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In May 2019, 96 cattle died from Pimelea toxicity in a period of 19 days after potential exposure, with the first deaths occurring within 5 days. After examining the circumstances, we suspect that several factors contributed to the deaths. These included that recently purchased stock and transported had access to flooded land containing Pimelea elongata. This weed species contains simplexin and 18 other compounds. Roots, flowers and seeds are significantly more toxic than the stem, branches and leaves. We suspect that thirsty and hungry stock consumed seed and roots from flooded pastures and consumed lethal doses of simplexin. Blood tests were not good indicators of the conditions. Management strategies are suggested.

Herein we present the synthesis, structure and NMR and mass spectroscopic analyses of the antioxidant 2-(3,5-dimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one (1), a member of the 2-aryl-2,3-dihydroquinolin-4(1H)-one family of molecules that have been shown to display a range of potent biological properties. The title molecule, prepared by an alternative methodology to that recently reported, crystallizes in the centrosymmetric space group P21/c with unit cell dimensions a = 11.775(17) A, b = 5.3592(8) A, c = 22.462(3) A and β = 96.576(11)°. Close analysis of the solid state structure reveals an array of weak N–H∙∙∙O hydrogen bonding as well as C–H∙∙∙O, and C–H∙∙∙π interactions between the neighboring molecules. The presence of 1 was also confirmed via NMR and mass spectroscopic analyses. Herein we present the solid state structure and results of mass spectroscopic and nuclear magnetic resonance analyses of the powerful antitumor compound 2-(3,5-dimethoxyphenyl)-2,3-dihydroquinolin-4(1H)-one prepared by an alternative synthetic avenue.

In personalized medicine, predictive biomarker testing is the basis for an appropriate choice of therapy for patients with cancer. An important tool for laboratories to ensure accurate results is participation in external quality assurance (EQA) programs. Several providers offer predictive EQA programs for different cancer types, test methods, and sample types. In 2013, a guideline was published on the requirements for organizing high-quality EQA programs in molecular pathology. Now, after six years, steps were taken to further harmonize these EQA programs as an initiative by IQNPath ABSL, an umbrella organization founded by various EQA providers. This revision is based on current knowledge, adds recommendations for programs developed for predictive biomarkers by in situ methodologies (immunohistochemistry and in situ hybridization), and emphasized transparency and an evidence-based approach. In addition, this updated version also has the aim to give an overview of current practices from various EQA providers. Electronic supplementary material The online version of this article (10.1007/s00428-020-02928-z) contains supplementary material, which is available to authorized users.

Ebola virus (EBOV) is one of the most lethal pathogens that can infect humans. The Ebola viral protein VP35 (EBOV VP35) inhibits host IFN-α/β production by interfering with host immune responses to viral invasion and is thus considered as a plausible drug target. The aim of this study was to identify potential novel lead compounds against EBOV VP35 using computational techniques in drug discovery. The 3D structure of the EBOV VP35 with PDB ID: 3FKE was used for molecular docking studies. An integrated library of 7675 African natural product was pre-filtered using ADMET risk, with a threshold of 7 and, as a result, 1470 ligands were obtained for the downstream molecular docking using AutoDock Vina, after an energy minimization of the protein via GROMACS. Five known inhibitors, namely, amodiaquine, chloroquine, gossypetin, taxifolin and EGCG were used as standard control compounds for this study. The area under the curve (AUC) value, evaluating the docking protocol obtained from the receiver operating characteristic (ROC) curve, generated was 0.72, which was considered to be acceptable. The four identified potential lead compounds of NANPDB4048, NANPDB2412, ZINC000095486250 and NANPDB2476 had binding affinities of −8.2, −8.2, −8.1 and −8.0 kcal/mol, respectively, and were predicted to possess desirable antiviral activity including the inhibition of RNA synthesis and membrane permeability, with the probable activity (Pa) being greater than the probable inactivity (Pi) values. The predicted anti-EBOV inhibition efficiency values (IC50), found using a random forest classifier, ranged from 3.35 to 11.99 μM, while the Ki values ranged from 0.97 to 1.37 μM. The compounds NANPDB4048 and NANPDB2412 had the lowest binding energy of −8.2 kcal/mol, implying a higher binding affinity to EBOV VP35 which was greater than those of the known inhibitors. The compounds were predicted to possess a low toxicity risk and to possess reasonably good pharmacological profiles. Molecular dynamics (MD) simulations of the protein–ligand complexes, lasting 50 ns, and molecular mechanisms Poisson-Boltzmann surface area (MM-PBSA) calculations corroborated the binding affinities of the identified compounds and identified novel critical interacting residues. The antiviral potential of the molecules could be confirmed experimentally, while the scaffolds could be optimized for the design of future novel anti-EBOV chemotherapeutics.

We designed a portable system using an open source microcontroller (μC) with built-in field programmable gate array (FPGA) for on-the-fly data acquisition and processing of optical data generated from rapidly pulsed infrared light emitting diodes (IR LEDs) for optical sensing of gases. The system is used for rapid pulse generation (ca. 2 μs short pulses with a typical repetition rate of 1 kHz) to drive the IR LED, as well as for the optical sensing data acquisition and processing on-thefly large data streams of ca. 2 Gbit/s. The flexibility and performance of the system is demonstrated. Each of the digitally processed signal pulses yielded one data point of analytical signal in time as a quasi-continuous data stream produced at a rate of between 1000 and 0.1 Hz. This microcontroller-based portable open source platform is then implemented in on-the-fly data acquisition and processing, of analytical signals enabling continuous gas sensing.

Ebola virus (EBOV) causes severe human disease with a high case fatality rate. The balance of evidence implies that the virus circulates in bats. The molecular basis for host-viral interactions, including the role for phosphorylation during infections, is largely undescribed. To address this, and to better understand the biology of EBOV, the phosphorylation of EBOV proteins was analyzed in virions purified from infected monkey Vero-E6 cells and bat EpoNi/22.1 cells using high-resolution mass spectrometry. All EBOV structural proteins were detected with high coverage, along with phosphopeptides. Phosphorylation sites were identified in all viral structural proteins. Comparison of EBOV protein phosphorylation in monkey and bat cells showed only partial overlap of phosphorylation sites, with shared sites found in NP, VP35, and VP24 proteins, and no common sites in the other proteins. Three-dimensional structural models were built for NP, VP35, VP40, GP, VP30 and VP24 proteins using available crystal structures or by de novo structure prediction to elucidate the potential role of the phosphorylation sites. Phosphorylation of one of the identified sites in VP35, Thr-210, was demonstrated to govern the transcriptional activity of the EBOV polymerase complex. Thr-210 phosphorylation was also shown to be important for VP35 interaction with NP. This is the first study to compare phosphorylation of all EBOV virion proteins produced in primate versus bat cells, and to demonstrate the role of VP35 phosphorylation in the viral life cycle. The results uncover a novel mechanism of EBOV transcription and identify novel targets for antiviral drug development.

The emergence of drug resistance against the known hookworm drugs namely albendazole and mebendazole and their reduced efficacies necessitate the need for new drugs. Chemically diverse natural products present plausible templates to augment hookworm drug discovery. The present work utilized pharmacoinformatics techniques to predict African natural compounds ZINC95486082, ZINC95486052 and euphohelionon as potential inhibitory molecules of the hookworm Necator americanus β tubulin gene. A library of 3390 compounds was screened against a homology-modelled structure of β tubulin. The docking results obtained from AutoDock Vina was validated with an acceptable area under the curve (AUC) of 0.714 computed from the receiver operating characteristic (ROC) curve. The three selected compounds had favourable binding affinities and were predicted to form no interactions with the resistance-associated mutations Phe167, Glu198 and Phe200. The compounds were predicted as anthelmintics using a Bayesian-based technique and were pharmacologically profiled to be druglike. Further molecular dynamics simulations and MM-PBSA calculations showed the compounds as promising anthelmintic drug leads. Novel critical residues comprising Leu246, Asn247 and Asn256 were also predicted for binding. Euphohelionon was selected as a template for the de novo fragment-based design of five compounds labelled A1, A2, A3, A4 and A5; with four of them having SAscore values below 6, denoting easy synthesis. All the five de novo molecules docked firmly in the binding pocket of the β tubulin with no binding interactions with the three known resistance mutation residues. Binding energies of −8.2, −7.6, −7.3, −7.2 and −6.8 kcal/mol were obtained for A1, A2, A3, A4 and A5, respectively. The identified compounds can serve as treasure troves from which future potent anthelmintics can be designed. The current study strives to assuage the hookworm disease burden, especially making available molecules with the potential to circumvent the chemoresistance.

Composite components regularly experience dynamic loads in service. Despite this, it is still difficult to obtain accurate mechanical properties of composite materials under high strain rate conditions. In this study, a new application of the Image-Based Inertial Impact (IBII) test methodology was developed, to generate an accurate in-plane transverse and shear moduli dataset from unidirectional (UD) off-axis composite specimens. The obtained dataset was consistent across different sample configurations, where results from the UD45$$^{\circ }$$ ∘ off-axis specimens agreed well with the UD90$$^{\circ }$$ ∘ values. Validation of the shear modulus identification was also undertaken by comparing the results from the UD90$$^{\circ }$$ ∘ and UD45$$^{\circ }$$ ∘ specimens with a multi-directional (MD) configuration. Here, it was found that MD±45$$^{\circ }$$ ∘ specimen shear modulus values where marginally lower than that from the UD specimens, in accordance with the lower fibre volume fraction of the MD laminate. Low strain rate sensitivities in the $$0.5-2\times$$ 0.5 - 2 × 10$$^{3}$$ 3 $$\hbox {s}^{-1}$$ s - 1 regime evidenced in this work suggest previously published data (often from split-Hopkinson bar tests) may include both a material and system i.e. testing apparatus response.

Engineering Geological Models (EGMs) comprise both conceptual ideas and observational data. The observational data is associated with aleatory uncertainty which can be reduced by acquiring more observations. The conceptual ideas are associated with epistemic uncertainty which can only be reduced if more knowledge is incorporated into the model. The conceptual ideas are the core of any EGM and provide the framework for the evaluation of the observational data. The most powerful capability of an EGM is the ability to anticipate what might be present at a project site and evaluate how the ground could adversely affect the project i.e. when developed correctly, an EGM allows an evaluation of what is might reasonably be foreseen at a site by an experienced contractor. This requires sophisticated conceptualization at an early stage in the project to anticipate what might be in the ground. Consequently, EGMs are much more than visualizations, they should represent an understanding of the geological conditions that are of engineering significance to the project, provide the framework for assembling engineering geological knowledge, support good geotechnical engineering decisions and allow an evaluation of potential geotechnical risks and possible project opportunities. Thematic collection: This article is part of the Ground models in engineering geology and hydrogeology collection available at: https://www.lyellcollection.org/cc/Ground-models-in-engineering-geology-and-hydrogeology

DisPLACE is a digital platform for the collection and interpretation of experiences of disability, past and present, by people with disabilities in collaboration with other students, researchers, disability service organisations, and the creative industries. The project prototype was launched in 2019, and the site is intended to serve as the first archive in the Netherlands to gather and analyse a broad range of historical sources on disabilities together, the first shared virtual environment to utilise the cultural heritage of disability, and the first to make these accessible online to people with a wide variety of disabilities. The project is part of a larger initiative by the BIB Network (Bronnen voor Inclusieve Burgerschap), working to stimulate the collection and interpretation of disability history. In this essay, three of the coordinators of the project reflect on the challenges of funding, designing, and developing content for the website in a university course for public history students. In the spirit of this edited collection, the authors describe some of the uncomfortable truths made apparent by this project, as a means to critically reflect on the realities of doing undervalued work in an imperfect world.

Background Preterm birth (PTB) is associated with increased infant mortality, and neurodevelopmental abnormalities among survivors. The aim of this study is to investigate temporal trends, patterns, and predictors of PTB in California from 2007 to 2016, based on the obstetric estimate of gestational age (OA). Methods A retrospective cohort study evaluated 435,280 PTBs from the 5,137,376 resident live births (8.5%) documented in the California Birth Statistical Master Files (BSMF) from 2007 to 2016. The outcome variable was PTB; the explanatory variables were birth year, maternal characteristics and health behaviors. Descriptive statistics and logistic regression analysis were used to identify subgroups with significant risk factors associated with PTB. Small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants were identified employing gestational age based on obstetric estimates and further classified by term and preterm births, resulting in six categories of intrauterine growth. Results The prevalence of PTB in California decreased from 9.0% in 2007 to 8.2% in 2014, but increased during the last 2 years, 8.4% in 2015 and 8.5% in 2016. Maternal age, education level, race and ethnicity, smoking during pregnancy, and parity were significant risk factors associated with PTB. The adjusted odds ratio (AOR) showed that women in the oldest age group (40–54 years) were almost twice as likely to experience PTB as women in the 20- to 24-year reference age group. The prevalence of PTB was 64% higher in African American women than in Caucasian women. Hispanic women showed less disparity in the prevalence of PTB based on education and socioeconomic level. The analysis of interactions between maternal characteristics and perinatal health behaviors showed that Asian women have the highest prevalence of PTB in the youngest age group (

Background Low birth weight (LBW) is a leading risk factor for infant morbidity and mortality in the United States. There are large disparities in the prevalence of LBW by race and ethnicity, especially between African American and White women. Despite extensive research, the practice of clinical and public health, and policies devoted to reducing the number of LBW infants, the prevalence of LBW has remained unacceptably and consistently high. There have been few detailed studies identifying the factors associated with LBW in California, which is home to a highly diverse population. The aim of this study is to investigate recent trends in the prevalence of LBW infants (measured as a percentage) and to identify risk factors and disparities associated with LBW in California. Methods A retrospective cohort study included data on 5,267,519 births recorded in the California Birth Statistical Master Files for the period 2005–2014. These data included maternal characteristics, health behaviors, information on health insurance, prenatal care use, and parity. Logistic regression models identified significant risk factors associated with LBW. Using gestational age based on obstetric estimates (OA), small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA) infants were identified for the periods 2007–2014. Results The number of LBW infants declined, from 37,603 in 2005 to 33,447 in 2014. However, the prevalence of LBW did not change significantly (6.9% in 2005 to 6.7% in 2014). The mean maternal age at first delivery increased from 25.7 years in 2005 to 27.2 years in 2014. The adjusted odds ratio showed that women aged 40 to 54 years were twice as likely to have an LBW infant as women in the 20 to 24 age group. African American women had a persistent 2.4-fold greater prevalence of having an LBW infant compared with white women. Maternal age was a significant risk factor for LBW regardless of maternal race and ethnicity or education level. During the period 2017–2014, 5.4% of the singleton births at 23–41 weeks based on OE of gestational age were SGA infants (preterm SGA + term SGA). While all the preterm SGA infants were LBW, both preterm AGA and term SGA infants had a higher prevalence of LBW. Conclusions In California, during the 10 years from 2005 to 2014, there was no significant decline in the prevalence of LBW. However, maternal age was a significant risk factor for LBW regardless of maternal race and ethnicity or education level. Therefore, there may be opportunities to reduce the prevalence of LBW by reducing disparities and improving birth outcomes for women of advanced maternal age. Electronic supplementary material The online version of this article (10.1186/s40748-018-0084-2) contains supplementary material, which is available to authorized users.

OBJECTIVES/GOALS: Mammals require iron for hemoglobin, respiration, immunity and as cofactor in enzymes. But free iron is toxic from the production of reactive oxygen species. Ferroportin is the sole exporter of cellular iron and it crucially determines cellular and systemic iron levels. Labile iron must be tightly regulated. This requires structural understanding. METHODS/STUDY POPULATION: We built structure of human ferroportin (FPN1) using the ab ignition prediction approaches of Rosetta/Robetta and by comparative modeling with distance restraints in MODELLER. Templates selected were from solute carrier protein families of distantly related orthologs and homologs including a proton coupled peptide transporter (PDB ID: 4IKV) and the bacterial iron transporter in outward-open and inward-open states, (PDB ID: 5AYM, 5AYO). Each model was validated by experimental mass spectrometry data. The energy minimized structural model was inserted into a lipid bilayer, placed in a rectangular simulation box, covered with TIP3P water solvent balanced with counterions and conditioned. Finally, we carried out 350 nanoseconds molecular dynamics simulations. RESULTS/ANTICIPATED RESULTS: Our first model of FPN1 (571aa), using Rosetta/Robetta ab initio approach, resembles the structure of the proton-dependent transporter, POT and consists of 12 transmembrane helices. The membrane spanning helices veer away from the orientation in the structure of 4IKV. The alternate model using MODELLER and the method of satisfaction of constraints, returned one template, the structure of Bdellovibrio bacteriovorus iron (Fe2+) transporter homolog (5AYN, 440aa) with sequence identity of 19%. Aligning FPN1 on the template sequence incorporating structural information revealed better conservation (29%). This model also comprises 12 transmembrane helices in two bundles separated by a large intracellular loop. The iron binding site predicted in both models match the structures of distant bacterial homologs. DISCUSSION/SIGNIFICANCE OF IMPACT: We are using these experimentally verified structures and functional data to answer questions about the mechanism of ferroportin iron transport, structural dynamics and the significance of mutations in ferroportin seen in different populations, especially the Q248H mutation found in Africans and black Americans with moderate to high prevalence.

A Radio Frequency Identification (RFID) Tag is designed for threshold detection of certain chemical vapors. The vapor presence is signaled to the reader by a digital alert and communication between the tag and reader is not interrupted. The detection mechanism comprises an inkjet printed conducting track on an elastomer that swells in response to vapor exposure. The expanded track breaks and triggers a tamper detection circuit integrated into the RFID tag transponder chip

OBJECTIVES The aim of this national audit was to assess adherence of services providing HIV care in the UK to national standards and guidelines regarding psychological support and the assessment of alcohol and recreational drug use (including chemsex drugs) in people living with HIV (PLWH). METHODS Participating sites completed a survey of their services' care pathways relating to psychological support and substance use. They performed a case-note review of up to 40 adult PLWH per service, reviewing sociodemographic and clinical information and assessment of psychological wellbeing, drug use and alcohol use. The surveys and case notes were assessed against relevant British HIV Association (BHIVA) guidelines and standards. RESULTS The survey was completed by 112 services. Of these, 73%, 82% and 73% had formal annual processes for assessing the psychological wellbeing, alcohol use and drug use, respectively, of PLWH. Case-note data were provided for 4486 PLWH from 119 sites. Audited rates of assessment of PLWH were 66.0% for psychological wellbeing, 68.0% for alcohol use, 58.4% for recreational drug use and 16.8% for chemsex drug use. Variation between clinical services was wide, with ranges from

Objective To compare maternal genotypes between women with and without significant prolongation of pregnancy in the setting of 17-alpha hydroxyprogesterone caproate (17-P) administration for the prevention of recurrent preterm birth (PTB). Design Case–control. Setting Three tertiary-care centres across the USA. Population Women (n = 99) with ≥ 1 prior singleton spontaneous PTB, receiving 17-P. Methods Women were classified as having successful prolongation of pregnancy during the 17-P treated pregnancy, in two ways: (1) Definition A: success/non-success based on difference in gestational age at delivery between 17-P-treated and untreated pregnancies (success: delivered ≥ 3 weeks later with 17-P) and (2) Definition B: success/non-success based on reaching term (success: delivered at term with 17-P). Main outcome measures To assess genetic variation, all women underwent whole exome sequencing. Between-group sequence variation was analysed with the Variant Annotation, Analysis, and Search Tool (VAAST). Genes scored by VAAST with P

Atlantic salmon are an ecologically and economically important migratory fish in the UK, whose stocks have been declining over the past 30 years. Future climate and water use changes have the potential to alter the reproductive behaviour and distribution of salmon within a river, by restricting times and ability to access suitable spawning areas. As the survival of emergent salmon juveniles is density dependent, understanding how climate-driven changes in flow affect the location of salmon redds is important for future conservation efforts. This study examined how flow conditions affect the distribution of redds within a UK chalk stream, the river Frome in Dorset. Sixteen years of redd distribution and flow data between 1980 and 2015 were analysed using linear mixed-effects modelling. Generally, highest redd densities occurred within middle reaches of the main river. Mean flow during the river Frome critical migration period (October–December) did not affect the density of redds directly but affected the relationship between redd density and distance from tidal limit: redd densities were spread more uniformly throughout the river under high flow conditions, whereas redds were more aggregated in the middle river reaches under low flow conditions. Together, these findings suggest that access to upstream spawning grounds was limited under low flow conditions, which could have negative repercussions on juvenile survival. This study has revealed the distribution of redds along the river Frome for the first time and provided a basis for further study into the effects of redd distribution on subsequent juvenile life stages.

Hong Kong has made considerable progress in reducing landslide hazards from man-made slopes. As a consequence, Hong Kong has recently commenced the systematic evaluation of landslides from natural slopes. This paper discusses the assessment approached adopted, limitations with the approach and the problems with landslide hazard assessment in general by means of a case study. The paper concludes that the current approach, whilst suitable for its original purpose, that is the rapid evaluation of the likely magnitude of landslide hazards at the review stage of a development, has limitations when used for systematic landslide assessments at existing developments. It is suggested that landslide hazard assessments to quantify ‘top events’, for example loss of life, would be an improved approach which would allow simplified quantitative risk assessment (QRA) to be undertaken. However, such an approach requires a significant level of engineering geological and engineering geomorphological input. In particular, the careful derivation of appropriate values of landslide magnitude and frequency, based on expert judgment and making use of available data, knowledge and experience.

BACKGROUND: Although induction of labor (IOL) of low-risk nulliparous women at 39 weeks reduces the risk of cesarean delivery compared with expectant management, concern regarding more frequent use of labor induction remains given that this intervention historically has been thought to incur greater resource utilization. OBJECTIVE: To determine whether planned elective labor induction at 39 weeks among low-risk nulliparous women, compared with expectant management, was associated with differences in health care resource utilization from the time of randomization through 8 weeks postpartum. STUDY DESIGN: This is a planned secondary analysis of a multi-center randomized trial in which low-risk nulliparous women were assigned to IOL at 39 weeks or expectant management. We assessed resource utilization post-randomization in three time periods: antepartum (AP), delivery admission, and discharge through 8 weeks postpartum (PP). RESULTS: Of 6096 women with data available, those in the IOL group (n = 3059) were significantly less likely in the AP period after randomization to have at least one ambulatory visit for routine prenatal care (32.4% vs. 68.4%), unanticipated care (0.5% vs. 2.6%), or urgent care (16.2% vs. 44.3%), or at least one antepartum hospitalization (0.8% vs. 2.2%, p0.05 for all). CONCLUSIONS: Women randomized to IOL had longer durations in labor and delivery, but significantly fewer AP visits, tests, and treatments, and shorter maternal and neonatal hospital durations post-delivery. These results demonstrate that the health outcome advantages associated with IOL are gained without incurring uniformly greater health care resource use. TRIAL REGISTRATION: ClinicalTrials.gov number NCT01990612

ObjectiveTo identify current maternal and infant predictors of infant mortality, including maternal sociodemographic and economic status, maternal perinatal smoking and obesity, mode of delivery, and infant birthweight and gestational age.MethodsThis retrospective study analyzed data from the linked birth and infant death files (birth cohort) and live births from the Birth Statistical Master files (BSMF) in California compiled by the California Department of Public Health for 2007-2015. The birth cohort study comprised 4,503,197 singleton births including 19,301 infant deaths during the nine-year study period. A subpopulation to study fetal growth consisted of 4,448,300 birth cohort records including 13,891 infant deaths.ResultsThe infant mortality rate (IMR) for singleton births decreased linearly (p ConclusionsWhile the overall IMR in California is declining, wide disparities in death rates persist in different groups, and these disparities are increasing. Our data indicate that maternal sociodemographic and economic factors, as well as maternal prepregnancy obesity and smoking during pregnancy, have a prominent effect on IMR though no causality can be inferred with the current data. These predictors are not typically addressed by direct medical care. Infant factors with a major effect on IMR are birthweight and gestational age-predictors that are addressed by active medical services. The highest value interventions to reduce IMR may be social and public health initiatives that mitigate disparities in sociodemographic, economic and behavioral risks for mothers.

ObjectiveTo determine recent trends in maternal prepregnancy body mass index (BMI) and to quantify its association with birth and maternal outcomes.MethodsA population-based retrospective cohort study included resident women with singleton births in the California Birth Statistical Master Files (BSMF) database from 2007 to 2016. There were 4,621,082 women included out of 5,054,968 women registered in the database. 433,886 (8.6%) women were excluded due to invalid or missing information for BMI. Exposures were underweight (BMI < 18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (≥ 30 kg/m2) at the onset of pregnancy. Obesity was subcategorized into class I (30.0-34.9 kg/m2), class II (35.0-39.9 kg/m2), and class III (≥ 40 kg/m2), while adverse outcomes examined were low birth weight (LBW), very low birth weight (VLBW), macrosomic births, preterm birth (PTB), very preterm birth (VPTB), small-for-gestational-age birth (SGA), large-for-gestational-age birth (LGA), and cesarean delivery (CD). Descriptive analysis, simple linear regression, and multivariate logistic regression were performed, and adjusted odds ratios (AORs) with 95% confidence intervals (CIs) for associations were estimated.ResultsOver the ten-year study period, the prevalence of underweight and normal weight women at time of birth declined by 10.6% and 9.7%, respectively, while the prevalence of overweight and obese increased by 4.3% and 22.9%, respectively. VLBW increased significantly with increasing BMI, by 24% in overweight women and by 76% in women with class III obesity from 2007 to 2016. Women with class III obesity also had a significant increase in macrosomic birth (170%) and were more likely to deliver PTB (33%), VPTB (66%), LGA (231%), and CD (208%) than women with a normal BMI. However, obese women were less likely to have SGA infants; underweight women were 51% more likely to have SGA infants than women with a normal BMI.ConclusionsIn California from 2007 to 2016, there was a declining trend in women with prepregnancy normal weight, and a rising trend in overweight and obese women, particularly obesity class III. Both extremes of prepregnancy BMI were associated with an increased incidence of adverse neonatal outcomes; however, the worse outcomes were prominent in those women classified as obese.

Objectives To use the estimates from the Global Burden of Disease Study 2016 to describe patterns of suicide mortality globally, regionally, and for 195 countries and territories by age, sex, and Socio-demographic index, and to describe temporal trends between 1990 and 2016. Design Systematic analysis. Main outcome measures Crude and age standardised rates from suicide mortality and years of life lost were compared across regions and countries, and by age, sex, and Socio-demographic index (a composite measure of fertility, income, and education). Results The total number of deaths from suicide increased by 6.7% (95% uncertainty interval 0.4% to 15.6%) globally over the 27 year study period to 817 000 (762 000 to 884 000) deaths in 2016. However, the age standardised mortality rate for suicide decreased by 32.7% (27.2% to 36.6%) worldwide between 1990 and 2016, similar to the decline in the global age standardised mortality rate of 30.6%. Suicide was the leading cause of age standardised years of life lost in the Global Burden of Disease region of high income Asia Pacific and was among the top 10 leading causes in eastern Europe, central Europe, western Europe, central Asia, Australasia, southern Latin America, and high income North America. Rates for men were higher than for women across regions, countries, and age groups, except for the 15 to 19 age group. There was variation in the female to male ratio, with higher ratios at lower levels of Socio-demographic index. Women experienced greater decreases in mortality rates (49.0%, 95% uncertainty interval 42.6% to 54.6%) than men (23.8%, 15.6% to 32.7%). Conclusions Age standardised mortality rates for suicide have greatly reduced since 1990, but suicide remains an important contributor to mortality worldwide. Suicide mortality was variable across locations, between sexes, and between age groups. Suicide prevention strategies can be targeted towards vulnerable populations if they are informed by variations in mortality rates. © Published by the BMJ Publishing Group Limited.

Engineering geological models should form a fundamental component of any geotechnical project as they provide a systematic methodology to support all of the engineering geological thought processes that must be worked through for successful project completion. The use of models as an approach to solving engineering geological problems, with the inherent requirement for prediction and verification, is also ideally suited to training and education. IAEG Commission C25 (Parry et al. in Bull Eng Geol Environ 73:689–706, 2014) proposed that engineering geological models could be divided into two profoundly different approaches and therefore different model types. Observational and Conceptual. However, the C25 Report perhaps lacks clarity regarding the differences between these two types of models and the way in which they work together. The conceptual approach is based on understanding the relationships between engineering geological units, their likely geometry, and anticipated distribution. This approach, and the models formed, are based on concepts formulated from knowledge and experience. When these models are proficiently developed they provide an extremely powerful tool for appreciating and communicating what is known about a site, what is conjectured and where significant uncertainties may remain. The conceptual model provides a framework for the evaluation of observational data which then forms an observational model which is constrained by real data in 3D space and time. The development of conceptual models should be a core activity for engineering geologists. The paper discusses the generation of conceptual models, gives examples of the problems that can arise when they are not used, and provides guidelines for their development.

UK guidelines recommend routine HIV testing in high prevalence emergency departments (ED) and targeted testing for HBV and HCV. The ‘Going Viral’ campaign implemented opt-out blood-borne virus (BBV) testing in adults in a high prevalence ED, to assess seroprevalence, uptake, linkage to care (LTC) rates and staff time taken to achieve LTC. Diagnosis status (new/known/unknown), current engagement in care, and severity of disease was established. LTC was defined as patient informed plus ⩾1 clinic visit. A total of 6211/24 981 ED attendees were tested (uptake 25%); 257 (4.1%) were BBV positive (15 co-infected), 84 (33%) required LTC. 100/147 (68%) HCV positives were viraemic; 44 (30%) required LTC (13 new, 16 disengaged). 26/54 (48%) HBV required LTC (seven new, 11 disengaged). 16/71 (23%) HIV required LTC (10 new, five disengaged). 26/84 (31%) patients requiring LTC had advanced disease (CD4 1, Fibroscan F3/F4 or liver cancer), including five with AIDS-defining conditions and three hepatocellular carcinomas. There were five BBV-related deaths. BBV prevalence was high (4.1%); most were HCV (2.4%). HIV patients were more successfully and quickly LTC than HBV or HCV patients. ED testing was valuable as one-third of those requiring LTC (new, disengaged or unknown status patients) had advanced disease.

The filoviruses Marburg virus (MARV) and Ebola virus (EBOV) cause hemorrhagic fever in humans and nonhuman primates, with high case fatality rates. MARV VP30 is known to be phosphorylated and to interact with nucleoprotein (NP), but its role in regulation of viral transcription is disputed. Here, we analyzed phosphorylation of VP30 by mass spectrometry, which resulted in identification of multiple phosphorylated amino acids. Modeling the full-length three-dimensional structure of VP30 and mapping the identified phosphorylation sites showed that all sites lie in disordered regions, mostly in the N-terminal domain of the protein. Minigenome analysis of the identified phosphorylation sites demonstrated that phosphorylation of a cluster of amino acids at positions 46 through 53 inhibits transcription. To test the effect of VP30 phosphorylation on its interaction with other MARV proteins, coimmunoprecipitation analyses were performed. They demonstrated the involvement of VP30 phosphorylation in interaction with two other proteins of the MARV ribonucleoprotein complex, NP and VP35. To identify the role of protein phosphatase 1 (PP1) in the identified effects, a small molecule, 1E7-03, targeting a noncatalytic site of the enzyme that previously was shown to increase EBOV VP30 phosphorylation was used. Treatment of cells with 1E7-03 increased phosphorylation of VP30 at a cluster of phosphorylated amino acids from Ser-46 to Thr-53, reduced transcription of MARV minigenome, enhanced binding to NP and VP35, and dramatically reduced replication of infectious MARV particles. Thus, MARV VP30 phosphorylation can be targeted for development of future antivirals such as PP1-targeting compounds. IMPORTANCE The largest outbreak of MARV occurred in Angola in 2004 to 2005 and had a 90% case fatality rate. There are no approved treatments available for MARV. Development of antivirals as therapeutics requires a fundamental understanding of the viral life cycle. Because of the close similarity of MARV to another member of Filoviridae family, EBOV, it was assumed that the two viruses have similar mechanisms of regulation of transcription and replication. Here, characterization of the role of VP30 and its phosphorylation sites in transcription of the MARV genome demonstrated differences from those of EBOV. The identified phosphorylation sites appeared to inhibit transcription and appeared to be involved in interaction with both NP and VP35 ribonucleoproteins. A small molecule targeting PP1 inhibited transcription of the MARV genome, effectively suppressing replication of the viral particles. These data demonstrate the possibility developing antivirals based on compounds targeting PP1.