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Purpose: Based on a potential shared pathophysiology tied to mast cell activity and neurogenic inflammation that may link pruritus and chronic cough (CC), this study, leveraging the All of Us database, examines the association between the two conditions., Materials and Methods: A nested case-control comparison was used to examine the association, identifying cases with SNOMED codes 418363000 (pruritus) and 68154008 (CC). Matching was performed on a 1:4 ratio by age, sex, and ethnicity using the MatchIt package in R, followed by maximum likelihood method to estimate odds ratios (ORs) and 95% confidence intervals from 2x2 contingency tables., Results: CC patients ( n  = 2,388) were more than twice as likely to be diagnosed with pruritus (OR: 2.65) and pruritus patients ( n  = 22,496) were more than twice as likely to be diagnosed with CC (OR: 2.57), than respective matched controls., Conclusions: These results highlight the potential bidirectional relationship between CC and pruritus, suggesting possible shared immune and neural pathways. Treatments like difelikefalin and nalbuphine that modulate these pathways, alongside P2X3 targeting agents, are emerging as potential therapeutic approaches for itch and chronic cough given the possible interconnected pathophysiology. This study's insights into the associations between pruritus and CC may pave the way for targeted therapeutic strategies that address their shared mechanisms.

Background: RPT193 is an orally administered small molecule antagonist of the human C-C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T-helper Type 2 (Th2) cells. We investigated single- and multiple-ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate-to-severe atopic dermatitis (AD)., Methods: This was a first-in-human randomized, placebo-controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate-to-severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects., Results: In healthy (n = 72) and AD subjects (n = 31), once-daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment-emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p < .05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193-treated versus placebo-treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures., Conclusions: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease., (© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background: Hidradenitis suppurativa (HS) has a high unmet need for better treatments. Biopsies are considered the gold standard for studying molecular alterations in skin. A reproducible, minimally invasive approach is needed for longitudinal monitoring in trials and in pediatric populations., Objective: To determine whether skin tape strips can detect molecular alterations in HS and identify biomarkers of disease activity., Methods: We performed RNA sequencing on tape strips collected from lesional and healthy-appearing (nonlesional) HS skin (n = 22) and healthy controls (n = 21). We correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies., Results: Tape strips detected upregulation of known HS biomarkers (eg, Interleukin[IL]-17A) in nonlesional and/or lesional skin and also identified novel clinically actionable targets, including OX40 and JAK3. The expression of Th17 and tumor necrosis factor-α pathways were highly correlated between tape strips and biopsies. HS clinical severity was significantly associated with expression of biomarkers (eg tumor necrosis factor-α , IL-17 A/F, OX40, JAK1-3, IL-4R) in HS lesional and/or nonlesional skin., Limitations: Sample size. Tape stripping is limited in depth., Conclusion: This study validates tape strips as a minimally-invasive approach to identify cutaneous biomarkers in HS. This provides a novel avenue for monitoring treatment efficacy and a potential step toward individualized therapy in HS., Competing Interests: Conflicts of interest KN, HH, MM, EA, MK, MM, DGS, SB, SCW, SG, JCR have no conflicts to disclose. SK is an employee of Mount Sinai and a consultant for AbbVie, Eli Lilly, Glenmark, Ichnos Sciences, Janssen, and Novartis. She serves on the Advisory Boards for Eli Lilly, Glenmark, Ichnos Sciences, Janssen, Abbvie, Argenx, Regeneron-Sanofi, Novartis, and UCB. She has received research funds from Pfizer, AbbVie, BMS, Incyte, Galderma and Acelyrin, and speaker bureau for AbbVie, Regeneron-Sanofi, Lilly, UCB, Janssen, Arcutis and Leo. ABG has received honoraria as an advisory board member and consultant for Amgen, AnaptypsBio, Avotres Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Dice Therapeutics, Eli Lilly, Janssen, Novartis, Sanofi, UCB, and Xbiotech and has received research/educational grants from AnaptypsBio, Moonlake Immunotherapeutics AG, Novartis, Bristol-Myers Squibb, and UCB Pharma (all paid to Mount Sinai School of Medicine). JGK has acted as a consultant for and/or received honoraria from AbbVie, Aclaris, Allergan, Almirall, Amgen, Arena, Aristea, Asana, Aurigene, Biogen Idec, Boehringer Ingelheim, Bristol-Myers Squibb, Escalier, Galapagos, Janssen, Lilly, MoonLake Immunotherapeutics, Nimbus, Novartis, Pfizer, Sanofi, Sienna Biopharmaceuticals, Sun Pharma, Target-Derm, UCB, Valeant, and Ventyx. James Krueger has received grant support (to The Rockefeller University) from AbbVie, Akros, Allergan, Amgen, Avillion, Biogen, Botanix, Boehringer Ingelheim, Bristol-Myers Squibb, Exicure, Innovaderm, Incyte, Janssen, Kyowa Kirin, Lilly, Nimbus Lackshmi, Novan, Novartis, PAREXEL, Pfizer, Regeneron, UCB, and Vitae Pharmaceuticals. EGY has served as a consultant for AbbVie, Amgen, Allergan, Asana Bioscience, Celgene, Concert, Dermira, DS Biopharma, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharmaceuticals, Lilly, Mitsubishi Tanabe, Novartis, Pfizer, Regeneron, Sanofi, and Union Therapeutics; a member of advisory boards of Allergan, Asana Bioscience, Celgene, DBV, Dermavant, Dermira, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Lilly, Novartis, Pfizer, Regeneron, and Sanofi; and a recipient of research grants from AbbVie, AnaptysBio, AntibioTx, Asana Bioscience, Boehringer-Ingelheim, Celgene, DBV, Dermavant, DS Biopharma, Galderma, Glenmark, Innovaderm, Janssen Biotech, Kiniksa Pharma, LEO Pharmaceuticals, Lilly, Medimmune, Sienna Biopharmaceuticals, Novan, Novartis, Ralexar, Regeneron, Pfizer, UCB, and Union Therapeutics., (Copyright © 2023 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Diphencyprone (DPCP) is a hapten that causes a delayed-type hypersensitivity reaction when applied topically. It has clinical uses in the treatment of various conditions such as melanoma metastases, warts, and alopecia areata, but the mechanisms are currently not well understood in humans. To further characterize the immunologic effects of DPCP, the authors performed a proteomic analysis of normal skin of eight healthy volunteers following a single application of DPCP and compared them with placebo-treated skin from the same volunteers. A total of 96 proteins were examined using the Olink immuno-oncology panel at 3 days (peak response), 14 days (partially resolved response), and 120 days (completely resolved response). Our analysis revealed significant upregulation of markers of immune cell activation (interleukin [IL] 8), vascular and tissue remodeling (matrix metallopeptidase 12 [MMP12], nitric oxide synthase 3 [NOS3]), antineoplastic markers (granzyme B [GZMB]), and the Th1 axis (interferon gamma [IFNG], chemokine (C-X-C motif) ligand [CXCL] 9, CXCL10, CXCL11) at days 3 and 14 compared with placebo (p < 0.05). In addition, several negative regulators of immune function such as programmed cell death 1 (PD1), programmed cell death ligand 1 (PDL1) (p < 0.001), and lymphocyte activation gene 3 (LAG3) (p < 0.05) were significantly upregulated at days 3 and 14. This induction of negative regulators may explain the seemingly paradoxical therapeutic benefits of DPCP in autoimmune conditions such as alopecia areata. The current analysis also indicated IL-4 upregulation only at day 3, followed by IL-12 upregulation only at day 14, suggesting a transient Th2 response followed by Th1 polarization. Overall, these data suggest a complex and evolving immunological delayed-type hypersensitivity response to a single application of DPCP over time. Future proteomic studies of samples from patients with melanoma metastases, warts, and alopecia areata treated long term with DPCP are needed to further evaluate its pharmacologic mechanisms., (© 2022 Japanese Dermatological Association.)

Competing Interests: Conflicts of interest Dr Lebwohl is an employee of Mount Sinai and receives research funds from: Abbvie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB Inc, and is a consultant for Aditum Bio, Almirall, AltruBio Inc, AnaptysBio, Arcutis, Inc, Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr Reddy's Laboratories, Evelo Biosciences, Evommune, Inc, Facilitation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd, LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. Elbogen is an employee of Mt Sinai and serves on the Advisory Board for Regeneron, consults for Ortho Dermatologics, and speaks for Bristol Myers Squibb. Authors Kresch, Weingarten, Guenin, Wei, and Correa da Rosa have no conflicts of interest to share.

Competing Interests: Conflicts of interest None disclosed.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterized by a heterogeneous and fluctuating disease course. To obtain a detailed molecular understanding of both the temporal and spatial variation in AD, we conducted a longitudinal case-control study, in which we followed a population, the GENAD (Gentofte AD) cohort, of mild-to-moderate patients with AD and matched healthy controls for more than a year. By the use of 1.5 mm minipunch biopsies, we obtained 393 samples from lesional, nonlesional, and healthy skin from multiple anatomical regions at different time points for transcriptomic profiling. We observed that the skin transcriptome was remarkably stable over time, with the largest variation being because of disease, individual, and skin site. Numerous AD-specific, differentially expressed genes were identified and indicated a disrupted skin barrier and activated immune response as the main features of AD. We also identified potentially novel targets in AD, including IL-37, MAML1, and several long noncoding RNAs. We envisage that the application of small biopsies, such as those introduced in this study, combined with omics technologies, will enable future skin research, in which multiple sampling from the same individual will give a more detailed, dynamic picture of how a disease fluctuates in time and space., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Diphencyprone (DPCP), a topical contact sensitizer, has shown efficacy in treating cutaneous melanoma metastases, including at times beyond the directly treated sites, but biomarkers indicative of treatment response have not been characterized. Thus, we performed a proteomic analysis of the skin and serum of five patients with cutaneous melanoma metastases treated with DPCP on days 0, 63, and 112 of the treatment course. In the serum, we found a significant upregulation ( P < 0.05) in 13 of 96 assessed immuno-oncology proteins after DPCP treatment. Upregulated proteins included those of the T helper 1 axis (CXCL9, CXCL10), immune checkpoint proteins (PD-1), and various proteins with roles in promoting tumor immunity such as CD80 and TNFRSF4/9. Given the positive clinical response to topical treatment noted in the five patients studied, these proteins may represent prognostic biomarkers in the serum for evaluating the efficacy of DPCP treatment of cutaneous melanoma metastases. Because DPCP does not lead to nonspecific immune-related adverse events seen with immune checkpoint inhibitors, our study provides evidence for potential tumor-specific systemic immune activation and systemic antitumor effectors elicited by topical DPCP., (© 2023 The Authors.)

Background: Although alopecia areata (AA) greatly impacts patients' quality of life (QoL), there is no adequate validation of AA-targeted QoL surveys in clinical trials, hindering sufficient representation of patient-reported outcomes., Objectives: Better understanding of patient-reported outcomes may guide treatment goals and future clinical trials., Methods: In a recent randomized controlled trial testing dupilumab in AA, patients were administered the Alopecia Areata Quality of Life Index (AA-QLI) and the Alopecia Areata Symptom Impact Scale (AASIS) surveys, specifically evaluating QoL in patients with AA. An in-depth analysis was performed to assess the utility of these questionnaires in this patient population, both at baseline and after treatment, and to determine a threshold for improved patient-reported outcomes., Results: While AASIS correlated with baseline Severity of Alopecia Tool (SALT) scores and with therapeutic response, AA-QLI showed no correlation with AA severity before or after treatment. Itch strongly correlated with serum IgE levels across both surveys. Using various approaches to estimate a discriminative threshold for decreased impact of AA on QoL (by AASIS) following treatment, a SALT score of 20 points or less post-treatment was associated with improved patient-reported outcomes, including both AA-related symptoms and items within the daily activities/feelings domain such as 'feeling sad' and 'feeling anxious or worry'., Conclusions: AASIS is better than AA-QLI to assess patient-reported outcomes. SALT ≤ 20 following treatment should be considered as a threshold for meaningful therapeutic outcome and as a clinical endpoint in future clinical trials for AA. What is already known about this topic? Alopecia areata greatly compromises quality of life, and affected patients have increased prevalences of depression, anxiety and social phobia. Despite the significant negative impact of the disease on patients' wellbeing, validation of targeted questionnaires in alopecia areata is lacking, and a therapeutic response threshold for improved patient-reported outcomes is unknown. What does this study add? This study investigated the utility of two different alopecia areata-targeted questionnaires - Alopecia Areata Quality of Life Index and Alopecia Areata Symptom Impact Scale (AASIS) - in a clinical trial setting. AASIS was found to correlate strongly with alopecia areata severity and clinical response. What are the clinical implications of this work? Patients with ≤ 20% scalp hair loss after treatment reported improvement in multiple quality-of-life items, suggesting this as a meaningful therapeutic outcome that may guide clinicians and improve the development of future clinical trials., (© 2022 British Association of Dermatologists.)

Competing Interests: None disclosed.

Significance: Melanoma is a deadly cancer that physicians struggle to diagnose early because they lack the knowledge to differentiate benign from malignant lesions. Deep machine learning approaches to image analysis offer promise but lack the transparency to be widely adopted as stand-alone diagnostics., Aim: We aimed to create a transparent machine learning technology (i.e., not deep learning) to discriminate melanomas from nevi in dermoscopy images and an interface for sensory cue integration., Approach: Imaging biomarker cues (IBCs) fed ensemble machine learning classifier (Eclass) training while raw images fed deep learning classifier training. We compared the areas under the diagnostic receiver operator curves., Results: Our interpretable machine learning algorithm outperformed the leading deep-learning approach 75% of the time. The user interface displayed only the diagnostic imaging biomarkers as IBCs., Conclusions: From a translational perspective, Eclass is better than convolutional machine learning diagnosis in that physicians can embrace it faster than black box outputs. Imaging biomarkers cues may be used during sensory cue integration in clinical screening. Our method may be applied to other image-based diagnostic analyses, including pathology and radiology.

Introduction: Recognition of faces of family members, friends, and colleagues is an important skill essential for everyday life. Individuals affected by prosopagnosia (face blindness) have difficulty recognizing familiar individuals. The prevalence of prosopagnosia has been estimated to be as high as 3%. Prosopagnosia can severely impact the quality of life of those affected, and it has been suggested to co-occur with conditions such as depression and anxiety., Methods: To determine real-world diagnostic frequency of prosopagnosia and the spectrum of its comorbidities, we utilized a large database of more than 7.5 million de-identified electronic health records (EHRs) from patients who received care at major academic health centers and Federally Qualified Health Centers in New York City. We designed a computable phenotype to search the database for diagnosed cases of prosopagnosia, revealing a total of n = 902 cases. In addition, data from a randomly sampled matched control population (n = 100,973) were drawn from the database for comparative analyses to study the condition's comorbidity landscape. Diagnostic frequency of prosopagnosia, epidemiological characteristics, and comorbidity landscape were assessed., Results: We observed prosopagnosia diagnoses at a rate of 0.012% (12 per 100,000 individuals). We discovered elevated frequency of prosopagnosia diagnosis for individuals who carried certain comorbid conditions, such as personality disorder, depression, epilepsy, and anxiety. Moreover, prosopagnosia diagnoses increased with the number of comorbid conditions., Conclusions: Results from this study show a wide range of comorbidities and suggest that prosopagnosia is vastly underdiagnosed. Findings imply important clinical consequences for the diagnosis and management of prosopagnosia as well as its comorbid conditions., Competing Interests: The authors have no financial interests to disclose., (© The Association for Clinical and Translational Science 2020.)

Cocaine use disorders (CUD) cause major morbidity and optimized prevention efforts are critical. It is unclear if trait impulsivity and exposure to cannabis or alcohol are associated with age trajectory of cocaine use (e.g., age of onset of heaviest use, or time of escalation), or with vulnerability to develop a CUD. This is an observational study with volunteers (≥ 18 years old), from a metropolitan area. The sample ( n = 1,010) included: n = 360 normal volunteers, n = 438 with cocaine dependence (CD) diagnoses, and n = 212 with other addictive diseases. Trait impulsivity was examined with BIS-11 scores. Maximal self-exposure to cannabis, alcohol, and cocaine were characterized dimensionally with Kreek-McHugh-Schluger-Kellogg (KMSK) scales. Time of escalation was defined as the interval between age of first use and age of onset of heaviest use. Onset of maximal use of cannabis (median age = 17) and alcohol (median age = 21) preceded that of cocaine (median age = 27), in volunteers with CD. Multivariate Cox regressions in volunteers with CD show that increasing self-exposure to cannabis was a predictor of earlier onset of heaviest use of cocaine. Also, more rapid time of escalation of alcohol was a predictor of more rapid time of escalation of cocaine. A multiple logistic regression shows that increasing self-exposure to cannabis or alcohol was a positive predictor of odds of CD diagnosis. Trait impulsivity and gender were not significant predictors in these multivariate analyses. This study shows that aspects of adolescent exposure to nonmedical cannabis and alcohol are predictors of early onset of CUD, and may be potentially targeted for prevention efforts. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The application of machine learning to longitudinal gene-expression profiles has demonstrated potential to decrease the assessment gap, between biochemical determination and clinical manifestation, of a patient's response to treatment. Although psoriasis is a proven testing ground for treatment-response prediction using transcriptomic data from clinically accessible skin biopsies, these biopsies are expensive, invasive, and challenging to obtain from certain body areas. Response prediction from blood biochemical measurements could be a cheaper, less invasive predictive platform. Longitudinal profiles for 92 inflammatory and 65 cardiovascular disease proteins were measured from the blood of psoriasis patients at baseline, and 4-weeks, following tofacitinib (janus kinase-signal transducer and activator of transcription-inhibitor) or etanercept (tumor necrosis factor-inhibitor) treatment, and predictive models were developed by applying machine-learning techniques such as bagging and ensembles. This data driven approach developed predictive models able to accurately predict the 12-week clinical endpoint for psoriasis following tofacitinib (area under the receiver operating characteristic curve [auROC] = 78%), or etanercept (auROC = 71%) treatment in a validation dataset, revealing a robust predictive protein signature including well-established psoriasis markers such as IL-17A and IL-17C, highlighting potential for biologically meaningful and clinically useful response predictions using blood protein data. Although most blood classifiers were outperformed by simple models trained using Psoriasis Area Severity Index scores, performance might be enhanced in future studies by measuring a wider variety of proteins., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. Design: This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants ( n = 15) were randomized 3:1 to receive two consecutive daily doses of Poly-ICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Methods: Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4 + T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Results: Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4 + T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. Conclusions: These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV + subjects indicating promise as an adjuvant for HIV therapeutic vaccines. Trial Registration: www.ClinicalTrials.gov, identifier: NCT02071095.

Background: The Kreek-McHugh-Schluger-Kellogg (KMSK) scales provide a rapid assessment of maximal self-exposure to specific drugs and can be used as a dimensional instrument. This study provides a re-evaluation of the KMSK scales for cannabis, alcohol, cocaine, and heroin in a relatively large multi-ethnic cohort, and also the first systematic comparison of gender-specific profiles of drug exposure with this scale., Methods: This was an observational study of n = 1,133 consecutively ascertained adult volunteers. The main instruments used were the SCID-I interview (DSM-IV criteria) and KMSK scales for cannabis, alcohol, cocaine, and heroin., Results: Participants were 852 volunteers (297 female) with specific DSM-IV abuse or dependence diagnoses, and 281 volunteers without any drug diagnoses (154 female). Receiver operating characteristic (ROC) curves were calculated for concurrent validity of KMSK scores with the respective DSM-IV dependence diagnoses. The areas under the ROC curves for men and women combined were 99.5% for heroin, 97% for cocaine, 93% for alcohol, and 85% for cannabis. Newly determined optimal KMSK "cutpoint" scores were identical for men and women for cocaine and heroin dependence diagnoses, but were higher in men than in women, for cannabis and alcohol dependence diagnoses., Conclusions: This study confirms the scales' effectiveness in performing rapid dimensional analyses for cannabis, alcohol, cocaine, and heroin exposure, in a cohort larger than previously reported, with "cutpoints" changed from initial determinations, based on this larger sample. The KMSK scales also detected gender differences in self-exposure to alcohol and cannabis that are associated with the respective dependence diagnoses., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Dysregulation of the stress response is implicated in drug addiction; therefore, polymorphisms in stress-related genes may be involved in this disease. An analysis was performed to identify associations between variants in 11 stress-related genes, selected a priori, and heroin addiction. Two discovery samples of American subjects of European descent (EA, n = 601) and of African Americans (AA, n = 400) were analyzed separately. Ancestry was verified by principal component analysis. Final sets of 414 (EA) and 562 (AA) variants were analyzed after filtering of 846 high-quality variants. The main result was an association of a non-coding SNP rs255105 in the CRH (CRF) receptor 2 gene (CRHR2), in the discovery EA sample (Pnominal = .00006; OR = 2.1; 95% CI 1.4-3.1). The association signal remained significant after permutation-based multiple testing correction. The result was corroborated by an independent EA case sample (n = 364). Bioinformatics analysis revealed that SNP rs255105 is associated with the expression of a downstream long intergenic non-coding RNA (lincRNA) gene AC005154.6. AC005154.6 is highly expressed in the pituitary but its functions are unknown. LincRNAs have been previously associated with adaptive behavior, PTSD, and alcohol addiction. Further studies are warranted to corroborate the association results and to assess the potential relevance of this lincRNA to addiction and other stress-related disorders., Competing Interests: The authors have declared that no competing interests exist.

Background: The impact of increasing non-medical cannabis use on vulnerability to develop opioid use disorders has received considerable attention, with contrasting findings. A dimensional analysis of self-exposure to cannabis and other drugs, in individuals with and without opioid dependence (OD) diagnoses, may clarify this issue. Objective: To examine the age of onset of maximal self-exposure to cannabis, alcohol, cocaine, and heroin, in volunteers diagnosed with OD, using a rapidly administered instrument (the KMSK scales). To then determine whether maximal self-exposure to cannabis, alcohol, and cocaine is a dimensional predictor of odds of OD diagnoses. Methods: This outpatient observational study examined maximal self-exposure to these drugs, in volunteers diagnosed with DSM-IV OD or other drug diagnoses, and normal volunteers. In order to focus more directly on opioid dependence diagnosis as the outcome, volunteers who had cocaine dependence diagnoses were excluded. Male and female adults of diverse ethnicity were consecutively ascertained from the community, and from local drug treatment programs, in 2002-2013 ( n = 574, of whom n = 94 had OD diagnoses). The age of onset of maximal self-exposure of these drugs was examined. After propensity score matching for age at ascertainment, gender, and ethnicity, a multiple logistic regression examined how increasing self-exposure to non-medical cannabis, alcohol and cocaine affected odds of OD diagnoses. Results: Volunteers with OD diagnoses had the onset of heaviest use of cannabis in the approximate transition between adolescence and adulthood (mean age = 18.9 years), and onset of heaviest use of alcohol soon thereafter (mean age = 20.1 years). Onset of heaviest use of heroin and cocaine was detected later in the lifespan (mean ages = 24.7 and 25.3 years, respectively). After propensity score matching for demographic variables, we found that the maximal self-exposure to cannabis and cocaine, but not to alcohol, was greater in volunteers with OD diagnoses, than in those without this diagnosis. Also, a multiple logistic regression detected that increasing self-exposure to cannabis and cocaine, but not alcohol, was a positive predictor of OD diagnosis. Conclusions/Importance: Increasing self-exposure to non-medical cannabis, as measured with a rapid dimensional instrument, was a predictor of greater odds of opioid dependence diagnosis, in propensity score-matched samples.

Aim: This study assesses whether genetic variants in stress-related genes are associated with prolonged abstinence from heroin in subjects that are not in long-term methadone treatment., Methods: Frequencies of 117 polymorphisms in 30 genes were compared between subjects with history of heroin addiction, either without agonist treatment (n = 129) or in methadone maintenance treatment (n = 923)., Results: SNP rs1500 downstream of CRHBP and an interaction of SNPs rs10482672 (NR3C1) and rs4234955 (NPY1R/NPY5R) were significantly associated with prolonged abstinence without agonist treatment., Conclusion: This study suggests that variability in stress-related genes may contribute to the ability of certain subjects to remain in prolonged abstinence from heroin, possibly due to higher resilience to stress.

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factor-related activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

A fundamental question in human susceptibility to bacterial infections is to what extent variability is a function of differences in the pathogen species or in individual humans. To focus on the pathogen species, we compared in the same individual the human adaptive T and B cell immune response to multiple strains of two major human pathogens, Staphylococcus aureus and Streptococcus pyogenes. We found wide variability in the acute adaptive immune response induced by various strains of a species, with a unique combination of activation within the two arms of the adaptive response. Further, this was also accompanied by a dramatic difference in the intensity of the specific protective T helper (Th) response. Importantly, the same immune response differences induced by the individual strains were maintained across multiple healthy human donors. A comparison of isogenic phage KO strains, demonstrated that of the pangenome, prophages were the major contributor to inter-strain immune heterogeneity, as the T cell response to the remaining "core genome" was noticeably blunted. Therefore, these findings extend and modify the notion of an adaptive response to a pathogenic bacterium, by implying that the adaptive immune response signature of a bacterial species should be defined either per strain or alternatively to the species' 'core genome', common to all of its strains. Further, our results demonstrate that the acquired immune response variation is as wide among different strains within a single pathogenic species as it is among different humans, and therefore may explain in part the clinical heterogeneity observed in patients infected with the same species.

Background and Objectives: Addictions to heroin or to cocaine are associated with substantial psychiatric comorbidity, including depression. Poly-drug self-exposure (eg, to heroin, cocaine, cannabis, or alcohol) is also common, and may further affect depression comorbidity., Methods: This case-control study examined the relationship of exposure to the above drugs and depression comorbidity. Participants were recruited from methadone maintenance clinics, and from the community. Adult male and female participants (n = 1,201) were ascertained consecutively by experienced licensed clinicians. The instruments used were the SCID-I, and Kreek-McHugh-Schluger-Kellogg (KMSK) scales, which provide a rapid dimensional measure of maximal lifetime self-exposure to each of the above drugs. This measure ranges from no exposure to high unit dose, high frequency, and long duration of exposure., Results: A multiple logistic regression with stepwise variable selection revealed that increasing exposure to heroin or to cocaine was associated greater odds of depression, with all cases and controls combined. In cases with an opioid dependence diagnosis, increasing cocaine exposure was associated with a further increase in odds of depression. However, in cases with a cocaine dependence diagnosis, increasing exposure to either cannabis or alcohol, as well as heroin, was associated with a further increase in odds of depression., Discussion and Conclusions: This dimensional analysis of exposure to specific drugs provides insights on depression comorbidity with addictive diseases, and the impact of poly-drug exposure., Scientific Significance: A rapid analysis of exposure to drugs of abuse reveals how specific patterns of drug and poly-drug exposure are associated with increasing odds of depression. This approach detected quantitatively how different patterns of poly-drug exposure can result in increased odds of depression comorbidity, in cases diagnosed with opioid versus cocaine dependence. (Am J Addict 2017;26:632-639)., (© 2017 American Academy of Addiction Psychiatry.)

Current atopic dermatitis (AD) models link epidermal abnormalities in lesional skin to cytokine activation. However, there is evolving evidence of systemic immune activation and detectable abnormalities in nonlesional skin. Because some of the best single correlations with severity (Scoring of AD, or SCORAD) are detected not only in lesional but also nonlesional skin and blood, more complex biomarker models of AD are needed. We thus performed extensive biomarker measures in these compartments using univariate and multivariate approaches to correlate disease biomarkers with SCORAD and with a combined hyperplasia score [thickness and keratin 16 (K16) mRNA] at baseline and after cyclosporine A treatment in 25 moderate to severe AD patients. Increases in serum cytokines and chemokines (IL-13, IL-22, CCL17) were found in AD versus healthy individuals and were reduced with treatment. SCORAD correlated with immune (IL-13, IL-22) and epidermal (thickness, K16) measures in lesional and, even more strongly, in nonlesional AD. Serum cytokines also had higher correlations with nonlesional markers at baseline and with treatment. Multivariate U statistics improved baseline and treatment-response SCORAD correlations. Nonlesional models showed the strongest correlations, with further improvement upon integration of serum markers. Even better correlations were obtained between biomarkers and the hyperplasia score. Larger cohorts are needed to confirm these preliminary data., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

There is an "assessment gap" between the moment a patient's response to treatment is biologically determined and when a response can actually be determined clinically. Patients' biochemical profiles are a major determinant of clinical outcome for a given treatment. It is therefore feasible that molecular-level patient information could be used to decrease the assessment gap. Thanks to clinically accessible biopsy samples, high-quality molecular data for psoriasis patients are widely available. Psoriasis is therefore an excellent disease for testing the prospect of predicting treatment outcome from molecular data. Our study shows that gene-expression profiles of psoriasis skin lesions, taken in the first 4 weeks of treatment, can be used to accurately predict (>80% area under the receiver operating characteristic curve) the clinical endpoint at 12 weeks. This could decrease the psoriasis assessment gap by 2 months. We present two distinct prediction modes: a universal predictor, aimed at forecasting the efficacy of untested drugs, and specific predictors aimed at forecasting clinical response to treatment with four specific drugs: etanercept, ustekinumab, adalimumab, and methotrexate. We also develop two forms of prediction: one from detailed, platform-specific data and one from platform-independent, pathway-based data. We show that key biomarkers are associated with responses to drugs and doses and thus provide insight into the biology of pathogenesis reversion., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Acetaminophen-related acute liver injury and liver failure (ALF) result from ingestion of supratherapeutic quantities of this analgesic, frequently in association with other forms of substance abuse including alcohol, opioids, and cocaine. Thus, overdosing represents a unique high-risk behavior associated with other forms of drug use disorder., Methods: We examined a series of 21 single nucleotide polymorphisms (SNPs) in 9 genes related to impulsivity and/or stress responsivity that may modify response to stress. Study subjects were 229 white patients admitted to tertiary care liver centers for ALF that was determined to be due to acetaminophen toxicity after careful review of historical and biochemical data. Identification of relevant SNPs used Sanger sequencing, TaqMan, or custom microarray. Association tests were carried out to compare genotype frequencies between patients and healthy white controls., Results: The mean age was 37 years, and 75.6% were female, with similar numbers classified as intentional overdose or unintentional (without suicidal intent, occurring for a period of several days, usually due to pain). There was concomitant alcohol abuse in 30%, opioid use in 33.6%, and use of other drugs of abuse in 30.6%. The genotype frequencies of 2 SNPs were found to be significantly different between the cases and controls, specifically SNP rs2282018 in the arginine vasopressin gene ( AVP, odds ratio 1.64) and SNP rs11174811 in the AVP receptor 1A gene ( AVPR1 A, odds ratio 1.89), both of which have been previously linked to a drug use disorder diagnosis., Conclusions: Patients who develop acetaminophen-related ALF have increased frequency of gene variants that may cause altered stress responsivity, which has been shown to be associated with other unrelated substance use disorders.

Mild versus severe psoriasis is often distinguished by clinical measures such as the extent of skin involvement or Psoriasis Area and Severity Index score, both of which use arbitrary boundaries. It is widely assumed that severe psoriasis involves higher levels of skin inflammation, but comparative molecular profiles of mild versus severe disease have not been performed. In this study, we used immunohistochemistry, reverse transcription PCR, and gene arrays to determine the phenotype of North American patients with mild psoriasis (n = 34, mean PASI score = 5.5) versus severe psoriasis (n = 23, mean PASI score = 23.2). Overall, skin inflammation, defined as the sum of T-cell infiltration/activation and IL-17-mediated epidermal responses, was not higher in severe psoriasis lesions. Surprisingly, mild psoriasis was characterized by higher numbers of T cells in skin lesions, higher IL-17A expression, and stronger expression of the core psoriasis transcriptome. In contrast, severe psoriasis was characterized by stronger expression of some epidermal response genes (TGFA, CALM1, SMPD3, and IL1RL2). However, a key molecular distinction was higher expression of negative immune regulatory genes (CTLA4, CD69 and PD-L1) in mild lesions compared with severe psoriasis lesions. These data have important implications for treating psoriasis across the spectrum of disease, as well as for potential mechanisms that allow psoriasis to progress to more extensive cutaneous disease., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: This study was designed to determine whether polymorphisms in acetylcholine receptors contribute to opioid dependence and/or cocaine dependence., Patients & Methods: The sample (n = 1860) was divided by drug and ancestry, and 55 polymorphisms (nine genes) were analyzed., Results: Of the 20 SNPs that showed nominally significant associations, the association of the African-specific CHRM4 SNP rs2229163 (Asn417=) with cocaine dependence survived correction for multiple testing (Pcorrected = 0.047). CHRM4 is located in a region of strong linkage disequilibrium on chromosome 11 that includes genes associated with schizophrenia. CHRM4 SNP rs2229163 is in strong linkage disequilibrium with several African-specific SNPs in DGKZ and AMBRA1., Conclusion: Cholinergic receptors' variants may contribute to drug addiction and have a potential role as pharmacogenetic markers., Competing Interests: Financial & competing interests disclosure This work was supported by the Dr Miriam and Sheldon G Adelson Medical Research Foundation, the Clinical and Translational Science Award no. UL1RR024143 from the National Center for Advancing Translational Sciences of the NIH (B Coller) and NSFC grant no. 31470070 from the Chinese Government (J Ott). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Background: Petrolatum is a common moisturizer often used in the prevention of skin infections after ambulatory surgeries and as a maintenance therapy of atopic dermatitis (AD). However, the molecular responses induced by petrolatum in the skin have never been assessed., Objective: We sought to define the cutaneous molecular and structural effects induced by petrolatum., Methods: Thirty-six healthy subjects and 13 patients with moderate AD (mean SCORAD score, 39) were studied by using RT-PCR, gene arrays, immunohistochemistry, and immunofluorescence performed on control skin, petrolatum-occluded skin, and skin occluded with a Finn chamber only., Results: Significant upregulations of antimicrobial peptides (S100A8/fold change [FCH], 13.04; S100A9/FCH, 11.28; CCL20/FCH, 8.36; PI3 [elafin]/FCH, 15.40; lipocalin 2/FCH, 6.94, human β-defensin 2 [DEFB4A]/FCH, 4.96; P < .001 for all) and innate immune genes (IL6, IL8, and IL1B; P < .01) were observed in petrolatum-occluded skin compared with expression in both control and occluded-only skin. Application of petrolatum also induced expression of key barrier differentiation markers (filaggrin and loricrin), increased stratum corneum thickness, and significantly reduced T-cell infiltrates in the setting of "normal-appearing" or nonlesional AD skin, which is known to harbor barrier and immune defects., Conclusions: Petrolatum robustly modulates antimicrobials and epidermal differentiation barrier measures. These data shed light on the beneficial molecular responses of petrolatum in barrier-defective states, such as AD and postoperative wound care., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Drug addiction, a leading health problem, is a chronic brain disease with a significant genetic component. Animal models and clinical studies established the involvement of glutamate and GABA neurotransmission in drug addiction. This study was designed to assess if 258 variants in 27 genes of these systems contribute to the vulnerability to develop drug addiction., Methods: Four independent analyses were conducted in a sample of 1860 subjects divided according to drug of abuse (heroin or cocaine) and ancestry (African and European)., Results: A total of 11 SNPs in eight genes showed nominally significant associations (P<0.01) with heroin and/or cocaine addiction in one or both ancestral groups but the associations did not survive correction for multiple testing. Of these SNPs, the GAD1 upstream SNP rs1978340 is potentially functional as it was shown to affect GABA concentrations in the cingulate cortex. In addition, SNPs GABRB3 rs7165224; DBI rs12613135; GAD1 SNPs rs2058725, rs1978340, rs2241164; and GRIN2A rs1650420 were previously reported in associations with drug addiction or related phenotypes., Conclusions: The study supports the involvement of genetic variation in the glutamatergic and GABAergic systems in drug addiction with partial overlap in susceptibility loci between cocaine and heroin addiction., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Psoriasis is present in all racial groups, but in varying frequencies and severity. Considering that small plaque psoriasis is specific to the Asian population and severe psoriasis is more predominant in the Western population, we defined Asian small and intermediate plaque psoriasis as psoriasis subtypes and compared their molecular signatures with the classic subtype of Western large plaque psoriasis. Two different characteristics of psoriatic spreading-vertical growth and radial expansion-were contrasted between subtypes, and genomic data were correlated to histologic and clinical measurements. Compared with Western large plaque psoriasis, Asian small plaque psoriasis revealed limited psoriasis spreading, but IL-17A and IL-17-regulated proinflammatory cytokines were highly expressed. Paradoxically, IL-17A and IL-17-regulated proinflammatory cytokines were lower in Western large plaque psoriasis, whereas T cells and dendritic cells in total psoriatic skin area were exponentially increased. Negative immune regulators, such as CD69 and FAS, were decreased in both Western large plaque psoriasis and psoriasis with accompanying arthritis or obesity, and their expression was correlated with psoriasis severity index. Based on the disease subtype comparisons, we propose that dysregulation of T-cell expansion enabled by downregulation of immune negative regulators is the main mechanism for development of large plaque psoriasis subtypes., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Achieving timely accrual into clinical research studies remains a challenge for clinical translational research. We developed an evaluation measure, the Accrual Index (AI), normalized for sample size and study duration, using data from the protocol and study management databases. We applied the AI retrospectively and prospectively to assess its utility., Methods: Accrual Target, Projected Time to Accrual Completion (PTAC), Evaluable Subjects, Dates of Recruitment Initiation, Analysis, and Completion were defined. AI is (% Accrual Target accrued/% PTAC elapsed). Changes to recruitment practices were described, and data extracted from study management databases., Results: December 2014 (or final) AI was analyzed for 101 studies initiating recruitment from 2007 to 2014. Median AI was ≥1 for protocols initiating recruitment in 2011, 2013, and 2014. The AI varied widely for studies pre-2013. Studies with AI > 4 utilized convenience samples for recruitment. Data-justified PTAC was refined in 2013-2014 after which the AI range narrowed. Protocol characteristics were not associated with study AI., Conclusion: Protocol AI reflects the relative agreement between accrual feasibility assessment (PTAC), and accrual performance, and is affected by recruitment practices. The AI may be useful in managing accountability, modeling accrual, allocating recruitment resources, and testing innovations in recruitment practices., (© 2015 Wiley Periodicals, Inc.)