Direct bilirubin levels observed in prolonged neonatal jaundice: a retrospective cohort study

OBJECTIVE: Prolonged neonatal jaundice is common and usually benign; however, assessment of bilirubin fractions is recommended to determine the need for further assessment for congenital liver disease, particularly biliary atresia. The direct (conjugated) bilirubin thresholds currently used are variable and poorly evidenced. Hence, we aimed to delineate direct bilirubin levels in disease-free neonates with prolonged jaundice. METHODS: We performed a retrospective cohort analysis of split bilirubin levels, and subsequent follow-up, for all neonates initially assessed in our prolonged neonatal jaundice clinic over 2 years. We plotted centile charts for total, direct and direct-total bilirubin ratio levels against age at sampling. The association was assessed using linear regression analysis. RESULTS: Data were collected for 420 neonates (501 blood samples) across an age range of 10-70 days. No significant liver disease was found. For each day of older age, total bilirubin fell by 3.72 µmol/L (95% CI 2.46 to 5.00) and direct bilirubin fell by 0.39 µmol/L (0.18 to 0.59). The ratio between the two did not change significantly (-0.0006 to +0.0034). The 95th centile for direct bilirubin was stable at ~25 µmol/L. Direct-total bilirubin ratio was very variable with some 95th centiles >30%. CONCLUSIONS: In a clinically relevant population of disease-free neonates with prolonged jaundice both the total and the direct bilirubin decreased with age. The absolute direct bilirubin is more useful clinically than the direct-total bilirubin ratio. Our results support National Institute for Health and Care Excellence guidance that conjugated bilirubin >25 µmol/L, or even more stringent criteria, constitutes an appropriate threshold for further investigation for neonatal liver disease

Using autoantibodies and cutaneous subset to develop outcome-based disease classification in systemic sclerosis

OBJECTIVE: To describe the associations between autoantibodies, presentation and outcome among systemic sclerosis (SSc) patients. We propose a new SSc classification incorporating antibodies and cutaneous subset. METHODS: Survival analysis was used to assess the effect of antibodies on organ disease and death. RESULTS: The study included 1325 subjects. The ACA+ limited cutaneous (lc)SSc group (n=374) had the highest 20-year survival (65.3%), lowest incidence of clinically-significant pulmonary fibrosis (csPF, 8.5%) and scleroderma renal crisis (SRC, 0.3%), low cardiac SSc incidence (4.9%), while pulmonary hypertension (PH) frequency was similar to the cohort average. The anti-Scl70+ lcSSc (n=138) and diffuse cutaneous (dc)SSc groups (n=149) had the highest csPF incidence (86.1% and 84% at 15 years). The dcSSc group had the lowest survival (32.4%) and the second highest incidence of cardiac SSc (12.9%) at 20 years, while in the lcSSc group other complications were rare, demonstrating the lowest incidence of PH (6.9%) and second highest survival (61.8%). The anti-RNA polymerase+ group (n=147) had the highest incidence of SRC (28.1%). The anti-U3RNP+ group (n=56) had the highest PH (33.8%) and cardiac SSc incidence (13.2%). Among lcSSc patients with other autoantibodies (n=295), risk of SRC and cardiac SSc was low, while other outcomes were similar to the cohort average. DcSSc patients with other antibodies (n=166) had poor prognosis, with the second lowest survival (33.6%) and frequent organ complications. CONCLUSION: We highlight the importance of autoantibodies, cutaneous subset and disease duration when assessing SSc morbidity and mortality. Our classification may benefit disease monitoring and clinical trial design

A numerical modelling and simulation of core-scale sandstone acidizing process: a study on the effect of temperature

A wide and comprehensive understanding of the chemical reactions and mechanisms of HBF4 is crucial as it significantly influences its performance in stimulating a sandstone formation. In general, it is well-known that HBF4 is able to provide a deeper penetration into the sandstone matrix before being spent due to its uniquely slow hydrolysis ability to produce HF. In the present study, a 3D numerical modelling and simulation were conducted to examine the capability of HBF4 in enhancing the porosity and permeability of the sandstone matrix. The model is built in COMSOL® Multiphysics commercial software of computational fluid dynamics (CFD) to simulate the acid core flooding process on sandstone core. The model had been validated against the experimental data in the literature. The results matched with the measured plot data very well. The effect of temperature on the performance HBF4 sandstone acidizing is evaluated in this study. The simulation results indicated that at low temperature of 25 °C, HBF4 is not very effective, as justified in its poor porosity and permeability increments of only 1.07 and 1.23, respectively. However, at elevated temperatures, the porosity and permeability enhancement also become increasingly more significant, which showed 1.26 and 2.06, respectively, at 65 °C; and 1.67 and 7.06, respectively, at 105 °C. Therefore, one can conclude that HBF4 acid treatment performed better at elevated temperatures due to increased hydrolysis rate, which is a governing function in HBF4 sandstone acidizing. Overall, this model had provided a reliable alternative to optimize various other parameters of HBF4 acid treatment

Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells.

We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)2D3). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (P<0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1alpha,25(OH)2D3 can be restored by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 nM) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1alpha,25(OH)2D3 plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1alpha,25(OH)2D3 plus TSA cooperatively upregulated eight (out of 1176) genes, including MAPK-APK2 and GADD45alpha. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45alpha induction by 1alpha,25(OH)2D3 alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45alpha was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1alpha,25(OH)2D3-insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors

A meeting report: OECD-GESIS Seminar on Translating and Adapting Instruments in Large-Scale Assessments (2018)

This report summarizes the main themes and conclusions from the OECD-GESIS Seminar on Translating and Adapting Instruments in Large-Scale Assessments, which took place at the Organization for Economic Co-operation and Development (OECD), Paris, in June 2018. The five sessions covered the topics (1) etic (universal) vs. emic (culture-specific) measurement instruments, (2) language- and culture-sensitive development of measurement instruments, (3) international guidelines vs. implementation in countries and by translators, (4) tools and technological developments, and (5) quality control of translations. Key players in the field presented on best practice, lessons learned, and innovations and also made suggestions for moving the field forward

The pan-PPAR agonist lanifibranor reduces development of lung fibrosis and attenuates cardiorespiratory manifestations in a transgenic mouse model of systemic sclerosis

Background: The TβRII∆k-fib transgenic (TG) mouse model of scleroderma replicates key fibrotic and vasculopathic complications of systemic sclerosis through fibroblast-directed upregulation of TGFβ signalling. We have examined peroxisome proliferator-activated receptor (PPAR) pathway perturbation in this model and explored the impact of the pan-PPAR agonist lanifibranor on the cardiorespiratory phenotype. Methods: PPAR pathway gene and protein expression differences from TG and WT sex-matched littermate mice were determined at baseline and following administration of one of two doses of lanifibranor (30 mg/kg or 100 mg/kg) or vehicle administered by daily oral gavage up to 4 weeks. The prevention of bleomycin-induced lung fibrosis and SU5416-induced pulmonary hypertension by lanifibranor was explored. Results: Gene expression data were consistent with the downregulation of the PPAR pathway in the TβRII∆k-fib mouse model. TG mice treated with high-dose lanifibranor demonstrated significant protection from lung fibrosis after bleomycin and from right ventricular hypertrophy following induction of pulmonary hypertension by SU5416, despite no significant change in right ventricular systolic pressure. Conclusions: In the TβRII∆k-fib mouse strain, treatment with 100 mg/kg lanifibranor reduces the development of lung fibrosis and right ventricular hypertrophy induced by bleomycin or SU5416, respectively. Reduced PPAR activity may contribute to the exaggerated fibroproliferative response to tissue injury in this transgenic model of scleroderma and its pulmonary complications

Integrated analysis of dermal blister fluid proteomics and genome-wide skin gene expression in systemic sclerosis: an observational study

Background: Skin fibrosis is a hallmark feature of systemic sclerosis. Skin biopsy transcriptomics and blister fluid proteomics give insight into the local environment of the skin. We have integrated these modalities with the aim of developing a surrogate for the modified Rodnan skin score (mRSS), using candidate genes and proteins from the skin and blister fluid as anchors to identify key analytes in the plasma. Methods: In this single-centre, prospective observational study at the Royal Free Campus, University College London, London, UK, transcriptional and proteomic analyses of blood and skin were performed in a cohort of patients with systemic sclerosis (n=52) and healthy controls (n=16). Weighted gene co-expression network analysis was used to explore the association of skin transcriptomics data, clinical traits, and blister fluid proteomic results. Candidate hub analytes were identified as those present in both blister and skin gene sets (modules), and which correlated with plasma (module membership >0·7 and gene significance >0·6). Hub analytes were confirmed using RNA transcript data obtained from skin biopsy samples from patients with early diffuse cutaneous systemic sclerosis at 12 months. Findings: We identified three modules in the skin, and two in blister fluid, which correlated with a diagnosis of early diffuse cutaneous systemic sclerosis. From these modules, 11 key hub analytes were identified, present in both skin and blister fluid modules, whose transcript and protein levels correlated with plasma protein concentrations, mRSS, and showed statistically significant correlation on repeat transcriptomic samples taken at 12 months. Multivariate analysis identified four plasma analytes as correlates of mRSS (COL4A1, COMP, SPON1, and TNC), which can be used to differentiate disease subtype. Interpretation: This unbiased approach has identified potential biological candidates that might be drivers of local skin pathogenesis in systemic sclerosis. By focusing on measurable analytes in the plasma, we generated a promising composite plasma protein biomarker that could be used for assessment of skin severity, case stratification, and as a potential outcome measure for clinical trials and practice. Once fully validated, the biomarker score could replace a clinical score such as the mRSS, which carries substantial variability. Funding: GlaxoSmithKline and UK Medical Research Council

Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis.

OBJECTIVES: Clinical heterogeneity is a cardinal feature of systemic sclerosis (SSc). Hallmark SSc autoantibodies are central to diagnosis and associate with distinct patterns of skin-based and organ-based complications. Understanding molecular differences between patients will benefit clinical practice and research and give insight into pathogenesis of the disease. We aimed to improve understanding of the molecular differences between key diffuse cutaneous SSc subgroups as defined by their SSc-specific autoantibodies METHODS: We have used high-dimensional transcriptional and proteomic analysis of blood and the skin in a well-characterised cohort of SSc (n=52) and healthy controls (n=16) to understand the molecular basis of clinical diversity in SSc and explore differences between the hallmark antinuclear autoantibody (ANA) reactivities. RESULTS: Our data define a molecular spectrum of SSc based on skin gene expression and serum protein analysis, reflecting recognised clinical subgroups. Moreover, we show that antitopoisomerase-1 antibodies and anti-RNA polymerase III antibodies specificities associate with remarkably different longitudinal change in serum protein markers of fibrosis and divergent gene expression profiles. Overlapping and distinct disease processes are defined using individual patient pathway analysis. CONCLUSIONS: Our findings provide insight into clinical diversity and imply pathogenetic differences between ANA-based subgroups. This supports stratification of SSc cases by ANA antibody subtype in clinical trials and may explain different outcomes across ANA subgroups in trials targeting specific pathogenic mechanisms

Confucian Principles: A Study of Chinese Americans’ Interpersonal Relationships in Selected Children’s Picturebooks

[[abstract]]There has not been enough critical analysis of children’s literature by and about Chinese Americans, especially when compared to other minority groups in the United States. In particular, Chinese American historical books lack extensive analysis. It is important to reflect cultural accuracy in literature and to help children develop clear concepts of self and others by providing precise cultural and physical characteristics of people. While cultural authenticity allows children the opportunity to see a reflection of real experiences within a book instead of seeing stereotypes or misrepresentations, obtaining correct information about a certain time period can help children to see images of immigration accurately represented in literature. Using the Confucian delineation of interpersonal relationships as the major criterion of cultural authenticity, this article examines three currently available children’s picturebooks set in the historical period between 1848 and 1885. In addition to exploring how Chinese Americans’ interpersonal relationships are portrayed in these children’s historical books, this article argues for more proactive inclusion of the diversity in selection of picturebooks.[[notice]]補正完