Cell-type-specific 3D epigenomes in the developing human cortex.

Lineage-specific epigenomic changes during human corticogenesis have been difficult to study owing to challenges with sample availability and tissue heterogeneity. For example, previous studies using single-cell RNA sequencing identified at least 9 major cell types and up to 26 distinct subtypes in the dorsal cortex alone1,2. Here we characterize cell-type-specific cis-regulatory chromatin interactions, open chromatin peaks, and transcriptomes for radial glia, intermediate progenitor cells, excitatory neurons, and interneurons isolated from mid-gestational samples of the human cortex. We show that chromatin interactions underlie several aspects of gene regulation, with transposable elements and disease-associated variants enriched at distal interacting regions in a cell-type-specific manner. In addition, promoters with increased levels of chromatin interactivity-termed super-interactive promoters-are enriched for lineage-specific genes, suggesting that interactions at these loci contribute to the fine-tuning of transcription. Finally, we develop CRISPRview, a technique that integrates immunostaining, CRISPR interference, RNAscope, and image analysis to validate cell-type-specific cis-regulatory elements in heterogeneous populations of primary cells. Our findings provide insights into cell-type-specific gene expression patterns in the developing human cortex and advance our understanding of gene regulation and lineage specification during this crucial developmental window.

Comparing serial and current liver stiffness measurements to predict decompensation in compensated advanced chronic liver disease patients.

BACKGROUND AND AIMS: The utility of serial liver stiffness measurements (LSM) to predict decompensation in patients with compensated advanced chronic liver disease (cACLD) remains unclear. We aimed to validate whether comparing serial LSM is superior to using the current LSM to predict liver-related events (LRE) in patients with cACLD. APPROACH AND RESULTS: In this retrospective analysis of an international registry, patients with cACLD and serial LSM were followed up until index LRE. We compared the performance of both the dynamic LSM changes and the current LSM in predicting LRE using Cox regression analysis, considering time zero of follow-up as the date of latest liver stiffness measurement. In all, 480 patients with cACLD with serial LSM were included from 5 countries. The commonest etiology of cACLD was viral (53%) and MASLD (34%). Over a median follow-up of 68 (IQR: 45 -92) months, 32% experienced a LSM decrease to levels below 10kPa (resolved cACLD) and 5.8% experienced LRE. Resolved cACLD were more likely to be nondiabetic and had better liver function. While a higher value of the current LSM was associated with higher LREs, LSM changes over time (LSM slope) were not associated with LRE. In multivariable Cox regression, neither the prior LSM nor the LSM slope added predictive value to latest liver stiffness measurement. CONCLUSIONS: Once the current LSM is known, previous LSM values do not add to the prediction of LREs in patients with cACLD.

Gene Balance Predicts Transcriptional Responses Immediately Following Ploidy Change in Arabidopsis thaliana.

The gene balance hypothesis postulates that there is selection on gene copy number (gene dosage) to preserve the stoichiometric balance among interacting proteins. This presupposes that gene product abundance is governed by gene dosage and that gene dosage responses are consistent for interacting genes in a dosage-balance-sensitive network or complex. Gene dosage responses, however, have rarely been quantified, and the available data suggest that they are highly variable. We sequenced the transcriptomes of two synthetic autopolyploid accessions of Arabidopsis (Arabidopsis thaliana) and their diploid progenitors, as well as one natural tetraploid and its synthetic diploid produced via haploid induction, to estimate transcriptome size and dosage responses immediately following ploidy change. Similar to what has been observed in previous studies, overall transcriptome size does not exhibit a simple doubling in response to genome doubling, and individual gene dosage responses are highly variable in all three accessions, indicating that expression is not strictly coupled with gene dosage. Nonetheless, putatively dosage balance-sensitive gene groups (Gene Ontology terms, metabolic networks, gene families, and predicted interacting proteins) exhibit smaller and more coordinated dosage responses than do putatively dosage-insensitive gene groups, suggesting that constraints on dosage balance operate immediately following whole-genome duplication and that duplicate gene retention patterns are shaped by selection to preserve dosage balance.

eHealth Tools That Assess and Track Health and Well-being in Children and Young People: Systematic Review.

BACKGROUND: eHealth tools that assess and track health outcomes in children or young people are an emerging type of technology that has the potential to reform health service delivery and facilitate integrated, interdisciplinary care. OBJECTIVE: The aim of this review is to summarize eHealth tools that have assessed and tracked health in children or young people to provide greater clarity around the populations and settings in which they have been used, characteristics of digital devices (eg, health domains, respondents, presence of tracking, and connection to care), primary outcomes, and risks and challenges of implementation. METHODS: A search was conducted in PsycINFO, PubMed or MEDLINE, and Embase in April 2020. Studies were included if they evaluated a digital device whose primary purpose was to assess and track health, focused on children or young people (birth to the age of 24 years), reported original research, and were published in peer-reviewed journals in English. RESULTS: A total of 39 papers were included in this review. The sample sizes ranged from 7 to 149,329 participants (median 163, mean 5155). More studies were conducted in urban (18/39, 46%) regions than in rural (3/39, 8%) regions or a combination of urban and rural areas (8/39, 21%). Devices were implemented in three main settings: outpatient health clinics (12/39, 31%), hospitals (14/39, 36%), community outreach (10/39, 26%), or a combination of these settings (3/39, 8%). Mental and general health were the most common health domains assessed, with a single study assessing multiple health domains. Just under half of the devices tracked children's health over time (16/39, 41%), and two-thirds (25/39, 64%) connected children or young people to clinical care. It was more common for information to be collected from a single informant (ie, the child or young person, trained health worker, clinician, and parent or caregiver) than from multiple informants. The health of children or young people was assessed as a primary or secondary outcome in 36% (14/39) of studies; however, only 3% (1/39) of studies assessed whether using the digital tool improved the health of users. Most papers reported early phase research (formative or process evaluations), with fewer outcome evaluations and only 3 randomized controlled trials. Identified challenges or risks were related to accessibility, clinical utility and safety, uptake, data quality, user interface or design aspects of the device, language proficiency or literacy, sociocultural barriers, and privacy or confidentiality concerns; ways to address these barriers were not thoroughly explored. CONCLUSIONS: eHealth tools that assess and track health in children or young people have the potential to enhance health service delivery; however, a strong evidence base validating the clinical utility, efficacy, and safety of tools is lacking, and more thorough investigation is needed to address the risks and challenges of using these emerging technologies in clinical care. At present, there is greater potential for the tools to facilitate multi-informant, multidomain assessments and longitudinally track health over time and room for further implementation in rural or remote regions and community settings around the world.

HPRep: Quantifying Reproducibility in HiChIP and PLAC-Seq Datasets.

HiChIP and PLAC-Seq are emerging technologies for studying genome-wide long-range chromatin interactions mediated by the protein of interest, enabling more sensitive and cost-efficient interrogation of protein-centric chromatin conformation. However, due to the unbalanced read distribution introduced by protein immunoprecipitation, existing reproducibility measures developed for Hi-C data are not appropriate for the analysis of HiChIP and PLAC-Seq data. Here, we present HPRep, a stratified and weighted correlation metric derived from normalized contact counts, to quantify reproducibility in HiChIP and PLAC-Seq data. We applied HPRep to multiple real datasets and demonstrate that HPRep outperforms existing reproducibility measures developed for Hi-C data. Specifically, we applied HPRep to H3K4me3 PLAC-Seq data from mouse embryonic stem cells and mouse brain tissues as well as H3K27ac HiChIP data from human lymphoblastoid cell line GM12878 and leukemia cell line K562, showing that HPRep can more clearly separate among pseudo-replicates, real replicates, and non-replicates. Furthermore, in an H3K4me3 PLAC-Seq dataset consisting of 11 samples from four human brain cell types, HPRep demonstrated the expected clustering of data that could not be achieved by existing methods developed for Hi-C data, highlighting the need for a reproducibility metric tailored to HiChIP and PLAC-Seq data.

Understanding eHealth Cognitive Behavioral Therapy Targeting Substance Use: Realist Review.

BACKGROUND: There is a growing body of evidence regarding eHealth interventions that target substance use disorders. Development and funding decisions in this area have been challenging, due to a lack of understanding of what parts of an intervention work in which context. OBJECTIVE: We conducted a realist review of the literature on electronic cognitive behavioral therapy (eCBT) programs for substance use with the goal of answering the following realist question: "How do different eCBT interventions for substance use interact with different contexts to produce certain outcomes?" METHODS: A literature search of published and gray literature on eHealth programs targeting substance use was conducted. After data extraction, in order to conduct a feasible realist review in a timely manner, the scope had to be refined further and, ultimately, only included literature focusing on eCBT programs targeting substance use. We synthesized the available evidence from the literature into Context-Mechanism-Outcome configurations (CMOcs) in order to better understand when and how programs work. RESULTS: A total of 54 papers reporting on 24 programs were reviewed. Our final results identified eight CMOcs from five unique programs that met criteria for relevance and rigor. CONCLUSIONS: Five strategies that may be applied to future eCBT programs for substance use are discussed; these strategies may contribute to a better understanding of mechanisms and, ultimately, may help design more effective solutions in the future. Future research on eCBT programs should try to understand the mechanisms of program strategies and how they lead to outcomes in different contexts.

Variation in the Microbiota Associated with Daphnia magna Across Genotypes, Populations, and Temperature.

Studies of how the microbiome varies among individuals, populations, and abiotic conditions are critical for understanding this key component of an organism's biology and ecology. In the case of Daphnia, aquatic microcrustaceans widely used in population/community ecology and environmental science studies, understanding factors that influence microbiome shifts among individuals is useful for both basic and applied research contexts. In this study, we assess differences in the microbiome among genotypes of D. magna collected from three regions along a large latitudinal gradient (Finland, Germany, and Israel). After being reared in the lab for many years, we sought to characterize any differences in genotype- or population-specific microbial communities, and to assess whether the microbiota varied among temperatures. Our study is similar to a recent comparison of the microbial communities among D. magna genotypes raised in different temperatures published by Sullam et al. (Microb Ecol 76(2):506-517, 2017), and as such represents one of the first examples of a reproducible result in microbiome research. Like the previous study, we find evidence for a strong effect of temperature on the microbiome of D. magna, although across a much smaller temperature range representing potential near-future climates. In addition, we find evidence that the microbiomes of D. magna genotypes from different regions are distinct, even years after being brought into the laboratory. Finally, our results highlight a potentially common finding in the expanding area of microbiome research-differences among treatments are not necessarily observed in the most abundant taxonomic groups. This highlights the importance of considering sampling scheme and depth of coverage when characterizing the microbiome, as different experimental designs can significantly impact taxon-specific results, even when large-scale effects are reproduced.

Maintenance of clinical response and consistent safety profile with up to 3 years of continuous treatment with guselkumab: Results from the VOYAGE 1 and VOYAGE 2 trials.

BACKGROUND: Long-term maintenance treatment is required for patients with psoriasis. OBJECTIVES: To evaluate the efficacy and safety of guselkumab in patients with moderate to severe psoriasis through 3 years of treatment. METHODS: In 2 ongoing, phase 3 trials of guselkumab (VOYAGE 1 and VOYAGE 2), the proportions of patients achieving at least 90% and 100% improvement in the Psoriasis Area and Severity Index (PASI 90 and PASI 100, respectively) and Investigator's Global Assessment (IGA) scores of 0/1 and 0 were summarized for the guselkumab group (including placebo-to-guselkumab crossover). Patients who met treatment failure rules were considered nonresponders. Safety outcomes (rates/100 patient-years [PY]) were evaluated based on data pooled across studies through week 156. RESULTS: Three-year response rates for the guselkumab group in VOYAGE 1 and VOYAGE 2, respectively, were 82.8% and 77.2% for PASI 90, 50.8% and 48.8% for PASI 100, 82.1% and 83.0% for IGA score of 0/1, and 53.1% and 52.9% for IGA score of 0. Safety event rates across studies occurred through week 156 as follows: serious adverse events, 5.68/100 PY; serious infections, 1.15/100 PY; nonmelanoma skin cancers, 0.28/100 PY; malignancies other than nonmelanoma skin cancer, 0.47/100 PY; and major adverse cardiovascular events, 0.28/100 PY. Week 156 and week 100 rates were consistent. LIMITATIONS: There was no comparator arm beyond 1 year. CONCLUSIONS: Guselkumab shows durable efficacy and a consistent safety profile in patients with moderate to severe psoriasis treated for up to 3 years.

Cytotoxicity and molecular activity of fenretinide and metabolites in T-cell lymphoid malignancy, neuroblastoma, and ovarian cancer cell lines in physiological hypoxia.

OBJECTIVE: All-trans-N-(4-hydroxyphenyl)retinamide or fenretinide (4-HPR) acts by reactive oxygen species (ROS) and dihydroceramides (DHCers). In early-phase clinical trials 4-HPR has achieved complete responses in T-cell lymphomas (TCL) and neuroblastoma (NB) and signals of activity in ovarian cancer (OV). We defined the activity of 4-HPR metabolites in N-(4-methoxyphenyl)retinamide (MPR), 4-oxo-N-(4-hydroxyphenyl)retinamide (oxoHPR), and the 4-HPR isomer 13-cis-fenretinide (cis-HPR) in NB, OV, and TCL cell lines cultured in physiological hypoxia. METHODS: We compared the effect of 4-HPR, cis-HPR, oxoHPR, and MPR on cytotoxicity, ROS, and DHCers in a panel of TCL, NB, and OV cell lines cultured in bone marrow level physiological hypoxia (5% O2), utilizing a fluorescence-based cytotoxicity assay (DIMSCAN), flow cytometry, and quantitative mass spectrometry. RESULTS: 4-HPR (10 µmol/l) achieved more than three logs of cell kill in nine of 15 cell lines. Cytotoxicity of 4-HPR and oxoHPR was comparable; in some cell lines, cis-HPR cytotoxicity was lower than 4-HPR, but additive when combined with 4-HPR. MPR was not cytotoxic. ROS and DHCers were equivalently increased by 4-HPR and oxoHPR in all cell lines (P<0.01), to a lesser extent by cis-HPR (P<0.01), and not increased in response to MPR (P>0.05). Mitochondrial membrane depolarization, caspase-3 cleavage, and apoptosis (TUNEL) were all significantly increased by 4-HPR and oxoHPR (P<0.01). CONCLUSION: Cytotoxic and pharmacodynamic activity was comparable with 4-HPR and oxoHPR, lower with cis-HPR, and MPR was inactive. Neither MPR or cis-HPR antagonized 4-HPR activity. These data support focusing on achieving high 4-HPR exposures for maximizing antineoplastic activity.

Hepatitis C prevalence and associated risk factors among individuals who are homeless and diagnosed with mental illness: At Home/Chez Soi Study, Vancouver, BC.

BACKGROUND: There is scarce evidence on prevalence of hepatitis C virus (HCV) infection among individuals who are homeless and diagnosed with severe mental illness. We aimed to investigate the prevalence of HCV infection and associated risk factors in a representative sample of adults from At Home study. METHODS: The Vancouver At Home study is part of the At Home/Chez Soi (AH/CS) project-a pragmatic randomized controlled trial of a Housing First intervention among homeless persons with mental illness in five Canadian cities between 2009 and 2013 with a 2-year follow-up period. RESULTS: Of 497 participants, 28% reported positive HCV serostatus. Educational level equal or less than eighth grade (AOR: 2.3, 95% CI: 1.1, 4.8), history of incarceration (AOR: 2.1, 95% CI: 1.2, 3.5), substance dependence (AOR: 2.0, 95% CI: 1.1, 3.7) and injection drug use during one month prior to the recruitment (AOR: 7.8, 95% CI: 4.0, 15.0) were associated with an increased risk of HCV infection. Having a psychotic disorder (AOR: 0.6, 95% CI: 0.3, 1.0) and age < 25 (AOR: 0.2, 95% CI: 0.0, 0.7) were associated with a lower risk. Blood tests performed on 30 participants agreed with self-report in 97% of cases [Kappa = 0.9 (95% CI: 0.6, 1.3), PABAK = 0.9]. CONCLUSION: The high prevalence of HCV among individuals who were homeless with mental illness underlies the importance of prevention and treatment of HCV in this population, especially those with concurrent substance use disorders. Self-report seems to be a valid tool for evaluation of the HCV status in this population.

Living With Dual Diagnosis and Homelessness: Marginalized Within a Marginalized Group.

Objective: Concurrent mental and substance use disorders or dual diagnosis are highly prevalent among individuals experiencing homelessness. Studies have indicated that dual diagnosis leads to poorer health outcomes and higher health service utilization among those affected. This study aims to estimate the prevalence of dual diagnoses among homeless populations in British Columbia (BC), Canada, and understand their characteristics and specific factors associated with dual diagnoses. Methods: The BC Health of the Homeless Survey is a cross-sectional study involving the homeless population of three cities in BC. The survey assessed addiction and concurrent disorders with standardized interviews-the Mini-International Neuropsychiatric Interview Plus, the Maudsley Addiction Profile, and the Brief Symptom Inventory-in a sample of 500 individuals who are homeless living in shelters or on the street. We characterized individuals after categorizing them into four groups: those without any current mental disorder, those with substance use disorders only, those with mental disorders only, and those with concurrent substance use and mental disorders. Focusing on the concurrent disorder group, we completed a multivariate analysis comparing individuals with dual diagnosis to those without concurrent disorders. Results: Consistent with previous studies, we found that individuals with dual diagnoses report more severe physical and psychological symptoms. Among the homeless, they were more likely to be Aboriginal and younger and more likely to not make it into a shelter. They also reported substantially more difficulties in getting the health care service that they need. Conclusions: Within this marginalized group, individuals with dual diagnosis were more likely to be from groups considered to be more vulnerable with more complex needs. They were having more problems accessing even basic support, such as shelters and health care. Without a systematic approach in providing appropriate care to individuals with dual diagnosis, the most vulnerable clients are not only the ones likely to suffer the most but also the ones having the most problems meeting their basic needs.

Evolutionary Conflict between Mobile DNA and Host Genomes.

The proportion of eukaryotic genomes composed of active or formerly active mobile elements (MEs) is known to vary widely across lineages, but the explanations for why remain largely unknown. Given that ME activity, like other forms of mutation, is thought to be (on average) slightly deleterious in terms of phenotypic effects, understanding the widespread proliferation of MEs in host genomes requires an evolutionary framework. To better develop such a framework, we review the spectrum of resolutions to the genetic conflict between MEs and their hosts: inactivation of MEs due to mutation accumulation, negative selection (or lack thereof) against hosts with high ME loads, silencing of MEs (by hosts or MEs), ME domestication by their hosts, and the horizontal transfer of MEs to new hosts. We also highlight ecological and evolutionary theory from which ME researchers might borrow in order to explain large-scale patterns of ME dynamics across systems. We hope that a synthesis of the surprisingly significant role played by MEs in the genome, as well as the spectrum of resolutions, applicable theory, and recent discoveries, will have two outcomes for future researchers: better parsing of known variation in ME proliferation patterns across genomes and the development of testable models and predictions regarding the evolutionary trajectory of MEs based on a combination of theory, the comparative method, experimental evolution, and empirical observations.

A novel chloroplast gene reported for flagellate plants.

PREMISE OF THE STUDY: Gene space in plant plastid genomes is well characterized and annotated, yet we discovered an unrecognized open reading frame (ORF) in the fern lineage that is conserved across flagellate plants. METHODS: We initially detected a putative uncharacterized ORF by the existence of a highly conserved region between rps16 and matK in a series of matK alignments of leptosporangiate ferns. We mined available plastid genomes for this ORF, which we now refer to as ycf94, to infer evolutionary selection pressures and assist in functional prediction. To further examine the transcription of ycf94, we assembled the plastid genome and sequenced the transcriptome of the leptosporangiate fern Adiantum shastense Huiet & A.R. Sm. KEY RESULTS: The ycf94 predicted protein has a distinct transmembrane domain but with no sequence homology to other proteins with known function. The nonsynonymous/synonymous substitution rate ratio of ycf94 is on par with other fern plastid protein-encoding genes, and additional homologs can be found in a few lycophyte, moss, hornwort, and liverwort plastid genomes. Homologs of ycf94 were not found in seed plants. In addition, we report a high level of RNA editing for ycf94 transcripts-a hallmark of protein-coding genes in fern plastomes. CONCLUSIONS: The degree of sequence conservation, together with the presence of a distinct transmembrane domain and RNA-editing sites, suggests that ycf94 is a protein-coding gene of functional significance in ferns and, potentially, bryophytes and lycophytes. However, the origin and exact function of this gene require further investigation.

Childhood Trauma and Lifetime Traumatic Brain Injury Among Individuals Who Are Homeless.

OBJECTIVES: To study the association of childhood trauma and lifetime prevalence of traumatic brain injury (TBI) among individuals who are homeless. DESIGN: Cross-sectional survey. SETTING: Three cities in British Columbia, Canada. PARTICIPANTS: Five hundred individuals who are homeless and 19 years of age or older in 2009. MEASUREMENTS: Traumatic brain injury was identified with National Survey of Homeless Assistance Providers and Clients (NSHAPC) and childhood trauma using the Childhood Trauma Questionnaire-Short Form (CTQ-SF). The relationship between childhood trauma and TBI was explored using multivariable logistic regression approach, adjusting for age, gender, any psychiatric diagnosis (anxiety disorder, mood disorder, psychosis), alcohol dependence, and substance dependence. The effect of number of childhood trauma types on TBI was also explored using multiple variables logistic regression approach adjusting for the same covariates. RESULTS: The prevalence of TBI was 63.6% and childhood maltreatment was 87.7% among the sample population. During childhood of 487 participants included in the analysis, 57.7% experienced physical abuse, 62.8% physical neglect, 45.8% sexual abuse, 62.4% emotional abuse, and 55.2% emotional neglect. After adjustment, childhood trauma (adjusted odds ratio [aOR] = 2.26; 95% confidence interval [CI], 1.04-5.02), childhood physical abuse (aOR = 2.13; 95% CI, 1.19-3.87; n = 487), and childhood emotional abuse (aOR = 1.95; 95% CI, 1.09-3.51; n = 487) were significantly associated with history of TBI. After adjustment, having 4 different types of childhood trauma (aOR = 2.81; 95% CI, 1.11-7.31) was significantly associated with higher odds of reporting TBI history. CONCLUSIONS: Childhood trauma is significantly associated with lifetime prevalence of TBI in homeless populations in British Columbia, Canada, indicating an added level of vulnerability in this population. In addition, these findings suggest a potential role for childhood trauma prevention strategies and services mindful of the patients' history of trauma for this particularly vulnerable population.

Efficacy and Safety of Toreforant, a Selective Histamine H4 Receptor Antagonist, for the Treatment of Moderate-to-Severe Plaque Psoriasis: Results from a Phase 2 Multicenter, Randomized, Double-blind, Placebo-controlled Trial.

BACKGROUND: Toreforant is a selective histamine H4 receptor antagonist. H4 receptor activation may play a role in immune-mediated inflammation in psoriasis. OBJECTIVE: To evaluate Toreforant efficacy and safety in patients with moderate-to-severe psoriasis. METHODS: Biologic-naïve patients were to be treated (30, 60, or 3 mg Toreforant or placebo) for 12 weeks and followed through week 16. In this adaptive-design study, assignments were guided by interim analyses. Primary and major secondary efficacy endpoints, evaluated using Bayesian analyses, were the proportions of patients achieving ≥75% improvement in Psoriasis Area and Severity Index (PASI) from baseline and achieving Investigator's Global Assessment (IGA) of cleared (0) or minimal (1), respectively, at week 12. RESULTS: Per interim analyses results, patients were randomized to 30 (n = 30) or 60 mg (n = 26) Toreforant or placebo (n = 6). The estimated mean difference in the PASI 75 response rate at week 12 from the posterior distributions compared to placebo was 14.1% (95% credible interval [CI], -0.1% to 30.9%) and 8.9% (95% CI, -5.0% to 24.3%) with 30 and 60 mg Toreforant, respectively. The posterior probabilities of 30 and 60 mg Toreforant inducing a greater response rate than placebo were 97.4% and 90.3%, respectively; neither met the 97.5% predefined success criterion. Results for the IGA 0/1 endpoint were similar. Toreforant was generally safe and well tolerated. No deaths, serious or opportunistic infections, active tuberculosis, or malignancies were reported. CONCLUSIONS: Toreforant efficacy at 30 and 60 mg was greater than placebo but did not meet predefined success criterion. J Drugs Dermatol. 2018;17(8):873-879.

Long-Term Efficacy of Guselkumab for the Treatment of Moderate-to-Severe Psoriasis: Results from the Phase 3 VOYAGE 1 Trial Through Two Years.

BACKGROUND: Due to the chronic nature of psoriasis, it is important to assess the sustained response of treatments over time. OBJECTIVE: To assess the efficacy of continuous treatment with guselkumab (an interleukin-23 blocker) through two years in the phase 3 VOYAGE 1 trial. METHODS: Patients were randomized to placebo, guselkumab, or adalimumab at baseline. Placebo-randomized patients crossed over to guselkumab at week 16 (placebo→guselkumab) and adalimumab-randomized patients crossed over to guselkumab at week 52 (adalimumab→guselkumab); all patients received open-label guselkumab beyond week 52. Efficacy was assessed based on the Psoriasis Area and Severity Index (PASI; proportion of patients achieving ≥75%, 90%, or 100% improvement [PASI 75/90/100]) and the Investigator's Global Assessment (IGA; proportion achieving nearly clear [IGA 0/1] or completely clear [IGA 0]). As pre-specified, efficacy data were analyzed using non-responder imputation (NRI; patients with missing data counted as non-responders) after applying treatment failure rules (TFR; patients meeting TFR counted as non-responders thereafter) through week 48 and by applying TFR only from week 52 through 100. All endpoints were also analyzed using NRI and As Observed methodology for the guselkumab group through week 100. RESULTS: The clinical responses were maintained through week 100 based on all three analyses. Based on pre-specified analyses, proportions of patients who achieved PASI 75, PASI 90, PASI 100, IGA 0/1, and IGA 0 were 94.8%, 82.1%, 49.0%, 82.4%, and 53.8%, respectively, at week 100. Results were similar for the placebo→guselkumab and adalimumab→guselkumab groups at week 100. As expected, proportions of patients achieving these endpoints were similar based on As Observed analyses and slightly lower when the more conservative NRI rules were applied. CONCLUSIONS: High levels of efficacy were maintained through two years of continuous treatment among guselkumab-treated patients, and efficacy improved through two years among adalimumab-treated patients who crossed over to guselkumab at one year. J Drugs Dermatol. 2018;17(8):826-832.

Efficacy and safety of guselkumab, an anti-interleukin-23 monoclonal antibody, compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment: Results from the phase III, double-blind, placebo- and active comparator-controlled VOYAGE 2 trial.

BACKGROUND: Phase II data suggested that guselkumab, an anti-interleukin-23 monoclonal antibody, was efficacious in psoriasis. OBJECTIVE: We sought to assess efficacy and safety of guselkumab in moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to guselkumab. METHODS: Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo→guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. Nonresponders received guselkumab. RESULTS: At week 16, more patients receiving guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) (P < .001). From weeks 28 to 48, better persistence of response was observed in guselkumab maintenance versus withdrawal groups (P < .001). Of adalimumab nonresponders who switched to guselkumab, 66.1% achieved PASI 90 at week 48. Guselkumab improved patient-reported outcomes. Adverse events were comparable among groups. LIMITATIONS: One-year follow-up limits retreatment data. CONCLUSIONS: Guselkumab is a highly effective, well-tolerated, maintenance therapy, including in adalimumab nonresponders.

Clinical efficacy and IL-17 targeting mechanism of Indigo naturalis as a topical agent in moderate psoriasis.

BACKGROUND: Indigo naturalis is a Traditional Chinese Medicine (TCM) ingredient long-recognized as a therapy for several inflammatory conditions, including psoriasis. However, its mechanism is unknown due to lack of knowledge about the responsible chemical entity. We took a different approach to this challenge by investigating the molecular profile of Indigo naturalis treatment and impacted pathways. METHODS: A randomized, double-blind, placebo-controlled clinical study was conducted using Indigo naturalis as topical monotherapy to treat moderate plaque psoriasis in a Chinese cohort (n = 24). Patients were treated with Indigo naturalis ointment (n = 16) or matched placebo (n = 8) twice daily for 8 weeks, with 1 week of follow-up. RESULTS: At week 8, significant improvements in Psoriasis Area and Severity Index (PASI) scores from baseline were observed in Indigo naturalis-treated patients (56.3% had 75% improvement [PASI 75] response) compared with placebo (0.0%). A gene expression signature of moderate psoriasis was established from baseline skin biopsies, which included the up-regulation of the interleukin (IL)-17 pathway as a key component; Indigo naturalis treatment resulted in most of these signature genes returning toward normal, including down-regulation of the IL-17 pathway. Using an in vitro keratinocyte assay, an IL-17-inhibitory effect was observed for tryptanthrin, a component of Indigo naturalis. CONCLUSIONS: This study demonstrated the clinical efficacy of Indigo naturalis in moderate psoriasis, and exemplified a novel experimental medicine approach to understand TCM targeting mechanisms. TRIAL REGISTRATION: NCT01901705 .

Efficacy and safety of ustekinumab in psoriatic arthritis patients with peripheral arthritis and physician-reported spondylitis: post-hoc analyses from two phase III, multicentre, double-blind, placebo-controlled studies (PSUMMIT-1/PSUMMIT-2).

OBJECTIVE: To evaluate ustekinumab efficacy and safety in psoriatic arthritis (PsA) patients with peripheral arthritis and physician-reported spondylitis (termed the 'spondylitis subset'). METHODS: Adults with active PsA (PSUMMIT-1/PSUMMIT-2, n=615/312) were randomised to ustekinumab 45 mg, 90 mg or placebo at week 0/week 4/q12 week. At week 16, patients with <5% improvement in tender and swollen joints entered blinded early escape. A subset of patients with physician-identified spondylitis was evaluated with spondylitis-specific assessments, including Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score employing C reactive protein (ASDAS-CRP), through week 24. RESULTS: 256/927 (27.6%) PSUMMIT-1/PSUMMIT-2 patients (placebo/ustekinumab, n=92/164) comprised the evaluable spondylitis subset. At week 24, in this analysis subset, significantly more patients achieved BASDAI20/50/70 responses (54.8%/29.3%/15.3% vs 32.9%/11.4%/0%; p≤0.002), improvement in BASDAI question 2 concerning axial pain (1.85 vs 0.24; p<0.001) and mean per cent ASDAS-CRP improvements (27.8% vs 3.9%; p<0.001) for ustekinumab versus placebo recipients, respectively. Comparable to the overall study population, significant improvements were also achieved in psoriasis, peripheral arthritis, enthesitis, dactylitis, physical function and peripheral joint radiographs in the spondylitis subset. CONCLUSIONS: In this post-hoc analysis of PsA patients with baseline peripheral arthritis and physician-reported spondylitis, ustekinumab-treated patients demonstrated significant improvements in axial signs and symptoms through week 24. TRIAL REGISTRATION NUMBER: PSUMMIT-1 (NCT01009086, EudraCT 2009-012264-14) and PSUMMIT-2 (NCT01077362, EudraCT 2009-012265-60); post-study results.