Perceptual thresholds for differences in CT noise texture.

Purpose: The average (fav) or peak (fpeak) noise power spectrum (NPS) frequency is often used as a one-parameter descriptor of the CT noise texture. Our study develops a more complete two-parameter model of the CT NPS and investigates the sensitivity of human observers to changes in it. Approach: A model of CT NPS was created based on its fpeak and a half-Gaussian fit (σ) to the downslope. Two-alternative forced-choice staircase studies were used to determine perceptual thresholds for noise texture, defined as parameter differences with a predetermined level of discrimination performance (80% correct). Five imaging scientist observers performed the forced-choice studies for eight directions in the fpeak/σ-space, for two reference NPSs (corresponding to body and lung kernels). The experiment was repeated with 32 radiologists, each evaluating a single direction in the fpeak/σ-space. NPS differences were quantified by the noise texture contrast (Ctexture), the integral of the absolute NPS difference. Results: The two-parameter NPS model was found to be a good representation of various clinical CT reconstructions. Perception thresholds for fpeak alone are 0.2 lp/cm for body and 0.4 lp/cm for lung NPSs. For σ, these values are 0.15 and 2 lp/cm, respectively. Thresholds change if the other parameter also changes. Different NPSs with the same fpeak or fav can be discriminated. Nonradiologist observers did not need more Ctexture than radiologists. Conclusions: fpeak or fav is insufficient to describe noise texture completely. The discrimination of noise texture changes depending on its frequency content. Radiologists do not discriminate noise texture changes better than nonradiologists.

Enhanced CTLA-4 blockade anti-tumor immunity with APG-157 combination in a murine head and neck cancer.

BACKGROUND: A phase I clinical study for patients with locally advanced H&N cancer with a new class of botanical drug APG-157 provided hints of potential synergy with immunotherapy. We sought to evaluate the efficacy of the combination of APG-157 and immune checkpoint inhibitors. METHODS: CCL23, UM-SCC1 (human), and SCCVII (HPV-), MEER (HPV+) (murine) H&N cancer cell lines were utilized for in vitro and in vivo studies. We measured tumor growth by treating the mice with APG-157, anti-PD-1, and anti-CTLA-4 antibody combinations (8 groups). The tumor microenvironments were assessed by multi-color flow cytometry, immunohistochemistry, and RNA-seq analysis. Fecal microbiome was analyzed by 16S rRNA sequence. RESULTS: Among the eight treatment groups, APG-157 + anti-CTLA-4 demonstrated the best tumor growth suppression (p = 0.0065 compared to the control), followed by anti-PD-1 + anti-CTLA-4 treatment group (p = 0.48 compared to the control). Immunophenotype showed over 30% of CD8+ T cells in APG-157 + anti-CTLA-4 group compared to 4%-5% of CD8+ T cells for the control group. Differential gene expression analysis revealed that APG-157 + anti-CTLA-4 group showed an enriched set of genes for inflammatory response and apoptotic signaling pathways. The fecal microbiome analysis showed a substantial difference of lactobacillus genus among groups, highest for APG-157 + anti-CTLA-4 treatment group. We were unable to perform correlative studies for MEER model as there was tumor growth suppression with all treatment conditions, except for the untreated control group. CONCLUSIONS: The results indicate that APG-157 and immune checkpoint inhibitor combination treatment could potentially lead to improved tumor control.

Race, Ethnicity, and Other Patient and Clinical Encounter Characteristics Associated with Patient Experiences of Access to Care.

The Press Ganey (PG) Outpatient Medical Practice Survey measures patients' experiences of healthcare access in the U.S. We aimed to identify differences in experiences of access to care by patient race, ethnicity, and other sociodemographic characteristics, an important first step in informing health policy and ensuring equitable healthcare delivery. We performed a cross-sectional analysis of PG surveys for adult outpatient visits within the University of Pennsylvania Health System from 2014-2017, including 119,373 unique patients. Compared with White patients, Black (odds ratio [OR] 0.84; 95% confidence interval [CI] 0.80-0.87), Asian (OR 0.62; 95% CI 0.58-0.66), and other/unknown race patients (OR 0.83; 95% CI 0.72-0.94) were each less likely to report the maximum score for timely access to care. Patients of all minoritized groups, as well as those whose primary language was not English, reported lower scores in secondary access measures related to communication and respect, compared to White and primarily English-speaking patients, respectively. Efforts to improve the experience of access to care among racial and ethnic minoritized patients are imperative to achieve equity in healthcare delivery.

Gigaxonin Suppresses Epithelial-to-Mesenchymal Transition of Human Cancer Through Downregulation of Snail.

Gigaxonin is an E3 ubiquitin ligase that plays a role in cytoskeletal stability. Its role in cancer is not yet clearly understood. Our previous studies of head and neck cancer had identified gigaxonin interacting with p16 for NFκB ubiquitination. To explore its role in cancer cell growth suppression, we analyzed normal and tumor DNA from cervical and head and neck cancers. There was a higher frequency of exon 8 SNP (c.1293 C>T, rs2608555) in the tumor (46% vs. 25% normal, P = 0.011) pointing to a relationship to cancer. Comparison of primary tumor with recurrence and metastasis did not reveal a statistical significance. Two cervical cancer cell lines, ME180 and HT3 harboring exon 8 SNP and showing T allele expression correlated with higher gigaxonin expression, reduced in vitro cell growth and enhanced cisplatin sensitivity in comparison with C allele expressing cancer cell lines. Loss of gigaxonin expression in ME180 cells through CRISPR-Cas9 or siRNA led to aggressive cancer cell growth including increased migration and Matrigel invasion. The in vitro cell growth phenotypes were reversed with re-expression of gigaxonin. Suppression of cell growth correlated with reduced Snail and increased e-cadherin expression. Mouse tail vein injection studies showed increased lung metastasis of cells with low gigaxonin expression and reduced metastasis with reexpression of gigaxonin. We have found an association between C allele expression and RNA instability and absence of multimeric protein formation. From our results, we conclude that gigaxonin expression is associated with suppression of epithelial-mesenchymal transition through inhibition of Snail. SIGNIFICANCE: Our results suggest that GAN gene exon 8 SNP T allele expression correlates with higher gigaxonin expression and suppression of aggressive cancer cell growth. There is downregulation of Snail and upregulation of e-cadherin through NFκB ubiquitination. We hypothesize that exon 8 T allele and gigaxonin expression could serve as diagnostic markers of suppression of aggressive growth of head and neck cancer.

Patient-Reported Outcomes and Mortality in Cutaneous Chronic Graft-vs-Host Disease.

Importance: Chronic graft-vs-host disease (GVHD) is associated with impaired quality of life and symptom burden. The independent association of skin involvement with patient-reported outcomes (PROs) and their utility as a clinical prognostic marker remain unknown. Identification of patients with cutaneous chronic GVHD and impaired PROs could assist in initial risk stratification and treatment selection. Objective: To compare the association of sclerotic and epidermal-type chronic GVHD with longitudinal PROs and to evaluate whether PROs can identify patients with cutaneous chronic GVHD at high risk for death. Design, Setting, and Participants: This multicenter prospective cohort study involved patients from the Chronic GVHD Consortium of 9 US medical centers, enrolled between August 2007 and April 2012, and followed up until December 2020. Participants included adults 18 years and older with a diagnosis of chronic GVHD requiring systemic immunosuppression and with skin involvement during the study period. Main Outcomes and Measures: Patient-reported symptom burden was assessed using the Lee Symptom Scale (LSS) skin subscale with higher scores indicating worse outcomes. Quality of life was measured using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) instrument with lower scores indicating worse outcomes. Nonrelapse mortality, overall survival, and their association with PROs at diagnosis were also assessed. Results: Among 436 patients with cutaneous chronic GVHD (median [IQR] age at transplant, 51 [41.5-56.6] years; 261 [59.9%] male), 229 patients had epidermal-type chronic GVHD (52.5%), followed by 131 with sclerotic chronic GVHD (30.0%), and 76 with combination disease (17.4%). After adjusting for confounders, patients with sclerotic chronic GVHD had mean FACT-BMT scores 6.1 points worse than those with epidermal disease (95% CI, 11.7-0.4; P = .04). Patients with combination disease had mean LSS skin subscale scores 9.0 points worse than those with epidermal disease (95% CI, 4.2-13.8; P < .001). Clinically meaningful differences were defined as at least 7 points lower for FACT-BMT and 11 points higher for LSS skin subscale. At diagnosis, clinically meaningful worsening in FACT-BMT score was associated with an adjusted odds of nonrelapse mortality increased by 9.1% (95% CI, 2.0%-16.7%; P = .01). Similarly, for clinically meaningful worsening in LSS skin subscale score, adjusted odds of nonrelapse mortality increased by 16.4% (95% CI, 5.4%-28.5%; P = .003). These associations held true after adjusting for clinical severity by the National Institutes of Health Skin Score. Conclusions and Relevance: The results of this cohort study demonstrated that skin chronic GVHD was independently associated with long-term PRO impairment, with sclerotic and combination disease carrying the highest morbidity. The degree of impairment at skin chronic GVHD diagnosis was a prognostic marker for mortality. Therefore, PROs could be useful for risk stratification and treatment selection in clinical practice and clinical trials.

CAR-T cell therapy targeting surface expression of TYRP1 to treat cutaneous and rare melanoma subtypes.

A major limitation to developing chimeric antigen receptor (CAR)-T cell therapies for solid tumors is identifying surface proteins highly expressed in tumors but not in normal tissues. Here, we identify Tyrosinase Related Protein 1 (TYRP1) as a CAR-T cell therapy target to treat patients with cutaneous and rare melanoma subtypes unresponsive to immune checkpoint blockade. TYRP1 is primarily located intracellularly in the melanosomes, with a small fraction being trafficked to the cell surface via vesicular transport. We develop a highly sensitive CAR-T cell therapy that detects surface TYRP1 in tumor cells with high TYRP1 overexpression and presents antitumor activity in vitro and in vivo in murine and patient-derived cutaneous, acral and uveal melanoma models. Furthermore, no systemic or off-tumor severe toxicities are observed in an immunocompetent murine model. The efficacy and safety profile of the TYRP1 CAR-T cell therapy supports the ongoing preparation of a phase I clinical trial.

Feasibility of Utilizing Electronic Dental Record Data and Periodontitis Case Definition to Automate Diagnosis.

Periodontitis is an irreversible disease leading to tooth loss, and 42% U.S. population suffers from periodontitis. Hence, diagnosing, monitoring, and determining its prevalence is critical to develop preventive strategies. However, a nationwide epidemiological study estimating the prevalence reported a concern about the discontinuation of such studies due to cost and ethical reasons. Therefore, this study determined the feasibility of utilizing electronic dental record (EDR) data and periodontitis case definition to automate periodontitis diagnosis. We utilized EDR data from the Indiana University School of Dentistry of 28,908 unique patients. We developed and tested a computer algorithm to diagnose periodontitis using the case definition. We found 44%, 22%, and 1% of patients with moderate, severe, and mild periodontitis, respectively. The algorithm worked with 100% sensitivity, specificity, and accuracy because of the excellent quality of the EDR data. We concluded the feasibility of providing automated periodontitis diagnosis from EDR data to conduct epidemiological studies across the US.

Incident Asthma, Asthma Exacerbations, and Asthma-Related Hospitalizations in Patients With Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) is thought to induce asthma via the "atopic march," but the effects of AD on incident asthma and asthma severity have not been fully characterized. OBJECTIVE: To determine risk of asthma, asthma exacerbations, and asthma-related hospitalizations among patients fwith AD. METHODS: A cohort study was conducted using electronic health records data from UK general practices from 1994 to 2015. Children (<18 years old) and adults (≥18 years) with AD were matched on age, practice, and index date to patients without AD. AD severity was categorized using treatments and dermatologist referrals. Outcomes were incident asthma among all patients and asthma exacerbation or hospitalization among patients with asthma. RESULTS: On comparing 409,341 children with AD (93.2% mild, 5.5% moderate, 1.3% severe) with 1,809,029 unaffected children, those with AD were found to be associated with a 2-fold greater risk of asthma compared with those without AD (hazard ratio, 1.96; 95% CI, 1.93-1.98). On comparing 625,083 adults with AD (65.7% mild, 31.4% moderate, and 2.9% severe) with 2,678,888 unaffected adults, AD was found to be associated with a 38% higher risk of asthma (hazard ratio, 1.38; 95% CI, 1.36-1.40). Asthmatic patients with AD also had a 21% to 63% greater risk of asthma exacerbations and a 20% to 64% greater risk of asthma-related hospitalizations compared with asthmatic patients without AD. Risk of asthma, asthma exacerbation, or asthma-related hospitalization increased with AD severity in a dose-dependent manner in both the pediatric and adult cohorts. CONCLUSIONS: AD, especially in children and when more severe, is associated with greater risk of asthma as well as greater risk of asthma exacerbations and hospitalizations among asthmatic patients.

Neuropsychiatric disorders in adults with atopic dermatitis: A population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) may be associated with an increased burden of neuropsychiatric outcomes such as anxiety and depression, but longitudinal data on the impact of AD severity is lacking, and a comprehensive assessment of neuropsychiatric disease in adults with AD is needed. OBJECTIVES: Determine risk of incident neuropsychiatric disease among adults with AD by severity. METHODS: A cohort study using electronic health records data from UK general practices from 1994 to 2015. Adults (≥18 years) with AD were matched on age, practice and index date to patients without AD. AD severity was categorized using treatments and dermatology referrals. Outcomes were incident anxiety, depression, bipolar disorder, schizophrenia, attention-deficit/hyperactivity disorder (ADHD), autism, obsessive-compulsive disorder (OCD), suicidality and completed suicide. RESULTS: Comparing 625,083 adults with AD to 2,678,888 adults without AD, AD was associated with higher risk of anxiety [HR 1.14 (1.13-1.15)], depression [1.14 (1.13-1.15)] and OCD [1.48 (1.38-1.58)] across all severities. Mild or moderate AD was also associated with higher risk of autism, ADHD, bipolar disorder and suicidality. CONCLUSIONS: Atopic dermatitis is associated with a higher risk of multiple neuropsychiatric conditions, but these risks differ by specific condition and AD severity. Clinicians should inquire about mental health in patients with AD.

Risk of atopic dermatitis and the atopic march paradigm in children of mothers with atopic illnesses: A birth cohort study from the United Kingdom.

BACKGROUND: Atopic dermatitis (AD) is thought to precede the onset of other allergic illness (OAI) in a temporal progression (ie, atopic march), yet the timing and progression has been questioned. It is also unclear how parental allergic illness impacts the development of these illnesses in offspring. OBJECTIVE: (1) Explore risk of incident AD and (2) timing of allergic disease onset in children of mothers with AD compared with mothers without AD from the United Kingdom. METHODS: We created a birth cohort of mother-child pairs using IQVIA Medical Research Data database and developed Cox proportional models to examine the above associations (hazard ratio, HR [95% confidence interval, CI]). RESULTS: Among 1,224,243 child-mother pairs, mean child (standard deviation) follow-up time was 10.8 (8.3) years and 50.1% were males (N = 600,905). Children were 59% (HR = 1.59 [1.57, 1.60]) more likely to have AD if their mothers had AD compared with no AD with mean age of first AD diagnosis at 3.3 (4.8) years. Most children with any diagnosis of AD present with AD first (91.0%); however, in those with asthma, only 67.8% developed AD first. CONCLUSION: Children born to mothers with AD are more prone to develop AD and some develop OAI first, suggesting that not all follow the same sequential pathway.

In utero or early in life exposure to antibiotics and the risk of childhood atopic dermatitis, a population-based cohort study.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory disease of the skin that begins early in life and can be lifelong. The purpose of our study was to evaluate whether fetal exposure and/or early life exposure of a child to antibiotics increases the risk of early onset AD. OBJECTIVE: We hypothesize that antibiotic exposure in utero or early in life (e.g., first 90 days) increases the likelihood that children develop AD. METHODS: Utilizing a large prospectively collected electronic medical records database, we studied the association of antibiotic exposure received in utero or very early in life and the relative risk of onset of AD in a population-based cohort study. Associations were estimated using proportional hazards models as hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: The risk of AD in childhood was increased after in utero or early life antibiotic exposure. For any in utero AB exposure the HR was 1.38 (1.36,1.39). However, penicillin demonstrated the strongest association with AD for both in utero exposure, 1.43 (1.41,1.44), and for childhood exposure, 1.81(1.79,1.82). HRs were higher in children born to mothers without AD than those with AD pointing to effect modification by maternal AD status. CONCLUSION: Children born to mothers exposed to antibiotics while in utero had, depending on the mother's history of AD, approximately a 20 to 40% increased risk of developing AD. Depending on the antibiotic, children who received antibiotics early-in-life had a 40 to 80% increased risk of developing AD. Our study, supports and refines the association between incident AD and antibiotic administration. It also adds population-based support to therapeutic attempts to treat AD by modifying skin microbiome.

Comparing gingivitis diagnoses by bleeding on probing (BOP) exclusively versus BOP combined with visual signs using large electronic dental records.

The major significance of the 2018 gingivitis classification criteria is utilizing a simple, objective, and reliable clinical sign, bleeding on probing score (BOP%), to diagnose gingivitis. However, studies report variations in gingivitis diagnoses with the potential to under- or over-estimating disease occurrence. This study determined the agreement between gingivitis diagnoses generated using the 2018 criteria (BOP%) versus diagnoses using BOP% and other gingival visual assessments. We conducted a retrospective study of 28,908 patients' electronic dental records (EDR) from January-2009 to December-2014, at the Indiana University School of Dentistry. Computational and natural language processing (NLP) approaches were developed to diagnose gingivitis cases from BOP% and retrieve diagnoses from clinical notes. Subsequently, we determined the agreement between BOP%-generated diagnoses and clinician-recorded diagnoses. A thirty-four percent agreement was present between BOP%-generated diagnoses and clinician-recorded diagnoses for disease status (no gingivitis/gingivitis) and a 9% agreement for the disease extent (localized/generalized gingivitis). The computational program and NLP performed excellently with 99.5% and 98% f-1 measures, respectively. Sixty-six percent of patients diagnosed with gingivitis were reclassified as having healthy gingiva based on the 2018 diagnostic classification. The results indicate potential challenges with clinicians adopting the new diagnostic criterion as they transition to using the BOP% alone and not considering the visual signs of inflammation. Periodic training and calibration could facilitate clinicians' and researchers' adoption of the 2018 diagnostic system. The informatics approaches developed could be utilized to automate diagnostic findings from EDR charting and clinical notes.

Risk of Inflammatory Bowel Disease in Patients With Atopic Dermatitis.

Importance: Data on the association between atopic dermatitis (AD) and inflammatory bowel disease (IBD) are inconsistent. Few studies have examined the association of AD or AD severity with risk of ulcerative colitis (UC) and Crohn disease (CD) separately. Objectives: To examine the risk of new-onset IBD, UC, and CD in children and adults with AD. Design, Setting, and Participants: This population-based cohort study assessed patients with AD matched with up to 5 controls on age, practice, and index date. Treatment exposure was used as a proxy for AD severity. Data were retrieved from The Health Improvement Network, a UK electronic medical record database, for January 1, 1994, to February 28, 2015. Data analysis was performed from January 8, 2020, to June 30, 2023. Main Outcomes and Measures: Outcomes of interest were incident IBD, UC, and CD. Logistic regression was used to examine the risk for each outcome in children and adults with AD compared with controls. Results: A total of 1 809 029 pediatric controls were matched to 409 431 children with AD (93.2% mild, 5.5% moderate, and 1.3% severe). The pediatric cohort ranged in median age from 4 to 5 years (overall range, 1-10 years), was predominantly male (936 750 [51.8%] controls, 196 996 [51.6%] with mild AD, 11 379 [50.7%] with moderate AD, and 2985 [56.1%] with severe AD), and with similar socioeconomic status. A total of 2 678 888 adult controls were matched to 625 083 adults with AD (65.7% mild, 31.4% moderate, and 2.9% severe). The adult cohort ranged in median age from 45 to 50 years (overall range, 30-68 years) and was predominantly female (1 445 589 [54.0%] controls, 256 071 [62.3%] with mild AD, 109 404 [55.8%] with moderate AD, and 10 736 [59.3%] with severe AD). In fully adjusted models, children with AD had a 44% increased risk of IBD (hazard ratio [HR], 1.44; 95% CI, 1.31-1.58) and a 74% increased risk of CD (HR, 1.74; 95% CI, 1.54-1.97), which increased with worsening AD; however, they did not have increased risk of UC (HR, 1.09; 95% CI, 0.94-1.27) except for those with severe AD (HR, 1.65; 95% CI, 1.02-2.67). Adults with AD had a 34% (HR, 1.34; 95% CI, 1.27-1.40) increased risk of IBD, a 36% (HR, 1.36; 95% CI, 1.26-1.47) increased risk of CB, and a 32% (HR, 1.32; 95% CI, 1.24-1.41) increased risk of UC, with risk increasing with worsening AD. Conclusion and Relevance: In this cohort study, children and adults with AD had an increased risk of IBD, with risk varying by age, AD severity, and IBD subtype. These findings provide new insights into the association between AD and IBD. Clinicians should be aware of these risks, particularly when selecting systemic treatments for AD in patients who may have coincident gastrointestinal symptoms.

Targeted and Logical Discovery of Piperazic Acid-Bearing Natural Products Based on Genomic and Spectroscopic Signatures.

A targeted and logical discovery method was devised for natural products containing piperazic acid (Piz), which is biosynthesized from ornithine by l-ornithine N-hydroxylase (KtzI) and N-N bond formation enzyme (KtzT). Genomic signature-based screening of a bacterial DNA library (2020 strains) using polymerase chain reaction (PCR) primers targeting ktzT identified 62 strains (3.1%). The PCR amplicons of KtzT-encoding genes were phylogenetically analyzed to classify the 23 clades into two monophyletic groups, I and II. Cultivating hit strains in media supplemented with 15NH4Cl and applying 1H-15N heteronuclear multiple bond correlation (HMBC) along with 1H-15N heteronuclear single quantum coherence (HSQC) and 1H-15N HSQC-total correlation spectroscopy (HSQC-TOCSY) NMR experiments detected the spectroscopic signatures of Piz and modified Piz. Chemical investigation of the hit strains prioritized by genomic and spectroscopic signatures led to the identification of a new azinothricin congener, polyoxyperuin B seco acid (1), previously reported chloptosin (2) in group I, depsidomycin D (3) incorporating two dehydropiperazic acids (Dpz), and lenziamides A and B (4 and 5), structurally novel 31-membered cyclic decapeptides in group II. By consolidating the phylogenetic and chemical analyses, clade-structure relationships were elucidated for 19 of the 23 clades. Lenziamide A (4) inhibited STAT3 activation and induced G2/M cell cycle arrest, apoptotic cell death, and tumor growth suppression in human colorectal cancer cells. Moreover, lenziamide A (4) resensitized 5-fluorouracil (5-FU) activity in both in vitro cell cultures and the in vivo 5-FU-resistant tumor xenograft mouse model. This work demonstrates that the genomic and spectroscopic signature-based searches provide an efficient and general strategy for new bioactive natural products containing specific structural motifs.

Incidence of Cardiovascular Disease and Venous Thromboembolism in Patients With Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) may increase risk for atherothrombotic and cardiovascular (CV) disease. OBJECTIVE: Determine CV disease and venous thromboembolism risk among patients with AD. METHODS: Cohort study using electronic health data from U.K. general practices in 1994 to 2015. Children (<18 y) and adults (≥18 y) with AD were matched to patients without AD on age, same practice, and encounter date. Treatments and specialist referrals served as proxies of AD severity. Outcomes were incident myocardial infarction, cerebrovascular accident (CVA), diabetes, hypertension, dyslipidemia, deep vein thrombosis (DVT), and pulmonary embolism. Cox regression analysis was used to compare outcomes in AD versus non-AD patients. RESULTS: Comparing 409,341 children with AD (93.2% mild, 5.5% moderate, and 1.3% severe) to 1,809,029 unaffected children, AD was associated with higher risk of DVT (hazard ratio [HR] 1.23; 95% confidence interval [95% CI] 1.02-1.48) and severe AD was associated with higher risk of CVA (HR 2.43; 95% CI 1.13-5.22) and diabetes (HR 1.46; 95% CI 1.06-2.01). Comparing 625,083 adults with AD (65.7% mild, 31.4% moderate, and 2.9% severe) to 2,678,888 unaffected adults, AD, especially when severe, was associated with higher risk of DVT (HR 1.14; 95% CI 1.11-1.18; and HR 1.64; 95% CI 1.49-1.82, respectively) and small but increased risks of CVA, diabetes, and dyslipidemia. Adults with severe AD had higher risk of myocardial infarction (HR 1.27; 95% CI 1.15-1.39), CVA (HR 1.21; 95% CI 1.13-1.30), diabetes (HR 1.15; 95% CI 1.09-1.22), dyslipidemia (HR 1.11; 95% CI 1.06-1.17), and pulmonary embolism (HR 1.39; 95% CI 1.21-1.60) compared with adults without AD. CONCLUSIONS: Atopic dermatitis, particularly when severe, is associated with small but increased risks of CV risk factors and events and significantly increased risk of venous thromboembolism.

Lung injury induces a polarized immune response by self-antigen-specific CD4+ Foxp3+ regulatory T cells.

Self-antigen-specific T cells are prevalent in the mature adaptive immune system but are regulated through multiple mechanisms of tolerance. However, inflammatory conditions such as tissue injury may allow these T cells to break tolerance and trigger autoimmunity. To understand how the T cell repertoire responds to the presentation of self-antigen under highly stimulatory conditions, we use peptide:major histocompatibility complex (MHC) class II tetramers to track the behavior of endogenous CD4+ T cells with specificity to a lung-expressed self-antigen in mouse models of immune-mediated lung injury. Acute injury results in the exclusive expansion of CD4+ regulatory T cells (Tregs) that is dependent on self-antigen recognition and interleukin-2 (IL-2). Conversely, conventional CD4+ T cells of the same self-antigen specificity remain unresponsive even following Treg ablation. Thus, the self-antigen-specific CD4+ T cell repertoire is poised to serve a regulatory function during acute tissue damage to limit further damage and the possibility of autoimmunity.

Dissecting neuron-specific functions of circadian genes using modified cell-specific CRISPR approaches.

Circadian behavioral rhythms in Drosophila melanogaster are regulated by about 75 pairs of brain neurons. They all express the core clock genes but have distinct functions and gene expression profiles. To understand the importance of these distinct molecular programs, neuron-specific gene manipulations are essential. Although RNAi based methods are standard to manipulate gene expression in a cell-specific manner, they are often ineffective, especially in assays involving smaller numbers of neurons or weaker Gal4 drivers. We and others recently exploited a neuron-specific CRISPR-based method to mutagenize genes within circadian neurons. Here, we further explore this approach to mutagenize three well-studied clock genes: the transcription factor gene vrille, the photoreceptor gene Cryptochrome (cry), and the neuropeptide gene Pdf (pigment dispersing factor). The CRISPR-based strategy not only reproduced their known phenotypes but also assigned cry function for different light-mediated phenotypes to discrete, different subsets of clock neurons. We further tested two recently published methods for temporal regulation in adult neurons, inducible Cas9 and the auxin-inducible gene expression system. The results were not identical, but both approaches successfully showed that the adult-specific knockout of the neuropeptide Pdf reproduces the canonical loss-of-function mutant phenotypes. In summary, a CRISPR-based strategy is a highly effective, reliable, and general method to temporally manipulate gene function in specific adult neurons.