Ancient technology and punctuated change: Detecting the emergence of the Edomite Kingdom in the Southern Levant.

While the punctuated equilibrium model has been employed in paleontological and archaeological research, it has rarely been applied for technological and social evolution in the Holocene. Using metallurgical technologies from the Wadi Arabah (Jordan/Israel) as a case study, we demonstrate a gradual technological development (13th-10th c. BCE) followed by a human agency-triggered punctuated "leap" (late-10th c. BCE) simultaneously across the entire region (an area of ~2000 km2). Here, we present an unparalleled, diachronic archaeometallurgical dataset focusing on elemental analysis of dozens of well-dated slag samples. Based on the results, we suggest punctuated equilibrium provides an innovative theoretical model for exploring ancient technological changes in relation to larger sociopolitical conditions-in the case at hand the emergence of biblical Edom-, exemplifying its potential for more general cross-cultural applications

Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington’s disease

Huntington’s disease, the most common inherited neurodegenerative disease, is characterized by a dramatic loss of deep-layer cortical and striatal neurons, as well as morbidity in midlife. Human genetic studies led to the identification of the causative gene, huntingtin. Recent genomic advances have also led to the identification of hundreds of potential interacting partners for huntingtin protein and many hypotheses as to the molecular mechanisms whereby mutant huntingtin leads to cellular dysfunction and death. However, the multitude of possible interacting partners and cellular pathways affected by mutant huntingtin has complicated efforts to understand the etiology of this disease, and to date no curative therapeutic exists. To address the general problem of identifying the disease-phenotype contributing genes from a large number of correlative studies, here we develop a synthetic lethal screening methodology for the mammalian central nervous system, called SLIC, for synthetic lethal in the central nervous system. Applying SLIC to the study of Huntington’s disease, we identify the age-regulated glutathione peroxidase 6 (Gpx6) gene as a modulator of mutant huntingtin toxicity and show that overexpression of Gpx6 can dramatically alleviate both behavioral and molecular phenotypes associated with a mouse model of Huntington’s disease. SLIC can, in principle, be used in the study of any neurodegenerative disease for which a mouse model exists, promising to reveal modulators of neurodegenerative disease in an unbiased fashion, akin to screens in simpler model organisms.National Institute of Neurological Disorders and Stroke (U.S.) (Award R01NS085880)William N. and Bernice E. Bumpus Foundation (Early Career Investigator Innovation Award)JPB FoundationEuropean Molecular Biology Organization (Long-term Fellowship

Prediction of adverse perinatal outcome by fetal biometry: comparison of customized and populationâ based standards

ObjectiveTo compare the predictive performance of estimated fetal weight (EFW) percentiles, according to eight growth standards, to detect fetuses at risk for adverse perinatal outcome.MethodsThis was a retrospective cohort study of 3437 Africanâ American women. Populationâ based (Hadlock, INTERGROWTHâ 21st, World Health Organization (WHO), Fetal Medicine Foundation (FMF)), ethnicityâ specific (Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)), customized (Gestationâ Related Optimal Weight (GROW)) and Africanâ American customized (Perinatology Research Branch (PRB)/NICHD) growth standards were used to calculate EFW percentiles from the last available scan prior to delivery. Prediction performance indices and relative risk (RR) were calculated for EFW â 90th percentiles, according to each standard, for individual and composite adverse perinatal outcomes. Sensitivity at a fixed (10%) falseâ positive rate (FPR) and partial (FPR â 90th percentile were also at risk for any adverse perinatal outcome according to the INTERGROWTHâ 21st (RRâ =â 1.4; 95%â CI, 1.0â 1.9) and Hadlock (RRâ =â 1.7; 95%â CI, 1.1â 2.6) standards, many times fewer cases (2â 5â fold lower sensitivity) were detected by using EFW >â 90th percentile, rather than EFW â 90th percentile were at increased risk of adverse perinatal outcomes according to all or some of the eight growth standards, respectively. The RR of a composite adverse perinatal outcome in pregnancies with EFW <â 10th percentile was higher for the mostâ stringent (NICHD) compared with the leastâ stringent (FMF) standard. The results of the complementary analysis of AUC suggest slightly improved detection of adverse perinatal outcome by more recent populationâ based (INTERGROWTHâ 21st) and customized (PRB/NICHD) standards compared with the Hadlock and FMF standards. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153734/1/uog20299.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153734/2/uog20299_am.pd

Changes in Triglyceride Levels Over Time and Risk of Type 2 Diabetes in Young Men

OBJECTIVE—The association between changes in triglyceride concentrations over time and diabetes is unknown. We assessed whether two triglyceride determinations obtained 5 years apart can predict incident type 2 diabetes

Using resource graphs to represent conceptual change

We introduce resource graphs, a representation of linked ideas used when reasoning about specific contexts in physics. Our model is consistent with previous descriptions of resources and coordination classes. It can represent mesoscopic scales that are neither knowledge-in-pieces or large-scale concepts. We use resource graphs to describe several forms of conceptual change: incremental, cascade, wholesale, and dual construction. For each, we give evidence from the physics education research literature to show examples of each form of conceptual change. Where possible, we compare our representation to models used by other researchers. Building on our representation, we introduce a new form of conceptual change, differentiation, and suggest several experimental studies that would help understand the differences between reform-based curricula.Comment: 27 pages, 14 figures, no tables. Submitted for publication to the Physical Review Special Topics Physics Education Research on March 8, 200

Patients with MEN1 are at an increased risk for venous thromboembolism VTE risk in MEN1

Background: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder predisposing to the development of multiple functional and non-functional neuroendocrine tumors (NETs). Only uncommon MEN1-associated functional NETs such as glucagonomas (&lt;1%) and ACTH-producing tumors (&lt;5%) are known to be associated with hypercoagulability. It is unknown if patients with MEN1 generally have increased risk of VTE. Methods: We queried a prospective natural history study of germline mutation positive MEN1 patients (n=286) between 1991-2019 for all lifetime events of VTE. Search terms were: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban and apixaban. Incidence rates were calculated accounting for age and sex. Comparison was made to published incidence rates in healthy populations, different types of cancer, and Cushing's syndrome. Results: Thirty-six subjects (median age 45 years, range 16-75) experienced a VTE event, yielding a prevalence rate of 12.9%. The age-sex adjusted incidence rate of VTE is 9.11 per 1,000 patient-years, with a sex-adjusted lifetime incidence rate of 2.81 per 1,000 patient-years. MEN1-associated lifetime incidence rates are ~two-fold higher than the estimated annual incidence rate in the general population and are comparable to known risk in the setting of various types of cancer. Approximately 80% were diagnosed with pancreatic NETs, of which 24% were insulinomas. Fourteen patients (42%) experienced peri-operative VTE events. Conclusions: MEN1 patients have an increased risk of VTE. Further mechanistic investigation and validation from other MEN1 cohorts are needed to confirm the increased prevalence of VTE in MEN1

Evidence-based decision support for pediatric rheumatology reduces diagnostic errors.

BACKGROUND: The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. METHODS: Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult® DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software ( unaided ), versus after use of the DDSS ( aided ). RESULTS: The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p \u3c 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an open book approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. CONCLUSIONS: These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists\u27 ability to evaluate and diagnose patients presenting with musculoskeletal complaints. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02205086

Development of intuitive rules: Evaluating the application of the dual-system framework to understanding children's intuitive reasoning

This is an author-created version of this article. The original source of publication is Psychon Bull Rev. 2006 Dec;13(6):935-53 The final publication is available at www.springerlink.com Published version: http://dx.doi.org/10.3758/BF0321390