A Population-Based Psychometric Validation Study of the Strengths and Difficulties Questionnaire – Hebrew Version

This study presents the psychometric properties of the Strengths and Difficulties Questionnaire – Hebrew version (SDQ-H), used in the Israel Survey on Mental Health among Adolescents (ISMEHA). The SDQ-H was administered to a representative sample of 611 adolescents and their mothers. Structural validity was evaluated by exploratory and confirmatory factor analysis and the Development and Well-Being Assessment (DAWBA) inventory was used as “gold standard” to test convergent and discriminant validity. Internal consistency and normative scores were established. Agreement was found with the original factor structure, except for the Peer problem scale. Concurrent and discriminant validity varied from fair to very good for most scales. Total Difficulties scores showed better discriminant validity for the adolescents’ than the mothers’ report for internalizing disorders, and the opposite for externalizing disorders. Internal consistency for the Total Difficulties was 0.77 and for the Hyperactivity scale it was 0.73. It was lower for the other scales, particularly for the Peer problems scale. The findings suggest reasonable psychometric properties of the SDQ-H. Comparisons with other translated SDQ versions are presented

Using a Human Challenge Model of Infection to Measure Vaccine Efficacy: A Randomised, Controlled Trial Comparing the Typhoid Vaccines M01ZH09 with Placebo and Ty21a

Background Typhoid persists as a major cause of global morbidity. While several licensed vaccines to prevent typhoid are available, they are of only moderate efficacy and unsuitable for use in children less than two years of age. Development of new efficacious vaccines is complicated by the human host-restriction of Salmonella enterica serovar Typhi (S. Typhi) and lack of clear correlates of protection. In this study, we aimed to evaluate the protective efficacy of a single dose of the oral vaccine candidate, M01ZH09, in susceptible volunteers by direct typhoid challenge. Methods and Findings We performed a randomised, double-blind, placebo-controlled trial in healthy adult participants at a single centre in Oxford (UK). Participants were allocated to receive one dose of double-blinded M01ZH09 or placebo or 3-doses of open-label Ty21a. Twenty-eight days after vaccination, participants were challenged with 104CFU S. Typhi Quailes strain. The efficacy of M01ZH09 compared with placebo (primary outcome) was assessed as the percentage of participants reaching pre-defined endpoints constituting typhoid diagnosis (fever and/or bacteraemia) during the 14 days after challenge. Ninety-nine participants were randomised to receive M01ZH09 (n = 33), placebo (n = 33) or 3-doses of Ty21a (n = 33). After challenge, typhoid was diagnosed in 18/31 (58.1% [95% CI 39.1 to 75.5]) M01ZH09, 20/30 (66.7% [47.2 to 87.2]) placebo, and 13/30 (43.3% [25.5 to 62.6]) Ty21a vaccine recipients. Vaccine efficacy (VE) for one dose of M01ZH09 was 13% [95% CI -29 to 41] and 35% [-5 to 60] for 3-doses of Ty21a. Retrospective multivariable analyses demonstrated that pre-existing anti-Vi antibody significantly reduced susceptibility to infection after challenge; a 1 log increase in anti-Vi IgG resulting in a 71% decrease in the hazard ratio of typhoid diagnosis ([95% CI 30 to 88%], p = 0.006) during the 14 day challenge period. Limitations to the study included the requirement to limit the challenge period prior to treatment to 2 weeks, the intensity of the study procedures and the high challenge dose used resulting in a stringent model. Conclusions Despite successfully demonstrating the use of a human challenge study to directly evaluate vaccine efficacy, a single-dose M01ZH09 failed to demonstrate significant protection after challenge with virulent Salmonella Typhi in this model. Anti-Vi antibody detected prior to vaccination played a major role in outcome after challenge

Analysing trajectories of a longitudinal exposure: A causal perspective on common methods in lifecourse research

Longitudinal data is commonly analysed to inform prevention policies for diseases that may develop throughout life. Commonly methods interpret the longitudinal data as a series of discrete measurements or as continuous patterns. Some of the latter methods condition on the outcome, aiming to capture ‘average’ patterns within outcome groups, while others capture individual-level pattern features before relating these to the outcome. Conditioning on the outcome may prevent meaningful interpretation. Repeated measurements of a longitudinal exposure (weight) and later outcome (glycated haemoglobin levels) were simulated to match three scenarios: one with no causal relationship between growth rate and glycated haemoglobin; two with a positive causal effect of growth rate on glycated haemoglobin. Two methods that condition on the outcome and one that did not were applied to the data in 1000 simulations. The interpretation of the two-step method matched the simulation in all causal scenarios, but that of the methods conditioning on the outcome did not. Methods that condition on the outcome do not accurately represent a causal relationship between a longitudinal pattern and outcome. Researchers considering longitudinal data should carefully determine if they wish to analyse longitudinal data as a series of discrete time points or by extracting pattern features

Olsalazine-Based Metal–Organic Frameworks as Biocompatible Platforms for H_2 Adsorption and Drug Delivery

The drug olsalazine (H_4olz) was employed as a ligand to synthesize a new series of mesoporous metal–organic frameworks that are expanded analogues of the well-known M_2(dobdc) materials (dobdc^4– = 2,5-dioxido-1,4-benzenedicarboxylate; M-MOF-74). The M_2(olz) frameworks (M = Mg, Fe, Co, Ni, and Zn) exhibit high surface areas with large hexagonal pore apertures that are approximately 27 Å in diameter. Variable temperature H_2 adsorption isotherms revealed strong adsorption at the open metal sites, and in situ infrared spectroscopy experiments on Mg_2(olz) and Ni_2(olz) were used to determine site-specific H_2 binding enthalpies. In addition to its capabilities for gas sorption, the highly biocompatible Mg_2(olz) framework was also evaluated as a platform for the delivery of olsalazine and other encapsulated therapeutics. The Mg_2(olz) material (86 wt % olsalazine) was shown to release the therapeutic linker through dissolution of the framework under simulated physiological conditions. Furthermore, Mg_2(olz) was used to encapsulate phenethylamine (PEA), a model drug for a broad class of bioactive compounds. Under simulated physiological conditions, Mg_2(olz)(PEA)_2 disassembled to release PEA from the pores and olsalazine from the framework itself, demonstrating that multiple therapeutic components can be delivered together at different rates. The low toxicity, high surface areas, and coordinatively unsaturated metal sites make these M_2(olz) materials promising for a range of potential applications, including drug delivery in the treatment of gastrointestinal diseases

Olsalazine-Based Metal–Organic Frameworks as Biocompatible Platforms for H_2 Adsorption and Drug Delivery

The drug olsalazine (H_4olz) was employed as a ligand to synthesize a new series of mesoporous metal–organic frameworks that are expanded analogues of the well-known M_2(dobdc) materials (dobdc^4– = 2,5-dioxido-1,4-benzenedicarboxylate; M-MOF-74). The M_2(olz) frameworks (M = Mg, Fe, Co, Ni, and Zn) exhibit high surface areas with large hexagonal pore apertures that are approximately 27 Å in diameter. Variable temperature H_2 adsorption isotherms revealed strong adsorption at the open metal sites, and in situ infrared spectroscopy experiments on Mg_2(olz) and Ni_2(olz) were used to determine site-specific H_2 binding enthalpies. In addition to its capabilities for gas sorption, the highly biocompatible Mg_2(olz) framework was also evaluated as a platform for the delivery of olsalazine and other encapsulated therapeutics. The Mg_2(olz) material (86 wt % olsalazine) was shown to release the therapeutic linker through dissolution of the framework under simulated physiological conditions. Furthermore, Mg_2(olz) was used to encapsulate phenethylamine (PEA), a model drug for a broad class of bioactive compounds. Under simulated physiological conditions, Mg_2(olz)(PEA)_2 disassembled to release PEA from the pores and olsalazine from the framework itself, demonstrating that multiple therapeutic components can be delivered together at different rates. The low toxicity, high surface areas, and coordinatively unsaturated metal sites make these M_2(olz) materials promising for a range of potential applications, including drug delivery in the treatment of gastrointestinal diseases

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Recurrence Risk of Autism in Siblings and Cousins: A Multinational, Population-Based Study

Objective:Familial recurrence risk is an important population-level measure of the combined genetic and shared familial liability of autism spectrumdisorder (ASD). Objectives were to estimate ASD recurrence risk among siblings and cousins by varying degree of relatedness and by sex.Method:This is a population-based cohort study of livebirths from 1998 to 2007 in California, Denmark, Finland, Israel, Sweden and WesternAustralia followed through 2011 to 2015. Subjects were monitored for an ASD diagnosis in their older siblings or cousins (exposure) and for their ASDdiagnosis (outcome). The relative recurrence risk was estimated for different sibling and cousin pairs, for each site separately and combined, and by sex.Results:During follow-up, 29,998 cases of ASD were observed among the 2,551,918 births used to estimate recurrence in ASD and 33,769 cases ofchildhood autism (CA) were observed among the 6,110,942 births used to estimate CA recurrence. Compared with the risk in unaffected families, therewas an 8.4-fold increase in the risk of ASD following an older sibling with ASD and a 17.4-fold increase in the risk of CA following an older sibling withCA. A 2-fold increase in the risk for cousin recurrence was observed for the 2 disorders. There also was a significant difference in sibling ASD recurrencerisk by sex.Conclusion:The present estimates of relative recurrence risks for ASD and CA will assist clinicians and families in understanding autism risk in thecontext of other families in their population. The observed variation by sex underlines the need to deepen the understanding of factors influencing ASD familial risk.</p

Comprehensive Evaluation of One-Carbon Metabolism Pathway Gene Variants and Renal Cell Cancer Risk

Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer.Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes.The strongest associations with RCC risk were observed for SLC19A1 (P(min-P) = 0.03) and MTHFR (P(min-P) = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake.To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings

Herpes Simplex Virus-Induced Epithelial Damage and Susceptibility to Human Immunodeficiency Virus Type 1 Infection in Human Cervical Organ Culture

Normal human premenopausal cervical tissue has been used to derive primary cell populations and to establish ex vivo organ culture systems to study infections with herpes simplex virus (HSV-1 or HSV-2) and human immunodeficiency virus type 1 (HIV-1). Infection with either HSV-1 or HSV-2 rapidly induced multinuclear giant cell formation and widespread damage in mucosal epithelial cells. Subsequent exposure of the damaged mucosal surfaces to HIV-1 revealed frequent co-localization of HSV and HIV-1 antigens. The short-term organ culture system provides direct experimental support for the epidemiological findings that pre-existing sexually transmitted infections, including primary and recurrent herpes virus infections at mucosal surfaces, represent major risk factors for acquisition of primary HIV-1 infection. Epithelial damage in combination with pre-existing inflammation, as described here for overtly normal human premenopausal cervix, creates a highly susceptible environment for the initiation and establishment of primary HIV-1 infection in the sub-mucosa of the cervical transformation zone