Multimodal analysis of dysregulated heme metabolism, hypoxic signaling, and stress erythropoiesis in Down syndrome.

Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), is characterized by delayed neurodevelopment, accelerated aging, and increased risk of many co-occurring conditions. Hypoxemia and dysregulated hematopoiesis have been documented in DS, but the underlying mechanisms and clinical consequences remain ill defined. We report an integrative multi-omic analysis of ∼400 research participants showing that people with DS display transcriptomic signatures indicative of elevated heme metabolism and increased hypoxic signaling across the lifespan, along with chronic overproduction of erythropoietin, elevated biomarkers of tissue-specific hypoxia, and hallmarks of stress erythropoiesis. Elevated heme metabolism, transcriptional signatures of hypoxia, and stress erythropoiesis are conserved in a mouse model of DS and associated with overexpression of select triplicated genes. These alterations are independent of the hyperactive interferon signaling characteristic of DS. These results reveal lifelong dysregulation of key oxygen-related processes that could contribute to the developmental and clinical hallmarks of DS.

Telehepatology Use and Satisfaction Among Vulnerable Cirrhosis Patients Across Three Healthcare Systems in the Coronavirus Disease Pandemic Era.

Background and Aims: Telehealth has emerged as an important mode of cirrhosis care delivery, but its use and satisfaction among vulnerable populations (eg, racial/ethnic minorities, socioeconomically disadvantaged, substance use disorders) are unknown. We evaluated digital capacity, telehealth use, satisfaction and associated factors among patients receiving hepatology care via telehealth (telehepatology) across 2 Veterans Affairs and 1 safety-net Healthcare systems. Methods: English- and Spanish-speaking adults with cirrhosis (N = 256) completed surveys on telehealth use and satisfaction, quality of life, pandemic stress, alcohol use and depression. Logistic regression analyses assessed telehealth use and general linear models evaluated telehealth satisfaction. Results: The mean age was 64.5 years, 80.9% were male and 35.9% Latino; 44.5% had alcohol-associated cirrhosis; 20.8% had decompensated cirrhosis; 100% had digital (phone/computer) capacity; and 75.0% used telehepatology in the prior 6 months. On multivariable analysis, participants with alcohol-associated (vs not) cirrhosis were less likely and those with greater pandemic stress were more likely to use telehepatology (odds ratio = 0.46 and 1.41, respectively; P < .05). Better quality of life was associated with higher telehepatology satisfaction and older age was associated with lower satisfaction (ß = 0.01 and -0.01, respectively; P < .05). Latinos had higher satisfaction, but alcohol use disorder was associated with less satisfaction with telehepatology visits (ß = 0.22 and -0.02, respectively; P < .05). Conclusion: Participants had high telehepatology capacity, yet demographics and alcohol-related problems influenced telehepatology use and satisfaction. Findings underscore the need for interventions to enhance patient experience with telehepatology for certain vulnerable groups including those with alcohol-associated cirrhosis in order to optimize care delivery.

Utilization of Dental Care and Oral Health Outcomes in the United States: Results from the National Health and Nutrition Examination Survey (2017-2020).

PURPOSE: This analysis aims to evaluate the association between the time since and reason for a patient's last dental appointment across clinical oral health outcomes. MATERIALS AND METHODS: We used data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES), a cross-sectional, nationally-representative survey of noninstitutionalized US adults. The predictors were the time since and the reason for the last dental appointment (routine vs. urgent). We examined the presence and number of missing teeth and teeth with untreated coronal and root caries. Multivariable regression models with interaction were used to assess the association between the time since the last dental appointment and clinical oral health outcomes among routine and urgent users separately. RESULTS: Two-thirds of the US population had a dental appointment within a year, while nearly 44 million individuals did not visit a dentist for the last three years. The odds of having teeth with untreated coronal or root caries increased with the length of time since the last appointment, and urgent users had worse dental outcomes compared to routine users. Compared to those who had a dental appointment within a year, individuals who had their last dental appointment more than 3 years ago had 2.94 times the average number of teeth with untreated caries among routine users (95%CI=2.39, 3.62) and 1.60 times the average among urgent users (95%CI=1.05, 2.43). CONCLUSIONS: Recent, routine dental appointments are associated with improved oral health outcomes. The outcomes reiterate how social determinants of health impact access to oral health care and oral health outcomes.

Assessment of suicidal thoughts and behaviors in adults: A systematic review of measure psychometric properties and implications for clinical and research utility.

High-quality clinical care and research on suicidal thoughts and behaviors (STBs) depends on availability and implementation of reliable and valid measures of STBs. In contrast to studies examining STB risk factors, screening instruments, or treatment, little research has rigorously examined the content, characteristics, and psychometric properties of STB measures themselves. This systematic review (1) identified STB measures that conform to empirically supported definitions of STBs, and (2) identified peer-reviewed papers reporting on the psychometric properties of these measures in adults. Data on psychometric properties and other measure characteristics were extracted. A total of 21 eligible measures were identified in the first stage. In the second stage, 70 articles (with 79 independent samples) were included with psychometric data in adult samples for 19 measures. Although there was support for strong internal consistency and content validity across many measures, face validity and clinical utility concerns were prevalent. Few measures comprehensively assessed suicidal behaviors, and interview-based assessments tended to show the strongest psychometric properties and clinical utility. Findings are discussed in the context of recommendations for improving existing measures, including future research to increase utility and translatability across clinical settings, delivery methods, and diverse populations.

The 4.2 ka event is not remarkable in the context of Holocene climate variability.

The "4.2 ka event" is a commonly described abrupt climate excursion that occurred about 4200 years ago. However, the extent to which this event is coherent across regional and larger scales is unclear. To objectively assess climate excursions in the Holocene we compile 1142 paleoclimate datasets that span all continents and oceans and include a wide variety of archive and proxy types. We analyze these data to determine the timing, significance and spatial imprint of climate excursions using an objective method that quantifies local, regional and global significance. Site-level excursions in temperature and hydroclimate are common throughout the Holocene, but significant global-scale excursions are rare. The most prominent excursion occurred 8200 years ago, when cold and dry conditions formed a large, significant excursion centered in the North Atlantic. We find additional significant excursions between 1600 and 1000 years ago, which agree with tree-ring data and annual-scale paleoclimate reconstructions, adding confidence and context to our findings. In contrast, although some datasets show significant climate excursions 4200 years ago, they do not occur in large, coherent spatial regions. Consequently, like most other periods in the Holocene, the "4.2 ka event" is not a globally significant climate excursion.

A Scalable and Surfactant-Free Emulsion Method for Producing Microbeads from Varied Biomass Feedstocks.

Despite national and international regulations, plastic microbeads are still widely used in personal care and consumer products (PCCPs). These exfoliants and rheological modifiers cause significant microplastic pollution in natural aquatic environments. Microbeads from nonderivatized biomass like cellulose and lignin can offer a sustainable alternative to these nondegradable microplastics, but processing this biomass into microbeads is challenging due to limited viable solvents and high biomass solution viscosities. To produce biomass microbeads of the appropriate size range for PCCPs (ca. 200-800 µm diameter) with shapes and mechanical properties comparable to those of commercial plastic microbeads, we used a surfactant-free emulsion/precipitation method, mixing biomass solutions in 1-ethyl-3-methylimidazolium acetate (EMImAc) with various oils and precipitating with ethanol. While yield of microbeads within the target size range highly depends on purification conditions, optimized protocols led to >90% yield of cellulose microbeads. Kraft lignin was then successfully incorporated into beads at up to 20 wt %; however, higher lignin contents result in emulsion destabilization unless surfactant is added. Finally, the microbead shape and surface morphology can be tuned using oils of varying viscosities and interfacial tensions. Dripping measurements and pendant drop tensiometry confirmed that the higher affinity of cellulose for certain oil/IL interfaces largely controlled the observed surface morphology. This work thus outlines how biomass composition, oil viscosity, and interfacial properties can be altered to produce more sustainable microbeads for use in PCCPs, which have desirable mechanical properties and can be produced over a wide range of shapes and surface morphologies.

The Opportunities and Risks of Large Language Models in Mental Health.

Unlabelled: Global rates of mental health concerns are rising, and there is increasing realization that existing models of mental health care will not adequately expand to meet the demand. With the emergence of large language models (LLMs) has come great optimism regarding their promise to create novel, large-scale solutions to support mental health. Despite their nascence, LLMs have already been applied to mental health-related tasks. In this paper, we summarize the extant literature on efforts to use LLMs to provide mental health education, assessment, and intervention and highlight key opportunities for positive impact in each area. We then highlight risks associated with LLMs' application to mental health and encourage the adoption of strategies to mitigate these risks. The urgent need for mental health support must be balanced with responsible development, testing, and deployment of mental health LLMs. It is especially critical to ensure that mental health LLMs are fine-tuned for mental health, enhance mental health equity, and adhere to ethical standards and that people, including those with lived experience with mental health concerns, are involved in all stages from development through deployment. Prioritizing these efforts will minimize potential harms to mental health and maximize the likelihood that LLMs will positively impact mental health globally.

Tau pathology in the dorsal raphe may be a prodromal indicator of Alzheimer's disease.

Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 25-80 years old without a known history of dementia, and its prevalence was comparable to the locus coeruleus (LC). By comparison, fewer cases were positive for other pathological proteins including α-synuclein, ß-amyloid, and TDP-43. To evaluate how early tau pathology impacts behavior, we overexpressed human P301L-tau in the DRN of mice and observed depressive-like behaviors and hyperactivity without deficits in spatial memory. Tau pathology was predominantly found in neurons relative to glia and colocalized with a significant proportion of Tph2-expressing neurons in the DRN. 5-HT neurons were also hyperexcitable in P301L-tauDRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs). Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1α and Frk expression, which suggests increased inflammatory signaling. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen. A significant proportion of this tau pathology colocalized with the serotonin reuptake transporter (SERT), suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together these results indicate that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to behavioral dysregulation, 5-HT neuronal dysfunction, and activation of local astrocytes which may be prodromal indicators of AD.

Nightside clouds and disequilibrium chemistry on the hot Jupiter WASP-43b.

Hot Jupiters are among the best-studied exoplanets, but it is still poorly understood how their chemical composition and cloud properties vary with longitude. Theoretical models predict that clouds may condense on the nightside and that molecular abundances can be driven out of equilibrium by zonal winds. Here we report a phase-resolved emission spectrum of the hot Jupiter WASP-43b measured from 5 µm to 12 µm with the JWST's Mid-Infrared Instrument. The spectra reveal a large day-night temperature contrast (with average brightness temperatures of 1,524 ± 35 K and 863 ± 23 K, respectively) and evidence for water absorption at all orbital phases. Comparisons with three-dimensional atmospheric models show that both the phase-curve shape and emission spectra strongly suggest the presence of nightside clouds that become optically thick to thermal emission at pressures greater than ~100 mbar. The dayside is consistent with a cloudless atmosphere above the mid-infrared photosphere. Contrary to expectations from equilibrium chemistry but consistent with disequilibrium kinetics models, methane is not detected on the nightside (2σ upper limit of 1-6 ppm, depending on model assumptions). Our results provide strong evidence that the atmosphere of WASP-43b is shaped by disequilibrium processes and provide new insights into the properties of the planet's nightside clouds. However, the remaining discrepancies between our observations and our predictive atmospheric models emphasize the importance of further exploring the effects of clouds and disequilibrium chemistry in numerical models.

The Evolving Role of Calcium Channel Blockers in Hypertension Management: Pharmacological and Clinical Considerations.

Worldwide, hypertension is the leading risk factor for cardiovascular disease and death. An estimated 122 million people, per the American Heart Association in 2023, have been diagnosed with this common condition. It is generally agreed that the primary goal in the treatment of hypertension is to reduce overall blood pressure to below 140/90 mmHg, with a more optimal goal of 130/80 mmHg. Common medications for treating hypertension include calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and diuretics. CCBs are one of the most widely studied agents and are generally recommended as first-line therapy alone and in combination therapies. This is largely based on the vast knowledge of CCB mechanisms and their minimal side effect profile. CCBs can be separated into two classes: dihydropyridine and non-dihydropyridine. Non-dihydropyridine CCBs act on voltage-dependent L-type calcium channels of cardiac and smooth muscle to decrease muscle contractility. Dihydropyridine CCBs act by vasodilating the peripheral vasculature. For many patients with only mild increases in systolic and diastolic blood pressure (e.g., stage 1 hypertension), the medical literature indicates that CCB monotherapy can be sufficient to control hypertension. In this regard, CCB monotherapy in those with stage 1 hypertension reduced renal and cardiovascular complications compared to other drug classes. Combination therapy with CCBs and angiotensin receptor blockers or angiotensin-converting enzyme inhibitors has been shown to be an effective dual therapy based on recent meta-analyses. This article is a review of calcium channel blockers and their use in treating hypertension with some updated and recent information on studies that have re-examined their use. As for new information, we tried to include some information from recent studies on hypertensive treatment involving calcium channel blockers.

Whole cervix imaging of collagen, muscle, and cellularity in term and preterm pregnancy.

Cervical softening and dilation are critical for the successful term delivery of a fetus, with premature changes associated with preterm birth. Traditional clinical measures like transvaginal ultrasound and Bishop scores fall short in predicting preterm births and elucidating the cervix's complex microstructural changes. Here, we introduce a magnetic resonance diffusion basis spectrum imaging (DBSI) technique for non-invasive, comprehensive imaging of cervical cellularity, collagen, and muscle fibers. This method is validated through ex vivo DBSI and histological analyses of specimens from total hysterectomies. Subsequently, retrospective in vivo DBSI analysis at 32 weeks of gestation in ten term deliveries and seven preterm deliveries with inflammation-related conditions shows distinct microstructural differences between the groups, alongside significant correlations with delivery timing. These results highlight DBSI's potential to improve understanding of premature cervical remodeling and aid in the evaluation of therapeutic interventions for at-risk pregnancies. Future studies will further assess DBSI's clinical applicability.

Covalent Functionalization of Silicon with Plasma-Grown "Fuzzy" Graphene: Robust Aqueous Photoelectrodes for CO2 Reduction by Molecular Catalysts.

Carbon electrodes are ideal for electrochemistry with molecular catalysts, exhibiting facile charge transfer and good stability. Yet for solar-driven catalysis with semiconductor light absorbers, stable semiconductor/carbon interfaces can be difficult to achieve, and carbon's high optical extinction means it can only be used in ultrathin layers. Here, we demonstrate a plasma-enhanced chemical vapor deposition process that achieves well-controlled deposition of out-of-plane "fuzzy" graphene (FG) on thermally oxidized Si substrates. The resulting Si|FG interfaces possess a silicon oxycarbide (SiOC) interfacial layer, implying covalent bonding between Si and the FG film that is consistent with the mechanical robustness observed from the films. The FG layer is uniform and tunable in thickness and optical transparency by deposition time. Using p-type Si|FG substrates, noncovalent immobilization of cobalt phthalocyanine (CoPc) molecular catalysts was employed for the photoelectrochemical reduction of CO2 in aqueous solution. The Si|FG|CoPc photocathodes exhibited good catalytic activity, yielding a current density of ∼1 mA/cm2, Faradaic efficiency for CO of ∼70% (balance H2), and stable photocurrent for at least 30 h at -1.5 V vs Ag/AgCl under 1-sun illumination. The results suggest that plasma-deposited FG is a robust carbon electrode for molecular catalysts and suitable for further development of aqueous-stable Si photocathodes for CO2 reduction.

Dominant stop-loss HNRNPA1 variants in juvenile-onset myopathy.

INTRODUCTION/AIMS: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1. METHODS: Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES). RESULTS: The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon. DISCUSSION: Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.

Provider Implicit Racial Bias in Pediatric Sickle Cell Disease.

BACKGROUND/OBJECTIVES: This study is to (1) assess implicit racial bias among pediatric providers and (2) use virtual patient (VP) vignettes to determine the impact of implicit racial bias on clinical decision-making in pediatric sickle cell disease (SCD) pain care. DESIGN/METHODS: This cross-sectional study was conducted at a mid-sized, freestanding children's hospital in the northeast. Participants (N = 52) were pediatric SCD providers (87% cisgender female, 90% White, M age = 38.78). Providers completed a demographic questionnaire, the race Implicit Association Test (IAT) with adult and child faces, and a measure of SCD explicit bias (5-point Likert scale). Providers also made clinical decisions for four VP vignettes depicting Black and White youth in the emergency department (ED) with either SCD or cancer pain. Frequency tables were calculated. RESULTS: On the race IAT, providers demonstrated a pro-White implicit bias for both adult (81%) and child (89%) faces. Responses to the explicit bias measure reflected low levels of agreement with negative stereotypes about SCD patients. No significant differences emerged in providers' pain treatment decisions for Black vs. White, or SCD vs. cancer VPs. CONCLUSIONS: Findings indicate pediatric providers harbor implicit racial bias similar to the general population. Findings from VP vignettes did not demonstrate that pain treatment decision-making differed based on race or diagnosis. This may be due to standardized protocols and procedures in the pediatric emergency setting. Future research is needed to clarify the role of implicit bias in clinical decision-making and the potential efficacy of treatment protocols in preventing biases from interfering with pediatric SCD pain care.

Oncogenic KRAS-dependent stromal interleukin-33 directs the pancreatic microenvironment to promote tumor growth.

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer associated fibroblasts (CAFs). The mechanisms underlying this conversion, including regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to target CAFs therapeutically have so far failed. Here, we show that signals from epithelial cells expressing oncogenic KRAS -a hallmark pancreatic cancer mutation- activate fibroblast autocrine signaling, which drives expression of the cytokine interleukin-33 (IL-33). Stromal IL-33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces IL-33 secretion. Using compartment-specific IL-33 knockout mice, we observed that lack of stromal IL-33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells and lymphocytes. Notably, loss of stromal IL-33 leads to an increase in CD8+ T cell infiltration and activation, and, ultimately, reduced tumor growth.

Investigations into the role of platelet-activating factor (PAF) in the peri-conception period of the mare.

Platelet-activating factor (PAF) has been implicated in a number of reproductive processes ranging from ovulation to embryo motility, but has not been widely explored in the mare. To identify the presence and examine the role of PAF in the equine periconception processes, targeted mass spectrometry coupled with chromatographic separation (LC-MS/MS) was performed on equine follicular fluid (FF), and PAF was quantitatively detected. Subsequently, untargeted high-resolution mass spectrometry-based lipidomic analysis was carried out to quantify PAF in different sized pre-ovulatory follicles, whereby different molecular species of PAF, PAF(14:0) and PAF(16:1), were both seen to be increasing with follicle diameter. These findings suggest that PAF within FF is increasing as preovulatory follicles approach ovulation. Additionally, immunofluorescence staining identified the PAF Receptor (PAFR) in the luminal pericellular, apical and basal aspect of equine oviductal epithelial cells. Lastly, an equine oviductal epithelial organoid model was generated, and showed that the addition of PAF significantly increased the ciliary beat frequency (CBF) (Hz), an action consistent with a role for PAF in embryo migration. It is proposed that the local action of PAF on the ciliated cells of the oviduct propels both the oocyte and the conceptus towards the uterus. In the mare, it appears that PAF is a contributor during the periconception period, potentially being a mediator in the mechanisms of ovulation and in the dialogue of very early pregnancy.

Single-fly genome assemblies fill major phylogenomic gaps across the Drosophilidae Tree of Life.

Long-read sequencing is driving rapid progress in genome assembly across all major groups of life, including species of the family Drosophilidae, a longtime model system for genetics, genomics, and evolution. We previously developed a cost-effective hybrid Oxford Nanopore (ONT) long-read and Illumina short-read sequencing approach and used it to assemble 101 drosophilid genomes from laboratory cultures, greatly increasing the number of genome assemblies for this taxonomic group. The next major challenge is to address the laboratory culture bias in taxon sampling by sequencing genomes of species that cannot easily be reared in the lab. Here, we build upon our previous methods to perform amplification-free ONT sequencing of single wild flies obtained either directly from the field or from ethanol-preserved specimens in museum collections, greatly improving the representation of lesser studied drosophilid taxa in whole-genome data. Using Illumina Novaseq X Plus and ONT P2 sequencers with R10.4.1 chemistry, we set a new benchmark for inexpensive hybrid genome assembly at US $150 per genome while assembling genomes from as little as 35 ng of genomic DNA from a single fly. We present 183 new genome assemblies for 179 species as a resource for drosophilid systematics, phylogenetics, and comparative genomics. Of these genomes, 62 are from pooled lab strains and 121 from single adult flies. Despite the sample limitations of working with small insects, most single-fly diploid assemblies are comparable in contiguity (>1 Mb contig N50), completeness (>98% complete dipteran BUSCOs), and accuracy (>QV40 genome-wide with ONT R10.4.1) to assemblies from inbred lines. We present a well-resolved multi-locus phylogeny for 360 drosophilid and 4 outgroup species encompassing all publicly available (as of August 2023) genomes for this group. Finally, we present a Progressive Cactus whole-genome, reference-free alignment built from a subset of 298 suitably high-quality drosophilid genomes. The new assemblies and alignment, along with updated laboratory protocols and computational pipelines, are released as an open resource and as a tool for studying evolution at the scale of an entire insect family.

JAK inhibition decreases the autoimmune burden in Down syndrome.

Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmune disorders and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. Here, we report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS. We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. We then report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. Analysis of the first 10 participants to complete the 16-week study shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. ClinicalTrials.gov identifier: NCT04246372.