Differential peripheral B cell phenotype in patients with primary Sjögren’s syndrome (pSS) compared to secondary Sjögren’s syndrome associated with systemic lupus erythematosus (SS/SLE)

Introduction: Peripheral B-cell abnormalities, a feature of both systemic lupus erythematosus (SLE) and primary Sjogren’s syndrome (pSS), are implicated in the pathogenesis of both diseases and correlate with disease activity. This study aims to investigate how the defective B-cell phenotype in pSS patients compares to patients with SS and SLE (SS/SLE), and whether abnormalities in B-cell phenotype could be related to differential B-cell lipid-raft expression and B-cell activating factor (BAFF) receptor function in patients with pSS and SLE and secondary SS (SS/SLE). Methods: Blood samples and clinical and laboratory parameters from 32 patients with pSS and SS/SLE and 13 age/sex matched HC were obtained. We used flow-cytometry to perform B-cell immunophenotyping and analysed lipid-raft expression (marker of B-cell activation). In vitro cultures were also used to assess lipid-raft expression in response to BAFF. Results: Patients with SS/SLE had a significantly decreased Bm1 and Bm5 and increased Bm2 populations compared to HC (p=0.031, p=0.035 and p=0.01, respectively), and increased Bm2 compared to pSS (p=0.027). Bm1-cells were decreased in both pSS and SS/SLE patients compared to HC (p=0.028 and p= 0.031, respectively). Both age and disease duration correlated strongly with Bm2’ cells in SS/SLE patients (r=0.9572, p= 0.0428), and the immunosuppressive treatment correlated negatively with the number of circulating Bm2 and Bm2’ cell in pSS (r = -0.54, p=0.01 and r = -0.56, p=0.008, respectively). B-cells from patients with pSS had a significant increase in lipid-raft expression compared to HC (p=0.01) and patients with SS/SLE (p<0.05). Lipid-raft levels correlated with BAFF-receptor expression in HC and SS/SLE B-cells (p=0.17, r=0.694) but not in pSS patients. Both disease activity score (ESSDAI) and IgG level correlated positively with lipid rafts expression in B cells from patients with pSS (r = 0.79, p=0.004 and r =0.53, p=0.04, respectively). Conclusion: Patients with SS/SLE had more significant B-cell abnormalities compared to HC and pSS, detectable even in a small number of patients. Also the relationship between lipid-raft and BAFF-receptor expression was altered between pSS and SS/SLE patients, and correlated with the disease activity and IgG levels in pSS group, suggesting that therapies targeting BAFF might be particularly successful in the SS/SLE sub-group of patients

Measuring Accuracy of Automated Parsing and Categorization Tools and Processes in Digital Investigations

This work presents a method for the measurement of the accuracy of evidential artifact extraction and categorization tasks in digital forensic investigations. Instead of focusing on the measurement of accuracy and errors in the functions of digital forensic tools, this work proposes the application of information retrieval measurement techniques that allow the incorporation of errors introduced by tools and analysis processes. This method uses a `gold standard' that is the collection of evidential objects determined by a digital investigator from suspect data with an unknown ground truth. This work proposes that the accuracy of tools and investigation processes can be evaluated compared to the derived gold standard using common precision and recall values. Two example case studies are presented showing the measurement of the accuracy of automated analysis tools as compared to an in-depth analysis by an expert. It is shown that such measurement can allow investigators to determine changes in accuracy of their processes over time, and determine if such a change is caused by their tools or knowledge.Comment: 17 pages, 2 appendices, 1 figure, 5th International Conference on Digital Forensics and Cyber Crime; Digital Forensics and Cyber Crime, pp. 147-169, 201

Lupus and Sjögren’s syndrome distinct disease endotypes clustered based on activity scores and immune profiles

Background: Sjögren’s syndrome (SS) is a chronic autoimmune disorder affecting approximately 0.1–0.4% of the general population with a female-to-male ratio of 9:1 usually diagnosed in the fourth and fifth decades of life [1]. Clinically, SS is typified by ocular and oral dryness developed as a consequence of the autoimmune process. It may occur either alone, as primary (p)SS, or secondary to other autoimmune disease, often rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or systemic sclerosis, secondary (s)SS. Objectives: 1) Identify the peripheral B and T cells abnormalities in patients with pSS, secondary SS associated with systemic lupus erythematosus (SLE) and SLE alone in comparison to healthy donors. 2) Correlate immune phenotypes with clinical features and serological parameters. 3) Identify distinct patients’ endotypes relevant for therapeutic strategies. Methods: Blood samples, clinical and laboratory parameters from 28 patients with pSS, 32 SLE, 15 SS/SLE and age/sex-matched HC were obtained. Immunophenotyping and lipid-raft analyses were performed by flow-cytometry. Results: There were distinct CD19+ B cells, and CD4+ and CD8+ T cell subpopulations observed in pSS, SLE and SS/SLE patients compared to healthy donors. SS/SLE have the most striking B cell phenotype abnormalities than patients with pSS or SLE (increased Bm2 cells and decreased early and late Bm5 cells).There were significant positive and negative correlations of immune cells with clinical parameters in pSS, SLE and SS/SLE patients. The fold-change of memory B cells was significantly reduced in all disease groups with comparison to healthy controls. Fold-change of CD8+ T responder cells were significantly reduced in all diseases, and similarly, CD4+ naïve T cells in SLE and SS/SLE. A highly significant increase in CD4+ T regulatory was observed in pSS. Hierarchical clustering of immune cells in patients yielded 5 distinct endotypes, with clustering reflected in patients with similar disease activity scores. Conclusions: This is the first comprehensive immunophenotype analysis performed patients with pSS, SLE and SS/SLE. We identified significant reduction in memory B cells fold-changed in all disease groups, reduction in CD4+ naïve T cells in SLE and SS/SLE and reduction in T responders in all disease CD8+ in comparison to healthy donors. The most significant T cell abnormalities were found in patients with SLE, however a significant correlation between lipid raft expression as marker of cell activation and disease activity score (ESSDAI) was found only in pSS patients. The five distinct disease endotype clustering showed distinct immune profile in patients with overlapping autoimmune conditions which is particularly relevant for stratification of therapy

Subchronic Exposure to TCDD, PeCDF, PCB126, and PCB153: Effect on Hepatic Gene Expression

We employed DNA microarray to identify unique hepatic gene expression patterns associated with subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other halogenated aromatic hydrocarbons (HAHs). Female Harlan Sprague-Dawley rats were exposed for 13 weeks to toxicologically equivalent doses of four different HAHs based on the toxic equivalency factor of each chemical: TCDD (100 ng/kg/day), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF; 200 ng/kg/day), 3,3′,4,4′,5-pentachlorobiphenyl (PCB126; 1,000 ng/kg/day), or 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB153; 1,000 μg/kg/day). Global gene expression profiles for each exposure, which account for 8,799 gene probe sets contained on Affymetrix RGU34A GeneChips, were compared by principal components analysis. The aryl hydrocarbon receptor (AhR) ligands TCDD, PeCDF, and PCB126 produced very similar global gene expression profiles that were unique from the nonAhR ligand PCB153, underscoring the extensive impact of AhR activation and/or the resulting hepatic injury on global gene expression in female rat liver. Many genes were co-expressed during the 13-week TCDD, PeCDF, or PCB126 exposures, including classical AhR-regulated genes and some genes not previously characterized as being AhR regulated, such as carcinoembryonic-cell adhesion molecule 4 (C-CAM4) and adenylate cyclase-associated protein 2 (CAP2). Real-time reverse-transcriptase polymerase chain reaction confirmed the increased expression of these genes in TCDD-, PeCDF-, and PCB126-exposed rats as well as the up- or down-regulation of several other novel dioxin-responsive genes. In summary, DNA microarray successfully identified dioxin-responsive genes expressed after exposure to AhR ligands (TCDD, PeCDF, PCB126) but not after exposure to the non-AhR ligand PCB153. Together, these findings may help to elucidate some of the fundamental features of dioxin toxicity and may further clarify the biologic role of the AhR signaling pathway

Craniopharyngioma in children: trends from a third consecutive single-center cohort study

OBJECTIVE: The management of children with craniopharyngioma has evolved over time, with a trend toward less invasive neurosurgical approaches as surgeons have sought to balance oncological control and treatment-related morbidity. To this end, the aim of this study was to evaluate the safety and effectiveness of the current management of children with craniopharyngioma compared to the previous management methods used at the authors’ treatment center. METHODS: A prospectively maintained database was searched over a 14-year period between January 1, 2005, and December 31, 2018, to identify all children 17 years of age or younger with a new diagnosis of craniopharyngioma. A retrospective case note review was performed for each child to extract data on the presentation, investigation, treatment, and outcome of their illness. Morbidity was assessed in the same fashion as in previous cohorts, according to the following categories: visual loss, pituitary dysfunction, hypothalamic dysfunction, neurological deficits, and cognitive impairment. RESULTS: In total, 59 children were identified with craniopharyngioma during the study period. A total of 92 operations were performed, including cyst drainage (35/92; 38.0%), craniotomy and resection (30/92; 32.6%), and transsphenoidal resection (16/92; 17.4%). Approximately two-thirds of all operations were performed using image guidance (66/92; 71.7%) and one-third were performed using endoscopy (27/92; 29.3%). The majority of children had adjuvant therapy comprising proton beam therapy (18/59; 30.5%) or conventional radiotherapy (16/59; 27.1%). The median follow-up duration was 44 months (range 1–142 months), and approximately one-half of the children had no evidence of residual disease on MRI studies (28/59; 47.5%). Of the remaining 31 children, there was a reduction in the volume of residual disease in 8 patients (8/59; 13.6%), stable residual disease in 18 (18/59; 30.5%), and tumor growth in 5 patients (5/59; 8.5%). There was significantly reduced morbidity (p < 0.05) in all categories in the current cohort compared with our last cohort (1996–2004). CONCLUSIONS: The authors’ institutional experience of pediatric craniopharyngioma confirms a trend toward less invasive neurosurgical procedures, most of which are now performed with the benefit of image guidance or endoscopy. Moreover, the authors have identified an expanding role for more targeted radiotherapy for children with residual disease. These advances have allowed for tumor control comparable to that achieved in previous cohorts, but with significantly reduced morbidity and mortality

Stratification of Patients With Sjögren’s Syndrome and Patients With Systemic Lupus Erythematosus According to Two Shared Immune Cell Signatures, With Potential Therapeutic Implications

OBJECTIVE: Similarities in the clinical and laboratory features of patients with primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE) have led to attempts to treat pSS and SLE patients with similar biologic therapeutics. However, the results of many clinical trials are disappointing, and no biologic treatments are licensed in pSS, while few are available for SLE patients with refractory disease. Identifying shared immunological features between pSS and SLE could lead to better treatment selection using a stratification approach. METHODS: Immune-phenotyping of 29 immune-cell subsets in peripheral blood from patients with pSS (n=45), SLE (n=29) and secondary SS associated with SLE (SLE/SS) (n=14) with low disease activity or in clinical remission, and sex-matched healthy controls (n=31), was performed using flow cytometry. Data were analysed using supervised machine learning (balanced random forest, sparse partial least squares discriminant analysis), logistic regression and multiple t-tests. Patients were stratified by k-means clustering, and clinical trajectory analysis. RESULTS: Patients with pSS and SLE had a similar immunological architecture despite having different clinical presentations and prognosis. K-means cluster analysis of the combined pSS, SLE and SLE/SS patient cohorts identified two endotypes characterized by distinct immune-cell profiles which spanned patient diagnoses. Logistic regression and machine learning models identified a signature of eight T-cell subsets that differentiated between the two endotypes with high accuracy (AUC=0.9979). Baseline and five-year clinical trajectory analysis identified differential damage scores and disease activity between the two endotypes. CONCLUSION: An immune-cell toolkit could differentiate patients across diseases with high accuracy for targeted therapeutic approaches

The response of the Antarctic Circumpolar Current to recent climate change

Observations show a significant intensification of the Southern Hemisphere westerlies, the prevailing winds between the latitudes of 30° and 60° S, over the past decades. A continuation of this intensification trend is projected by climate scenarios for the twenty-first century. The response of the Antarctic Circumpolar Current and the carbon sink in the Southern Ocean to changes in wind stress and surface buoyancy fluxes is under debate. Here we analyse the Argo network of profiling floats and historical oceanographic data to detect coherent hemispheric-scale warming and freshening trends that extend to depths of more than 1,000 m. The warming and freshening is partly related to changes in the properties of the water masses that make up the Antarctic Circumpolar Current, which are consistent with the anthropogenic changes in heat and freshwater fluxes suggested by climate models. However, we detect no increase in the tilt of the surfaces of equal density across the Antarctic Circumpolar Current, in contrast to coarse-resolution model studies. Our results imply that the transport in the Antarctic Circumpolar Current and meridional overturning in the Southern Ocean are insensitive to decadal changes in wind stress

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression