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Purpose: Recent studies have shown that hypohydration can increase renal injury. However, the contribution of hypohydration to the extent of renal injury is often confounded by exercise induced muscle damage. Therefore, the aim of the present study was to investigate the effect of manipulating hydration status during moderate-intensity cycling in the heat on biomarkers of renal injury., Methods: Following familiarisation, fourteen active males (age: 21 [20-22] y; BMI: 22.1 ± 1.9 kg/m 2 ; V ˙ O 2peak : 55 ± 9 mL/kg/min) completed two experimental trials, in a randomised cross-over design. Experimental trials consisted of up to 120 min of intermittent cycling (~ 50% W peak ) in the heat (~ 35 °C, ~ 50% relative humidity). During exercise, subjects consumed either a water volume equal to 100% body mass losses (EU) or minimal water (HYP; 75-100 mL) to induce ~ 3% body mass loss. Blood and urine samples were collected at baseline, 30 min post-exercise and 24 h post-baseline, with an additional urine sample collected immediately post-exercise., Results: Thirty minutes post-exercise, body mass and plasma volume were lower in HYP than EU (P < 0.001), whereas serum and urine osmolality (P < 0.001), osmolality-corrected urinary kidney injury molecule-1 concentrations (HYP: 2.74 [1.87-5.44] ng/mOsm, EU: 1.15 [0.84-2.37] ng/mOsm; P = 0.024), and percentage change in osmolality-corrected urinary neutrophil gelatinase-associated lipocalin concentrations (HYP: 61 [17-141] %, EU: 7.1 [- 4 to 24] %; P = 0.033) were greater in HYP than EU., Conclusion: Hypohydration produced by cycling in the heat increased renal tubular injury, compared to maintaining euhydration with water ingestion., (© 2023. The Author(s).)

Diamond possesses exceptional physical properties due to its remarkably strong carbon-carbon bonding, leading to significant resilience to structural transformations at very high pressures and temperatures. Despite several experimental attempts, synthesis and recovery of the theoretically predicted post-diamond BC8 phase remains elusive. Through quantum-accurate multimillion atom molecular dynamics (MD) simulations, we have uncovered the extreme metastability of diamond at very high pressures, significantly exceeding its range of thermodynamic stability. We predict the post-diamond BC8 phase to be experimentally accessible only within a narrow high pressure-temperature region of the carbon phase diagram. The diamond to BC8 transformation proceeds through premelting followed by BC8 nucleation and growth in the metastable carbon liquid. We propose a double-shock compression pathway for BC8 synthesis, which is currently being explored in experiments at the National Ignition Facility.

We previously reported potent ligands and inhibitors of Mycobacterium tuberculosis dethiobiotin synthetase ( Mt DTBS), a promising target for antituberculosis drug development (Schumann et al., ACS Chem Biol . 2021, 16 , 2339-2347); here, the unconventional origin of the fragment compound they were derived from is described for the first time. Compound 1 (9b-hydroxy-6b,7,8,9,9a,9b-hexahydrocyclopenta[3,4]cyclobuta[1,2- c ]chromen-6(6aH)-one), identified by an in silico fragment screen, was subsequently shown by surface plasmon resonance to have dose-responsive binding ( K D = 0.6 mM). Clear electron density was revealed in the DAPA substrate binding pocket when 1 was soaked into Mt DTBS crystals, but the density was inconsistent with the structure of 1 . Here, we show that the lactone of 1 hydrolyzes to a carboxylic acid ( 2 ) under basic conditions, including those of the crystallography soak, with a subsequent ring opening of the component cyclobutane ring forming a cyclopentylacetic acid ( 3 ). Crystals soaked directly with authentic 3 produced an electron density that matched that of crystals soaked with presumed 1 , confirming the identity of the bound ligand. The synthetic utility of fortuitously formed 3 enabled the subsequent compound development of nanomolar inhibitors. Our findings represent an example of chemical modification within drug discovery assays and demonstrate the value of high-resolution structural data in the fragment hit validation process.

Tungsten (W) is a material of choice for the divertor material due to its high melting temperature, thermal conductivity, and sputtering threshold. However, W has a very high brittle-to-ductile transition temperature, and at fusion reactor temperatures (≥1000 K), it may undergo recrystallization and grain growth. Dispersion-strengthening W with zirconium carbide (ZrC) can improve ductility and limit grain growth, but much of the effects of the dispersoids on microstructural evolution and thermomechanical properties at high temperatures are still unknown. We present a machine learned Spectral Neighbor Analysis Potential for W-ZrC that can now be used to study these materials. In order to construct a potential suitable for large-scale atomistic simulations at fusion reactor temperatures, it is necessary to train on ab initio data generated for a diverse set of structures, chemical environments, and temperatures. Further accuracy and stability tests of the potential were achieved using objective functions for both material properties and high temperature stability. Validation of lattice parameters, surface energies, bulk moduli, and thermal expansion is confirmed on the optimized potential. Tensile tests of W/ZrC bicrystals show that although the W(110)-ZrC(111) C-terminated bicrystal has the highest ultimate tensile strength (UTS) at room temperature, observed strength decreases with increasing temperature. At 2500 K, the terminating C layer diffuses into the W, resulting in a weaker W-Zr interface. Meanwhile, the W(110)-ZrC(111) Zr-terminated bicrystal has the highest UTS at 2500 K.

Contrast-induced nephropathy (CIN) is a major complication of imaging in patients with chronic kidney disease (CKD). The publication of an academic randomized controlled trial (RCT; n = 83) reporting oral (N)-acetylcysteine (NAC) to reduce CIN led to > 70 clinical trials, 23 systematic reviews, and 2 large RCTs showing no benefit. However, no mechanistic studies were conducted to determine how NAC might work; proposed mechanisms included renal artery vasodilatation and antioxidant boosting. We evaluated the proposed mechanisms of NAC action in participants with healthy and diseased kidneys. Four substudies were performed. Two randomized, double-blind, placebo-controlled, three-period crossover studies (n = 8) assessed the effect of oral and intravenous (i.v.) NAC in healthy kidneys in the presence/absence of iso-osmolar contrast (iodixanol). A third crossover study in patients with CKD stage III (CKD3) (n = 8) assessed the effect of oral and i.v. NAC without contrast. A three-arm randomized, double-blind, placebo-controlled parallel-group study, recruiting patients with CKD3 (n = 66) undergoing coronary angiography, assessed the effect of oral and i.v. NAC in the presence of contrast. We recorded systemic (blood pressure and heart rate) and renal (renal blood flow (RBF) and glomerular filtration rate (GFR)) hemodynamics, and antioxidant status, plus biomarkers of renal injury in patients with CKD3 undergoing angiography. Primary outcome for all studies was RBF over 8 hours after the start of i.v. NAC/placebo. NAC at doses used in previous trials of renal prophylaxis was essentially undetectable in plasma after oral administration. In healthy volunteers, i.v. NAC, but not oral NAC, increased blood pressure (mean area under the curve (AUC) mean arterial pressure (MAP): mean difference 29 h⋅mmHg, P = 0.019 vs. placebo), heart rate (28 h⋅bpm, P < 0.001), and RBF (714 h⋅mL/min, 8.0% increase, P = 0.006). Renal vasodilatation also occurred in the presence of contrast (RBF 917 h⋅mL/min, 12% increase, P = 0.005). In patients with CKD3 without contrast, only a rise in heart rate (34 h⋅bpm, P = 0.010) and RBF (288 h⋅mL/min, 6.0% increase, P = 0.001) occurred with i.v. NAC, with no significant effect on blood pressure (MAP rise 26 h⋅mmHg, P = 0.156). Oral NAC showed no effect. In patients with CKD3 receiving contrast, i.v. NAC increased blood pressure (MAP rise 52 h⋅mmHg, P = 0.008) but had no effect on RBF (151 h⋅mL/min, 3.0% increase, P = 0.470), GFR (29 h⋅mL/min/1.73m², P = 0.122), or markers of renal injury. Neither i.v. nor oral NAC affected plasma antioxidant status. We found oral NAC to be poorly absorbed and have no reno-protective effects. Intravenous, not oral, NAC caused renal artery vasodilatation in healthy volunteers but offered no protection to patients with CKD3 at risk of CIN. These findings emphasize the importance of mechanistic clinical studies before progressing to RCTs for novel interventions. Thousands were recruited to academic clinical trials without the necessary mechanistic studies being performed to confirm the approach had any chance of working., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Introduction: Patients who require mechanical ventilation after self-poisoning with ingested organophosphorus (OP) insecticides often die. Aspiration of stomach contents may contribute to lung injury and lethality. This study was designed to assess the severity of direct and indirect pulmonary injury created by pulmonary instillation of mixtures of OP insecticide, solvent (Solv) and porcine gastric juice (GJ) compared to controls., Methods: Terminally anaesthetised minipigs (groups n  = 5) were exposed to sham bronchoscopy or given mixtures (0.5 mL/kg) of: saline, GJ, OP insecticide and GJ (OP + GJ), or Solv and GJ (Solv + GJ), placed into the right lung, and monitored for 48 h. Lung injury was assessed through analysis of bronchoalveolar lavage fluid (BALF), computed tomography and histopathology., Results: OP + GJ created a direct lung injury consisting of neutrophil infiltration, oedema and haemorrhage, as well as indirect injury to the other lung. OP + GJ directly-injured lung parenchyma had increased concentrations of BALF protein, albumin, IL-6, IL-8 and C-reactive protein (CRP) at 24 h ( p  < 0.05), and BALF protein, albumin and CRP at 48 h ( p  < 0.05), when compared with controls. Aspiration of GJ produced similar direct effects to OP + GJ but less indirect lung injury. Lung injury was less severe after Solv + GJ, for combined lung histopathology scores (vs. OP + GJ, p  < 0.05) and for the proportion of directly-injured lung that was poorly/non-aerated at 48 h., Conclusion: Pulmonary instillation of OP + GJ created more lung damage than controls or Solv + GJ. In patients with severe OP insecticide poisoning and reduced consciousness, early airway protection is likely to reduce pulmonary damage.

Mycobacterium tuberculosis dethiobiotin synthase ( Mt DTBS) is a crucial enzyme involved in the biosynthesis of biotin in the causative agent of tuberculosis, M. tuberculosis . Here, we report a binder of Mt DTBS, cyclopentylacetic acid 2 ( K D = 3.4 ± 0.4 mM), identified via in silico screening. X-ray crystallography showed that 2 binds in the 7,8-diaminopelargonic acid (DAPA) pocket of Mt DTBS. Appending an acidic group to the para-position of the aromatic ring of the scaffold revealed compounds 4c and 4d as more potent binders, with K D = 19 ± 5 and 17 ± 1 μM, respectively. Further optimization identified tetrazole 7a as a particularly potent binder ( K D = 57 ± 5 nM) and inhibitor ( K i = 5 ± 1 μM) of Mt DTBS. Our findings highlight the first reported inhibitors of Mt DTBS and serve as a platform for the further development of potent inhibitors and novel therapeutics for the treatment of tuberculosis.

Pediatric functional constipation (FC) reportedly affects at least 1 in 10 children worldwide. Parent and family education is a key component for successful treatment, yet there is little research exploring what information families need and how to best support them. The aim of this review is to synthesize current evidence on the experiences and information needs of parents caring for a child with FC. We systematically searched published research and completed screening against a priori inclusion criteria. Thirteen studies (n = 10 quantitative, n = 3 qualitative) were included. We found 2 main themes, precarious footing and profound and pervasive effects. Heavy caregiving burdens fueled doubts, misinformation, relationship breakdown, and treatment deviation. In light of clinical recommendations, our findings reveal a potential mismatch between parents' needs and care provision for FC. It is likely that both parents and health care providers would benefit from resources and interventions to improve care related to pediatric FC.

Background: Pediatric functional constipation (FC) is a common but serious medical condition. Despite significant effects on children, families, and the health care system, the condition is typically undertreated. Parents carry the primary responsibility for complex treatment programs; therefore, understanding their experiences and needs may offer a critical perspective toward improving clinical care., Objective: The aim of this study is to understand and give voice to parents' experiences and information needs when caring for a child with FC. The ultimate objective is to build an evidence base suitable for creating a digital knowledge translation tool to better support parents caring for a child with FC., Methods: This qualitative design used an interpretive description methodology to generate findings aimed at improving clinical care. One-on-one, in-depth interviews were completed either in person or through web-based teleconferencing to explore parents' perspectives. Data collection and analysis occurred concurrently., Results: Analysis of 16 interviews generated 4 major themes: living in the shadows; not taken seriously, with a subtheme of persevering and advocating; missing information and misinformation; and self-doubt and strained relationships. One minor theme of affirmative influences that foster resilience and hope was identified., Conclusions: Parents have unmet needs for support and information related to pediatric FC. To address gaps in current care provision, decision makers may consider interventions for clinicians, resources for parents, and shifting care models to better meet parents' needs., (©Alison P Thompson, Shannon E MacDonald, Eytan Wine, Shannon D Scott. Originally published in JMIR Pediatrics and Parenting (http://pediatrics.jmir.org), 20.01.2021.)

Dimensions of character are often overlooked in professional practice at the expense of the development of technical competence and operational efficiency. Drawing on philosophical accounts of virtue ethics and positive psychology, the present work attempts to elevate the role of 'good' character in the professional domain. A 'good' professional is ideally one that exemplifies dimensions of character informed by sound judgement. A total of 2340 professionals, from five discrete professions, were profiled based on their valuation of qualities pertaining to character and judgement. Profile differences were subsequently examined in the self-reported experience of professional purpose towards a wider societal 'good'. Analysis of covariance, controlling for stage of career, revealed that professionals valuing character reported higher professional purpose than those overweighting the importance of judgement or valuing neither character nor judgement, F (3, 2054) = 7.92, p  < .001. No differences were found between the two groups valuing character, irrespective of whether judgement was valued simultaneously. This profiling analysis of entry-level and in-service professionals, based on their holistic character composition, paves the way for fresh philosophical discussion regarding what constitutes a 'good' professional and the interplay between character and judgement. The empirical findings may be of substantive value in helping to recognise how the dimensions of character and judgement may impact upon practitioners' professional purpose., Competing Interests: Conflict of interestAll the authors declare they have no conflict of interest, financial or personal, (© The Author(s) 2019.)

The human dedicator of cytokinesis (DOCK) family consists of 11 structurally conserved proteins that serve as atypical RHO guanine nucleotide exchange factors (RHO GEFs). These regulatory proteins act as mediators in numerous cellular cascades that promote cytoskeletal remodeling, playing roles in various crucial processes such as differentiation, migration, polarization, and axon growth in neurons. At the molecular level, DOCK DHR2 domains facilitate nucleotide dissociation from small GTPases, a process that is otherwise too slow for rapid spatiotemporal control of cellular signaling. Here, we provide an overview of the biological and structural characteristics for the various DOCK proteins and describe how they differ from other RHO GEFs and between DOCK subfamilies. The expression of the family varies depending on cell or tissue type, and they are consequently implicated in a broad range of disease phenotypes, particularly in the brain. A growing body of available structural information reveals the mechanism by which the catalytic DHR2 domain elicits nucleotide dissociation and also indicates strategies for the discovery and design of high-affinity small-molecule inhibitors. Such compounds could serve as chemical probes to interrogate the cellular function and provide starting points for drug discovery of this important class of enzymes., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives The challenges of bioscience courses such as anatomy and physiology in nursing education are well documented. Virtual reality has recently become accessible and may support student engagement. The purpose of this project was to describe students' engagement and experiences with virtual reality in a first-year nursing course on anatomy, physiology, and health assessment. Methods We used a cross-sectional design and collected both quantitative and qualitative data. The Exploratory Learning Model guided our work. Results Students perceived their engagement to be higher in virtual reality compared to other teaching methods. Their experiences were positive with students reporting that they found it easy to use, it helped their learning, and they recommended more of it. Conclusions Virtual reality is an accessible tool for supporting student engagement. The Exploratory Learning Model is a useful conceptualization for integrating virtual reality into a course. Future research on the relationship between virtual reality and learning achievements is warranted.

We present a scale-bridging approach based on a multi-fidelity (MF) machine-learning (ML) framework leveraging Gaussian processes (GP) to fuse atomistic computational model predictions across multiple levels of fidelity. Through the posterior variance of the MFGP, our framework naturally enables uncertainty quantification, providing estimates of confidence in the predictions. We used density functional theory as high-fidelity prediction, while a ML interatomic potential is used as low-fidelity prediction. Practical materials' design efficiency is demonstrated by reproducing the ternary composition dependence of a quantity of interest (bulk modulus) across the full aluminum-niobium-titanium ternary random alloy composition space. The MFGP is then coupled to a Bayesian optimization procedure, and the computational efficiency of this approach is demonstrated by performing an on-the-fly search for the global optimum of bulk modulus in the ternary composition space. The framework presented in this manuscript is the first application of MFGP to atomistic materials simulations fusing predictions between density functional theory and classical interatomic potential calculations.

Background: The last decade has seen increasing calls for patient and public involvement in health-related research due to an ideological shift toward more equitable methods of knowledge development and an effort to increase the usability and relevance of knowledge by improving outcomes in clinical practice. Patient engagement includes simply informing patients to offering complete decision-making autonomy to individuals, groups, communities, caregivers, friends, and families who have personal experience and knowledge of a health issue. Despite the use of patient engagement methods in research, evaluation has lagged, resulting in a knowledge gap that makes it difficult to foster capacity and sustainability for patients and researchers alike since little is known about how effective patient collaborations in research are built, maintained, or improved. This study centers on pediatric functional constipation, a common condition that affects children and families. Since parents play a pivotal role in treatment, they are an optimal group to engage in improving the resources and support available to them., Objective: This study aims to use patient-engagement methods to establish a research collaboration with parents to cocreate a digital knowledge translation tool for parents caring for a child with functional constipation and formally evaluate the patient engagement processes within this project to build the science of patient engagement in research., Methods: Members of the parent collaborator group will be recruited from previous participants who expressed interest in the development of a digital knowledge translation tool. The group will collaborate with the research team to create a tool to address patients' support and information needs when caring for a child with functional constipation. The parent collaborator group will then be evaluated in a multimethod study design. Data will be digitally and anonymously collected from all members of the parent collaborator group, using the validated Public and Patient Engagement Evaluation Tool (PPEET) patient questionnaire. Descriptive statistics will be used to report group characteristics and question responses. Qualitative analysis will be used to understand open-ended question responses. Specifically, directed content analysis will be used to assess themes of the Patient Engagement in Research (PEIR) Framework with a combination of deductive and inductive analyses. Findings will be integrated into the discussion if there are sufficient commonalities and inter-relationships. The final manuscript will include reporting of each element as described by the Good Reporting of a Mixed Methods Study criteria., Results: Recruitment is planned for June 2020. Data collection for the evaluation of patient engagement processes will occur upon completion of the digital knowledge translation tool. The results of this study are expected to be published by the end of 2020., Conclusions: This study will provide valuable information about parents' experiences participating in child-health research and is a fundamental step in building the science of patient engagement in research., International Registered Report Identifier (irrid): PRR1-10.2196/19108., (©Alison P Thompson, Shannon E MacDonald, Eytan Wine, Shannon D Scott. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 04.08.2020.)

A natural extension of the descriptors used in the Spectral Neighbor Analysis Potential (SNAP) method is derived to treat atomic interactions in chemically complex systems. Atomic environment descriptors within SNAP are obtained from a basis function expansion of the weighted density of neighboring atoms. This new formulation instead partitions the neighbor density into partial densities for each chemical element, thus leading to explicit multielement descriptors. For N elem chemical elements, the number of descriptors increases as [Formula: see text], while the computational cost of the force calculation as implemented in LAMMPS is limited to [Formula: see text] and the favorable linear scaling in the number of atoms is retained. We demonstrate these chemically aware descriptors by producing an interatomic potential for indium phosphide capable of capturing high-energy defects that result from radiation damage cascades. This new explicit multielement SNAP method reproduces the relaxed defect formation energies with substantially greater accuracy than weighted-density SNAP, while retaining accurate representation of the bulk indium phosphide properties.

The ATP-grasp superfamily of enzymes shares an atypical nucleotide-binding site known as the ATP-grasp fold. These enzymes are involved in many biological pathways in all domains of life. One ATP-grasp enzyme, d-alanine-d-alanine ligase (Ddl), catalyzes ATP-dependent formation of the d-alanyl-d-alanine dipeptide essential for bacterial cell wall biosynthesis and is therefore an important antibiotic drug target. Ddl is activated by the monovalent cation (MVC) K + , but despite its clinical relevance and decades of research, how this activation occurs has not been elucidated. We demonstrate here that activating MVCs bind adjacent to the active site of Ddl from Thermus thermophilus and used a combined biochemical and structural approach to characterize MVC activation. We found that Tt Ddl is a type II MVC-activated enzyme, retaining activity in the absence of MVCs. However, the efficiency of Tt Ddl increased ∼20-fold in the presence of activating MVCs, and it was maximally activated by K + and Rb + ions. A strict dependence on ionic radius of the MVC was observed, with Li + and Na + providing little to no Tt Ddl activation. To understand the mechanism of MVC activation, we solved crystal structures of Tt Ddl representing distinct catalytic stages in complex with K + , Rb + , or Cs + Comparison of these structures with apo Tt Ddl revealed no evident conformational change on MVC binding. Of note, the identified MVC binding site is structurally conserved within the ATP-grasp superfamily. We propose that MVCs activate Ddl by altering the charge distribution of its active site. These findings provide insight into the catalytic mechanism of ATP-grasp enzymes., Competing Interests: Conflict of interest—The authors declare that they have no conflicts of interest with the contents of this article., (© 2020 Pederick et al.)

Objective: To synthesize current evidence about experiences and information needs of parents/caregivers managing pediatric fever., Methods: We used systematic review methodology with an a priori protocol. We searched Medline, Embase, PsycINFO, CINAHL and ProQuest Dissertations and Theses Global, from 2000 to May 2018., Results: We included thirty-six studies (n = 29 quantitative, n = 7 qualitative; 15,727 participants). Quantitative data contained four themes; 1) caregivers seek information about pediatric fever, 2) low knowledge is coupled with misconceptions and anxiety, 3) fever assessment and management practices vary, 4) demographic factors (e.g., ethnicity, age, socioeconomic status, education) influence information needs and health practices. Qualitative data contained three themes; 1) tension between logic and emotion, 2) responsibility contrasted with sense of vulnerability, 3) seeking support and information to build confidence., Conclusion: Parents often overestimate the risks associated with pediatric fever and struggle to make decisions during a child's febrile illness - leading to caregiving actions that may not reflect current clinical recommendations. Parents seek knowledge about how to care for a febrile child at home and what indicators should prompt them to seek medical attention., Practice Implications: In addition to providing clear, reliable information, interventions that address educational, pragmatic, and emotional domains may be effective in supporting parents., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims and Objectives: To explore parents' experiences with paediatric fever to understand their needs for information and support., Background: Paediatric fever is a normal part of childhood, and multiple episodes of fever are a common occurrence between infancy and adulthood. Despite this expectation, paediatric fever often sparks fear and anxiety amongst parents. Existing research has primarily focused on measuring parental deficits, so a more in-depth exploration is helpful to understand the complexities of caring for a febrile child., Design: Qualitative descriptive study., Methods: Purposive sampling of N = 15 parents from a paediatric emergency department presenting with a febrile child. Semi-structured interviews were conducted in-person or via telephone. Thematic analysis was used to understand the data in the light of our research question. Reporting follows the consolidated criteria for reporting qualitative research checklist., Results: We found themes of (a) parental confidence through caregiving tasks, (b) emergent feelings of inadequacy, (i) referrals and limitations of community practice, (c) information needs and (d) information sources. Whereas parents were initially confident accessing information, providing care, making decisions and managing symptoms, new signs/symptoms sparked a change in parents' emotions, coping and behaviour. Parents routinely search for information about paediatric fever and value reliable, accessible resources., Conclusions: Our findings highlight parents' strengths assessing fever and effectively managing symptoms. We are encouraged by the potential for these results to inform the development of empowering resources to help parents make child health decisions during paediatric fever., Relevance to Clinical Practice: Findings provide an evidence base for researchers, clinicians and policymakers to improve care for paediatric patients and families. Parents want clear, reliable and accessible information about decision points associated with paediatric fever. Resources with an empowerment focus may help parents maintain a sense of control when caring for a febrile child., (© 2019 John Wiley & Sons Ltd.)

Machine learning of the quantitative relationship between local environment descriptors and the potential energy surface of a system of atoms has emerged as a new frontier in the development of interatomic potentials (IAPs). Here, we present a comprehensive evaluation of machine learning IAPs (ML-IAPs) based on four local environment descriptors-atom-centered symmetry functions (ACSF), smooth overlap of atomic positions (SOAP), the spectral neighbor analysis potential (SNAP) bispectrum components, and moment tensors-using a diverse data set generated using high-throughput density functional theory (DFT) calculations. The data set comprising bcc (Li, Mo) and fcc (Cu, Ni) metals and diamond group IV semiconductors (Si, Ge) is chosen to span a range of crystal structures and bonding. All descriptors studied show excellent performance in predicting energies and forces far surpassing that of classical IAPs, as well as predicting properties such as elastic constants and phonon dispersion curves. We observe a general trade-off between accuracy and the degrees of freedom of each model and, consequently, computational cost. We will discuss these trade-offs in the context of model selection for molecular dynamics and other applications.

The objective of this review was to assess the evidence on relaxation training for management of paediatric headaches. Our methodology was a rapid review of English-language peer reviewed published literature focused on studies evaluating relaxation training as a primary or adjunct management option for headache in a paediatric population (0 to 18 years of age). Seven studies involving 571 children were included in the review. The quality of evidence was very low using GRADE criteria. Headache frequency, duration, and intensity were the primary outcomes in the included studies. Results for the effects of relaxation training for paediatric headache are inconsistent. Four of the seven studies reported decreased headache frequency, two of the five studies reported decreased headache duration, and two of the six studies reported decreased headache intensity following relaxation training. No adverse events were reported. The current state of the evidence for relaxation training for management of paediatric headache is both inconsistent and of very low quality. High-quality research evaluating the effects of relaxation training for paediatric headaches is required to advance the field.

We consider a confined sheared active polar liquid crystal with a uniform orientation and study the effect of variations in the magnitude of polarization. Restricting our analysis to one-dimensional geometries, we demonstrate that with asymmetric boundary conditions, this system is characterized, macroscopically, by a linear shear stress vs. shear strain relationship that does not pass through the origin: At a zero strain rate, the fluid sustains a non-zero stress. Analytic solutions for the polarization, density, and velocity fields are derived for asymptotically large or small systems and are shown by comparison with precise numerical solutions to be good approximations for finite-size systems.

Bifidobacteria play a vital role in human nutrition and health by shaping and maintaining the gut ecosystem. In order to exert a beneficial effect, a sufficient population of bifidobacteria must colonise the host. In this study, we developed a miniaturised high-throughput in vitro assay for assessing the colonising ability of bacterial strains in human cells. We also investigated a variety of components isolated from different milk sources for their ability to increase the adherence of Bifidobacterium longum subsp. infantis ATCC 15697, a common member of the gastrointestinal microbiota of breastfed infants, to HT-29 cells. Both conventional and miniaturised colonisation assays were employed to examine the effect of 13 different milk-derived powders on bacterial adherence, including positive controls which had previously resulted in increased bifidobacterial adherence (human milk oligosaccharides and a combination of 3'- and 6'-sialylactose) to intestinal cells. Immunoglobulin G enriched from bovine whey and goat milk oligosaccharides resulted in increased adhesion (3.3- and 8.3-fold, respectively) of B. infantis to the intestinal cells and the miniaturised and conventional assays were found to yield comparable and reproducible results. This study highlights the potential of certain milk components to favourably modulate adhesion of bifidobacteria to human intestinal cells.

Quantitative understanding and control of water and impurity desorption from steel surfaces are crucial for high-voltage, pulsed power, vacuum technology, catalysis, and environmental applications. We apply a suite of modeling techniques, ranging from electronic density functional theory, to classical molecular dynamics (MD) and grand canonical Monte Carlo (GCMC) methods to study the thermodynamics and kinetics of fast water desorption from different surfaces of hematite Fe 2 O 3 and Cr 2 O 3 . Water binding energies on chromium oxide are found to be higher than iron oxide at zero temperature. MD simulations are conducted on Fe 2 O 3 surfaces using thermodynamically consistent initial water inventory deduced with GCMC. The resulting time- and temperature-dependent desorption profiles on the Fe 2 O 3 [Formula: see text] surfaces show multi-water cooperative behavior which cannot be deduced from zero temperature predictions, but which are in reasonable agreement with simple Temkin isotherm model estimates if finite temperature effects are incorporated into the Temkin binding energy parameter. Qualitatively different desorption behaviors associated with the [Formula: see text] and [Formula: see text] facets are discussed.

Background: Accurate time-energy budgets summarise an animal's energy expenditure in a given environment, and are potentially a sensitive indicator of how an animal responds to changing resources. Deriving accurate time-energy budgets requires an estimate of time spent in different activities and of the energetic cost of that activity. Bio-loggers (e.g., accelerometers) may provide a solution for monitoring animals such as fur seals that make long-duration foraging trips. Using low resolution to record behaviour may aid in the transmission of data, negating the need to recover the device., Methods: This study used controlled captive experiments and previous energetic research to derive time-energy budgets of juvenile Australian fur seals ( Arctocephalus pusillus) equipped with tri-axial accelerometers. First, captive fur seals and sea lions were equipped with accelerometers recording at high (20 Hz) and low (1 Hz) resolutions, and their behaviour recorded. Using this data, machine learning models were trained to recognise four states-foraging, grooming, travelling and resting. Next, the energetic cost of each behaviour, as a function of location (land or water), season and digestive state (pre- or post-prandial) was estimated. Then, diving and movement data were collected from nine wild juvenile fur seals wearing accelerometers recording at high- and low- resolutions. Models developed from captive seals were applied to accelerometry data from wild juvenile Australian fur seals and, finally, their time-energy budgets were reconstructed., Results: Behaviour classification models built with low resolution (1 Hz) data correctly classified captive seal behaviours with very high accuracy (up to 90%) and recorded without interruption. Therefore, time-energy budgets of wild fur seals were constructed with these data. The reconstructed time-energy budgets revealed that juvenile fur seals expended the same amount of energy as adults of similar species. No significant differences in daily energy expenditure (DEE) were found across sex or season (winter or summer), but fur seals rested more when their energy expenditure was expected to be higher. Juvenile fur seals used behavioural compensatory techniques to conserve energy during activities that were expected to have high energetic outputs (such as diving)., Discussion: As low resolution accelerometry (1 Hz) was able to classify behaviour with very high accuracy, future studies may be able to transmit more data at a lower rate, reducing the need for tag recovery. Reconstructed time-energy budgets demonstrated that juvenile fur seals appear to expend the same amount of energy as their adult counterparts. Through pairing estimates of energy expenditure with behaviour this study demonstrates the potential to understand how fur seals expend energy, and where and how behavioural compensations are made to retain constant energy expenditure over a short (dive) and long (season) period., Competing Interests: The authors declare there are no competing interests.

Dethiobiotin synthetase from Mycobacterium tuberculosis (MtDTBS) is a promising antituberculosis drug target. Small-molecule inhibitors that target MtDTBS provide a route towards new therapeutics for the treatment of antibiotic-resistant tuberculosis. Adenosine diphosphate (ADP) is an inhibitor of MtDTBS; however, structural studies into its mechanism of inhibition have been unsuccessful owing to competitive binding to the enzyme by crystallographic precipitants such as citrate and sulfate. Here, a crystallographic technique termed precipitant-ligand exchange has been developed to exchange protein-bound precipitants with ligands of interest. Proof of concept for the exchange method was demonstrated using cytidine triphosphate (CTP), which adopted the same binding mechanism as that obtained with traditional crystal-soaking techniques. Precipitant-ligand exchange also yielded the previously intractable structure of MtDTBS in complex with ADP solved to 2.4 Å resolution. This result demonstrates the utility of precipitant-ligand exchange, which may be widely applicable to protein crystallography.

The Spectral Neighbor Analysis Potential (SNAP) is a classical interatomic potential that expresses the energy of each atom as a linear function of selected bispectrum components of the neighbor atoms. An extension of the SNAP form is proposed that includes quadratic terms in the bispectrum components. The extension is shown to provide a large increase in accuracy relative to the linear form, while incurring only a modest increase in computational cost. The mathematical structure of the quadratic SNAP form is similar to the embedded atom method (EAM), with the SNAP bispectrum components serving as counterparts to the two-body density functions in EAM. The effectiveness of the new form is demonstrated using an extensive set of training data for tantalum structures. Similar to artificial neural network potentials, the quadratic SNAP form requires substantially more training data in order to prevent overfitting. The quality of this new potential form is measured through a robust cross-validation analysis.

Direct intracerebroventricular injection of angiotensin II (ANG II) causes increases in blood pressure and salt and water intake, presumably mimicking an effect mediated by an endogenous mechanism. The subfornical organ (SFO) is a potential source of cerebrospinal fluid (CSF), ANG I, and ANG II, and thus we hypothesized that the SFO has a secretory function. Endogenous levels of angiotensinogen (AGT) and renin are very low in the brain. We therefore examined the immunohistochemical localization of angiotensin peptides and AGT in the SFO, and AGT in the CSF in two transgenic models that overexpress either human AGT (A + mice), or both human AGT (hAGT) and human renin (SRA mice) in the brain. Measurements were made at baseline and following volumetric depletion of CSF. Ultrastructural analysis with immunoelectron microscopy revealed that superficially located ANG I/ANG II and AGT immunoreactive cells in the SFO were vacuolated and opened directly into the ventricle. Withdrawal of CSF produced an increase in AGT in the CSF that was accompanied by a large decline in AGT immunoreactivity within SFO cells. Our data provide support for the hypothesis that the SFO is a secretory organ that releases AGT and possibly ANG I/ANG II into the ventricle at least under conditions when genes that control the renin-angiotensin system are overexpressed in mice., (Copyright © 2017 the American Physiological Society.)

Constructing activity budgets for marine animals when they are at sea and cannot be directly observed is challenging, but recent advances in bio-logging technology offer solutions to this problem. Accelerometers can potentially identify a wide range of behaviours for animals based on unique patterns of acceleration. However, when analysing data derived from accelerometers, there are many statistical techniques available which when applied to different data sets produce different classification accuracies. We investigated a selection of supervised machine learning methods for interpreting behavioural data from captive otariids (fur seals and sea lions). We conducted controlled experiments with 12 seals, where their behaviours were filmed while they were wearing 3-axis accelerometers. From video we identified 26 behaviours that could be grouped into one of four categories (foraging, resting, travelling and grooming) representing key behaviour states for wild seals. We used data from 10 seals to train four predictive classification models: stochastic gradient boosting (GBM), random forests, support vector machine using four different kernels and a baseline model: penalised logistic regression. We then took the best parameters from each model and cross-validated the results on the two seals unseen so far. We also investigated the influence of feature statistics (describing some characteristic of the seal), testing the models both with and without these. Cross-validation accuracies were lower than training accuracy, but the SVM with a polynomial kernel was still able to classify seal behaviour with high accuracy (>70%). Adding feature statistics improved accuracies across all models tested. Most categories of behaviour -resting, grooming and feeding-were all predicted with reasonable accuracy (52-81%) by the SVM while travelling was poorly categorised (31-41%). These results show that model selection is important when classifying behaviour and that by using animal characteristics we can strengthen the overall accuracy., Competing Interests: The authors have declared that no competing interests exist.

Background: Migrant and seasonal farmworking (MSFW) women patients experience substantially more intimate partner violence (IPV) than the general population, but few health-care providers screen patients for IPV. While researchers have examined screening practices in health-care settings, none have exclusively focused on MSFW women., Objective: The aim of this phenomenological study was to explore the experiences of health-care providers who have screened for and/or addressed IPV with MSFW women patients., Design: Researchers utilized descriptive phenomenology to capture the lived experiences of these health-care providers. Data were analysed using Colaizzi's seven-stage framework., Setting and Participants: Interviews were conducted with nine female participants - all of whom: (i) were clinically active health-care providers within the MSFW community, (ii) were bilingual in English and Spanish or had access to a translator, (iii) had treated MSFW patients who had experienced IPV and (iv) were at least 18 years of age., Results: Participants' experiences were reflected in four emergent themes: (i) provider-centered factors, (ii) patient-centered factors, (iii) clinic-centered factors and (iv) community-centered factors. Participants described barriers to establish routine IPV assessment, decrease patient ambivalence and increase on-site support and community resources., Discussion and Conclusions: This study aimed to generate a greater understanding of the experiences of health-care providers with screening for and addressing IPV with MSFW patients. Implications and recommendations for research, clinical practice and policy are provided., (© 2015 The Authors. Health Expectations Published by John Wiley & Sons Ltd.)

Adherent-invasive Escherichia coli (AIEC) have been implicated in the aetiology of Crohn's disease (CD), a chronic inflammatory bowel condition. It has been proposed that AIEC-infected macrophages produce high levels of pro-inflammatory cytokines thus contributing to the inflammation observed in CD. AIEC can replicate in macrophages and we wanted to determine if bacterial replication was linked to the high level of cytokine production associated with AIEC-infected macrophages. Therefore, we undertook a genetic analysis of the metabolic requirements for AIEC replication in the macrophage and we show that AIEC replication in this niche is dependent on bacterial glycolysis. In addition, our analyses indicate that AIEC have access to a wide range of nutrients in the macrophage, although the levels of purines and pyrimidines do appear to be limiting. Finally, we show that the macrophage response to AIEC infection is indistinguishable from the response to the non-replicating glycolysis mutant (ΔpfkAB) and a non-pathogenic strain of E. coli, MG1655. Therefore, AIEC does not appear to subvert the normal macrophage response to E. coli during infection.

The liver is an important integrator of nutrient metabolism, yet no liver-derived factors regulating nutrient preference or carbohydrate appetite have been identified. Here we show that the liver regulates carbohydrate intake through production of the hepatokine fibroblast growth factor 21 (FGF21), which markedly suppresses consumption of simple sugars, but not complex carbohydrates, proteins, or lipids. Genetic loss of FGF21 in mice increases sucrose consumption, whereas acute administration or overexpression of FGF21 suppresses the intake of both sugar and non-caloric sweeteners. FGF21 does not affect chorda tympani nerve responses to sweet tastants, instead reducing sweet-seeking behavior and meal size via neurons in the hypothalamus. This liver-to-brain hormonal axis likely represents a negative feedback loop as hepatic FGF21 production is elevated by sucrose ingestion. We conclude that the liver functions to regulate macronutrient-specific intake by producing an endocrine satiety signal that acts centrally to suppress the intake of "sweets.", (Copyright © 2016 Elsevier Inc. All rights reserved.)

Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)-salt. Intracerebroventricular delivery of the endoplasmic reticulum stress-reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt. Increased saline-intake returned after tauroursodeoxycholic acid was terminated. Decreased saline-intake was also observed after intracerebroventricular infusion of 4-phenylbutyrate, another chemical chaperone. Immunoreactivity to CCAAT homologous binding protein, a marker of irremediable endoplasmic reticulum stress, was increased in the subfornical organ and supraoptic nucleus of DOCA-salt mice, but the signal was absent in control and CCAAT homologous binding protein-deficient mice. Electron microscopy revealed abnormalities in endoplasmic reticulum structure (decrease in membrane length, swollen membranes, and decreased ribosome numbers) in the subfornical organ consistent with endoplasmic reticulum stress. Subfornical organ-targeted adenoviral delivery of GRP78, a resident endoplasmic reticulum chaperone, decreased DOCA-salt-induced saline-intake. The increase in saline-intake in response to DOCA-salt was blunted in CCAAT homologous binding protein-deficient mice, but these mice exhibited a normal hypertensive response. We conclude that (1) brain endoplasmic reticulum stress mediates the saline-intake, but not blood pressure response to DOCA-salt, (2) DOCA-salt causes endoplasmic reticulum stress in the subfornical organ, which when attenuated by GRP78 blunts saline-intake, and (3) CCAAT homologous binding protein may play a functional role in DOCA-salt-induced saline-intake. The results suggest a mechanistic distinction between the importance of endoplasmic reticulum stress in mediating effects of DOCA-salt on saline-intake and blood pressure., (© 2015 American Heart Association, Inc.)

S-P467L mice expressing dominant negative peroxisome proliferator-activated receptor-γ selectively in vascular smooth muscle exhibit impaired vasodilation, augmented vasoconstriction, hypertension, and tachycardia. We hypothesized that tachycardia in S-P467L mice is a result of baroreflex dysfunction. S-P467L mice displayed increased sympathetic traffic to the heart and decreased baroreflex gain and effectiveness. Carotid arteries exhibited inward remodeling but no changes in distensibility or stress/strain. Aortic depressor nerve activity in response to increased arterial pressure was blunted in S-P467L mice. However, the arterial pressure and heart rate responses to aortic depressor nerve stimulation were unaltered in S-P467L mice, suggesting that the central and efferent limbs of the baroreflex arc remain intact. There was no transgene expression in nodose ganglion and no change in expression of the acid-sensing ion channel-2 or -3 in nodose ganglion. There was a trend toward decreased expression of transient receptor potential vanilloid-1 receptor mRNA in nodose ganglion, but no difference in the immunochemical staining of transient receptor potential vanilloid-1 receptor in the termination area of the left aortic depressor nerve in S-P467L mice. Although there was no difference in the maximal calcium response to capsaicin in cultured nodose neurons from S-P467L mice, there was decreased desensitization of transient receptor potential vanilloid-1 receptor channels. In conclusion, S-P467L mice exhibit baroreflex dysfunction because of a defect in the afferent limb of the baroreflex arc caused by impaired vascular function, altered vascular structure, or compromised neurovascular coupling. These findings implicate vascular smooth muscle peroxisome proliferator activated receptor-γ as a critical determinant of neurovascular signaling., (© 2014 American Heart Association, Inc.)

We have developed a new ReaxFF reactive force field parametrization for ammonium nitrate. Starting with an existing nitramine/TATB ReaxFF parametrization, we optimized it to reproduce electronic structure calculations for dissociation barriers, heats of formation, and crystal structure properties of ammonium nitrate phases. We have used it to predict the isothermal pressure-volume curve and the unreacted principal Hugoniot states. The predicted isothermal pressure-volume curve for phase IV solid ammonium nitrate agreed with electronic structure calculations and experimental data within 10% error for the considered range of compression. The predicted unreacted principal Hugoniot states were approximately 17% stiffer than experimental measurements. We then simulated thermal decomposition during heating to 2500 K. Thermal decomposition pathways agreed with experimental findings.

The etiology of Crohn's disease (CD) is complex and involves both host susceptibility factors (i.e., the presence of particular genetic alleles) and environmental factors, including bacteria. In this regard, adherent-invasive Escherichia coli (AIEC), have recently emerged as an exciting potential etiological agent of CD. AIEC are distinguished from commensal strains of E. coli through their ability to adhere to and invade epithelial cells and replicate in macrophages. Recent molecular analyses have identified genes required for both invasion of epithelial cells and replication in the macrophage. However, these genetic studies, in combination with recent genome sequencing projects, have revealed that the pathogenesis of this group of bacteria cannot be explained by the presence of AIEC-specific genes. In this article, we review the role of AIEC as a pathobiont in the pathology of CD. We also describe the emerging link between AIEC and autophagy, and we propose a model for AIEC pathogenesis.

An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V(2)-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (~15 mmHg) hypertension in sRA mice. Abdominal aortas and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V(1A) receptor mRNA, but no significant changes in V(2) receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V(2) receptors.

The dependence of the reaction initiation mechanism of pentaerythritol tetranitrate (PETN) on shock orientation and shock strength is investigated with molecular dynamics simulations using a reactive force field and the multiscale shock technique. In the simulations, a single crystal of PETN is shocked along the [110], [001], and [100] orientations with shock velocities in the range 3-10 km/s. Reactions occur with shock velocities of 6 km/s or stronger, and reactions initiate through the dissociation of nitro and nitrate groups from the PETN molecules. The most sensitive orientation is [110], while [100] is the most insensitive. For the [001] orientation, PETN decomposition via nitro group dissociation is the dominant reaction initiation mechanism, while for the [110] and [100] orientations the decomposition is via mixed nitro and nitrate group dissociation. For shock along the [001] orientation, we find that CO-NO(2) bonds initially acquire more kinetic energy, facilitating nitro dissociation. For the other two orientations, C-ONO(2) bonds acquire more kinetic energy, facilitating nitrate group dissociation.

While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.

Risk-need assessment is widely accepted as best practice with juvenile offenders and is underpinned by a healthy research literature on risk assessment inventories. Previous studies have found both similarities and differences on risk measures when gender and racial/ethnic subgroups have been compared. Differential validity has been examined, but differential prediction has been overlooked. The current study undertook gender and ethnic comparisons for a large sample (n = 3568) of community-based juvenile offenders who were evaluated using the Australian Adaptation of the Youth Level of Service/Case Management Inventory (YLS/CMI-AA). Analyses showed various gender and ethnic differences at the item level, across domain scores and on the total inventory score, but not for validity indices. However, 1-year reoffending rates for youth in three classification categories (low, moderate, high) varied by gender and ethnicity. The findings were related to contemporary understandings of the risk factors for offending and the dynamics of crime for gender/ethnic subgroups. It is argued that in spite of these subgroup differences, a generic inventory such as the YLS/CMI-AA can be used fairly with various subgroups. Recommendations for how this could be accomplished are provided., ((PsycINFO Database Record (c) 2012 APA, all rights reserved).)

Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.