Soy Protein Containing Diet Attenuates Murine Drug Exposure and Activity via Hepatic and Intestinal Cytochrome P450 Induction.

Pharmacokinetic variability in drug plasma exposure between different studies within the same species is not unexpected due to a variety of factors (such as differences in formulation, active pharmaceutical ingredient salt form and solid-state, genetic strain, sex, environmental, disease status, bioanalysis methods, circadian rhythms, etc.) although variability from within the same research group typically does not occur to a great degree because these variables are commonly controlled. Surprisingly, a pharmacology proof of concept study with a previously validated tool compound from the literature failed to show expected response in murine glucose-6-phosphate isomerase-induced arthritis model which was tied to compound plasma exposure unexpectedly 10-fold lower than exposure observed from early pharmacokinetic study confirming adequate exposure prior to proof of concept. A systematic series of studies were conducted to investigate causes for exposure difference between pharmacology and pharmacokinetic studies identifying the presence or absence of soy protein in animal chow as the causative variable. Cyp3a11 expression in intestine and liver was determined to increase in a time dependent manner in mice switched to diets containing soybean meal compared with mice on diets without soybean meal. The repeated pharmacology experiments using the soybean meal free diet achieved plasma exposures that were maintained above the EC50 and showed efficacy and proof of concept for the target. This effect was further confirmed with marker CYP3A4 substrates in follow on mouse studies. The role of soy protein containing diets on CYP expression necessitates the inclusion of controlling rodent diet as a variable for preventing possible exposure differences between studies. SIGNIFICANCE STATEMENT: The presence of soybean meal protein in murine diet increased clearance and decreased oral exposure for select cytochrome 3A4 substrates. Related effects were also observed on select liver enzyme expression.

Preclinical species gene expression database: Development and meta-analysis.

The evaluation of toxicity in preclinical species is important for identifying potential safety liabilities of experimental medicines. Toxicology studies provide translational insight into potential adverse clinical findings, but data interpretation may be limited due to our understanding of cross-species biological differences. With the recent technological advances in sequencing and analyzing omics data, gene expression data can be used to predict cross species biological differences and improve experimental design and toxicology data interpretation. However, interpreting the translational significance of toxicogenomics analyses can pose a challenge due to the lack of comprehensive preclinical gene expression datasets. In this work, we performed RNA-sequencing across four preclinical species/strains widely used for safety assessment (CD1 mouse, Sprague Dawley rat, Beagle dog, and Cynomolgus monkey) in ∼50 relevant tissues/organs to establish a comprehensive preclinical gene expression body atlas for both males and females. In addition, we performed a meta-analysis across the large dataset to highlight species and tissue differences that may be relevant for drug safety analyses. Further, we made these databases available to the scientific community. This multi-species, tissue-, and sex-specific transcriptomic database should serve as a valuable resource to enable informed safety decision-making not only during drug development, but also in a variety of disciplines that use these preclinical species.

Web-Based and mHealth Interventions for Intimate Partner Violence Victimization Prevention: A Systematic Review.

Mobile health (mHealth) technologies are increasingly used across health programming including intimate partner violence (IPV) prevention to optimize screening, educational outreach, and linkages to care via telehealth. We systematically evaluated current web-based and mHealth interventions, which include web- or mobile-based delivery methods for primary, secondary, and tertiary IPV victimization prevention. We searched MEDLINE/PubMed, Embase, CINAHL, PsycINFO, Open Grey, and Google Scholar for empirical studies published 1998-2019. Studies were included if they considered empirical data, participants in adult romantic relationships, IPV as a primary or secondary outcome, and an mHealth component. The Mixed Methods Appraisal Tool was used to record critical ratings of quality among studies selected for inclusion. We assessed variation in targeted populations, types of IPV addressed, and mHealth approaches used. Of 133 studies identified for full-text review, 31 were included. Computer-based screening with or without integrated education was the most common mHealth approach (n = 8, 26%), followed by safety decision aids (n = 7, 23%). Feasibility and acceptability were found to be generally high where assessed (23% of studies, n = 7). There was limited evidence around whether mHealth interventions better addressed population needs compared to conventional interventions. mHealth tools for IPV prevention are especially acceptable in health-care settings, on mobile phone platforms, or when connecting victims to health care. Despite enthusiasm in pilot projects, evidence for efficacy compared to conventional IPV prevention approaches is limited. A major strength of mHealth IPV prevention programming is the ability to tailor interventions to individual victim needs without extensive human resource expenditure by providers.

Web-based and mHealth interventions for intimate partner violence prevention: a systematic review protocol.

INTRODUCTION: Victims of intimate partner violence (IPV), or those individuals susceptible to IPV victimisation or perpetration, may benefit from participation in primary, secondary or tertiary interventions to address or mitigate exposure to violence despite mixed evidence of IPV intervention effectiveness. However, participation in such programmes is limited by poor access, sociocultural barriers and programme cost. As the world fast approaches universal access to the internet, web-based technologies and low-cost smartphones, new avenues to provide preventive health services including mobile health (mHealth) tools, platforms and services have emerged. The objective of this systematic review is to assess current web-based and mHealth interventions, which include web-based or mobile-based delivery methods for IPV prevention. Interpersonal violence is defined as perpetration or victimisation of a physical, psychological or sexual nature among adults. Interventions may be at the primary, secondary or tertiary level of the public health model. METHODS AND ANALYSIS: This systematic review will incorporate studies focused on any empirical prevention intervention intended for IPV victims or perpetrators of any gender where one or more components is web based or mobile based. Articles will be retrieved from the following academic databases: MEDLINE/PubMed, Embase, CINAHL, PsycInfo and Open Grey, as well Google Scholar. Results will be limited to articles reporting primary data, published since 1998, and in English, Spanish, Portuguese or French. Data extraction procedures will follow Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. The Mixed Methods Appraisal Tool, a critical appraisal tool, will be used to record ratings of quality and risk of bias among studies selected for inclusion. Content analysis and between-study comparisons will be used to answer the objectives of this review. ETHICS AND DISSEMINATION: Results from this review will be published in an open access format for the benefit of both academic and non-academic audiences, including community organisations and individuals seeking mHealth strategies to reduce and prevent IPV. TRIAL REGISTRATION NUMBER: CRD42019123006.

N-functionalized carbon nanotubes as a source and precursor of N-nitrosodimethylamine: implications for environmental fate, transport, and toxicity.

Hazardous byproducts may be generated during the environmental processing of engineered nanomaterials. Here, we explore the ability of carbon nanotubes with nitrogen-containing surface groups (N-CNTs) to generate N-nitrosodimethylamine (NDMA) during chemical disinfection. Unexpectedly, we observed that commercial N-CNTs with amine, amide, or N-containing polymer (PABS) surface groups are a source of NDMA. As-received powders can leach up to 50 ng of NDMA per mg of N-CNT in aqueous suspension; presumably NDMA originates as a residue from N-CNT manufacturing. Furthermore, reaction of N-CNTs with free chlorine, monochloramine, and ozone generated byproduct NDMA at yields comparable to those reported for natural organic matter. Chlorination also altered N-CNT surface chemistry, with X-ray photoelectron spectroscopy indicating addition of Cl, loss of N, and an increase in surface O. Although these changes can increase N-CNT suspension stability, they do not enhance their acute toxicity in E. coli bioassays above that observed for as-received powders. Notably, however, dechlorination of reacted N-CNTs with sulfite completely suppresses N-CNT toxicity. Collectively, our work demonstrates that N-CNTs are both a source and precursor of NDMA, a probable human carcinogen, while chemical disinfection can produce CNTs exhibiting surface chemistry and environmental behavior distinct from that of native (i.e., as-received) materials.

Long-term survival in TARP syndrome and confirmation of RBM10 as the disease-causing gene.

TARP syndrome, comprising Talipes equinovarus, atrial septal defect (ASD), Robin sequence (micrognathia, glossoptosis, and cleft palate), and persistence of the left superior vena cava, is an X-linked condition with pre- or postnatal lethality in affected males. Based on linkage studies and massively parallel sequencing of X-chromosome exons in two families, the disease-causing gene was identified as RBM10. We identified a maternally inherited frameshift mutation in an unrelated patient, confirming RBM10 as the disease gene. This is the first reported individual with TARP syndrome who survived past early infancy, thus expanding the phenotypic spectrum of this disorder. In addition to the characteristic cleft palate, ASD, and persistent superior vena cava, he had low-set and posteriorly angulated ears, upslanting palpebral fissures, cryptorchidism, and structural brain abnormalities including partial agenesis of the corpus callosum, dysplastic enlarged caudate, and cerebellar hypoplasia with megacisterna magna. Preterm delivery, suspected pulmonary hypoplasia, and pulmonary hypertension resulted in chronic lung disease. At the age of 3(7)/(12) years, he remained ventilator-dependent at night, and he was fed exclusively through a gastro-jejunal tube. Sensorineural hearing loss required a hearing aid. Optic atrophy and cortical visual impairment were noted. He was unable to sit independently, was non-communicative and he had severe intellectual disability. Atrial flutter required recurrent ablation of intra-atrial re-entry pathways. The mother's heterozygosity for the RBM10 mutation underscored the importance of accurate diagnosis and counseling for TARP syndrome.

Exome sequencing identifies ACSF3 as a cause of combined malonic and methylmalonic aciduria.

We used exome sequencing to identify the genetic basis of combined malonic and methylmalonic aciduria (CMAMMA). We sequenced the exome of an individual with CMAMMA and followed up with sequencing of eight additional affected individuals (cases). This included one individual who was identified and diagnosed by searching an exome database. We identify mutations in ACSF3, encoding a putative methylmalonyl-CoA and malonyl-CoA synthetase as a cause of CMAMMA. We also examined a canine model of CMAMMA, which showed pathogenic mutations in a predicted ACSF3 ortholog. ACSF3 mutant alleles occur with a minor allele frequency of 0.0058 in ∼1,000 control individuals, predicting a CMAMMA population incidence of ∼1:30,000. ACSF3 deficiency is the first human disorder identified as caused by mutations in a gene encoding a member of the acyl-CoA synthetase family, a diverse group of evolutionarily conserved proteins, and may emerge as one of the more common human metabolic disorders.