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We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Eur

Introduction: Chronic low back pain (cLBP) poses significant challenges, often addressed through avoidance or distraction. Emerging evidence suggests that mind-body interventions, like our novel Mind Your Pain (MyP) smartphone mobile application, may offer relief. We conducted a single-arm, mixed-methods neuroimaging study to assess the degree to which treatment response to our 8-week intervention, as measured by the reduction in the Pain, Enjoyment of Life and General Activity Scale (PEG), was associated with enhanced pain-related insula activation over time., Methods: Twenty-nine individuals with cLBP completed patient-reported assessments, qualitative sensory testing (QST) measures, and neuroimaging pre- and post-MyP. Functional MRI data during experimental heat pain on the left forearm were collected and analyzed, comparing responders (≥50% reduction in PEG scores) and non-responders., Results: MyP led to significant decreases in PEG scores overall. Furthermore, MyP responders exhibited increased pain-related activation in key brain regions, including the contralateral posterior insula, bilateral ventral anterior insula, ventral anterior cingulate, dorsolateral prefrontal cortex, and nucleus accumbens. Although baseline behavioral and sensory measures did not differ between the two responder groups, baseline neural differences related to the impact of the endogenous back pain were observed., Discussion: MyP appears to modify pain response and underlying neural circuitry, suggesting neural changes in interoception may serve as biomarkers for mind-body interventions in cLBP. This study highlights the potential of MyP as a novel approach for cLBP management, warranting further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Strigo, Guerra, Torrisi, Murphy, Toor, Goldman, Alter, Vu, Hecht, Lotz, Simmons and Mehling.)

Introduction: Several countries prioritize patient safety in their health policies. In Portugal, following the implementation of the National Plan for Patient Safety (NPPS) 2015-2020, the research team of the National School of Public Health (NSPH) carried out extensive work to continue improving aspects of the previous Plan. This work was focused on identifying the strengths and weaknesses of NPPS 2015-2020 and aspects related to its applicability and main challenges and opportunities for the implementation of the NPPS 2021-2026., Methods: Methodological dynamic process was based on the most relevant international and national guidelines and the feedback from key patient safety stakeholders. We developed a cross-sectional mixed-methods study from January to August 2021. We used documentation and periodical reports from National Health Service (NHS) healthcare institutions as secondary sources of information. For primary data collection, we used an online survey (applied to elements in the different quality and safety structures of hospitals and primary care units), interviews, and focus groups to collect information from patient safety experts., Results and Discussion: Strengthening safety culture, patient safety training, communication, leadership involvement, patient and family engagement, and monitorization process is considered essential. We also identified local limitations such as the lack of resources and protected time for the healthcare professionals and lack of leadership involvement on patient safety strategies for dedicating to patient safety actions. Most of the patient safety stakeholders agreed that the safety and health of clinical teams and new modalities of healthcare (such as telemedicine, home hospitalization, home care) should be a priority for patient safety strategies., Conclusions: In our study, we used a robust methodology with a participatory process involving different stakeholders. An alignment between local, regional, and national levels in terms of measuring indicators, the definition of priorities, and actions and activities to improve patient safety is recommended. Reinforced partnerships and alignment between the institution's mission, and safety priorities will be crucial to enhance patient safety. Additionally, this work highlights the added value for health systems achieved through strong partnerships between public administration and academic institutions to improve healthcare quality and patient safety., Competing Interests: The research team of the National School of Public Health were responsible for the methodological design of the study, collection and analysis of data. Even though V.F. is the Director of DQH and C.P. works in the same department, it must be made clear that they were in no way whatsoever involved in the methodological design and data collection, analysis, and discussion presented in this paper., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel on behalf of NOVA National School of Public Health.)

We verified the prevalence of adequacy in prenatal care considering nutritional assistance and associated factors. It is a cross-sectional study, part of Maternar Cohort Study, conducted between 2018-2019 in Southern Brazil. Women were interviewed during hospitalization in the immediate postpartum period and data were collected from the prenatal chart. Prenatal adequacy and nutritional care were assessed according to criteria from the Brazilian Ministry of Health. Two outcome models were constructed. Outcome 1 consisted of minimal coverage (early prenatal start and minimum number of visits) and exams, and Outcome 2 comprised minimal coverage, exams, and nutritional assistance. Poisson regression was used to estimate prevalence ratios. A total of 802 women were analyzed, and we identified 57% of adequacy of Outcome 1. Unplanned pregnancy (PR = 0.76; 95%CI: 0.68-0.86), parity (PR = 0.88; 95%CI: 0.83-0.94) and prenatal care outside Porto Alegre, Rio Grande do Sul State (PR = 0.80; 95%CI: 0.69-0.92), were associated with lower prenatal adequacy frequencies. Outcome 2 was considered adequate for 10.2% of women. Follow-up by different professionals during prenatal care was associated with lower adequacy (PR = 0.49; 95%CI: 0.28-0.86). Women with high-risk pregnancies had a higher frequency of adequacy in Outcome 1 (PR = 1.21; 95%CI: 1.07-1.37) and in Outcome 2 (PR = 1.75; 95%CI: 1.16-2.64). General adequacy was considered low in both outcomes. There was a lack of nutritional assistance during prenatal care. Characteristics such as pregnancy planning, lower parity, prenatal care in Porto Alegre, follow-up by the same professional and high-risk pregnancy were predictors for the adequacy of prenatal care.

Objective: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC., Methods: ARA-positive patients (n = 99) with at least 5 years' follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort., Results: Analysis of 641,489 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10 -5 ), CTNND2 (rs1859082; P = 5.58 × 10 -5 ), HECW2 (rs16849716; P = 1.2 × 10 -4 ), and GPATCH2L (rs935332; P = 4.92 × 10 -5 ) with SRC. Further, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC ( P = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L ( P = 0.026) and glomerular expression of CTNND2 ( P = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP., Conclusion: Increased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.

Purpose: To evaluate the effect of N-Acetylcysteine (NAC) in newborn rats submitted to hypoxia and reoxygenation (H/R) conditions in an experimental model of necrotizing enterocolitis., Methods: Eight pregnant rats and their 70 cubs were used (5 groups) and exposed to H/R conditions and received NAC at different times. The animals in the H/R groups were placed in a gas chamber (100% CO2) for 10 minutes and then reoxygenated for 10 minutes (100% O2), twice a day for the first three days of life, with a six-hour span between events. On the third day of life, the animals were anesthetized, laparotomized and the intestines were resected., Results: The H/R and NAC groups showed changes in the intestinal wall in relation to the number, height and width of the villi when compared to the control group (p<0.0001), but with better preservation of structures in the NAC group. There were no differences between groups regarding the number (%) of mitoses., Conclusion: The administration of NAC decreased the lesions in the intestinal wall of rats submitted to H/R, therefore suggesting that this drug can be used to prevent the development of necrotizing enterocolitis in newborns.

The introduction of next generation sequencing (NGS) for stem cell donor registry typing has contributed to faster identification of compatible stem cell donors. However, the successful search for a matched unrelated donor for some patient groups is still affected by their ethnicity. In this study, DNA samples from 714 National Health Service (NHS) Cord Blood Bank donors were typed for HLA-A, -B, -C, -DRB1, -DRB345, -DQA1, -DQB1, -DPA1 and -DPB1 by NGS. Analysis of the ethnic diversity showed a high level of diversity, with the cohort comprising of 62.3% European and 37.7% of either multi-ethnic or non-European donors, of which 12.3% were multi-ethnic. The HLA diversity was further confirmed using PyPop analysis, 405 distinct alleles were observed in the overall NHS-CBB cohort, of which 37 alleles are non-CWD, including A*31:14N, B*35:68:02, C*14:23 and DQA1*05:10. Furthermore, HLA-DQA1 and HLA-DPA1 analysis showed 12% and 10%, respectively, of the alleles currently submitted to IMGT, confirming further diversity of the NHS-CBB cohort. The application of 11 HLA loci resolution by NGS revealed a high level of diversity in the NHS-CBB cohort. The incorporation of this data coupled with ethnicity data could lead to improved donor selection, contributing to better clinical outcomes for patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Minimal residual disease (MRD) monitoring is of prognostic importance in childhood acute lymphoblastic leukemia (ALL). The detection of immunoglobulin and T-cell receptor gene rearrangements by real-time quantitative PCR (RT-PCR) is considered the gold standard for this evaluation. However, more accessible methods also show satisfactory performance. This study aimed to compare MRD analysis by four-color flow cytometry (FC) and qualitative standard PCR on days 35 and 78 of chemotherapy and to correlate these data with patients' clinical characteristics. Forty-two children with a recent diagnosis of ALL, admitted to a public hospital in Brazil for treatment in accordance with the Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI LLA-2009), were included. Bone marrow samples collected at diagnosis and on days 35 and 78 of treatment were analyzed for the immunophenotypic characterization of blasts by FC and for the detection of clonal rearrangements by standard PCR. Paired analyses were performed in 61/68 (89.7%) follow-up samples, with a general agreement of 88.5%. Disagreements were resolved by RT-PCR, which evidenced one false-negative and four false-positive results in FC, as well as two false-negative results in PCR. Among the prognostic factors, a significant association was found only between T-cell lineage and MRD by standard PCR. These results show that FC and standard PCR produce similar results in MRD detection of childhood ALL and that both methodologies may be useful in the monitoring of disease treatment, especially in regions with limited financial resources.

Extended molecular characterization of HLA genes in the IHWG reference B-lymphoblastoid cell lines (B-LCLs) was one of the major goals for the 17th International HLA and Immunogenetics Workshop (IHIW). Although reference B-LCLs have been examined extensively in previous workshops complete high-resolution typing was not completed for all the classical class I and class II HLA genes. To address this, we conducted a single-blind study where select panels of B-LCL genomic DNA samples were distributed to multiple laboratories for HLA genotyping by next-generation sequencing methods. Identical cell panels comprised of 24 and 346 samples were distributed and typed by at least four laboratories in order to derive accurate consensus HLA genotypes. Overall concordance rates calculated at both 2- and 4-field allele-level resolutions ranged from 90.4% to 100%. Concordance for the class I genes ranged from 91.7 to 100%, whereas concordance for class II genes was variable; the lowest observed at HLA-DRB3 (84.2%). At the maximum allele-resolution 78 B-LCLs were defined as homozygous for all 11 loci. We identified 11 novel exon polymorphisms in the entire cell panel. A comparison of the B-LCLs NGS HLA genotypes with the HLA genotypes catalogued in the IPD-IMGT/HLA Database Cell Repository, revealed an overall allele match at 68.4%. Typing discrepancies between the two datasets were mostly due to the lower-resolution historical typing methods resulting in incomplete HLA genotypes for some samples listed in the IPD-IMGT/HLA Database Cell Repository. Our approach of multiple-laboratory NGS HLA typing of the B-LCLs has provided accurate genotyping data. The data generated by the tremendous collaborative efforts of the 17th IHIW participants is useful for updating the current cell and sequence databases and will be a valuable resource for future studies., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: To learn the weaknesses and strengths of safety culture as expressed by the dimensions measured by the Hospital Survey on Patient Safety Culture (HSOPSC) at hospitals in the various cultural contexts. The aim of this study was to identify studies that have used the HSOPSC to collect data on safety culture at hospitals; to survey their findings in the safety culture dimensions and possible contributions to improving the quality and safety of hospital care., Data Sources: Medline (via PubMed), Web of Science and Scopus were searched from 2005 to July 2016 in English, Portuguese and Spanish., Study Selection: Studies were identified using specific search terms and inclusion criteria. A total of 33 articles, reporting on 21 countries, was included., Data Extraction: Scores were extracted by patient safety culture dimensions assessed by the HSOPSC. The quality of the studies was evaluated by the STROBE Statement., Results: The dimensions that proved strongest were 'Teamwork within units' and 'Organisational learning-continuous improvement'. Particularly weak dimensions were 'Non-punitive response to error', 'Staffing', 'Handoffs and transitions' and 'Teamwork across units'., Conclusion: The studies revealed a predominance of hospital organisational cultures that were underdeveloped or weak as regards patient safety. For them to be effective, safety culture evaluation should be tied to strategies designed to develop safety culture hospital-wide.

The development of techniques to define the human leucocyte antigen (HLA) region has proven to be challenging due to its high level of polymorphism. Within a clinical laboratory, a technique for high-resolution HLA typing, which is rapid and cost effective is essential. NGS has provided a rapid, high-resolution HLA typing solution, which has reduced the number of HLA ambiguities seen with other typing methods. In this study, the One Lambda NXType NGS kit was tested on the Ion Torrent PGM platform. A total of 362 registry donors from four ethnic populations (Europeans, South Asians, Africans and Chinese) were NGS HLA typed across 9-loci (HLA-A, -B, -C, -DRB1,-DRB345 -DQB1 and -DPB1). Concordance rates of 91%-98% were obtained (for HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1) when compared to historical PCR-SSO HLA types, and the identification of uncommon alleles such as A*24:07:01 and C*04:82 were observed. A turnaround time of four days was achieved for typing 44 samples. However, some limitations were observed; primer locations did not allow all ambiguities to be resolved for HLA Class II where Exon I and IV amplification are needed (HLA-DRB1*04:07:01/04:92, HLA-DRB1*09:01:02/*09:21 and HLA-DRB1*12:01:01/*12:10). This study has demonstrated high-resolution typing by NGS can be achieved in an acceptable turnaround time for a clinical laboratory; however, the Ion Torrent workflow has some technical limitations that should be addressed., (© 2018 John Wiley & Sons Ltd.)

Patients with juvenile systemic lupus erythematosus (JSLE) usually have an increase in fat mass and decrease in lean body mass. The purpose of this study was to assess the effect of a nutritional intervention on changes in body composition and food consumption of adolescents with JSLE compared with a control group and its variation over time and to assess the association of total fat mass with clinical parameters. This randomized controlled study evaluated 31 girls. Body composition and food intake were evaluated at baseline. The patients were randomly allocated into a nutritional intervention group and a control group. The intervention group received monthly nutritional guidelines for 9 months. After this period, evaluations were repeated. The carbohydrates intake decreased in the intervention group compared with the control group (p = 0.031) at the end of the study period. Additionally, a significant decrease was observed in the intake of energy (p = 0.023), carbohydrates (p = 0.031), protein (p = 0.024), total fat (p = 0.027), saturated fat (p = 0.012), and trans fat (p = 0.029) in the intervention group between baseline and the end of the study. There was an average increase of 3.7 kg (95% CI 0.8-6.5) in the total fat mass (p = 0.013) and 0.36 kg/m 2 (95% CI 0.10-0.62) in the appendicular fat mass (p = 0.007) in the control group during the study period; this finding was not observed in the intervention group. A 9-month nutritional intervention in JSLE patients improved their eating habits and protected against the excessive gain of weight and body fat.

Objective: NKX2-5 is a homeobox transcription factor that is required for the formation of the heart and vessels during development, with significant postnatal down-regulation and reactivation in disease states, characterized by vascular remodeling. The purpose of this study was to investigate mechanisms that activate NKX2-5 expression in diseased vessels, such as systemic sclerosis (scleroderma; SSc)-associated pulmonary hypertension (PH), and to identify genetic variability that potentially underlies susceptibility to specific vascular complications., Methods: We explored NKX2-5 expression in biopsy samples from patients with SSc-associated PH and in pulmonary artery smooth muscle cells (PASMCs) from patients with scleroderma. Disease-associated putative functional single-nucleotide polymorphisms (SNPs) at the NKX2-5 locus were cloned and studied in reporter gene assays. SNP function was further examined through protein-DNA binding assays, chromatin immunoprecipitation assays, and RNA silencing analyses., Results: Increased NKX2-5 expression in biopsy samples from patients with SSc-associated PH was localized to remodeled vessels and PASMCs. Meta-analysis of 2 independent scleroderma cohorts revealed an association of rs3131917 with scleroderma (P = 0.029). We demonstrated that disease-associated SNPs are located in a novel functional enhancer, which increases NKX2-5 transcriptional activity through the binding of GATA-6, c-Jun, and myocyte-specific enhancer factor 2C. We also characterized an activator/coactivator transcription-enhancer factor domain 1 (TEAD1)/Yes-associated protein 1 (YAP1) complex, which was bound at rs3095870, another functional SNP, with TEAD1 binding the risk allele and activating the transcription of NKX2-5., Conclusion: NKX2-5 is genetically associated with scleroderma, pulmonary hypertension, and fibrosis. Functional evidence revealed a regulatory mechanism that results in NKX2-5 transcriptional activation in PASMCs through the interaction of an upstream promoter and a novel downstream enhancer. This mechanism can act as a model for NKX2-5 activation in cardiovascular disease characterized by vascular remodeling., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objectives: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc., Methods: This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method., Results: Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants., Conclusions: We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Current treatment strategies for childhood ALL result in long-term remission for approximately 90% of patients. However, the therapeutic response is worse among those who relapse. Several risk stratification approaches based on clinical and biological aspects have been proposed to intensify treatment in patients with high risk of relapse and reduce toxicity on those with a greater probability of cure. The detection of residual leukemic cells (minimal residual disease, MRD) is the most important prognostic factor to identify high-risk patients, allowing redefinition of chemotherapy. In the last decades, several standardized research protocols evaluated MRD using immunophenotyping by flow cytometry and/or real-time quantitative polymerase chain reaction at different time points during treatment. Both methods are highly sensitive (10(-3) a 10(-5)), but expensive, complex, and, because of that, require qualified staff and frequently are restricted to reference centers. The aim of this article was to review technical aspects of immunophenotyping by flow cytometry and real-time quantitative polymerase chain reaction to evaluate MRD in ALL.

Introduction: Minimal residual disease is an important independent prognostic factor that can identify poor responders among patients with acute lymphoblastic leukemia., Objective: The aim of this study was to analyze minimal residual disease using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements by conventional polymerase chain reaction followed by homo-heteroduplex analysis and to compare this with real-time polymerase chain reaction at the end of the induction period in children with acute lymphoblastic leukemia., Methods: Seventy-four patients diagnosed with acute lymphoblastic leukemia were enrolled. Minimal residual disease was evaluated by qualitative polymerase chain reaction in 57 and by both tests in 44. The Kaplan-Meier and multivariate Cox methods and the log-rank test were used for statistical analysis., Results: Nine patients (15.8%) were positive for minimal residual disease by qualitative polymerase chain reaction and 11 (25%) by real-time polymerase chain reaction considering a cut-off point of 1×10(-3) for precursor B-cell acute lymphoblastic leukemia and 1×10(-2) for T-cell acute lymphoblastic leukemia. Using the qualitative method, the 3.5-year leukemia-free survival was significantly higher in children negative for minimal residual disease compared to those with positive results (84.1%±5.6% versus 41.7%±17.3%, respectively; p-value=0.004). There was no significant association between leukemia-free survival and minimal residual disease by real-time polymerase chain reaction. Minimal residual disease by qualitative polymerase chain reaction was the only variable significantly correlated to leukemia-free survival., Conclusion: Given the difficulties in the implementation of minimal residual disease monitoring by real-time polymerase chain reaction in most treatment centers in Brazil, the qualitative polymerase chain reaction strategy may be a cost-effective alternative., (Copyright © 2015 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved.)

Introduction: Clinical diversity in systemic sclerosis (SSc) reflects multifaceted pathogenesis and the effect of key growth factors or cytokines operating within a disease-specific microenvironment. Dermal interstitial fluid sampling offers the potential to examine local mechanisms and identify proteins expressed within lesional tissue. We used multiplex cytokine analysis to profile the inflammatory and immune activity in the lesions of SSc patients., Methods: Dermal interstitial fluid sample from the involved forearm skin, and synchronous plasma samples were collected from SSc patients (n = 26, diffuse cutaneous SSc (DcSSc) n = 20, limited cutaneous SSc (LcSSc) n = 6), and healthy controls (HC) (n = 10) and profiled by Luminex® array for inflammatory cytokines, chemokines, and growth factors., Results: Luminex® profiling of the dermal blister fluid showed increased inflammatory cytokines (median interleukin ( IL)-6 in SSc 39.78 pg/ml, HC 5.51 pg/ml, p = 0.01, median IL-15 in SSc 6.27 pg/ml, HC 4.38 pg/ml, p = 0.03), chemokines (monocyte chemotactic protein (MCP)-3 9.81 pg/ml in SSc, 7.18 pg/ml HC, p = 0.04), and profibrotic growth factors (platelet derived growth factor (PDGF)-AA 10.38 pg/ml versus 6.94 pg/ml in HC, p = 0.03). In general dermal fluid and plasma cytokine levels did not correlate, consistent with predominantly local production of these factors within the dermal lesions, rather than leakage from the serum. In hierarchical clustering and network analysis IL-6 emerged as a key central mediator., Conclusions: Our data confirm that an immuno-inflammatory environment and aberrant vascular repair are intimately linked to fibroblast activation in lesional skin in SSc. This non-invasive method could be used to profile disease activity in the clinic, and identifies key inflammatory or pro-fibrotic proteins that might be targeted therapeutically. Distinct subgroups of SSc may be defined that show innate or adaptive immune cytokine signatures.

There is compelling evidence that particulate matter (PM) increases lung cancer risk by triggering systemic inflammation, and leukocyte DNA hypomethylation. However, previous investigations focused on repeated element sequences from LINE-1 and Alu families. Tandem repeats, which display a greater propensity to mutate, and are often hypomethylated in cancer patients, have never been investigated in individuals exposed to PM. We measured methylation of three tandem repeats (SATα, NBL2, and D4Z4) by polymerase chain reaction-pyrosequencing on blood samples from truck drivers and office workers (60 per group) in Beijing, China. We used lightweight monitors to measure personal PM2.5 (PM with aerodynamic diameter ≤2.5 µm) and elemental carbon (a tracer of PM from vehicular traffic). Ambient PM10 data were obtained from air quality measuring stations. Overall, an interquartile increase in personal PM2.5 and ambient PM10 levels was associated with a significant covariate-adjusted decrease in SATα methylation (-1.35% 5-methyl cytosine [5mC], P = 0.01; and -1.33%5mC; P = 0.01, respectively). Effects from personal PM2.5 and ambient PM10 on SATα methylation were stronger in truck drivers (-2.34%5mC, P = 0.02; -1.44%5mC, P = 0.06) than office workers (-0.95%5mC, P = 0.26; -1.25%5mC, P = 0.12, respectively). Ambient PM10 was negatively correlated with NBL2 methylation in truck drivers (-1.38%5mC, P = 0.03) but not in office workers (1.04%5mC, P = 0.13). Our result suggests that PM exposure is associated with hypomethylation of selected tandem repeats. Measuring tandem-repeat hypomethylation in easy-to-obtain blood specimens might identify individuals with biological effects and potential cancer risk from PM exposure., (Copyright © 2014 Wiley Periodicals, Inc.)

We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P=1.71 × 10(-34) , OR=1.43[1.26-1.60]) and rs1234317-T (P=1.16 × 10(-28) , OR=1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5' region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5' risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait., Competing Interests: The authors have declared that no competing interests exist.

Objective: To detect markers for minimal residual disease monitoring based on conventional polymerase chain reaction for immunoglobulin, T-cell receptor rearrangements and the Sil-Tal1 deletion in patients with acute lymphocytic leukemia., Methods: Fifty-nine children with acute lymphocytic leukemia from three institutions in Minas Gerais, Brazil, were prospectively studied. Clonal rearrangements were detected by polymerase chain reaction followed by homo/heteroduplex clonality analysis in DNA samples from diagnostic bone marrow. Follow-up samples were collected on Days 14 and 28-35 of the induction phase. The Kaplan-Meier and multivariate Cox methods were used for survival analysis., Results: Immunoglobulin/T-cell receptor rearrangements were not detected in 5/55 children screened (9.0%). For precursor-B acute lymphocytic leukemia, the most frequent rearrangement was IgH (72.7%), then TCRG (61.4%), and TCRD and IgK (47.7%); for T-acute lymphocytic leukemia, TCRG (80.0%), and TCRD and Sil-Tal deletion (20.0%) were the most common. Minimal residual disease was detected in 35% of the cases on Day 14 and in 22.5% on Day 28-35. Minimal residual disease on Day 28-35, T-acute lymphocytic leukemia, and leukocyte count above 50 x 10(9)/L at diagnosis were bad prognostic factors for leukemia-free survival in univariate analysis. Relapse risk for minimal residual disease positive relative to minimal residual disease negative children was 8.5 times higher (95% confidence interval: 1.02-70.7)., Conclusion: Immunoglobulin/T-cell receptor rearrangement frequencies were similar to those reported before. Minimal residual disease is an independent prognostic factor for leukemia-free survival, even when based on a non-quantitative technique, but longer follow-ups are needed.

Objective: The aim of this study was to describe the prevalence of main hereditary thrombophilias, Janus kinase 2 (JAK2) V617F mutation, antiphospholipid antibody syndrome (APS), and hyperhomocysteinemia in Brazilian children and adolescents diagnosed with portal vein thrombosis (PVT) without associated hepatic disease., Methods: A cross-sectional study was carried out with 32 children with PVT in accompaniment at Hospital das Clínicas of the Universidade Federal de Minas Gerais from January 1990 to July 2011. Laboratory evaluation of thrombophilias was performed from September 2010 to July 2011., Results: Thirty-two patients were evaluated; 59% were boys. Median age at diagnosis was 2.4 years. Mean time of patients' accompaniment was between 4.7 and 5.2 years. The presence of hereditary and acquired thrombophilias occurred in 34.4% of patients, and 9 of them also showed other risk factors in the previous history evaluation. Risk factors were absent in the previous history of 18 patients (56.3%). Two patients showed persistent high titres of anticardiolipin antibodies. Hyperhomocysteinemia was not observed. One patient was heterozygous for factor V Leiden and prothrombin G20210A mutation (3.1%). Eleven patients (34.4%) showed heterozygous methylenetetrahydrofolate reductase (MTHFR) C677T, and no patient had the JAK2V617F mutation., Conclusions: Even after investigation of main hereditary and acquired thrombophilia, PVT remains without apparent cause in most patients. Nevertheless, association of local and systemic risk factors seems to be important also in the pediatric age group. Therefore, despite the low prevalence, a complete investigation, which includes both hereditary and acquired thrombophilias, may be necessary.

Objectives: The aims of this study were to measure levels of sleep, stress, and depression, as well as health-related quality of life, and to assess the neurocognitive profiles in a sample of adolescents with idiopathic musculoskeletal pain., Methods: Nineteen adolescents with idiopathic musculoskeletal pain and 20 age-matched healthy control subjects were evaluated regarding their levels of sleep and stress, as well as quality of life, and underwent neurocognitive testing., Results: The sample groups consisted predominantly of females (84%), and the socioeconomic status did not differ between the two groups. In addition, the occurrence of depressive symptoms was similar between the two groups; specifically, 26% of the idiopathic musculoskeletal pain patients and 30% of the control subjects had scores indicative of depression. Teenagers in the group with idiopathic musculoskeletal pain reported poorer quality of life and sleep scores than those in the control group. Regarding stress, patients had worse scores than the control group; whereas 79% of the adolescents with idiopathic musculoskeletal pain met the criteria for a diagnosis of stress, only 35% of the adolescents in the control group met the criteria. In both groups, we observed scores that classified adolescents as being in the resistance phase (intermediate) and exhaustion phase (pathological) of distress. However, the idiopathic musculoskeletal pain group more frequently reported symptomatic complaints of physical and emotional distress. The neurocognitive assessment showed no significant impairments in either group., Conclusion: Adolescents with idiopathic musculoskeletal pain did not exhibit cognitive impairments. However, adolescents with idiopathic musculoskeletal pain did experience intermediate to advanced psychological distress and lower health-related quality of life, which may increase their risk of cognitive dysfunction in the future.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong genetic component and is characterized by chronic inflammation and the production of anti-nuclear auto-antibodies. In the era of genome-wide association studies (GWASs), elucidating the genetic factors present in SLE has been a very successful endeavor; 28 confirmed disease susceptibility loci have been mapped. In this review, we summarize the current understanding of the genetics of lupus and focus on the strongest associated risk loci found to date (P <1.0 × 10-8). Although these loci account for less than 10% of the genetic heritability and therefore do not account for the bulk of the disease heritability, they do implicate important pathways, which contribute to SLE pathogenesis. Consequently, the main focus of the review is to outline the genetic variants in the known associated loci and then to explore the potential functional consequences of the associated variants. We also highlight the genetic overlap of these loci with other autoimmune diseases, which indicates common pathogenic mechanisms. The importance of developing functional assays will be discussed and each of them will be instrumental in furthering our understanding of these associated variants and loci. Finally, we indicate that performing a larger SLE GWAS and applying a more targeted set of methods, such as the ImmunoChip and next generation sequencing methodology, are important for identifying additional loci and enhancing our understanding of the pathogenesis of SLE.

Chronic myeloproliferative diseases without the Philadelphia chromosome marker (Ph-), although first described 60 years ago, only became the subject of interest after the turn of the millennium. In 2001, the World Health Organization (WHO) defined the classification of this group of diseases and in 2008 they were renamed myeloproliferative neoplasms based on morphological, cytogenetic and molecular features. In 2005, the identification of a recurrent molecular abnormality characterized by a gain of function with a mutation in the gene encoding Janus kinase 2 (JAK2) paved the way for greater knowledge of the pathophysiology of myeloproliferative neoplasms. The JAK2 mutation is found in 90-98% of polycythemia vera and in about 50% essential thrombocytosis and primary myelofibrosis. In addition to the JAK2 mutation, other mutations involving TET2 (ten-eleven translocation), LNK (a membrane-bound adaptor protein); IDH1/2 (isocitrate dehydrogenase 1/2 enzyme); ASXL1 (additional sex combs-like 1) genes were found in myeloproliferative neoplasms thus showing the importance of identifying molecular genetic alterations to confirm diagnosis, guide treatment and improve our understanding of the biology of these diseases. Currently, polycythemia vera, essential thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and mastocytosis are included in this group of myeloproliferative neoplasms, but are considered different situations with individualized diagnostic methods and treatment. This review updates pathogenic aspects, molecular genetic alterations, the fundamental criteria for diagnosis and the best approach for each of these entities.

Given the complex array of emotional and medical issues that may arise when making a decision about amniocentesis, women may find that their spiritual and/or religious beliefs can comfort and assist their decision-making process. Prior research has suggested that Latinas' spiritual and/or religious beliefs directly influence their amniocentesis decision. A more intimate look into whether Latinas utilize their beliefs during amniocentesis decision-making may provide an opportunity to better understand their experience. The overall goal of this study was to describe the role structured religion and spirituality plays in Latinas' daily lives and to evaluate how religiosity and spirituality influences health care decisions, specifically in prenatal diagnosis. Semi-structured interviews were conducted with eleven women who were invited to describe their religious beliefs and thoughts while considering the option of amniocentesis. All participants acknowledged the influence of religious and/or spiritual beliefs in their everyday lives. Although the women sought comfort and found validation in their beliefs and in their faith in God's will during their amniocentesis decision-making process, results suggest the risk of procedure-related complications played more of a concrete role than their beliefs.

Systemic lupus erythematosus (SLE) is an autoimmune disease which behaves as a complex genetic trait. At least 20 SLE risk susceptibility loci have been mapped using both candidate gene and genome-wide association strategies. The gene encoding the pro-inflammatory cytokine, IL18, has been reported as a candidate gene showing an association with SLE. This pleiotropic cytokine is expressed in a range of immune cells and has been shown to induce interferon-γ and tumour necrosis factor-α. Serum interleukin-18 has been reported to be elevated in patients with SLE. Here we aimed to densely map single nucleotide polymorphisms (SNPs) across IL18 to investigate the association across this locus. We genotyped 36 across IL18 by Illumina bead express in 372 UK SLE trios. We also genotyped these SNPs in a further 508 non-trio UK cases and were able to accurately impute a dense marker set across IL18 in WTCCC2 controls with a total of 258 SNPs. To improve the study's power, we also imputed a total of 158 SNPs across the IL18 locus using data from an SLE genome-wide association study and performed association testing. In total, we analysed 1818 cases and 10 770 controls in this study. Our large well-powered study (98% to detect odds ratio = 1.5, with respect to rs360719) showed that no individual SNP or haplotype was associated with SLE in any of the cohorts studied. We conclude that we were unable to replicate the SLE association with rs360719 located upstream of IL18. No evidence for association with any other common variant at IL18 with SLE was found.

Introduction: In recent years, reports of attentional deficits in schizophrenic patients and in their biological relatives have rapidly increased, including an important effort to search for the endophenotypes in order to link specific genes to this illness. Posner et al. developed a test, the Attention Network Test (ANT), to study the neural networks. This test provides a separate measure for each one of the three anatomically-defined attention networks (alerting, orienting and executive control)., Methodology: In this paper, we investigate the attentional performance in 32 schizophrenic patients, 29 unaffected first degree relatives and 29 healthy controls using the ANT through a study of family association. We have studied the efficiency of the segregated executive control, alerting and orienting networks by measuring how response latencies (reaction time) were modified by the cue position and the flanking stimuli. We also studied the familial association of these attentional alterations., Results: The ANOVA revealed main effects of flanker and cue condition and a significant interaction effect between flanker and groups studied. The schizophrenic patients and their relatives had a longer median reaction time than the control group. The probands and their relatives significantly differed from the healthy controls in terms of their conflict resolution; however, the alerting network appeared to be conserved., Conclusions: Our results support the thesis of a specific attentional deficit in schizophrenia and show the segregation of the three attentional networks. The family association of these reported alterations supports the idea of a potential endophenotype in schizophrenia.

Background: Splanchnic vein thrombosis can be the presenting manifestation of myeloproliferative neoplasms. However, the diagnosis of a myeloproliferative neoplasm in these patients is often problematic, and more objective criteria are needed., Aim: To determine the frequency of the mutation JAK2V617F in patients with splanchnic vein thromboses., Methods: A consecutive series of 108 adult patients with portal vein thrombosis (n = 77) and Budd-Chiari syndrome (n = 31) referred for hemostasis evaluation was retrospectively studied, with a median follow-up of 51 months (1-104)., Results: One or more prothrombotic risk factors were present in 63% of the patients. Twenty-four (22%) out of the 108 patients presented the JAK2V617F, including 2 cirrhotic patients. Most had a low mutated allele burden (median 16.5%). JAK2V617F was present in all four patients with a previous diagnosis of a myeloproliferative neoplasm. In nine JAK2V617F-positive patients, the diagnosis of a myeloproliferative neoplasm was made at the thrombosis work-up, during follow-up or after JAK2V617F detection. Among the other 11 patients carrying the mutation, 2 patients have died, 4 had no evidence suggesting a myeloproliferative neoplasm, 1 had a normal bone marrow biopsy, and the other 4 could not be persuaded to undergo a biopsy. Among the patients without an overt myeloproliferative neoplasm, 15 out of 99 (15%) presented the JAK2V617F mutation. None of the JAK2V617F-negative patients have developed signs of a myeloproliferative neoplasm during follow-up., Conclusions: Our findings suggest that JAK2V617F occurs in a high proportion of patients with splanchnic vein thrombosis, and reinforces the diagnostic utility of JAK2V617F testing in this setting.

Background and Objectives: The Short Form 12 (SF-12) has not been validated for long-term dialysis patients. The study compared physical and mental component summary (PCS/MCS) scores from the SF-36 with those from the embedded SF-12 in a national cohort of dialysis patients., Design, Setting, Participants, & Measurements: All 44,395 patients who had scorable SF-36 and SF-12 from January 1, 2006, to December 31, 2006, and were treated at Fresenius Medical Care, North America facilities were included. Death and first hospitalization were followed for up to 1 year from the date of survey. Correlation and agreement were obtained between PCS-36 and PCS-12 and MCS-36 and MCS-12; then Cox models were constructed to compare associated hazard ratios (HRs) between them., Results: Physical and mental dimensions both exhibited excellent intraclass correlation coefficients of 0.94. Each incremental point for both PCS-12 and PCS-36 was associated with a 2.4% lower adjusted HR of death and 0.4% decline in HR for first hospitalization (both P < 0.0001). Corresponding improvement in HR of death for each MCS point was 1.2% for MCS-12 and 1.3% for MCS-36, whereas both had similar 0.6% lower HR for hospitalization per point (all P < 0.0001)., Conclusions: The use of the SF-12 alone or as part of a larger survey is valid in dialysis patients. Composite scores from the SF-12 and SF-36 have similar prognostic association with death and hospitalization risk. Prospective longitudinal studies of SF-12 surveys that consider responsiveness to specific clinical, situational, and interventional changes are needed in this population.

Background: Incremental achievement of quality indicator goals has been associated with progressive improvement in mortality and hospitalization risk in hemodialysis (HD) patients., Study Design: Descriptive cross-sectional study., Setting & Participants: All 33,879 HD patients treated at Fresenius Medical Care North America facilities for >90 days with scorable 36-Item Short Form Health Survey responses from January 1, 2006, to December 31, 2006., Predictor: We hypothesized that achieving up to 5 HD goals before the survey (albumin >or= 4.0 g/dL, hemoglobin of 11-12 g/dL, equilibrated Kt/V >or= 1.2, phosphorus of 3.5-5.5 mg/L, and absence of HD catheter) results in better self-reported quality of life (QoL)., Outcomes & Measurements: Distributions of Physical and Mental Component Summary (PCS/MCS) scores within and across quality indicator categories determined during the prior 90 days from survey date (compared using analysis of covariance and linear regression models, with adjustment for case-mix and each of the quality indicators)., Results: Incremental achievement of up to 5 goals was associated with progressively higher PCS and MCS scores (both P for trend < 0.001). Compared with patients meeting all 5 goals (n = 4,208; reference group), case-mix-adjusted PCS score was lower by 1.8 point with only 4 goals met (n = 11,785), 3.4 points for 3 goals (n = 10,906), 4.9 points for 2 goals (n = 5,119), 5.9 points for 1 goal (n = 1,592), and 7.8 points in the 269 patients who failed to meet any goal (each P < 0.001 vs the reference group). The corresponding decreases in case-mix-adjusted MCS scores were 1.0 point for 4 goals met, 1.7 point for 3 goals, 2.3 points for 2 goals, 3.0 points for 1 goal, and 4.7 points with no goal met, with each P < 0.001 compared with the MCS score from patients who achieved all 5 goals., Limitations: Potential residual confounding from unmeasured covariates., Conclusion: Patients progressively meeting more quality goals report incrementally better QoL. Further studies are needed to determine whether prospective achievement of quality goals will result in improved QoL for HD patients.

The most solidly established risk factors for laryngeal cancer are tobacco and alcohol. As for occupational factors, the only established carcinogen is exposure to strong inorganic acid mists. However, asbestos, pesticides, paints, gasoline, diesel engine emissions, dusts, and other factors have been reported in the literature as occupational agents that increase the risk of laryngeal cancer. A hospital-based case-control study was conducted to investigate occupational risk factors for laryngeal cancer. Detailed data on smoking, alcohol consumption, and occupational history were collected for 122 laryngeal cancers and 187 controls matched by frequency (according to sex and age). Laryngeal cancer was associated with exposure to respirable free crystalline silica (OR = 1.83; 95%CI: 1.00-3.36), soot (from coal, coke, fuel oil, or wood) (odds ratio - OR = 1.78; 95% confidence interval - 95%CI: 1.03-3.03), fumes (OR = 2.55; 95%CI: 1.14-5.67), and live animals (OR = 1.80; 95%CI: 1.02-3.19).