Cumulative trauma, adversity, and loss among juvenile justice-involved girls: Implications for health disparities.

Adverse childhood experiences (ACEs) are social determinants of health that increase morbidity and mortality and are prevalent among juvenile justice-involved (JJI) youth. ACEs drive health-risk behaviors (e.g., substance use) that reflect maladaptive coping, increase arrest risk, and overlap with posttraumatic risk-seeking theoretically and reckless/self-destructive behaviors diagnostically. However, little is known, especially among girls, about cumulative developmental adversity burden distress (i.e., total cumulative/lifespan stressor reactivity, grief-specific and adversity-related symptoms, and adversity-driven maladaptive coping strategies by age 18) and associated health risk impacts. Therefore, we assessed (a) developmental adversity burden indicators capturing expanded ACEs (E-ACEs; reflecting cumulative losses and traumatic events), cumulative distress, and risk characteristics; (b) potential racial/ethnic differences in developmental adversity burden; and (c) predictors of maladaptive coping among 223 JJI girls. Participants averaged 15 E-ACEs, endorsing 61.0% of stressor reactivity reactions, 58.4% of cumulative grief-specific symptoms, 55.7% (avoidance) to 73.2% (arousal) of adversity-related symptoms, and 45.0% of adversity-driven maladaptive coping strategies. White JJI girls endorsed significantly higher stressor reactivity and maladaptive coping than Latina girls (e.g., 38.8% vs. 14.6% suicide attempts), ds = 0.56-0.71. Adaptive LASSO analyses of maladaptive coping highlighted primary contributions from stressor reactivity, arousal alterations (excluding reckless/self-destructive behaviors), and cognition/mood alterations but not E-ACEs, grief, avoidance, or intrusions. Participants reported high levels of all cumulative developmental adversity burden indicators (e.g., 81.6% reported reckless/self-destructive behaviors). Results support cumulative, adversity-informed, universal precautions and assessments. Further, emotion regulation interventions targeting stressor reactivity, cognition/mood alterations, and/or arousal alterations may be useful for JJI youth with maladaptive coping.

The effect of obstructive sleep apnea severity on PTSD symptoms during the course of esketamine treatment: a retrospective clinical study.

STUDY OBJECTIVES: Intranasal administration of esketamine is Food and Drug Administration-approved for treatment-resistant depression. In a recent retrospective case series, we show that it has promise in reducing symptoms of posttraumatic stress disorder (PTSD) as well. Untreated obstructive sleep apnea (OSA) is prevalent among veterans with PTSD and has been shown to interfere with other PTSD treatments. In the current study, we examined whether OSA impacts esketamine's effectiveness in reducing symptoms of PTSD or depression. METHODS: Participants were 60 veterans with a diagnosis of major depressive disorder and PTSD who received intranasal esketamine treatment at the San Diego Veterans Affairs (VA) Medical Center. We used growth-curve modeling to examine changes in depression and PTSD symptoms following esketamine treatments and, in the subset of individuals screened for OSA (n = 24, all prescribed positive airway pressure therapy), examined the impacts of OSA severity on these trajectories. RESULTS: We first showed that both PTSD and depressive symptoms significantly decreased over the course of esketamine treatment. In the subset of veterans screened for OSA, individuals with lower OSA severity reported the greatest reduction in PTSD symptoms, while veterans with the most severe OSA reported the least reduction in PTSD symptoms. Depression response was not affected by severity of OSA in this analysis. CONCLUSIONS: Veterans with PTSD and depression tend to benefit from esketamine treatment, but OSA may interfere with esketamine effectiveness. Comorbid OSA should be assessed for and treated to maximize esketamine's benefits in PTSD. CITATION: Titone MK, Hunt C, Bismark A, et al. The effect of obstructive sleep apnea severity on PTSD symptoms during the course of esketamine treatment: a retrospective clinical study. J Clin Sleep Med. 2023;19(12):2043-2051.

A retrospective analysis of haemolytic reactions to intravenous immunoglobulin using data from the Transfusion-Transmitted Injuries Surveillance System (Ontario).

BACKGROUND AND OBJECTIVES: Haemolysis can occur following intravenous immunoglobulin (IVIG) infusion. Haemovigilance data were analysed using a novel approach for including two control groups with no haemolysis to IVIG. Objectives included a summary of all reactions to IVIG, rate estimates and analysis of haemolytic reactions including risk factors. MATERIALS AND METHODS: Canadian haemovigilance data from Ontario (2013-2021), IVIG distribution and transfusion data from the blood supplier, and data from a large local transfusion registry were used. An 'other-reactions' control group included patients with IVIG reactions that were not haemolytic, and registry patients with no-reaction were the 'no-reaction controls'. Descriptive analysis and two logistic regression models for the different control groups were performed. RESULTS: One thousand one hundred and seventy reactions were included. Most common were febrile non haemolytic (26.1%), minor allergic (24.5%) and IVIG headache (15.3%) followed by haemolytic 10.9% (128/1170). Haemolytic reaction rates decreased over time: rates since 2020 estimated between 1.5 and 2.9/1000 kg IVIG used. The regression model for other-reaction controls identified two risk factors for haemolysis: non-O blood group recipients compared with group O recipients (p value = 0.0106) and IVIG dose per 10 g increase (OR 1.359; 95% CI 1.225-1.506). The model using no-reaction controls gave similar results and also showed no pre-medication was associated with a higher risk of haemolysis (OR 29.084; 95% CI 1.989-425.312). CONCLUSION: The frequency of haemolytic reactions has decreased over time. We confirmed non-O blood group recipients and IVIG dose as risk factors for haemolysis and raise the hypothesis that no pre-medication may increase the risk of haemolysis.

Veterans who focus on sexual assault trauma show slower between-session habituation and symptom reduction during prolonged exposure treatment for posttraumatic stress disorder.

OBJECTIVE: Prolonged exposure (PE) is an effective treatment for posttraumatic stress disorder (PTSD), but veterans with sexual assault (SA) trauma often discontinue it prematurely. Elevated dropout rates may be due to SA triggering more intense and complex emotions that are more difficult to habituate during imaginal exposures; SA during PE has yet to be examined as a moderator of distress habituation or symptom reduction. METHOD: Participants were N = 65 veterans (n = 12 SA treatment focus; n = 10 SA history but not treatment focus; n = 43 no SA history) enrolled in a clinical trial of a preparatory sleep intervention followed by PE. The sample was representative of the veteran population. Growth curve modeling was used to examine differences in peak subjective units of distress scale (SUDS) ratings across imaginal exposures and changes in biweekly PTSD symptom assessments between veterans who did versus did not focus on SA during PE and between veterans who did versus did not endorse a history of SA. RESULTS: Peak SUDS ratings and PTSD symptoms declined slower among veterans who focused on an SA trauma relative to those who did not. In contrast, participants who endorsed SA history showed similar declines in distress and PTSD symptoms relative to veterans with no SA history. CONCLUSIONS: Veterans who focus on SA during PE may take longer to habituate to trauma content and experience resolution of PTSD symptoms. Awareness of this pattern could allow clinicians to deliver PE more effectively to veterans focusing on an SA trauma. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Linked Patient and Provider Impressions of Outpatient Teleneurology Encounters.

Background and Objectives: Teleneurology is common in clinical practice partly due to the SARS CoV-2 pandemic. Impressions about teleneurology from patients and providers alike are generally favorable; some of the reported benefits include ease of access to specialized health care, savings of time and money, and similar quality of care as an in-person visit. However, comparisons between patient and provider impressions about the same teleneurology encounter have not been described. In this study, we describe patient impressions about a teleneurology encounter and evaluate concordance with provider impressions about the same encounter. Methods: Patients and providers at the University of Pennsylvania Hospital Neurology Department were surveyed about their impressions of teleneurology between April 27, 2020, and June 16, 2020. A convenience sample of patients, whose providers completed a questionnaire, were contacted by telephone to solicit their impressions about the same encounter. Unique questionnaires for patients and providers focused on similar themes, such as adequacy of technology, assessment of history obtained, and overall quality of the visit. Summaries of patient responses are reported with the raw percent agreement between patients and providers for similar questions. Results: One hundred thirty-seven patients completed the survey; 64 (47%) were male and 73 (53%) were female. Sixty-six (47%) patients had a primary diagnosis of PD, 42 (30%) a non-PD/parkinsonism movement disorder, and 29 (21%) a nonmovement disorder neurologic disease. One hundred one (76%) were established patient visits and 36 (26%) were new patient visits. Provider responses from 8 different physicians were included. Most of the patients responded that the ease of joining their visit, their comfort engaging with their physicians during their visit, understanding their plan of care after their visit, and the quality of care from their teleneurology visit were satisfactory. Patients and providers agreed about their impressions of the quality of the history obtained (87% agreement), patient-provider relationship (88% agreement), and overall quality of their experience (70% agreement). Discussion: Patients had favorable impressions about their clinical experience with teleneurology and expressed an interest in incorporating telemedicine visits into their ongoing care. Patients and providers were highly concordant for the history obtained, patient-provider relationship, and overall quality.

Extrinsic and Intrinsic Modulators of Anaphylaxis.

The severity of anaphylaxis is determined by many factors. The allergenic source as well as the age of the affected individual and the route of allergen exposure encompass the major contributors of the clinical outcome. Moreover, the severity can be modulated further by intrinsic and extrinsic factors. Among these, the genetic predisposition, certain comorbidities such as uncontrolled asthma, and hormonal fluctuations have been proposed as intrinsic and antihypertensive medications or physical activity as extrinsic factors. Recent advances have highlighted immunologic pathways that may exacerbate the response to allergens through receptors on mast cells, basophils, platelets, and other granulocytes. Atopy, platelet-activating factor acetylhydrolase deficiency, hereditary alpha tryptasemia, and clonal mast cell disorders are examples associated with genetic alterations that may predispose to severe anaphylaxis. Identifying risk factors that lower the threshold of reactivity or increase the severity of multisystem reactions is important in the management of this patient population.

Sleep efficiency predicts improvements in fear extinction and PTSD symptoms during prolonged exposure for veterans with comorbid insomnia.

Prolonged exposure (PE) is an evidenced-based psychotherapy for PTSD, but many Veterans fail to achieve a clinically meaningful response. Sleep issues are prevalent in Veterans and may interfere with PE by disrupting the learning and consolidation of fear extinction memories during PE exposures. Here, we examined whether changes in fear extinction across imaginal exposures and PTSD symptoms during PE were predicted by diary-assessed levels of nightly sleep efficiency (SE; i.e., percent of time in bed spent sleeping), which may indirectly index sleep fragmentation and sleep-facilitated memory processes. Participants were Veterans with PTSD and comorbid insomnia (N = 40) participating in a clinical trial of cognitive-behavioral therapy for insomnia plus PE. SE was measured via nightly sleep diaries, fear extinction was operationalized as a reduction in peak distress between weekly imaginal exposures, and PTSD symptoms were assessed bi-weekly. Cross-lagged panel models revealed that higher sleep efficiency during the week predicted lower peak distress at the subsequent imaginal exposure and lower PTSD symptoms at the subsequent assessment, whereas PTSD symptoms and peak distress did not predict subsequent sleep efficiency. Efficient sleep may facilitate fear extinction and PTSD reduction during PE. Targeting sleep efficiency could improve PE effectiveness for Veterans with comorbid insomnia.

The Role of Myositis-Specific Autoantibodies and the Management of Interstitial Lung Disease in Idiopathic Inflammatory Myopathies: A Systematic Review.

OBJECTIVE: To evaluate the role of myositis-specific autoantibodies (MSAs) in interstitial lung disease (ILD), management of idiopathic inflammatory myopathies (IIM) associated ILD, and if there is a role for MSA specific management of ILD. METHODS: A systematic review was performed examining how MSAs relate to ILD manifestations in IIM patients and comparing treatment outcomes with varying immunosuppressive regimens. RESULTS: 112 papers were included in this analysis. Patients with anti-aminoacyl tRNA synthetase (anti-ARS) and anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibodies had consistently higher rates of ILD than other MSA groups. Anti-ARS positive patients had higher rates of chronic ILD whereas anti-MDA5 positive patients had higher rates of rapidly progressive ILD (RP-ILD). The most common high-resolution computed tomography (HRCT) patterns for ILD in anti-ARS and anti-MDA5 positive patients were nonspecific interstitial pneumonia (NSIP) and unclassifiable respectively. Anti-transcription intermediary factor 1-gamma (anti-TIF1-γ), anti-Mi-2, anti-nuclear matrix protein 2 (anti-NXP-2), and anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (anti-HMGCR) antibodies were associated with a decreased risk of ILD. Small sample sizes, a lack of head-to-head trials, and non-randomized designs prevented drawing meaningful conclusions with respect to immunosuppressive management. CONCLUSION: Clear relationships exist with regards to the ILD manifestations of certain MSAs. Standard therapy for IIM associated ILD (IIM-ILD) is glucocorticoids with the addition of others immunosuppressives in patients with or at risk of RP-ILD as well as in refractory cases. Immunosuppressives should be preferentially used in MSA populations in which they have been studied and shown to be efficacious.

Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets.

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell-like (SCL) subtype driven by activator protein-1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

Effect of Bidirectional Insertion of External Skeletal Fixation Pins on Axial Pullout Strength in Canine Cadaveric Bone.

OBJECTIVE: The aim of this study was to evaluate the effect of bidirectional insertion on axial pullout strength of tapered run out (TRO), traditional negative profile (TNP) and positive profile (PP) pins. STUDY DESIGN: Cadaveric adult canine tibiae were harvested. Tapered run out pins (Group 1) were inserted unidirectionally to the desired position; bidirectionally past the desired position, then withdrawn to the desired position (Group 2); and bidirectionally as described for Group 2, repeated twice (Group 3). Traditional negative profile pins (Group 4-6) and PP pins (Group 9-11) were placed in the same manner. Tapered run out (Group 7), TNP (Group 8) and PP pins (Group 12) were driven unidirectionally such that the shaft of the pin violated the cis-cortex. A servohydraulic testing machine extracted the pins and measured axial peak pullout strength. RESULTS: Positive profile pins had significantly greater pullout strength than TRO and TNP pins placed unidirectionally to the desired position. Method of insertion had no effect on peak pullout strength of TNP pins. TRO and PP pins inserted unidirectionally to the desired position had significantly greater peak pullout strengths than insertion bidirectionally or if the shaft of the pin violated the cis-cortex. CONCLUSION: The authors recommend that pins used for external skeletal fixation should be placed unidirectionally to the desired position with fluoroscopic guidance, intra-operative depth gauge measurements or measurements from preoperative radiographs. Repositioning pins results in loss of peak pullout strength with TRO and PP pins.

Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states.

Single-cell RNA sequencing has revealed extensive transcriptional cell state diversity in cancer, often observed independently of genetic heterogeneity, raising the central question of how malignant cell states are encoded epigenetically. To address this, here we performed multiomics single-cell profiling-integrating DNA methylation, transcriptome and genotype within the same cells-of diffuse gliomas, tumors characterized by defined transcriptional cell state diversity. Direct comparison of the epigenetic profiles of distinct cell states revealed key switches for state transitions recapitulating neurodevelopmental trajectories and highlighted dysregulated epigenetic mechanisms underlying gliomagenesis. We further developed a quantitative framework to directly measure cell state heritability and transition dynamics based on high-resolution lineage trees in human samples. We demonstrated heritability of malignant cell states, with key differences in hierarchal and plastic cell state architectures in IDH-mutant glioma versus IDH-wild-type glioblastoma, respectively. This work provides a framework anchoring transcriptional cancer cell states in their epigenetic encoding, inheritance and transition dynamics.

Comparison of weight per volume and protein nitrogen units in non-standardized allergen extracts: implications for prescribing subcutaneous immunotherapy.

BACKGROUND: Allergen extracts used in subcutaneous immunotherapy can be standardized or non-standardized. Standardized extracts are available in specific biological potencies, presumably making their biological activity more consistent. The majority of allergen extracts are non-standardized and may have less consistent potencies. Non-standardized extracts are labeled as weight per volume or protein nitrogen units (PNUs). Neither method provides direct information regarding the extract's biologic potency. The purpose of this study was to compare weight per volume versus PNU concentrations for 4 non-standardized allergen extracts prepared by two allergen manufacturers. The potencies were compared to current North American practice recommendations. METHODS: The weight per volume and PNU values were provided for 4 non-standardized extracts-birch, short ragweed, dog hair and Alternaria-from HollisterStier and Stallergenes Greer. Weight per volume and PNU concentrations were compared for each of these extracts from both manufacturers. From the raw data, we calculated the corresponding PNU values for a weight per volume of 1:100 and 1:200 for each extract. Similarly, we calculated the corresponding weight per volume including a range of PNU values, for 1000, 2000, 3000, 4000 and 5000 PNU/ml. RESULTS: Birch extract has low PNU concentration, below 5000, for a weight per volume of 1:200 for both HollisterStier and Stallergenes Greer. In contrast, for both HollisterStier and Stallergenes Greer ragweed extract, a weight per volume of 1:200 corresponds to a PNU concentration greater than 5000. Dog extract for a weight per volume of 1:200, and even for 1:100, corresponds to very low PNUs for both companies. For Alternaria, corresponding PNU concentrations for HollisterStier is low at only 500 while over 5000 for Stallergenes Greer. CONCLUSIONS: Our results show variability when comparing weight per volume and PNU concentrations for both Hollister-Stier and Stallergenes Greer products. We suggest selecting a PNU dose that corresponds to a weight per volume of 1:200 as this may improve patient safety. Our recommendations for starting PNU dose for the four non-standardized extracts are 1500 for birch, 5000 for ragweed, 25 for dog, and 500 for Alternaria when using HollisterStier products; 2300 for birch, 5000 for ragweed, 1200 for dog, and 5000 for Alternaria when using Stallergenes Greer products. If the starting PNU concentration is considerably below 5000 for a weight per volume of 1:200 slow up-titration is advised. Conversely, for PNU concentrations above 5000 for weight per volume of 1:200 we suggest a maintenance dose of 5000 PNU.

Targeting the IL-5 pathway in eosinophilic asthma: a comparison of mepolizumab to benralizumab in the reduction of peripheral eosinophil counts.

BACKGROUND: Mepolizumab and benralizumab are biologics approved for severe eosinophilic asthma. Mepolizumab is an anti-interlukin-5 (IL-5) antibody while benralizumab is an anti-interleukin-5 receptor alpha (IL-5Rα) antibody targeting the IL-5 receptor on eosinophils. Both therapies reduce oral corticosteroid requirements and asthma exacerbations. However, no head-to-head studies have been published. The aim of the present study was to compare the efficacy of peripheral eosinophil reduction of mepolizumab and benralizumab. METHODS: A retrospective chart review was conducted on patients with severe eosinophilic asthma who were approved for either IL-5 agent. Patients with noted non-adherence or those who were on fluctuating doses of corticosteroids for non-asthma related illnesses were excluded. The last detectable eosinophil count for each patient prior to start of therapy was compared to the highest eosinophil count noted after therapy start with at least 30 days of adherence. RESULTS: Thirty-six patients taking mepolizumab and 19 patients taking benralizumab met the inclusion criteria and had both pre-treatment and post-treatment eosinophil counts. Baseline characteristics were not statistically different between those on mepolizumab and benralizumab therapy. The mean pre-therapy serum eosinophil count did not statistically differ between patients on mepolizumab (597.2 cells/µL) compared to benralizumab (521.6 cells/µL), p = 0.3769. While both therapies resulted in a significant decrease in eosinophil count (p < 0.0001); the mean decrease did not statistically differ between patients taking mepolizumab compared to those on benralizumab, p = 0.9079. Nonetheless, 100% of patients receiving benralizumab had undetectable eosinophil counts post-therapy compared to 31% of patients receiving mepolizumab (p < 0.0001). CONCLUSION: Both mepolizumab and benralizumab are potent targets of the IL-5 pathway with the ability to significantly reduce peripheral eosinophil counts. While there is there is no statistical difference in the magnitude of eosinophil reduction offered by each agent, benralizumab is able to decrease peripheral eosinophil counts to 0 cells/µL in more patients than mepolizumab.

Child Maltreatment and the Child Welfare System as Environmental Factors in the International Classification of Functioning.

The WHO defines child maltreatment as any form of neglect, exploitation, and physical, emotional, or sexual abuse, committed against children under the age of 18. Youth involved in the child welfare system report more maltreatment experiences and environmental turbulence (e.g., number of moves, caseworkers), placing them at greater risk for poorer physical and mental health. The International Classification of Functioning, Disability, and Health (ICF) provides a framework to describe health conditions and severity of disabilities for an individual and/or group in the context of environmental factors. The Maltreatment and Adolescent Pathways (MAP) study is a longitudinal study, assessing self-reports on variables (e.g., child maltreatment history, trauma symptoms, dating violence, and substance use) of youth in an urban child protection service system. This study focuses on 11 of the 24 MAP publications that pertain to health and functioning, which can be considered applicable to the ICF framework, following established linking rules. The purpose of this study is to analyze these MAP sub-studies, with maltreatment and involvement in the child welfare system as environmental factors that impact the functioning of child welfare-involved youth. Findings indicate significant relationships across environmental factors (i.e., child maltreatment histories, child welfare system involvement), health conditions (i.e., trauma symptomatology, psychological distress, intellectual disabilities), and functioning problems (i.e., substance use, adolescent dating violence, sexual risk-taking, coping motives, sleep problems). The interrelated nature of these factors in the MAP sub-studies suggests the value of the ICF model to a holistic health view of use to practitioners supporting system-involved youth, clarifying unattended environmental factors in guiding service provision for foster care and/or maltreated youth.

Factors associated with dropout in a lifestyle modification program for weight management in children and adolescents.

BACKGROUND: Significant dropout rates remain a serious concern in pediatric weight control program, but few studies have identified predictors of dropout. AIMS: The objective of the study is to identify factors associated with dropout from a pediatric lifestyle modification weight control program at different phases. METHODS: Data on overweight and obese participants (n = 242) aged 11-18 years in the Intervention for Childhood and Adolescent Obesity via Activity and Nutrition (ICAAN) study were collected at baseline, 6-months, and 24-months through self-report and a laboratory test. Logistic regression analysis was performed for those who dropped out during the first 6-months, and multivariate generalized estimating equation analysis identified longitudinal factors associated with those who dropped out after 24 months. RESULTS: Lower family functioning (OR = 2.30, 95% CI [1.18-4.46]), exercise group (OR = 0.36, 95% CI [0.15-0.86]), lower initial attendance rate (OR = 6.09, 95% CI [2.94-12.6]), and non-self -referral pathways (OR = 2.35, 95% CI [1.05-5.27]) were significantly associated with 6-month dropouts. For late dropout, lower family functioning (OR = 1.71, 95% CI [1.06-2.77]) and lower initial attendance rates (OR = 2.06, 95% CI [1.12-3.81]) remained significant. CONCLUSION: Family function and initial attendance rate were associated with lower dropout rates. Developing a supportive family environment and focusing on the early-stage factors at the intervention's outset may reduce overall dropout rates in obesity prevention intervention.

FOXA1 Mutations Reveal Distinct Chromatin Profiles and Influence Therapeutic Response in Breast Cancer.

Mutations in the pioneer transcription factor FOXA1 are a hallmark of estrogen receptor-positive (ER+) breast cancers. Examining FOXA1 in ∼5,000 breast cancer patients identifies several hotspot mutations in the Wing2 region and a breast cancer-specific mutation SY242CS, located in the third ß strand. Using a clinico-genomically curated cohort, together with breast cancer models, we find that FOXA1 mutations associate with a lower response to aromatase inhibitors. Mechanistically, Wing2 mutations display increased chromatin binding at ER loci upon estrogen stimulation, and an enhanced ER-mediated transcription without changes in chromatin accessibility. In contrast, SY242CS shows neomorphic properties that include the ability to open distinct chromatin regions and activate an alternative cistrome and transcriptome. Structural modeling predicts that SY242CS confers a conformational change that mediates stable binding to a non-canonical DNA motif. Taken together, our results provide insights into how FOXA1 mutations perturb its function to dictate cancer progression and therapeutic response.

Predictive value of serum albumin-to-globulin ratio for incident chronic kidney disease: A 12-year community-based prospective study.

BACKGROUND: Inflammation plays a pivotal role in the pathogenesis of chronic kidney disease (CKD). Significant association between serum albumin-to-globulin (AG) ratio and inflammation led us to investigate the prognostic value of serum AG ratio for incident CKD. METHODS: The predictive value of serum AG ratio, white blood cell (WBC), and C-reactive protein (CRP) for CKD development was assessed in 8,057 non-CKD participants from a community-based, prospective cohort in Korea. Serum AG ratio was calculated by following equation: serum albumin (g/L)/[serum total protein (g/L)-serum albumin (g/L)]. Incident CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 and/or proteinuria of more than 1+ on dipstick. RESULTS: Median serum AG ratio was 1.38 (interquartile range, 1.28-1.52). During a mean follow-up duration of 9.1±3.7 years, 1,732 participants (21.5%) developed CKD. In a multivariable Cox analysis, a low serum AG ratio was significantly associated with an increased risk of incident CKD (Q1, serum AG ratio <1.26: hazard ratio [HR] = 1.651, 95% confidence interval [CI] = 1.406-1.938, Q5 as reference; per 0.2 decrease, HR = 1.170, 95% CI = 1.109-1.234). Serum AG ratio was the only indicator to improve the predictability of CKD development (net reclassification index = 0.158, P <0.001; integrated discrimination improvement = 0.005, P <0.001), compared with WBC or CRP. CONCLUSIONS: This study demonstrates that low serum AG ratio is an independent predictor for CKD development and exhibits a stronger predictive value than other inflammatory markers. These findings suggest that determining serum AG ratio may be more valuable for predicting adverse kidney outcomes in non-CKD populations.

ARID1A determines luminal identity and therapeutic response in estrogen-receptor-positive breast cancer.

Mutations in ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, are the most common alterations of the SWI/SNF complex in estrogen-receptor-positive (ER+) breast cancer. We identify that ARID1A inactivating mutations are present at a high frequency in advanced endocrine-resistant ER+ breast cancer. An epigenome CRISPR-CAS9 knockout (KO) screen identifies ARID1A as the top candidate whose loss determines resistance to the ER degrader fulvestrant. ARID1A inactivation in cells and in patients leads to resistance to ER degraders by facilitating a switch from ER-dependent luminal cells to ER-independent basal-like cells. Cellular plasticity is mediated by loss of ARID1A-dependent SWI/SNF complex targeting to genomic sites of the luminal lineage-determining transcription factors including ER, forkhead box protein A1 (FOXA1) and GATA-binding factor 3 (GATA3). ARID1A also regulates genome-wide ER-FOXA1 chromatin interactions and ER-dependent transcription. Altogether, we uncover a critical role for ARID1A in maintaining luminal cell identity and endocrine therapeutic response in ER+ breast cancer.

Role of FAD-I in Fusobacterial Interspecies Interaction and Biofilm Formation.

: RadD, a major adhesin of oral fusobacteria, is part of a four-gene operon encoding the small lipoprotein FAD-I and two currently uncharacterized small proteins encoded by the rapA and rapB genes. Previously, we described a role for FAD-I in the induction of human B-defensin 2 (hBD2) upon contact with oral epithelial cells. Here, we investigated potential roles for fad-I, rapA, and rapB in interspecies interaction and biofilm formation. Gene inactivation mutants were generated for each of these genes in the nucleatum and polymorphum subspecies of Fusobacterium nucleatum and characterized for their adherence to partner species, biofilm formation, and operon transcription. Binding to Streptococcus gordonii was increased in all mutant strains with Δfad-I having the most significant effect. This increased adherence was directly proportional to elevated radD transcript levels and resulted in significantly different architecture and height of the biofilms formed by Δfad-I and S. gordonii compared to the wild-type parent. In conclusion, FAD-I is important for fusobacterial interspecies interaction as its lack leads to increased production of the RadD adhesin suggesting a role of FAD-I in its regulation. This regulatory effect does not require the presence of functional RadD.

Correction: Shokeen, B., et al. Role of FAD-I in Fusobacterial Interspecies Interaction and Biofilm Formation. Microorganisms 2020, 8, 70.

The authors wish to make the following corrections to this paper [...].