical systems) can be combined with lower-fidelity, high-coverage calculations (e.g., an existing database of GGA calculations) in a robust and scalable manner to yield improved phase stability predictions. We demonstrate our scheme using legacy GGA(+\textit{U}) calculations and new r$^2$SCAN meta-GGA calculations from the Materials Project and illustrate its application to solid and aqueous phase stability. We discuss practical considerations for constructing mixed phase diagrams and present guidelines for prioritizing high-fidelity calculations for maximum benefit.

Introduction World Trade Center (WTC) responders have a high risk of early-onset cognitive impairment (CI), but little is known about the etiology including the extent to which CI in WTC responders is accompanied by cortical atrophy as is common in progressive diseases causing age-related CI such as Alzheimer’s disease and related dementias. In the current study, we entrained an artificial neural network (ANN) to determine the accuracy of cortical thickness (CTX) on magnetic resonance imaging to identify World Trade Center responders at midlife (aged 44–65 years) with possible dementia. Methods A total of 119 WTC responders (57 with CI and 62 with intact cognition) underwent a structural MRI scanning protocol including T1-weighted MPRAGE as part of two imaging studies. The discovery study was divided into training and validation samples, while a second replication sample was used. An ANN was trained using regional CTX measured across 34 unilateral regions of interest (ROIs) using Freesurfer software and ‘Desikan-Killiany’ brain atlas. The discovery sample was used for model development, and the replication sample was used to evaluate predictive accuracy. Results In the WTC responder cohort, the ANN algorithm showed high discrimination performance for CI. The ANN model using regional CTX data from both hemispheres achieved an area under the receiver operating characteristic curve (AUC) of 0.96 95% C.I. ​= ​[0.91–1.00] (Accuracy ​= ​96.0%, Precision ​= ​97.8%, Recall ​= ​95.8%, Sensitivity ​= ​95.8%, Specificity ​= ​98.0%, F1 ​= ​96.8%) for the discovery sample and AUC ​= ​0.90 [0.70–1.00] (Accuracy ​= ​90.0%, Precision ​= ​90.0%, Sensitivity ​= ​90.0%, Specificity ​= ​90.0%, F1 ​= ​90.0%) in the replication sample. Conclusion Analysis of bilateral regional CTX data derived from T1-weighted MPRAGE images by ANN analysis demonstrated excellent accuracy in distinguishing WTC responders with early-onset CI.

[The Late Triassic Chapeng thrust and the Dengzhangzi Basin system in the Yanshan Mountains of the North China Craton were an antiformal stack duplex with a frontal depression. , Abstract The configuration and kinematics of fold‐thrust belts are essential for clarifying the plate boundary conditions through which ancient orogenic belts evolved. Temporal and spatial variations in extension versus contraction within convergent plate margins are related to changes in plate kinematics and subduction geometry. The Yanshan Mountains, located along the northeastern margin of the North China Craton and bounded by the Central Asian Orogenic Belt to the north and the Pacific subduction zone to the east, underwent multiple phases of intra‐continental deformation during the Mesozoic. The issue of whether early Mesozoic deformation was extensional or contractional has remained controversial. New regional structural mapping and detailed sedimentological investigations, coupled with age constraints provided by zircon U‐Pb geochronology, provide sufficient temporal and spatial resolution to show that shortening and thrust‐top basin systems dominated during the early Mesozoic. Our results show that the Dengzhangzi Basin within the Lingyuan fold‐thrust belt developed during the construction of a major Late Triassic Chapeng antiformal‐stack duplex system, with episodic, east‐vergent forward‐breaking thrusts and subsequent ‘beheading’ by out‐of‐sequence, top‐to‐east thrusting in the latest Triassic or earliest Jurassic. The neighbouring Guojiadian Basin in the east was generated during top‐to‐SSE sinistral transpression along the Niuyingzi thrust system in the Middle to earliest Late Jurassic. These results support a new model of early craton decratonization involving (a) thrusting along the northern margin of the North China Craton and (b) transpressional deformation in the east driven by the Central Asian Ocean collision and flat‐slab subduction of the Palaeo‐Pacific Plate beneath the East Asian continental margin. Our findings suggest that large‐scale shortening and crustal/lithospheric thickening, triggered by flat‐slab subduction in the North China Craton, were fundamental components of craton decratonization. Subsequent slab roll‐back during the Cretaceous led to lithospheric thinning and crustal extension in the North China Craton.]

Background Trilaciclib is an intravenous (IV) cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Preliminary data showed that adding trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly increased overall survival (OS) compared with GCb alone among patients with metastatic triple-negative breast cancer (mTNBC) (Tan et al., Lancet Oncol. 2019;20:1587-1601). Here, final antitumor efficacy results (objective response rate [ORR], progression-free survival [PFS], and OS) are reported for the whole study population, and in cohorts according to CDK4/6 dependence and level of programmed death ligand-1 (PD-L1) expression. Methods This was a randomized, open-label, phase 2 study of patients with mTNBC who had received ≤2 previous lines of chemotherapy in the recurrent/metastatic setting (NCT02978716). Patients were randomized (1:1:1) to receive GCb on days 1 and 8 (group 1, n=34), trilaciclib prior to GCb on days 1 and 8 (group 2, n=33), or trilaciclib alone on days 1 and 8 and prior to GCb on days 2 and 9 (group 3, n=35), in 21-day cycles. PFS and OS (prespecified secondary endpoints) were assessed in the intention-to-treat (ITT) population, and ORR in response-evaluable patients. Patient tumors were characterized as CDK4/6 independent (basal-like) or indeterminate (HER2-enriched, normal-like, luminal A/B) according to the established PAM50 signature, or CDK4/6 dependent (luminal androgen receptor) or indeterminate (basal-like 1/2, mesenchymal) according to the established Lehmann signature. PD-L1 expression was scored as negative or positive if Results Median follow-up was 8.4 months (range: 0.1-25.7) for group 1, 14.0 months (1.3-33.6) for group 2, and 15.3 months (3.5-33.7) for group 3. The ORR among response-evaluable patients was 7/24 (29.2%) in group 1, 15/30 (50.0%) in group 2, and 12/31 (38.7%) in group 3. Median PFS (95% confidence interval [CI]) in the ITT population was 5.7 (3.3, 9.9) months in group 1, 9.4 (6.1, 11.9) months in group 2, and 7.3 (6.2, 13.9) months in group 3, with hazard ratios (HRs) of 0.62 (P = 0.2099) and 0.63 (P = 0.1816), for groups 2 and 3 versus group 1, respectively. Overall, 73.5%, 39.4%, and 57.1% of patients in groups 1, 2, and 3 had died. Median OS (95% CI) was 12.6 (6.3, 15.6) months in group 1, not reached (NR) (10.2, NR) in group 2 (HR = 0.31, P = 0.0016), and 17.8 (12.9, 32.7) months in group 3 (HR = 0.40, P = 0.0004). For groups 2 and 3 combined, median OS was 19.8 (14.0, NR) months (HR = 0.37, P Conclusions Mature data from this study confirm that administering trilaciclib prior to GCb enhances antitumor efficacy compared with GCb alone, with statistically significant improvements in OS. Subgroup analyses suggest that adding trilaciclib prior to GCb benefits patients regardless of CDK4/6 dependence status and PD-L1 expression. Additional immune subtyping analyses are ongoing and will be presented. Group 1Group 2Group 3PD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePatients, n171016101616ORR, n (%)4 (23.5)3 (30.0)8 (50.0)4 (40.0)7 (43.8)4 (25.0)Median PFS, months (95% CI)3.5 (2.2, NR)9.5 (5.2, NR)7.9 (4.3, NR)11.9 (8.8, NR)9.0 (6.2, NR)6.9 (6.4, NR)P value (Wald Test)––0.3470.6040.0690.766HR (95% CI)––0.70 (0.3, 1.5)0.76 (0.3, 2.2)0.46 (0.2, 1.1)1.16 (0.4, 3.1)Median OS, months (95% CI)10.5 (6.3, 18.8)13.9 (12.6, NR)20.1 (10.2, NR)NR (9.4, NR)32.7 (15.3, NR)17.8 (12.9, NR)P value (Wald Test)––0.0280.0830.020.239HR (95% CI)––0.35 (0.1, 0.9)0.34 (0.1, 1.2)0.33 (0.1, 0.8)0.57 (0.2, 1.5)HR and P values are for comparisons between group 2 versus group 1, and group 3 versus group 1.+ve, positive; –ve, negative; CI, confidence interval; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival. Citation Format: Joyce O'Shaughnessy, Gail S Wright, Anu R Thummala, Michael A Danso, Lazar Popovic, Timothy J Pluard, Hyo S Han, Željko Vojnović, Nikola Vasev, Ling Ma, Donald A Richards, Sharon T Wilks, Dušan Milenković, Jie Xiao, Jessica A Sorrentino, Janet Horton, Antoinette R Tan. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-06.

The eastern foothills in the Colombian Eastern Cordillera have been an important oil-producing region since the discovery of the Cupiagua and Cusiana fields. Three organic-rich units are considered to be the main source rocks. The Aptian Fómeque and the Cenomanian-Coniacian Chipaque Formations comprise a siliciclastic to locally carbonate shallow marine shelf succession with type-II kerogen, whereas the Paleocene Los Cuervos Formation consists of marginal marine to nonmarine siliciclastic rocks with type-III kerogen. We modeled the petroleum systems of these three source units to characterize the hydrocarbon generation-accumulation processes within the basin. The structural record of the Eastern Cordillera shows that the most important tectonic event began in early Oligocene with contractional deformation along the Soapaga through Guaicaramo faults during early Miocene, culminating during the Pliocene with the Cusiana and Yopal faults. These variable rates of burial and exhumation resulted in contrasting time-temperature histories for each of the source rocks. The Fómeque Formation reached the oil window during the Paleocene in the south and the Eocene to the north. In contrast, the Chipaque Formation generation started during Early Oligocene in the south and by Late Oligocene to the north. Conversely, maturation for the Los Cuervos Formation was uniform along the foothills, reaching the oil window during Late Oligocene. Charge history modeling suggested that the Albian sandstones reservoirs were filled between Oligocene to Miocene. In contrast, the proven reservoirs in the area (the Upper Cretaceous, Paleocene, and Eocene sandstones) were filled by late Miocene, with a second episode of recent charge in the Eocene reservoirs, and perhaps active, from the Los Cuervos Formation. The results of this work proved that petroleum system modeling is useful not only to characterize generation-migration processes but it also can be used as a prediction tool in structurally complex areas such as the Colombian foothills.

Background Childhood exposure to air pollution has been linked with maladaptive cognitive development; however, less is known about the association between prenatal fine particulate matter (PM2.5) exposure and childhood behavior. Objectives Our aim was to assess the association between prenatal PM2.5 exposure and behavioral development in 4-6 year old children residing in Mexico City. Methods We used data from 539 mother-child pairs enrolled in a prospective birth cohort in Mexico City. We estimated daily PM2.5 exposure using a 1 km2 satellite-based exposure model and averaged over each trimester of pregnancy. We assessed childhood behavior at 4-6 years of age using the parent-completed Behavioral Assessment Scale for Children (BASC-2) composite scores and subscales. We used linear regression models to estimate change in BASC-2 T-scores with trimester specific 5-μg/m3 increases in PM2.5. All models were mutually adjusted for PM2.5 exposures during the other trimesters, maternal factors including age, education, socioeconomic status, depression, and IQ, child’s age at study visit, and season. We additionally assessed sex-specific effects by including an interaction term between PM2.5 and sex. Results Higher first trimester PM2.5 exposure was associated with reduced Adaptive Skills scores (β: -1.45, 95% CI: -2.60, -0.30). Lower scores on the Adaptive Skills composite score and subscales indicate poorer functioning. For PM2.5 exposure during the first trimester, decrements were consistent across adaptive subscale scores including Adaptability (β: -1.51, 95% CI: -2.72, -0.30), Social Skills (β: -1.63, 95% CI: -2.90, -0.36), and Functional Communication (β: -1.21, 95% CI: -2.21, -0.21). The association between 1st trimester PM2.5 and depression was stronger in males than females (β for males: 1.52, 95% CI: -0.41, 3.45; β for females: -0.13, 95% CI: -1.99, 1.72; p-int: 0.07). Conclusions Exposure to PM2.5 during early pregnancy may be associated with impaired behavioral development in children, particularly for measures of adaptive skills. These results suggest that air pollution impacts behavioral domains as well as cognition, and that the timing of exposure may be critical.

Prozone is a known phenomenon affecting immunoassays causing falsely low or negative results when excess target is present in the test system. For assays used to evaluate immune-mediated platelet (PLT) transfusion refractoriness, prozone-like phenomenon has been described in solid-phase human leukocyte antigen (HLA) antibody testing and can be mitigated by diluting samples or pretreating samples with ethylenediaminetetraacetic acid (EDTA) or dithiothreitol. Prozone phenomenon has not yet been described in solid-phase red blood cell (RBC) adherence PLT crossmatch assays. CASE REPORT: A 40-year-old female with myeloid sarcoma and PLT transfusion refractoriness underwent repeated solid-phase PLT crossmatches; however, crossmatch-compatible PLTs units did not yield adequate PLT count responses. Class I HLA antibody testing with neat, diluted, and EDTA-pretreated serum demonstrated significant prozone-like effect and the presence of numerous high strength HLA antibodies. Based on this HLA antibody profile, HLA antigen-negative PLTs gave an adequate PLT count response. It was noted that the HLA types of her crossmatch-compatible PLTs were incompatible with her HLA antibody profile (eg, HLA-A2). With ABO-identical, HLA-A2-positive PLT units, a solid-phase PLT crossmatch was repeated using undiluted and diluted EDTA plasma. Undiluted EDTA plasma demonstrated negative or weakly positive PLT crossmatches while the diluted EDTA plasma demonstrated strongly positive PLT crossmatches. CONCLUSION: The prozone phenomenon can cause false-negative results in solid-phase RBC adherence PLT crossmatch assays, which can be mitigated with sample dilution. In immune-mediated PLT transfusion-refractory patients with high-strength HLA antibodies, sample dilution should be considered to correctly identify compatible PLT inventory.

Undifferentiated carcinoma of the esophagus and gastroesophageal junction is a recently recognized entity in the fifth edition of the World Health Organization Classification of Digestive Tumors and is diagnostically challenging, particularly on small biopsies. SMARCA4 and SMARCA2 are chromatin remodeling genes with key roles in oncogenesis. We retrieved 14 cases of SMARCA4/SMARCA2-deficient undifferentiated carcinoma of the gastroesophageal junction and esophagus from the authors' institutions. The tumors showed similar histologic findings: the sheet-like proliferation of tumor cells characterized by discohesion, large nuclei, and prominent macronucleoli with many tumor cells exhibiting a rhabdoid appearance. In 8 cases, adjacent specialized intestinal metaplasia was noted and 3 cases exhibited adjacent high-grade dysplasia. Immunohistochemically, tumors variably expressed keratins and disclosed loss of expression of SMARCA4 in 12 and SMARCA2 in 7 cases. In 2 cases SMARCA2 alone was lost without SMARCA4 loss. A mutant p53 immunohistochemical pattern was seen in 4 of 4 cases, 3 of which showed diffuse, strong nuclear expression, and 1 case displayed a complete loss of nuclear expression of p53, including invasive carcinoma and associated dysplasia, when present. Limited clinical follow-up was available, but 3 patients died of disease within 0.6, 2, and 7 months of diagnosis. We present the first series of undifferentiated carcinoma of the esophagus and gastroesophageal junction with this characteristic morphology associated with loss of SMARCA4 and/or SMARCA2 expression. This tumor type likely arises from dedifferentiation of a lower grade carcinoma in some cases, and Barrett esophagus and appears to be associated with an aggressive clinical course.

DNA polymerase (pol) β catalyzes two reactions at DNA gaps generated during base excision repair, gap-filling DNA synthesis and lyase-dependent 5´-end deoxyribose phosphate removal. The lyase domain of pol β has been proposed to function in DNA gap recognition and to facilitate DNA scanning during substrate search. However, the mechanisms and molecular interactions used by pol β for substrate search and recognition are not clear. To provide insight into this process, a comparison was made of the DNA binding affinities of WT pol β, pol λ, and pol μ, and several variants of pol β, for 1-nt-gap-containing and undamaged DNA. Surprisingly, this analysis revealed that mutation of three lysine residues in the lyase active site of pol β, 35, 68, and 72, to alanine (pol β KΔ3A) increased the binding affinity for nonspecific DNA ∼11-fold compared with that of the WT. WT pol μ, lacking homologous lysines, displayed nonspecific DNA binding behavior similar to that of pol β KΔ3A, in line with previous data demonstrating both enzymes were deficient in processive searching. In fluorescent microscopy experiments using mouse fibroblasts deficient in PARP-1, the ability of pol β KΔ3A to localize to sites of laser-induced DNA damage was strongly decreased compared with that of WT pol β. These data suggest that the three lysines in the lyase active site destabilize pol β when bound to DNA nonspecifically, promoting DNA scanning and providing binding specificity for gapped DNA.

Trilaciclib is a cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression in patients with extensive-stage small-cell lung cancer. Trilaciclib is a substrate and time-dependent inhibitor of cytochrome P450 3A4 and an inhibitor of multidrug and toxin extrusion 1, multidrug and toxin extrusion 2-K, organic cation transporter 1, and organic cation transporter 2. Here, we investigate the pharmacokinetic drug-drug interaction potential of trilaciclib.Two phase I studies were conducted as prospective, open-label, fixed-sequence drug-drug interaction studies in healthy subjects (n = 57, n = 20) to investigate potential interactions between intravenously administered trilaciclib (200 or 240 mg/mCoadministration with trilaciclib had minimal effects on the exposure (area under the plasma concentration-time curve from time 0 to infinity) of midazolam (geometric least-square mean ratio [GMR] vs midazolam alone 1.065; 90% confidence interval [CI] 0.984-1.154) but statistically significantly increased plasma exposure (GMR 1.654; 90% CI 1.472-1.858) and decreased renal clearance (GMR 0.633; 90% CI 0.572-0.701) of metformin. Coadministration of trilaciclib with rifampin or itraconazole decreased trilaciclib area under the plasma concentration-time curve from time 0 to infinity by 17.3% (GMR 0.827; 90% CI 0.785-0.871) and 14.0% (GMR 0.860; 0.820-0.902), respectively, vs trilaciclib alone. Population pharmacokinetic modeling showed no significant effect of trilaciclib on topotecan clearance.Overall, the drug-drug interaction and safety profiles of trilaciclib in these studies support its continued use in patients with extensive-stage small-cell lung cancer.Study 106: EudraCT number: 2019-002303-18; Study 114: not applicable; Study 03: Clinicaltrials.org: NCT02514447; August 2015.

Background: Sensorimotor difficulties significantly interfere with daily activities, and when undiagnosed in early life, they may increase the risk of later life cognitive and mental health disorders. Subtests from the Luria-Nebraska Neuropsychological Battery (LNNB) discriminate sensorimotor impairments predictive of sensorimotor dysfunction. However, scoring the LNNB sensorimotor assessment is highly subjective and time consuming, impeding the use of this task in epidemiologic studies. Aim: To train and validate a novel automated and image-derived scoring approach to the LNNB neuro-motor tasks for use in adolescents and young adults. Methods: We selected 46 adolescents (19.6 +/− 2.3 years, 48% male) enrolled in the prospective Public Health Impact of Metal Exposure (PHIME) study. We visually recorded the administration of five conventional sensorimotor LNNB tasks and developed automated scoring alternatives using a novel mathematical approach combining optic flow fields from recorded image sequences on a frame-by-frame basis. We then compared the conventional and image-derived LNNB task scores using Pearson’s correlations. Finally, we provided the accuracy of the novel scoring approach with Receiver Operating Characteristic (ROC) curves and the area under the ROC curves (AUC). Results: Image-derived LNNB task scores strongly correlated with conventional scores, which were assessed and confirmed by multiple administrators to limit subjectivity (Pearson’s correlation ≥ 0.70). The novel image-derived scoring approach discriminated participants with low motility (

The purpose of this paper was to determine whether recommendations made by King & Murphy (Journal of Autism and Developmental Disorders 44:2717–2733, 2014) in their review of the evidence on autistic people in contact with the criminal justice system (CJS) have been addressed. Research published since 2013 was systematically examined and synthesised. The quality of 47 papers was assessed using the Mixed Methods Appraisal Tool. Findings suggest a limited amount of good quality research has been conducted that has focused on improving our understanding of autistic people in contact with the CJS since 2013. Methodological limitations make direct comparisons between autistic and non-autistic offenders difficult. Autistic people commit a range of crimes and appear to have unique characteristics that warrant further exploration (i.e., vulnerabilities, motivations for offending).

Methods and structural and topographic data for regional profiles.

With the goal of accelerating the design and discovery of metal–organic frameworks (MOFs) for electronic, optoelectronic, and energy storage applications, we present a dataset of predicted electronic structure properties for thousands of MOFs carried out using multiple density functional approximations. Compared to more accurate hybrid functionals, we find that the widely used PBE generalized gradient approximation (GGA) functional severely underpredicts MOF band gaps in a largely systematic manner for semi-conductors and insulators without magnetic character. However, an even larger and less predictable disparity in the band gap prediction is present for MOFs with open-shell 3d transition metal cations. With regards to partial atomic charges, we find that different density functional approximations predict similar charges overall, although hybrid functionals tend to shift electron density away from the metal centers and onto the ligand environments compared to the GGA point of reference. Much more significant differences in partial atomic charges are observed when comparing different charge partitioning schemes. We conclude by using the dataset of computed MOF properties to train machine-learning models that can rapidly predict MOF band gaps for all four density functional approximations considered in this work, paving the way for future high-throughput screening studies. To encourage exploration and reuse of the theoretical calculations presented in this work, the curated data is made publicly available via an interactive and user-friendly web application on the Materials Project.

World Trade Center (WTC) responders exposed to traumatic and environmental stressors during rescue and recovery efforts have higher prevalence (23%) of persistent, clinically significant WTC-related post-traumatic stress disorder (WTC-PTSD). Here, we applied eigenvector centrality (EC) metrics and data driven methods on resting state functional magnetic resonance (fMRI) outcomes to investigate neural mechanisms underlying WTC-PTSD and to identify how EC shifts in brain areas relate to WTC-exposure and behavioral symptoms. Nine brain areas differed significantly and contributed the most to differentiate functional neuro-profiles between WTC-PTSD and non-PTSD responders. The association between WTC-exposure and EC values differed significantly between WTC-PTSD and non-PTSD in the right anterior parahippocampal gyrus and left amygdala (p= 0.010; p= 0.005, respectively, adjusted for multiple comparisons). Within WTC-PTSD, the index of PTSD symptoms was positively associated with EC values in the right anterior parahippocampal gyrus and brainstem. Our understanding of functional changes in neural mechanisms underlying WTC-related PTSD is key to advance intervention and treatment.

Andean orogenesis is expressed in the diverse deformational records of crustal structures and sedimentary basins in western South America. Here we summarize retroarc structural styles within the Andean orogenic belt and foreland basin system through consideration of regional contractional fault geometries, their kinematic interactions with other structures, and the comparative involvement of crystalline basement and sedimentary cover rocks. In assessing the controls on structural style, we emphasize the importance of precursor conditions and employ the concept of tectonic inheritance to identify four factors that influence Andean deformation. (1) Structural inheritance involves the reactivation of preexisting faults or basement fabrics and accompanying inversion of sedimentary basins. (2) Stratigraphic inheritance is exemplified by the preferential localization of interconnected thin-skinned structures above regional décollements developed in wedge-shaped stratigraphic packages versus isolated basement-involved thick-skinned fault structures formed in provinces with limited cover strata. (3) Rheological properties guide the activation of new structures by means of the integrated strength, rock and mineral composition, fluid content and pressure, and associated mechanical heterogeneities and anisotropies that define crustal and lithospheric architecture. (4) Thermal structure in the form of initial thermal conditions and later thermal perturbations (such as cooling/heating episodes related to arc magmatism, subducting slab dynamics, or lithospheric removal) can promote inboard advance or outboard retreat of deformation. Spatial and temporal variations in the relative importance of these four inherited attributes likely resulted in a complex evolution of structural styles during Andean shortening. The major styles include: (1) thin-skinned fold-thrust systems affecting principally cover strata with ramp-flat structures above gently dipping regional décollements that ultimately root in middle to upper crustal levels; (2) thick-skinned basement-involved block uplifts delineated by isolated high-angle reverse fault structures that penetrate deeply and may root in the lower crust; (3) pre-Andean (preorogenic) and (4) Andean (synorogenic) extensional basins that have been inverted by fault reactivation during later shortening; (5) upper-crustal backthrust belts linked to deeper foreland-directed structures; and (6) salt-involved contractional structures with weak décollement horizons that facilitate lateral flow of evaporite facies. These structural styles are not mutually exclusive and may overlap in time and space. We propose that evaluation of the contrasting roles of structural, stratigraphic, rheological, and thermal inheritance will help explain how numerous Andean structures do not bear simple relationships to the history of plate convergence, subduction, and magmatism along the western margin of South America.

Variations in subduction configuration and mantle dynamics can be detected in retroarc foreland basins. Modern and ancient examples from western South America show how discrete geodynamic mechanisms drive regional unconformity development in the Andean foreland basin. Positive dynamic topography in the basin, fold-thrust belt, and broader convergent plate margin can be generated by (1) flat slab subduction, (2) slab window formation, (3) slab breakoff, (4) elevated intraplate (in-plane) stress, or (5) mantle flow variations. A survey of long duration (>1–20 Myr) unconformities considers these and alternative mechanisms, including (6) local shortening-induced uplift in the frontal thrust belt and proximal foreland, (7) growth and advance of a broad flexural forebulge in the distal foreland, (8) uplift of intraforeland basement blocks along crustal-scale reverse faults, (9) tectonic quiescence with regional isostatic rebound, and (10) diminished accommodation or sediment supply due to changes in sea level, climate, erosion, or sediment transport. These contrasting mechanisms can be readily observed in the modern foreland, particularly in the case of increased interplate coupling during active flat slab subduction and slab window generation associated with subduction of an active oceanic spreading ridge. In the ancient record, the operative geodynamic mechanisms can be distinguished on the basis of the spatial distribution, stratigraphic position, paleoenvironmental context, and duration of foreland unconformities within the Cretaceous to Quaternary geodynamic framework of the Andean orogenic system.

Conventionally, high-throughput computational materials searches start from an input set of bulk compounds extracted from material databases, and this set is screened for candidate materials for specific applications. In contrast, many functional materials, and especially semiconductors, are heavily engineered alloys or solid solutions of multiple compounds rather than a single bulk compound. To improve our ability to design functional materials, in this work we propose a framework and open-source code to automatically construct possible "alloy pairs" and "alloy systems" and detect "alloy members" from a set of existing, experimental or calculated ordered compounds, without requiring any additional metadata beyond their crystal structure. We provide analysis tools to estimate stability across each alloy. As a demonstration, we apply this framework to all inorganic materials in the Materials Project database to create a new database of over 600,000 unique alloy pair entries that can then be used in materials discovery studies to search for materials with tunable properties. This new database has been incorporated into the Materials Project website and linked with corresponding material identifiers for any user to query and explore. Using an example of screening for p-type transparent conducting materials, we demonstrate how using this methodology reveals candidate material systems that might otherwise have been excluded by a traditional screening. This work lays a foundation from which materials databases can go beyond stoichiometric compounds, and approach a more realistic description of compositionally tunable materials.

This contribution assesses models for basin formation in the Altiplano. New magnetostratigraphy, palynology, and 40Ar/39Ar and U-Pb geochronology from the central Corque Syncline demonstrate that the 7.4 km-thick section was deposited between 36.7 and 18.7 Ma. The base of the section post-dates exhumation in both the Western and Eastern cordilleras, precluding deposition in a classic retroarc foreland basin setting. Rotated paleomagnetic vectors indicate counterclockwise rotation of 0.8°/Myr since the early Oligocene. Detrital zircon provenance data confirm previous interpretations of Eocene–early Oligocene derivation from the Western Cordillera and a subsequent switch to an Eastern Cordilleran source. Flexural modeling indicates that loads consistent with paleoelevation estimates cannot account for all subsidence. Rather, the timing and magnitude of subsidence is consistent with Eocene emplacement and Oligocene–early Miocene resteepening of a flat slab. Integration of the magmatic, basin, and deformation history provides a coherent model of the effects of flat subduction on the overriding plate. In this model flat subduction controlled basin formation in the upper plate, with subsidence enhanced in front of the zone of flat subduction but reduced over the crest of the flat slab. We conclude that the Altiplano was conditioned for plateau formation by Eocene–Oligocene flat subduction. Thematic collection: This article is part of the Fold-and-thrust belts collection available at: https://www.lyellcollection.org/cc/fold-and-thrust-belts Supplementary material:https://doi.org/10.6084/m9.figshare.c.5664345

Unconformities in foreland basins may be generated by tectonic processes that operate in the basin, adjacent fold-thrust belt, and broader convergent margin. Foreland basin unconformities represent shifts from high accommodation to nondepositional or erosional conditions in which the interruption of subsidence precludes net sediment accumulation. This study explores the genesis of long duration (>1–20 Myr) unconformities and condensed stratigraphic sections by considering modern and ancient examples from the Andes. These cases highlight potential geodynamic mechanisms of accommodation reduction and hiatus development in Andean-type retroarc foreland settings, including: (a) shortening-induced uplift in the frontal thrust belt and proximal foreland; (b) growth and advance of a broad, low-relief flexural forebulge; (c) uplift of intraforeland basement blocks; (d) tectonic quiescence with regional isostatic rebound; (e) cessation of thrust loading and flexural subsidence during oblique convergence; (f) diminished accommodation or sediment supply due to changes in sea level, climate, erosion, or transport; (g) basinwide uplift during flat-slab subduction; and (h) dynamic uplift associated with slab window formation, slab breakoff, elevated intraplate (in-plane) stress, or related mantle process. These contrasting mechanisms can be distinguished on the basis of the spatial distribution, structural context, stratigraphic position, paleoenvironmental conditions, and duration of unconformities and condensed sections. Thematic collection: This article is part of the Fold-and-thrust belts collection available at: https://www.lyellcollection.org/cc/fold-and-thrust-belts

BACKGROUND: Working memory (WM) is critical for problem solving and reasoning. Beginning in infancy, children show WM capacity increasing with age but there are few validated tests of WM in very young children. Because rapid brain development may increase susceptibility to adverse impacts of prenatal neurotoxicant exposure, such as lead, tests of WM in very young children would help to delineate onset of developmental problems and windows of susceptibility. PURPOSE: Our objective was to assess the feasibility of administering a Delayed Spatial Alternation Task (DSAT) to measure WM among 18- and 24-month old children enrolled in an ongoing longitudinal birth cohort study and compare DSAT performance with age and general cognitive development. We further explored whether prenatal lead exposure impacted DSAT performance. METHODS: We assessed 457 mother-child pairs participating in the Programming Research in Obesity, GRowth, Environment and Social Stressors (PROGRESS) Study in Mexico City. The DSAT and Bayley Scales of Infant Development (BSID-III) were administered at 18- and 24-months. Lead was measured in maternal blood collected during pregnancy (MBPb) and in a subsample of children at 24-months (CBPb). We regressed DSAT measures on MBPb and CBPb, child sex, and maternal age, education, socioeconomic status, and household smoking. We compared DSAT performance to BSID-III performance with adjusted residuals. RESULTS: 24-month children perform better on the DSAT than 18-month children; 24-month subjects reached a higher level on the DSAT (3.3 (0.86) vs. 2.4 (0.97), p < 0.01), and had a higher number of correct responses (20.3 vs. 17.2, p < 0.01). In all DSAT parameters, females performed better than males. Maternal education predicted better DSAT performance; household smoking predicted worse DSAT performance. A higher number of correct responses was associated with higher BSID-III Cognitive scales at 18 months (r = 0.20, p < 0.01) and 24 months (r = 0.27, p < 0.01). MBPb and CPBb did not significantly predict DSAT performance. CONCLUSION: Improved performance on the DSAT with increasing age, the positive correlation with the BSID-III cognitive and language scales and the correlation with common sociodemographic predictors of neurodevelopment demonstrate the validity of the DSAT as a test of infant development.

Formaldehyde (FA) is a simple biological aldehyde that is produced inside cells by several processes such as demethylation of DNA and proteins, amino acid metabolism, lipid peroxidation and one carbon metabolism (1-C). Although accumulation of excess FA in cells is known to be cytotoxic, it is unknown if an increase in FA level might be associated with mitochondrial dysfunction. We choose to use primary human fibroblasts cells in culture (foreskin, FSK) as a physiological model to gain insight into whether an increase in the level of FA might affect cellular physiology, especially with regard to the mitochondrial compartment. FSK cells were exposed to increasing concentrations of FA, and different cellular parameters were studied. Elevation in intracellular FA level was achieved and was found to be cytotoxic by virtue of both apoptosis and necrosis and was accompanied by both G2/M arrest and reduction in the time spent in S phase. A gene expression assessment by microarray analysis revealed FA affected FSK cells by altering expression of many genes including genes involved in mitochondrial function and electron transport. We were surprised to observe increased DNA double-strand breaks (DSBs) in mitochondria after exposure to FA, as revealed by accumulation of γH2A.X and 53BP1 at mitochondrial DNA foci. This was associated with mitochondrial structural rearrangements, loss of mitochondrial membrane potential and activation of mitophagy. Collectively, these results indicate that an increase in the cellular level of FA can trigger mitochondrial DNA double-strand breaks and dysfunction.

Historically, patients who developed malignant hyperthermia had an extremely high rate of mortality. Today, if treated appropriately, patients who experience an episode of malignant hyperthermia will most likely survive. This dramatic decrease in mortality associated with malignant hyperthermia is due to several factors, including an increased understanding of the disease, improved diagnostic and monitoring equipment, and the development of lifesaving pharmacologic agents. This article presents the very likely case of acute malignant hyperthermia in a 24-year-old man with special needs, who presented for restorative dentistry under general anesthesia in the outpatient clinic of The Ohio State University's College of Dentistry.

Recognizing detrital contributions from sediment source regions is fundamental to provenance studies of active and ancient orogenic settings. Detrital zircon U-Pb geochronology of unconsolidated sands from modern rivers that have source catchments with contrasting bedrock signatures provides insight into the fidelity of U-Pb age signatures in discriminating tectonic provenance and downstream propagation of environmental signals. We present 1705 new detrital zircon U-Pb ages for 15 samples of unconsolidated river sands from 12 modern rivers over a large spatial extent of Ecuador (∼1°N–5°S and ∼79°–77°W).Results show distinctive U-Pb age distributions with characteristic zircon age populations for various tectonic provinces along the Andean convergent margin, including the forearc, magmatic arc, and internal (hinterland) and external (foreland) segments of the fold-thrust belt. (1) Forearc and magmatic arc (Western Cordillera) river sands are characterized by Neogene–Quaternary age populations from magmatic sources. (2) Rivers in the hinterland (Eastern Cordillera) segment of the Andean fold-thrust belt have substantial populations of Proterozoic and Paleozoic ages, representing upper Paleozoic–Mesozoic sedimentary and metasedimentary rocks of ultimate cratonic origin. (3) River sands in the frontal fold-thrust belt (Subandean Zone to Oriente Basin) show distinctive bimodal Jurassic age populations, a secondary Triassic population, and subordinate Early Cretaceous ages representative of Mesozoic plutonic and metamorphic bedrock.Detrital zircon U-Pb results from a single regional watershed (Rio Pastaza) spanning the magmatic arc to foreland basin show drastic downstream variations, including the downstream loss of magmatic arc and hinterland signatures and abrupt introduction and dominance of selected sources within the fold-thrust belt. Disproportionate contributions from Mesozoic crystalline metamorphic rocks, which form high-elevation, high-relief areas subject to focused precipitation and active tectonic deformation, are likely the product of focused erosion and high volumes of local sediment input from the frontal fold-thrust belt, leading to dilution of upstream signatures from the hinterland and magmatic arc.

In the northwestern sector of the Zagros foreland basin, axial fluvial systems initially delivered fine‐grained sediments from northwestern source regions into a contiguous basin, and later transverse fluvial systems delivered coarse‐grained sediments from northeastern sources into a structurally partitioned basin by fold‐thrust deformation. Here we integrate sedimentologic, stratigraphic, palaeomagnetic and geochronologic data from the northwestern Zagros foreland basin to define the Neogene history of deposition and sediment routing in response to progressive advance of the Zagros fold‐thrust belt. This study constrains the depositional environments, timing of deposition and provenance of nonmarine clastic deposits of the Injana (Upper Fars), Mukdadiya (Lower Bakhtiari) and Bai‐Hasan (Upper Bakhtiari) Formations in the Kurdistan region of Iraq. Sediments of the Injana Formation (~12.4–7.75 Ma) were transported axially (orogen‐parallel) from northwest to southeast by meandering and low‐sinuosity channel belt system. In contrast, during deposition of the Mukdadiya Formation (~7.75–5 Ma), sediments were delivered transversely (orogen‐perpendicular) from northeast to southwest by braided and low‐sinuosity channel belt system in distributive fluvial megafans. By ~5 Ma, the northwestern Zagros foreland basin became partitioned by growth of the Mountain Front Flexure and considerable gravel was introduced in localized alluvial fans derived from growing topographic highs. Foredeep accumulation rates during deposition of the Injana, Mukdadiya and Bai‐Hasan Formations averaged 350, 400 and 600 m/Myr respectively, suggesting accelerated accommodation generation in a rapidly subsiding basin governed by flexural subsidence. Detrital zircon U‐Pb age spectra show that in addition to sources of Mesozoic‐Cenozoic cover strata, the Injana Formation was derived chiefly from Palaeozoic‐Precambrian (including Carboniferous and latest Neoproterozoic) strata in an axial position to the northwest, likely from the Bitlis‐Puturge Massif and broader Eastern Anatolia. In contrast, the Mukdadiya and Bai‐Hasan Formations yield distinctive Palaeogene U‐Pb age peaks, particularly in the southeastern sector of the study region, consistent with transverse delivery from the arc‐related terranes of the Walash and Naopurdan volcano‐sedimentary groups (Gaveh‐Rud domain?) and Urumieh‐Dokhtar magmatic arc to the northeast. These temporal and spatial variations in stratigraphic framework, depositional environments, sediment routing and compositional provenance reveal a major drainage reorganization during Neogene shortening in the Zagros fold‐thrust belt. Whereas axial fluvial systems initially dominated the foreland basin during early orogenesis in the Kurdistan region of Iraq, transverse fluvial systems were subsequently established and delivered major sediment volumes to the foreland as a consequence of the abrupt deformation advance and associated topographic growth in the Zagros.

Carbon dioxide drawdown resulting from enhanced chemical weathering during orogenesis has been invoked to explain late Cenozoic global cooling. Establishing chemical weathering records from the India-Asia collision zone is important to test this hypothesis because uplift of the Tibetan Plateau is thought to be responsible for Cenozoic cooling. However, proxies for the intensity of chemical weathering can be affected by additional factors, such as sediment grain size and provenance. Here we report major element compositions and calculated chemical weathering intensity records of three size fractions (0-5, 5-20, 20-63 mu m) from the Dahonggou section of the Qaidam Basin in the northeastern Tibetan Plateau, and compare those records with published provenance data from the same section. Results show that the indices of the fine (0-5 mu m) fraction vary in coordination with provenance shifts, but variations of the 5-20 and 20-63 mu m fractions are less affected by provenance variations. Comparison with Upper Continental Crust reveals that some labile elements are not leached but instead are enriched in the fine fraction, indicating that it does not faithfully record chemical weathering intensity. In addition, weathering can result in clay mineral transformation instead of elemental variations, complicating the relationship between element-based parameters and weathering intensity. This work suggests that changes in sediment provenance must be accounted for when inferring variations in chemical weathering intensity on the basis of element-based weathering intensity indices of the clay fraction.

The growth and deformation history of the Qilian-Nan Shan thrust belt bounding the NE Qaidam Basin figures importantly in testing models of Tibetan Plateau uplift during the India-Asia collision. However, debate exists about the onset of uplift and exhumation of the Qilian-Nan Shan, with timing estimates ranging from early Paleocene to late Miocene. Here we report integrated analyses of magnetostratigraphy, anisotropy of magnetic susceptibility, sediment provenance, and paleoclimate (using environmental magnetic parameters) for Cenozoic fluvio-lacustrine strata from the Dahonggou section south of the Qilian-Nan Shan. The results are interpreted to demonstrate an early Miocene (ca. 20 Ma) onset of sediment accumulation in this location, with clastic sediment derived initially from the southern Qimen Tagh highland. The sediment source then switched to the northern part of the Qilian Shan region after ca. 18.5 Ma, consistent with initial uplift and exhumation of the Qilian Shan. Thereafter, two additional provenance shifts reveal progressive southward propagation of deformation in the Qilian-Nan Shan. As a result of this southward growth of Qilian-Nan Shan topography, precipitation increased after ca. 11 Ma at the study site due to orographic interception of moisture from the south. This work improves our understanding of the depositional age, sediment provenance, and paleoclimate history of the Qaidam Basin and reveals a prolonged history of Qilian-Nan Shan deformation and uplift, which may have accelerated during the late Miocene.

HIV-related prevention and intervention efforts for deaf adults with mental illness have been developed in the absence of empirical data regarding the risk behaviors in which this group eng...

Social isolation affects our emotions, behavior and interactions. Worldwide, individuals experienced prolonged periods of isolation during the first wave of the COVID-19 pandemic when authorities-imposed restrictions to reduce the spread of the virus. In this study, we investigated the effects of social isolation on emotional and behavioral outcomes in young adults from Lombardy, Italy, a global hotspot of COVID-19. We leveraged baseline (pre-social isolation) and follow-up (mid- or post-isolation) data collected from young adults enrolled in the ongoing, longitudinal Public Health Impact of Metals Exposure (PHIME) study. At baseline, 167 participants completed the ASEBA questionnaires (ASR/YSR) by web link or in person; 65 completed the ASR 12–18 weeks after the onset of restrictions. Using the sign test and multiple linear regression models, we examined differences in ASR scores between baseline and follow-up adjusting for sex, age, pre-pandemic IQ and time with social restrictions (weeks). Further, we examined interactions between sex and time in social isolation. Participants completed the ASR after spending an average of 14 weeks in social isolation (range 12–18 weeks). Thought problems increased between baseline and follow-up (median difference 1.0; 1st, 3rd quartile: −1.0, 4.0; p = 0.049). Among males, a longer time in social isolation (≥14 weeks) was associated with increased rule-breaking behaviors of 2.8 points. These results suggest the social isolation related to COVID-19 adversely impacted mental health. In particular, males seem to externalize their condition. These findings might help future interventions and treatment to minimize the consequences of social isolation experience in young adults.

Background The history of how our knowledge of celiac disease (CD) evolved points to its importance in children. Although it is now appreciated that CD can present at any age, it was originally thought to occur only in children and, if untreated, led to serious consequences. Content This review includes a brief discussion of small bowel physiology and the pathogenesis of CD. Next, the varied clinical presentations of CD in children are reviewed, including both gastrointestinal and nongastrointestinal manifestations and how these contribute to the difficulty in diagnosis. In addition, information on specific conditions that are associated with CD is presented, particularly as it applies to diagnostic testing of apparently asymptomatic children. The review will also focus on diagnostic testing available for CD and their general performance characteristics. The review will end with a comparison between published guidelines from the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition for diagnosis of pediatric CD. In particular, this review will focus on differences in the incorporation of serologic and genetic testing, and the role of biopsies in the pediatric population. Summary It is important for laboratorians to understand the evolution of diagnostic guidelines for pediatric CD and how serologic and genetic testing are being applied to and interpreted in this particular patient group.

BACKGROUND AND AIM: With the growing climate crisis, particulate matter (PM) air pollution is expected to increasingly impact human health with effects magnified in vulnerable populations including...

BACKGROUND AND AIM: Exposure to neurotoxic metals occurs as a mixture, yet most studies consider single exposures, potentially missing the combined effects of environmental metals. Further, health ...

PURPOSETo provide recommendations on the best strategies for the management and on the best timing and treatment (surgical and radiotherapeutic) of the axilla for patients with early-stage breast cancer.METHODSOntario Health (Cancer Care Ontario) and ASCO convened a Working Group and Expert Panel to develop evidence-based recommendations informed by a systematic review of the literature.RESULTSThis guideline endorsed two recommendations of the ASCO 2017 guideline for the use of sentinel lymph node biopsy in patients with early-stage breast cancer and expanded on that guideline with recommendations for radiotherapy interventions, timing of staging after neoadjuvant chemotherapy (NAC), and mapping modalities. Overall, the ASCO 2017 guideline, seven high-quality systematic reviews, 54 unique studies, and 65 corollary trials formed the evidentiary basis of this guideline.RECOMMENDATIONSRecommendations are issued for each of the objectives of this guideline: (1) To determine which patients with early-stage breast cancer require axillary staging, (2) to determine whether any further axillary treatment is indicated for women with early-stage breast cancer who did not receive NAC and are sentinel lymph node–negative at diagnosis, (3) to determine which axillary strategy is indicated for women with early-stage breast cancer who did not receive NAC and are pathologically sentinel lymph node–positive at diagnosis (after a clinically node-negative presentation), (4) to determine what axillary treatment is indicated and what the best timing of axillary treatment for women with early-stage breast cancer is when NAC is used, and (5) to determine which are the best methods for identifying sentinel nodes. Additional information is available at www.asco.org/breast-cancer-guidelines .