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.

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.

Deep sequencing of natural and experimental populations of Drosophila melanogaster reveals biases in the spectrum of new mutations.

Mutations provide the raw material of evolution, and thus our ability to study evolution depends fundamentally on having precise measurements of mutational rates and patterns. We generate a data set for this purpose using (1) de novo mutations from mutation accumulation experiments and (2) extremely rare polymorphisms from natural populations. The first, mutation accumulation (MA) lines are the product of maintaining flies in tiny populations for many generations, therefore rendering natural selection ineffective and allowing new mutations to accrue in the genome. The second, rare genetic variation from natural populations allows the study of mutation because extremely rare polymorphisms are relatively unaffected by the filter of natural selection. We use both methods in Drosophila melanogaster, first generating our own novel data set of sequenced MA lines and performing a meta-analysis of all published MA mutations (∼2000 events) and then identifying a high quality set of ∼70,000 extremely rare (≤0.1%) polymorphisms that are fully validated with resequencing. We use these data sets to precisely measure mutational rates and patterns. Highlights of our results include: a high rate of multinucleotide mutation events at both short (∼5 bp) and long (∼1 kb) genomic distances, showing that mutation drives GC content lower in already GC-poor regions, and using our precise context-dependent mutation rates to predict long-term evolutionary patterns at synonymous sites. We also show that de novo mutations from independent MA experiments display similar patterns of single nucleotide mutation and well match the patterns of mutation found in natural populations.

BRIM-P: A phase I, open-label, multicenter, dose-escalation study of vemurafenib in pediatric patients with surgically incurable, BRAF mutation-positive melanoma.

BACKGROUND: Vemurafenib, a selective inhibitor of BRAF kinase, is approved for the treatment of adult stage IIIc/IV BRAF V600 mutation-positive melanoma. We conducted a phase I, open-label, dose-escalation study in pediatric patients aged 12-17 years with this tumor type (NCT01519323). PROCEDURE: Patients received vemurafenib orally until disease progression. Dose escalation was conducted using a 3 + 3 design. Patients were monitored for dose-limiting toxicities (DLTs) during the first 28 days of treatment to determine the maximum tolerated dose (MTD). Safety/tolerability, tumor response, and pharmacokinetics were evaluated. RESULTS: Six patients were enrolled (720 mg twice daily [BID], n = 3; 960 mg BID [n = 3]). The study was terminated prematurely due to low enrollment. No DLTs were observed; thus, the MTD could not be determined. All patients experienced at least one adverse event (AE); the most common were diarrhea, headache, photosensitivity, rash, nausea, and fatigue. Three patients experienced serious AEs, one patient developed secondary cutaneous malignancies, and five patients died following disease progression. Mean steady-state plasma concentrations of vemurafenib following 720 mg and 960 mg BID dosing were similar or higher, respectively, than in adults. There were no objective responses. Median progression-free survival and overall survival were 4.4 months (95% confidence interval [CI] = 2.7-5.2) and 8.1 months (95% CI = 5.1-12.0), respectively. CONCLUSIONS: A recommended and effective dose of vemurafenib for patients aged 12-17 years with metastatic or unresectable melanoma was not identified. Extremely low enrollment in this trial highlights the importance of considering the inclusion of adolescents with adult cancers in adult trials.

HLA-DRB1*11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (sJIA) is an often severe, potentially life-threatening childhood inflammatory disease, the pathophysiology of which is poorly understood. To determine whether genetic variation within the MHC locus on chromosome 6 influences sJIA susceptibility, we performed an association study of 982 children with sJIA and 8,010 healthy control subjects from nine countries. Using meta-analysis of directly observed and imputed SNP genotypes and imputed classic HLA types, we identified the MHC locus as a bona fide susceptibility locus with effects on sJIA risk that transcended geographically defined strata. The strongest sJIA-associated SNP, rs151043342 [P = 2.8 × 10(-17), odds ratio (OR) 2.6 (2.1, 3.3)], was part of a cluster of 482 sJIA-associated SNPs that spanned a 400-kb region and included the class II HLA region. Conditional analysis controlling for the effect of rs151043342 found that rs12722051 independently influenced sJIA risk [P = 1.0 × 10(-5), OR 0.7 (0.6, 0.8)]. Meta-analysis of imputed classic HLA-type associations in six study populations of Western European ancestry revealed that HLA-DRB1*11 and its defining amino acid residue, glutamate 58, were strongly associated with sJIA [P = 2.7 × 10(-16), OR 2.3 (1.9, 2.8)], as was the HLA-DRB1*11-HLA-DQA1*05-HLA-DQB1*03 haplotype [6.4 × 10(-17), OR 2.3 (1.9, 2.9)]. By examining the MHC locus in the largest collection of sJIA patients assembled to date, this study solidifies the relationship between the class II HLA region and sJIA, implicating adaptive immune molecules in the pathogenesis of sJIA.

Global population divergence and admixture of the brown rat (Rattus norvegicus).

Native to China and Mongolia, the brown rat (Rattus norvegicus) now enjoys a worldwide distribution. While black rats and the house mouse tracked the regional development of human agricultural settlements, brown rats did not appear in Europe until the 1500s, suggesting their range expansion was a response to relatively recent increases in global trade. We inferred the global phylogeography of brown rats using 32 k SNPs, and detected 13 evolutionary clusters within five expansion routes. One cluster arose following a southward expansion into Southeast Asia. Three additional clusters arose from two independent eastward expansions: one expansion from Russia to the Aleutian Archipelago, and a second to western North America. Westward expansion resulted in the colonization of Europe from which subsequent rapid colonization of Africa, the Americas and Australasia occurred, and multiple evolutionary clusters were detected. An astonishing degree of fine-grained clustering between and within sampling sites underscored the extent to which urban heterogeneity shaped genetic structure of commensal rodents. Surprisingly, few individuals were recent migrants, suggesting that recruitment into established populations is limited. Understanding the global population structure of R. norvegicus offers novel perspectives on the forces driving the spread of zoonotic disease, and aids in development of rat eradication programmes.

Multi-parametric MRI characterization of inflammation in murine skeletal muscle.

Myopathies often display a common set of complex pathologies that include muscle weakness, inflammation, compromised membrane integrity, fat deposition, and fibrosis. Multi-parametric, quantitative, non-invasive imaging approaches may be able to resolve these individual pathological components. The goal of this study was to use multi-parametric MRI to investigate inflammation as an isolated pathological feature. Proton relaxation, diffusion tensor imaging (DTI), quantitative magnetization transfer (qMT-MRI), and dynamic contrast enhanced (DCE-MRI) parameters were calculated from data acquired in a single imaging session conducted 6-8 hours following the injection of λ-carrageenan, a local inflammatory agent. T2 increased in the inflamed muscle and transitioned to bi-exponential behavior. In diffusion measurements, all three eigenvalues and the apparent diffusion coefficient increased, but λ3 had the largest relative change. Analysis of the qMT data revealed that the T1 of the free pool and the observed T1 both increased in the inflamed tissue, while the ratio of exchanging spins in the solid pool to those in the free water pool (the pool size ratio) significantly decreased. DCE-MRI data also supported observations of an increase in extracellular volume. These findings enriched the understanding of the relation between multiple quantitative MRI parameters and an isolated inflammatory pathology, and may potentially be employed for other single or complex myopathy models.

Multi-parametric MRI characterization of healthy human thigh muscles at 3.0 T - relaxation, magnetization transfer, fat/water, and diffusion tensor imaging.

Muscle diseases commonly have clinical presentations of inflammation, fat infiltration, fibrosis, and atrophy. However, the results of existing laboratory tests and clinical presentations are not well correlated. Advanced quantitative MRI techniques may allow the assessment of myo-pathological changes in a sensitive and objective manner. To progress towards this goal, an array of quantitative MRI protocols was implemented for human thigh muscles; their reproducibility was assessed; and the statistical relationships among parameters were determined. These quantitative methods included fat/water imaging, multiple spin-echo T2 imaging (with and without fat signal suppression, FS), selective inversion recovery for T1 and quantitative magnetization transfer (qMT) imaging (with and without FS), and diffusion tensor imaging. Data were acquired at 3.0 T from nine healthy subjects. To assess the repeatability of each method, the subjects were re-imaged an average of 35 days later. Pre-testing lifestyle restrictions were applied to standardize physiological conditions across scans. Strong between-day intra-class correlations were observed in all quantitative indices except for the macromolecular-to-free water pool size ratio (PSR) with FS, a metric derived from qMT data. Two-way analysis of variance revealed no significant between-day differences in the mean values for any parameter estimate. The repeatability was further assessed with Bland-Altman plots, and low repeatability coefficients were obtained for all parameters. Among-muscle differences in the quantitative MRI indices and inter-class correlations among the parameters were identified. There were inverse relationships between fractional anisotropy (FA) and the second eigenvalue, the third eigenvalue, and the standard deviation of the first eigenvector. The FA was positively related to the PSR, while the other diffusion indices were inversely related to the PSR. These findings support the use of these T1 , T2 , fat/water, and DTI protocols for characterizing skeletal muscle using MRI. Moreover, the data support the existence of a common biophysical mechanism, water content, as a source of variation in these parameters.

Serum amyloid A overrides Treg anergy via monocyte-dependent and Treg-intrinsic, SOCS3-associated pathways.

The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti-inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (T(reg)). Intriguingly, SAA reverses T(reg) anergy via its interaction with monocytes to activate distinct mitogenic pathways in T(reg) but not effector T cells. This selective responsiveness of T(reg) correlates with their diminished expression of SOCS3 and is antagonized by T(reg)-specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports T(reg) expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses.

Quantitative effects of inclusion of fat on muscle diffusion tensor MRI measurements.

PURPOSE: To determine the minimum water percentage in a muscle region of interest that would allow diffusion tensor (DT-) MRI data to reflect the diffusion properties of pure muscle accurately. MATERIALS AND METHODS: Proton density-weighted images with and without fat saturation were obtained at the mid-thigh in four subjects. Co-registered DT-MR images were used to calculate the diffusion tensor's eigenvalues and fractional anisotropy. RESULTS: The eigenvalues transitioned monotonically as a function of water signal percentage from values near to those expected for pure fat to those for pure muscle. Also, the fractional anisotropy transitioned monotonically from 0.50 (fat) to 0.20 (muscle). For water signal percentages >55%, none of the diffusion indices differed significantly from those for regions of >90% muscle. CONCLUSION: Accounting for the T1 and T2 values of muscle and fat and the pulse sequence properties, it is concluded that, as a conservative estimate, regions must contain at least 76% muscle tissue to reflect the diffusion properties of pure muscle accurately.

Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope.

OBJECTIVE: Associations between shared epitope (SE)-encoding HLA-DRB1 alleles and rheumatoid arthritis (RA) are well established. However, only a limited number of studies have investigated these alleles in patients with childhood-onset RA, which is defined as rheumatoid factor- and/or anti-citrullinated protein antibody-positive juvenile idiopathic arthritis. The aims of this study were to investigate the largest cohort of patients with childhood-onset RA for association with SE alleles and to determine whether there is a hierarchy of risk based on the amino acid sequence of the SE. METHODS: High-resolution HLA-DRB1 genotypes were obtained for 204 patients with childhood-onset RA and 373 healthy control subjects. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated for different SE-encoding HLA-DRB1 alleles. In addition, genotype ORs were calculated for combinations of SE alleles classified into S(2) , S(3P) , or L alleles, based on amino acid sequences in position 70-74 of the DRß1 chain, as proposed by Tezenas du Montcel et al. RESULTS: We confirmed associations between HLA-DRB1 SE alleles and childhood-onset RA (76% of patients carried 1 or 2 SE alleles compared with 46% of control subjects; OR 3.81, 95% CI 2.4-6.0, P < 1 × 10(-7) ). We also observed associations between individual SE alleles (HLA-DRB1*0101, *0401, *0404, *0405, *0408, and *1001) and childhood-onset RA. Genotype-specific risk estimates suggested a hierarchy of risk, with the highest risk among individuals heterozygous for S(2) /S(3P) (OR 22.3, 95% CI 9.9-50.5, P < 0.0001). CONCLUSION: We confirm the association between SE-encoding HLA-DRB1 alleles and susceptibility to childhood-onset RA. The excess risk conferred by carriage of the combination of S(2) and S(3P) risk alleles suggests that children with DRß1 chains containing the KRAA and QRRAA or RRRAA sequences are especially susceptible to RA.

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.

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).

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.

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.

Alternative activation in systemic juvenile idiopathic arthritis monocytes.

Systemic juvenile idiopathic arthritis (SJIA) is a chronic autoinflammatory condition. The association with macrophage activation syndrome, and the therapeutic efficacy of inhibiting monocyte-derived cytokines, has implicated these cells in SJIA pathogenesis. To characterize the activation state (classical/M1 vs. alternative/M2) of SJIA monocytes, we immunophenotyped monocytes using several approaches. Monocyte transcripts were analyzed by microarray and quantitative PCR. Surface proteins were measured at the single cell level using flow cytometry. Cytokine production was evaluated by intracellular staining and ELISA. CD14(++)CD16(-) and CD14(+)CD16(+) monocyte subsets are activated in SJIA. A mixed M1/M2 activation phenotype is apparent at the single cell level, especially during flare. Consistent with an M2 phenotype, SJIA monocytes produce IL-1ß after LPS exposure, but do not secrete it. Despite the inflammatory nature of active SJIA, circulating monocytes demonstrate significant anti-inflammatory features. The persistence of some of these phenotypes during clinically inactive disease argues that this state reflects compensated inflammation.

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.

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.