Synergistic Coordination of Chromatin Torsional Mechanics and Topoisomerase Activity.

DNA replication in eukaryotes generates DNA supercoiling, which may intertwine (braid) daughter chromatin fibers to form precatenanes, posing topological challenges during chromosome segregation. The mechanisms that limit precatenane formation remain unclear. By making direct torque measurements, we demonstrate that the intrinsic mechanical properties of chromatin play a fundamental role in dictating precatenane formation and regulating chromatin topology. Whereas a single chromatin fiber is torsionally soft, a braided fiber is torsionally stiff, indicating that supercoiling on chromatin substrates is preferentially directed in front of the fork during replication. We further show that topoisomerase II relaxation displays a strong preference for a single chromatin fiber over a braided fiber. These results suggest a synergistic coordination-the mechanical properties of chromatin inherently suppress precatenane formation during replication elongation by driving DNA supercoiling ahead of the fork, where supercoiling is more efficiently removed by topoisomerase II. VIDEO ABSTRACT.

The miniature CRISPR-Cas12m effector binds DNA to block transcription.

CRISPR-Cas are prokaryotic adaptive immune systems. Cas nucleases generally use CRISPR-derived RNA guides to specifically bind and cleave DNA or RNA targets. Here, we describe the experimental characterization of a bacterial CRISPR effector protein Cas12m representing subtype V-M. Despite being less than half the size of Cas12a, Cas12m catalyzes auto-processing of a crRNA guide, recognizes a 5'-TTN' protospacer-adjacent motif (PAM), and stably binds a guide-complementary double-stranded DNA (dsDNA). Cas12m has a RuvC domain with a non-canonical catalytic site and accordingly is incapable of guide-dependent cleavage of target nucleic acids. Despite lacking target cleavage activity, the high binding affinity of Cas12m to dsDNA targets allows for interference as demonstrated by its ability to protect bacteria against invading plasmids through silencing invader transcription and/or replication. Based on these molecular features, we repurposed Cas12m by fusing it to a cytidine deaminase that resulted in base editing within a distinct window.

Chitinase 3-like-1 Inhibits Innate Antitumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα- and CD24-Siglec10-Mediated Phagocytosis.

Innate immune responses such as phagocytosis are critically linked to the generation of adaptive immune responses against the neoantigens in cancer and the efferocytosis that is essential for homeostasis in diseases characterized by lung injury, inflammation, and remodeling as in chronic obstructive pulmonary disease (COPD). Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it inhibits adaptive immune responses by stimulating immune checkpoint molecules (ICPs) and portends a poor prognosis. CHI3L1 is also induced in COPD where it regulates epithelial cell death. In this study, we demonstrate that pulmonary melanoma metastasis inhibits macrophage phagocytosis by stimulating the CD47-SIRPα and CD24-Siglec10 phagocytosis checkpoint pathways while inhibiting macrophage "eat me" signals from calreticulin and HMGB1. We also demonstrate that these effects on macrophage phagocytosis are associated with CHI3L1 stimulation of the SHP-1 and SHP-2 phosphatases and inhibition of the accumulation and phosphorylation of cytoskeleton-regulating nonmuscle myosin IIa. This inhibition of innate immune responses such as phagocytosis provides a mechanistic explanation for the ability of CHI3L1 to stimulate ICPs and inhibit adaptive immune responses in cancer and diseases such as COPD. The ability of CHI3L1 to simultaneously inhibit innate immune responses, stimulate ICPs, inhibit T cell costimulation, and regulate a number of other oncogenic and inflammation pathways suggests that CHI3L1-targeted therapeutics are promising interventions in cancer, COPD, and other disorders.

Induction of a memory-like CD4+ T-cell phenotype by airway smooth muscle cells.

In asthma, CD4+ T-cell interaction with airway smooth muscle (ASM) may enhance its contractile properties and promote its proliferation. However, less is known about the effects of this interaction on T cells. To explore the consequences of interaction of CD4+ T cells with ASM we placed the cells in co-culture and analyzed the phenotypic and functional changes in the T cells. Effector status as well as cytokine expression was assessed by flow cytometry. An increase in CD45RA-CD45RO+ memory T cells was observed after co-culture; however, these cells were not more responsive to CD3/28 restimulation. A reduction in mitochondrial coupling and an increase in the production of mitochondrial reactive oxygen species by CD4+ T cells post-restimulation suggested altered mitochondrial metabolism after co-culture. RNA sequencing analysis of the T cells revealed characteristic downregulation of effector T-cell-associated genes, but a lack of upregulation of memory T-cell-associated genes. The results of this study demonstrate that ASM cells can induce a phenotypic shift in CD4+ T cells into memory-like T cells but with reduced capacity for activation.

Etoposide promotes DNA loop trapping and barrier formation by topoisomerase II.

Etoposide is a broadly employed chemotherapeutic and eukaryotic topoisomerase II poison that stabilizes cleaved DNA intermediates to promote DNA breakage and cytotoxicity. How etoposide perturbs topoisomerase dynamics is not known. Here we investigated the action of etoposide on yeast topoisomerase II, human topoisomerase IIα and human topoisomerase IIß using several sensitive single-molecule detection methods. Unexpectedly, we found that etoposide induces topoisomerase to trap DNA loops, compacting DNA and restructuring DNA topology. Loop trapping occurs after ATP hydrolysis but before strand ejection from the enzyme. Although etoposide decreases the innate stability of topoisomerase dimers, it increases the ability of the enzyme to act as a stable roadblock. Interestingly, the three topoisomerases show similar etoposide-mediated resistance to dimer separation and sliding along DNA but different abilities to compact DNA and chirally relax DNA supercoils. These data provide unique mechanistic insights into the functional consequences of etoposide on topoisomerase II dynamics.

Overnight Electroencephalogram to Forecast Epilepsy Development in Children with Autism Spectrum Disorders.

OBJECTIVE: To establish the utility of long-term electroencephalogram (EEG) in forecasting epilepsy onset in children with autism spectrum disorder (ASD). STUDY DESIGN: A single-institution, retrospective analysis of children with ASD, examining long-term overnight EEG recordings collected over a period of 15 years, was conducted. Clinical EEG findings, patient demographics, medical histories, and additional Autism Diagnostic Observation Schedule data were examined. Predictors for the timing of epilepsy onset were evaluated using survival analysis and Cox regression. RESULTS: Among 151 patients, 17.2% (n = 26) developed unprovoked seizures (Sz group), while 82.8% (n = 125) did not (non-Sz group). The Sz group displayed a higher percentage of interictal epileptiform discharges (IEDs) in their initial EEGs compared with the non-Sz group (46.2% vs 20.0%, P = .01). The Sz group also exhibited a greater frequency of slowing (42.3% vs 13.6%, P < .01). The presence of IEDs or slowing predicted an earlier seizure onset, based on survival analysis. Multivariate Cox proportional hazards regression revealed that the presence of any IEDs (HR 3.83, 95% CI 1.38-10.65, P = .01) or any slowing (HR 2.78, 95% CI 1.02-7.58, P = .046 significantly increased the risk of developing unprovoked seizures. CONCLUSION: Long-term EEGs are valuable for predicting future epilepsy in children with ASD. These findings can guide clinicians in early education and potential interventions for epilepsy prevention.

A new hip fracture risk index derived from FEA-computed proximal femur fracture loads and energies-to-failure.

Hip fracture risk assessment is an important but challenging task. Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur. We developed a global FEA-computed fracture risk index to increase the prediction accuracy of hip fracture incidence. PURPOSE: Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur to compute the force (fracture load) and energy necessary to break the proximal femur in a particular loading condition. The fracture loads and energies-to-failure are individually associated with incident hip fracture, and provide different structural information about the proximal femur. METHODS: We used principal component analysis (PCA) to develop a global FEA-computed fracture risk index that incorporates the FEA-computed yield and ultimate failure loads and energies-to-failure in four loading conditions of 110 hip fracture subjects and 235 age- and sex-matched control subjects from the AGES-Reykjavik study. Using a logistic regression model, we compared the prediction performance for hip fracture based on the stratified resampling. RESULTS: We referred the first principal component (PC1) of the FE parameters as the global FEA-computed fracture risk index, which was the significant predictor of hip fracture (p-value < 0.001). The area under the receiver operating characteristic curve (AUC) using PC1 (0.776) was higher than that using all FE parameters combined (0.737) in the males (p-value < 0.001). CONCLUSIONS: The global FEA-computed fracture risk index increased hip fracture risk prediction accuracy in males.

Bilateral centromedian nucleus of thalamus responsive neurostimulation for pediatric-onset drug-resistant epilepsy.

Neuromodulation therapies offer an efficacious treatment alternative for patients with drug-resistant epilepsy (DRE), particularly those unlikely to benefit from surgical resection. Here we present our retrospective single-center case series of patients with pediatric-onset DRE who underwent responsive neurostimulation (RNS) depth electrode implantation targeting the bilateral centromedian nucleus (CM) of the thalamus between October 2020 and October 2022. Sixteen patients were identified; seizure outcomes, programming parameters, and complications at follow-up were reviewed. The median age at implantation was 13 years (range 3.6-22). Six patients (38%) were younger than 12 years of age at the time of implantation. Ictal electroencephalography (EEG) patterns during patients' most disabling seizures were reliably detected. Ten patients (62%) achieved 50% or greater reduction in seizure frequency at a median 1.3 years (range 0.6-2.6) of follow-up. Eight patients (50%) experienced sensorimotor side effects, and three patients (19%) had superficial pocket infection, prompting the removal of the RNS device. Side effects of stimulation were experienced mostly in monopolar-cathodal configuration and alleviated with programming change to bipolar configuration or low-frequency stimulation. Closed-loop neurostimulation using RNS targeting bilateral CM is a feasible and useful therapy for patients with pediatric-onset DRE.

MutL binds to 3' resected DNA ends and blocks DNA polymerase access.

DNA mismatch repair removes mis-incorporated bases after DNA replication and reduces the error rate a 100-1000-fold. After recognition of a mismatch, a large section of up to a thousand nucleotides is removed from the daughter strand followed by re-synthesis. How these opposite activities are coordinated is poorly understood. Here we show that the Escherichia coli MutL protein binds to the 3' end of the resected strand and blocks access of Pol I and Pol III. The cryo-EM structure of an 85-kDa MutL-DNA complex, determined to 3.7 Å resolution, reveals a unique DNA binding mode that positions MutL at the 3' end of a primer-template, but not at a 5' resected DNA end or a blunt DNA end. Hence, our work reveals a novel role for MutL in the final stages of mismatch repair by preventing premature DNA synthesis during removal of the mismatched strand.

Validating a Pragmatic Measure of Evidence-Based Practice (EBP) Delivery: Therapist Reports of EBP Strategy Delivery and Associations with Child Outcome Trajectories.

Pragmatic measures of evidence-based practice (EBP) implementation can support and evaluate implementation efforts. We examined the predictive validity of therapist reports of EBP strategy delivery for children's mental health outcomes. Data were obtained from 1,380 sessions with 248 children delivered by 76 therapists in two county systems. Children (Mage=11.8 years, SD = 3.7) presented with internalizing (52%), externalizing (27%), trauma (16%), and other (5%) concerns. Therapists reported their delivery of EBP strategies on a revised version of the EBP Concordant Care Assessment (ECCA; Brookman-Frazee, et al., Administration and Policy in Mental Health and Mental Health Services Research, 48, 155-170, 2021) that included 25 content (e.g., parenting, cognitive behavioral) and 12 technique strategies (e.g., modeling, practice/role-play). On average, 5.6 ECCA session reports (SD = 2.3) were obtained for each client, and caregivers reported symptoms on the Brief Problem Checklist (Chorpita, et al., Journal of Consulting and Clinical Psychology, 78(4), 526-536, 2010) at baseline, weekly over two months, and again at four months. Multilevel models examined whether the mean extensiveness of each EBP strategy predicted trajectories of child outcomes. More individual technique (6 of 12) than content strategies (1 of 25) were associated with outcome trajectories. For techniques, more extensive use of Performance Feedback and Live Coaching and less extensive use of Addressing Barriers were associated with greater declines in total symptoms, and more extensive use of Establishing/Reviewing Goals, Tracking/Reviewing Progress, and Assigning/Reviewing Homework was associated with declines in externalizing symptoms. For content, more extensive use of Cognitive Restructuring was associated with declines in total symptoms. In addition, higher average extensiveness ratings of the top content strategy across sessions was associated with greater declines in total and externalizing symptoms. Therapist-reported delivery of some EBP strategies showed evidence of predictive validity and may hold utility in indexing quality of care.

Amycolatopsis from Desert Specialist Fungus-Growing Ants Suppresses Contaminant Fungi Using the Antibiotic ECO-0501.

Symbiotic Actinobacteria help fungus-growing ants suppress fungal pathogens through the production of antifungal compounds. Trachymyrmex ants of the southwest desert of the United States inhabit a unique niche far from the tropical rainforests in which most fungus-growing ant species are found. These ants may not encounter the specialist fungal pathogen Escovopsis known to threaten colonies of other fungus-growing ants. It is unknown whether Actinobacteria associated with these ants antagonize contaminant fungi and, if so, what the chemical basis of such antagonism is. We find that Pseudonocardia and Amycolatopsis strains isolated from three desert specialist Trachymyrmex species do antagonize diverse contaminant fungi isolated from field-collected ant colonies. We did not isolate the specialist fungal pathogen Escovopsis in our sampling. We trace strong antifungal activity from Amycolatopsis isolates to the molecule ECO-0501, an antibiotic that was previously under preclinical development as an antibacterial agent. In addition to suppression of contaminant fungi, we find that this molecule has strong activity against ant-associated Actinobacteria and may also play a role in bacterial competition in this niche. By studying interspecies interactions in a previously unexplored niche, we have uncovered novel bioactivity for a structurally unique antibiotic. IMPORTANCE Animal hosts often benefit from chemical defenses provided by microbes. These molecular defenses are a potential source of novel antibiotics and offer opportunities for understanding how antibiotics are used in ecological contexts with defined interspecies interactions. Here, we recover contaminant fungi from nests of Trachymyrmex fungus-growing ants of the southwest desert of the United States and find that they are suppressed by Actinobacteria isolated from these ants. The antibiotic ECO-0501 is an antifungal agent used by some of these Amycolatopsis bacterial isolates. This antibiotic was previously investigated in preclinical studies and known only for antibacterial activity.

Structured discharge documentation reduces sex-based disparities in statin prescription in vascular surgery patients.

OBJECTIVE: Perioperative statin use has been shown to improve survival in vascular surgery patients. In 2018, the Northern California Vascular Study Group implemented a quality initiative focused on the use of a SmartText in the discharge summary. We hypothesized that structured discharge documentation would decrease sex-based disparities in evidence-based medical therapy. METHODS: A retrospective analysis was conducted using Vascular Quality Initiative eligible cases at a single institution. Open or endovascular procedures in the abdominal aorta or lower extremity arteries from 2016 to 2021 were included. Bivariate analysis identified factors associated with statin use and sex. Multivariate logistic regression was performed with the end point of statin prescription at discharge and aspirin prescription at discharge. An interaction term assessed the differential impact of the initiative on both sexes. Analysis was then stratified by prior aspirin or statin prescription. An interrupted time series analysis was used to evaluate the trend in statin prescription over time. RESULTS: Overall, 866 patients were included, including 292 (34%) female and 574 (66%) male patients. Before implementation, statins were prescribed in 77% of male and 62% of female patients (P < .01). After implementation, there was no statistically significant difference in statin prescription (91% in male vs 92% in female patients, P = .68). Female patients saw a larger improvement in the adjusted odds of statin prescription compared with male patients (odds ratio: 3.1, 95% confidence interval: 1.1-8.6, P = .04). For patients not prescribed a statin preoperatively, female patients again saw an even larger improvement in the odds of being prescribed a statin at discharge (odds ratio: 6.4, 95% confidence interval: 1.8-22.7, P < .01). Interrupted time series analysis demonstrated a sustained improvement in the frequency of prescription for both sexes over time. The unadjusted frequency of aspirin prescription also improved by 3.5% in male patients vs 5.5% in female patients. For patients not prescribed an aspirin preoperatively, we found that the frequency of aspirin prescription significantly improved for both male (19% increase, P = .006) and female (31% increase, P = .001) patients. There was no significant difference in the perioperative outcomes between male and female patients before and after standardized discharge documentation. CONCLUSIONS: A simple, low-cost regional quality improvement initiative eliminated sex-based disparities in statin prescription at a single institution. These findings highlight the meaningful impact of regional quality improvement projects. Future studies should examine the potential for structured discharge documentation to improve patient outcomes and reduce disparities.

Proatherogenic conditions promote autoimmune T helper 17 cell responses in vivo.

Patients with systemic autoimmune diseases show increased incidence of atherosclerosis. However, the contribution of proatherogenic factors to autoimmunity remains unclear. We found that atherogenic mice (herein referred to as LDb mice) exhibited increased serum interleukin-17, which was associated with increased numbers of T helper 17 (Th17) cells in secondary lymphoid organs. The environment within LDb mice was substantially favorable for Th17 cell polarization of autoreactive T cells during homeostatic proliferation, which was considerably inhibited by antibodies directed against oxidized low-density lipoprotein (oxLDL). Moreover, the uptake of oxLDL induced dendritic-cell-mediated Th17 cell polarization by triggering IL-6 production in a process dependent on TLR4, CD36, and MyD88. Furthermore, self-reactive CD4(+) T cells that expanded in the presence of oxLDL induced more profound experimental autoimmune encephalomyelitis. These findings demonstrate that proatherogenic factors promote the polarization and inflammatory function of autoimmune Th17 cells, which could be critical for the pathogenesis of atherosclerosis and other related autoimmune diseases.

Fecal microbiota transplantation for patients with active ulcerative colitis: A cost-effectiveness analysis.

BACKGROUND AND AIM: Growing studies have demonstrated clinical benefits of fecal microbiota transplantation (FMT) therapy (administered by colonoscopy, enema, or both) for active ulcerative colitis (UC). This study aimed to evaluate the cost-effectiveness of standard treatment with and without FMT therapy for mild-to-moderate active UC from the perspective of US healthcare provider. METHODS: A 10-year Markov model was developed to evaluate the costs and quality-adjusted life-years (QALYs) of standard treatment plus FMT therapy versus standard treatment alone. Model inputs were retrieved from publish data in literature. Base-case and sensitivity analyses were performed. RESULTS: In the base-case analysis, standard treatment plus FMT therapy was more effective than standard treatment alone (by 0.068 QALYs). Comparing to standard treatment alone, standard treatment plus FMT therapy varied from cost-saving to incremental cost, subject to the number of FMT administrations. One-way sensitivity analysis identified the relative risk of achieving remission with FMT therapy to be the most influential factor on the incremental cost-effectiveness ratio of standard treatment plus FMT therapy. Monte-Carlo simulations showed that standard treatment plus FMT therapy with 3 and 6 administrations per FMT course was cost-effective (at willingness-to-pay threshold = 50 000 USD/QALY) in 90.77% and 67.03% of time, respectively. CONCLUSIONS: Standard treatment plus FMT therapy appears to be more effective in gaining higher QALYs than standard therapy alone for patients with mild-to-moderate active UC. Cost-effectiveness of standard treatment plus FMT therapy is highly subject to the relative improvement in achieving remission with standard therapy plus FMT therapy and number of FMT administrations per FMT course.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY BIOMARKERS AND MICROPERIMETRY FEATURES IN BEHÇET'S UVEITIS.

PURPOSE: To evaluate the parafoveal macular microvasculature and the macular function in patients with retinal vasculitis associated with Behçet's uveitis. METHODS: In 14 patients with inactive Behçet's uveitis and 26 control individuals (13 with nonocular Behçet's syndrome and 13 healthy subjects), we analyzed the retinal nerve fiber layer, ganglion cell layer, full retinal thickness, foveal avascular zone area and sectorial parafoveal vascular density in the superficial vascular plexus, intermediate capillary plexus, and deep capillary plexus using SPECTRALIS optical coherence tomography (OCT) 2 and OCT angiography. Macular sensitivity was analyzed using an MP-3 microperimeter. RESULTS: Eighteen eyes (78%) had a best-corrected visual acuity ≥ 20/25. Significant differences were found in Behçet's uveitis in comparison with the controls on the OCT and OCT angiography: 14.8%, 22.4%, and 14.9% ganglion cell layer thinning in the global, nasal, and inferior sectors, respectively; 6%, 13.2%, and 7.5% full retinal thickness thinning in the superior, nasal, and inferior sectors; and 16.8%, 14.9%, 23.6%, 15.8%, and 12.6% mean deep capillary plexus density reduction in the global, superior, nasal, inferior, and temporal sectors. Microperimetry data demonstrated significant mean reductions of 21% and 23.6% in central and average macular sensitivities and 28.8%, 40.4%, 27.7%, and 24.2% in the superior, nasal, inferior, and temporal sectors, respectively. Outer plexiform layer elevations were observed in Behçet's uveitis (69.6%). CONCLUSION: Behçet's uveitis presented structural and functional macular damage despite good best-corrected visual acuity, mainly affecting the nasal sector and the deep capillary plexus. On OCT and OCT angiography, quantitative and qualitative changes can be valuable biomarkers of ocular involvement in Behçet's syndrome.

Screening for parent and child ADHD in urban pediatric primary care: pilot implementation and stakeholder perspectives.

BACKGROUND: ADHD commonly co-occurs in children and parents. When ADHD is untreated in parents, it contributes to negative child developmental and treatment outcomes. Screening for parent and child ADHD co-occurrence in pediatric primary care may be an effective strategy for early identification and treatment. There is no data on whether this screening model can be implemented successfully and there exists limited guidance on how to effectively approach parents about their own ADHD in pediatric settings. Even greater sensitivity may be required when engaging with families living in urban, low SES communities due to systemic inequities, mistrust, and stigma. METHODS: The current pilot study described the first 6 months of implementation of a parent and child ADHD screening protocol in urban pediatric primary care clinics serving a large population of families insured through Medicaid. Parents and children were screened for ADHD symptoms at annual well-child visits in pediatric primary care clinics as part of standard behavioral health screening. Independent stakeholder group meetings were held to gather feedback on factors influencing the implementation of the screening and treatment strategies. Mixed methods were used to examine initial screening completion rates and stakeholder perspectives (i.e., parents, primary care office staff, pediatricians, and behavioral health providers) on challenges of implementing the screening protocol within urban pediatric primary care. RESULTS: Screening completion rates were low (19.28%) during the initial 6-month implementation period. Thematic analysis of stakeholder meetings provided elaboration on the low screening completion rates. Identified themes included: 1) divergence between provider enthusiasm and parent hesitation; 2) parent preference versus logistic reality of providers; 3) centering the experiences of people with marginalized identities; and 4) sensitivity when discussing parent mental health and medication. CONCLUSIONS: Findings highlight the importance of developing flexible approaches to screening parent and child ADHD in urban pediatric health settings and emphasize the importance of cultural sensitivity when working with marginalized and under-resourced families. TRIAL REGISTRATION: NCT04240756 (27/01/2020).

After the Crisis: Racial/Ethnic Disparities and Predictors of Care Use Following Youth Psychiatric Emergencies.

OBJECTIVE: Youth psychiatric emergencies have increased at alarming rates, and disproportionately so for youth of color. Outpatient follow-up care is critical for positive youth outcomes, but rates of follow-up remain low, especially for racial/ethnic minoritized youth. Mobile crisis response can initiate care connection. The current study (1) describes the population who received mobile crisis response (MCR) within the nation's largest county public mental health system, (2) assesses rates of follow-up outpatient services after MCR, and (3) examines racial/ethnic disparities in outpatient services and correlates of receipt of therapy dose (≥8 sessions). METHOD: Administrative claims for MCR and outpatient services for youth ages 0 to 18 were abstracted from the Los Angeles County Department of Mental Health. RESULTS: From October 2016-2019, 20,782 youth received a MCR, 52.5% of youth were female, and youth mean age was 13.41 years. The majority of youth (91.8%) received some outpatient services after their first MCR. However, only 56.7% of youth received ≥1 therapy session. In a logistic regression, youth age, gender, race/ethnicity, primary language, primary diagnosis, insurance status, MCR call location, and MCR disposition significantly predicted receipt of ≥8 therapy sessions. CONCLUSIONS: Findings highlight disparities in therapy receipt for Asian American Pacific Islander, Black, and White youth (relative to Latinx youth), older youth, youth whose MCR was initiated from a police station call, and youth whose MCR did not result in hospitalization. We discuss priorities for quality improvement for MCR processes and strategies to promote linkage to care to achieve mental health equity.

Dermatology in Contemporary Times: Building Awareness of Social Media's Association With Adolescent Skin Disease and Mental Health.

BACKGROUND: The contribution of psychological disorders to the burden of skin disease has been poorly explored in adolescent patients. The review aims to provide insights into the psychological, social, occupational, and social medias' association with acne, atopic dermatitis (AD), and aesthetics in adolescent patients. METHODS: The project used a modified Delphi process comprising face-to-face discussions followed up online.  The systematic literature search results informed the 14 draft statements. During an expert panel meeting, the draft statements underwent the panel's evaluation at a workshop, followed by a plenary discussion adopting five statements using evidence from the literature coupled with the panel's opinions and experiences.  Results: Studies reported an association between poor sleep, social impairment, and mental health disorders, including body dysmorphic disorder (BDD) with acne or AD in adolescents with acne or AD. Education for patients and parents may improve self-management skills and self-responsibility, promoting better outcomes for acne and AD. The use of certain types of social media can contribute to unrealistic expectations regarding the outcomes of cosmetic procedures. Social media use may also be associated with, and potentially contribute to unrealistic appearance expectations and certain mental health conditions. However, social media use may have benefits, such as connection, diversity, social support, increased self-esteem, safe identity experimentation, and an increased opportunity for self-disclosure.  Conclusions: The association with negative life events, BDD, suicidal ideation, depression, and anxiety are thought to be high for adolescent patients with acne or AD. Using social media for information has both positive and negative aspects. Awareness of the risks and benefits of receiving health information about dermatological disease among adolescents needs to be improved through the education of patients and clinicians. Action-oriented items need to be developed to help dermatologists address these issues in clinical practice.Rieder EA, Andriessen A, Cutler V, et al. Dermatology in contemporary times: building awareness of social media's association with adolescent skin disease and mental health. J Drugs Dermatol. 2023;22(8):817-825. doi:10.36849/JDD.7596.

Derrone Targeting the TGF Type 1 Receptor Kinase Improves Bleomycin-Mediated Pulmonary Fibrosis through Inhibition of Smad Signaling Pathway.

Transforming growth factor-ß (TGF-ß) has a strong impact on the pathogenesis of pulmonary fibrosis. Therefore, in this study, we investigated whether derrone promotes anti-fibrotic effects on TGF-ß1-stimulated MRC-5 lung fibroblast cells and bleomycin-induced lung fibrosis. Long-term treatment with high concentrations of derrone increased the cytotoxicity of MRC-5 cells; however, substantial cell death was not observed at low concentrations of derrone (below 0.05 µg/mL) during a three-day treatment. In addition, derrone significantly decreased the expressions of TGF-ß1, fibronectin, elastin, and collagen1α1, and these decreases were accompanied by downregulation of α-SMA expression in TGF-ß1-stimulated MRC-5 cells. Severe fibrotic histopathological changes in infiltration, alveolar congestion, and alveolar wall thickness were observed in bleomycin-treated mice; however, derrone supplementation significantly reduced these histological deformations. In addition, intratracheal administration of bleomycin resulted in lung collagen accumulation and high expression of α-SMA and fibrotic genes-including TGF-ß1, fibronectin, elastin, and collagen1α1-in the lungs. However, fibrotic severity in intranasal derrone-administrated mice was significantly less than that of bleomycin-administered mice. Molecular docking predicted that derrone potently fits into the ATP-binding pocket of the TGF-ß receptor type 1 kinase domain with stronger binding scores than ATP. Additionally, derrone inhibited TGF-ß1-induced phosphorylation and nuclear translocations of Smad2/3. Overall, derrone significantly attenuated TGF-ß1-stimulated lung inflammation in vitro and bleomycin-induced lung fibrosis in a murine model, indicating that derrone may be a promising candidate for preventing pulmonary fibrosis.

Kasugamycin Is a Novel Chitinase 1 Inhibitor with Strong Antifibrotic Effects on Pulmonary Fibrosis.

Pulmonary fibrosis is a devastating lung disease with few therapeutic options. CHIT1 (chitinase 1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through the regulation of TGF-ß (transforming growth factor-ß) signaling and effector function. Therefore, CHIT1 is a potential therapeutic target for pulmonary fibrosis. This study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis. Extensive screening of small molecule libraries identified the aminoglycoside antibiotic kasugamycin (KSM) as a potent CHIT1 inhibitor. Elevated concentrations of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In in vivo bleomycin- and TGF-ß-stimulated murine models of pulmonary fibrosis, KSM showed impressive antifibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that KSM inhibits fibrotic macrophage activation, fibroblast proliferation, and myofibroblast transformation. Null mutation of TGFBRAP1 (TGF-ß-associated protein 1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of KSM in in vivo lungs and in vitro fibroblasts responses. KSM inhibits the physical association between CHIT1 and TGFBRAP1, suggesting that the antifibrotic effect of KSM is mediated through regulation of TGFBRAP1, at least in part. These studies demonstrate that KSM is a novel CHIT1 inhibitor with a strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.