Objective
To determine the frequency of subclinical synovitis on musculoskeletal ultrasonography (MSUS) in juvenile idiopathic arthritis (JIA) and correlate patient‐ and provider‐reported outcome ...measures with MSUS synovitis.
Method
JIA patients with an active joint count (AJC) of >4 underwent a 42‐joint MSUS performed at baseline and 3 months. B‐mode and power Doppler images were obtained and scored (range 0–3) for each of the 42 joints. Outcomes evaluated included physician global assessment of disease activity (PhGA), patient global assessment of disease activity (PtGA), patient pain, Childhood Health Assessment Questionnaire (C‐HAQ), and AJC. Subclinical synovitis was defined as synovitis detected by MSUS only. Generalized estimation equations were used to test the relationship between clinical arthritis (positive/negative) and subclinical synovitis (positive/negative). Spearman's correlation coefficients (rs) were calculated to determine the association between MSUS synovitis and patient‐ and physician‐reported outcomes.
Results
In 30 patients, subclinical synovitis was detected in 30% of joints. Clinical arthritis of the fingers, wrists, and knee joints was significantly associated with MSUS synovitis in these joints. PtGA and the C‐HAQ had a moderate (rs = 0.44, P = 0.014) to weak (rs = 0.37, P = 0.045) correlation with MSUS synovitis. There was a statistically significant strong correlation between MSUS synovitis and PhGA (rs = 0.61, P = 0.001), but a weak correlation with AJC (rs = 0.37, P = 0.048) at the follow‐up visit.
Conclusion
Subclinical synovitis was commonly observed in this cohort of JIA patients. The fair‐to‐moderate correlation of MSUS synovitis with patient‐ and provider‐reported outcomes suggests that MSUS assesses a different, possibly more objective, domain not determined by traditional JIA outcome measurements.
Persons with cystic fibrosis are at high risk of pulmonary nontuberculous mycobacterial infection, with a national prevalence estimated at 13%. The risk of nontuberculous mycobacteria associated with ...specific environmental exposures, and the correlation with climatic conditions in this population has not been described.
To describe the association of pulmonary nontuberculous mycobacteria with individual exposures to water and soil aerosols, and the population associations of these infections with climatic factors.
We conducted a nested case-control study within a cohort study of pulmonary nontuberculous mycobacteria prevalence at 21 geographically diverse national cystic fibrosis centers. Incident nontuberculous mycobacterial infection cases (at least one prior negative culture followed by one positive culture) were age- and sex-matched to culture-negative controls. Exposures to water and soil were assessed by administering a standardized questionnaire. Cohort prevalence at each of the 21 centers was correlated with climatic conditions in the same area through linear regression modeling.
Overall, 48 cases and 85 control subjects were enrolled. Indoor swimming was associated with incident infection (adjusted odds ratio, 5.9, 95% confidence interval, 1.3-26.1), although only nine cases (19%) and five control subjects (6%) reported indoor swimming in the 4 months prior to infection. Exposure to showering and municipal water supply was common among both cases and control subjects: 77% of cases and 76% of control subjects reported showering at least daily. In linear regression, average annual atmospheric water vapor content was significantly predictive of center prevalence (P = 0.0019), with R(2) = 0.40.
Atmospheric conditions explain more of the variation in disease prevalence than individual behaviors. The risk of specific exposures may vary by geographic region due to differences in conditions favoring mycobacterial growth and survival. However, because exposure to these organisms is ubiquitous and behaviors are similar among persons with and without pulmonary nontuberculous mycobacteria, genetic susceptibility beyond cystic fibrosis is likely to be important for disease development. Common individual risk factors in high-risk populations remain to be identified.
PDBe: Protein Data Bank in Europe Gutmanas, Aleksandras; Alhroub, Younes; Battle, Gary M ...
Nucleic acids research,
01/2014, Letnik:
42, Številka:
Database issue
Journal Article
Recenzirano
Odprti dostop
The Protein Data Bank in Europe (pdbe.org) is a founding member of the Worldwide PDB consortium (wwPDB; wwpdb.org) and as such is actively engaged in the deposition, annotation, remediation and ...dissemination of macromolecular structure data through the single global archive for such data, the PDB. Similarly, PDBe is a member of the EMDataBank organisation (emdatabank.org), which manages the EMDB archive for electron microscopy data. PDBe also develops tools that help the biomedical science community to make effective use of the data in the PDB and EMDB for their research. Here we describe new or improved services, including updated SIFTS mappings to other bioinformatics resources, a new browser for the PDB archive based on Gene Ontology (GO) annotation, updates to the analysis of Nuclear Magnetic Resonance-derived structures, redesigned search and browse interfaces, and new or updated visualisation and validation tools for EMDB entries.
Protein-tyrosine phosphatases (PTPs), along with protein-tyrosine kinases, play key roles in cellular signaling. All Class I PTPs contain an essential active site cysteinyl residue, which executes a ...nucleophilic attack on substrate phosphotyrosyl residues. The high reactivity of the catalytic cysteine also predisposes PTPs to oxidation by reactive oxygen species, such as H
2O
2. Reversible PTP oxidation is emerging as an important cellular regulatory mechanism and might contribute to diseases such as cancer. We exploited these unique features of PTP enzymology to develop proteomic methods, broadly applicable to cell and tissue samples, that enable the comprehensive identification and quantification of expressed classical PTPs (PTPome) and the oxidized subset of the PTPome (oxPTPome). We find that mouse and human cells and tissues, including cancer cells, display distinctive PTPomes and oxPTPomes, revealing additional levels of complexity in the regulation of protein-tyrosine phosphorylation in normal and malignant cells.
Display omitted
► Proteomic approach monitors classical protein-tyrosine phosphatase (PTP) expression ► Modified method measures the fraction of PTPs that are oxidized ► Different cancer cell lines contain unique PTP oxidation profiles ► Method can be combined with phosphotyrosine proteomics to suggest PTP substrates
A method for quantifying the expression of reduced and oxidized protein tyrosine phosphatases (PTPs) shows that healthy and cancer cells have distinct PTP proteomes and reveals the extensive posttranslational regulation of these enzymes.
This introduction to the
Journal of Business Research special issue on anti-consumption briefly defines and highlights the importance of anti-consumption research, provides an overview of the latest ...studies in the area, and suggests an agenda for future research on anti-consumption.
Abstract
Context:
Long-term follow-up data on premature ovarian insufficiency (POI) in childhood cancer survivors are limited.
Objective:
To describe the prevalence of POI, its risk factors, and ...associated long-term adverse health outcomes.
Design:
Cross-sectional.
Setting:
The St. Jude Lifetime Cohort Study, an established cohort in a tertiary care center.
Patients:
Nine hundred twenty-one participants (median age, 31.7 years) were evaluated at a median of 24.0 years after cancer diagnosis.
Main Outcome Measure:
POI was defined by persistent amenorrhea combined with a follicle-stimulating hormone level >30 IU/L before age 40. Multivariable Cox regression was used to study associations between demographic or treatment-related risk factors and POI. Multivariable logistic regression was used to study associations between POI and markers for cardiovascular disease, bone mineral density (BMD), and frailty. Exposure to alkylating agents was quantified using the validated cyclophosphamide equivalent dose (CED).
Results:
The prevalence of POI was 10.9%. Independent risk factors for POI included ovarian radiotherapy at any dose and CED ≥8000 mg/m2. Patients with a body mass index ≥30 kg/m2 at the time of the St. Jude Lifetime Cohort assessment were less likely to have a diagnosis of POI. Low BMD and frailty were independently associated with POI.
Conclusion:
High-dose alkylating agents and ovarian radiotherapy at any dose are associated with POI. Patients at the highest risk should be offered fertility preservation whenever feasible. POI contributes to poor general health outcomes in childhood cancer survivors; further studies are needed to investigate the role of sex hormone replacement in improving such outcomes.
We report on the prevalence, risk factors, and consequences on general health of premature ovarian insufficiency in a cohort of 921 long-term survivors of childhood cancers.
Immune checkpoint therapy has resulted in minimal clinical response in many pediatric cancers. We sought to understand the influence of immune checkpoint inhibition using anti-PD-1 and anti-CTLA-4 ...antibodies individually, in combination, and after chemotherapy on immune responses in minimal and established murine neuroblastoma models. We also sought to understand the role of the tumor microenvironment (TME) and PD-L1 expression and their alteration post-chemotherapy in our models and human tissues. PD-L1 expression was enriched in human tumor-associated macrophages and up-regulated after chemotherapy. In a murine minimal disease model, single and dual immune checkpoint blockade promoted tumor rejection, improved survival, and established immune memory with long-term anti-tumor immunity against re-challenge. In an established tumor model, only dual immune checkpoint blockade showed efficacy. Interestingly, dual immune checkpoint therapy distinctly influenced adaptive and innate immune responses, with significant increase in CD8
+
CD28
+
PD-1
+
T cells and inflammatory macrophages (CD11b
hi
CD11c
−
F4/80
+
Ly6C
hi
) in tumor-draining lymph nodes. Adding chemotherapy before immunotherapy provided significant survival benefit for mice with established tumors receiving anti-PD-1 or dual immune checkpoint blockade. Our findings demonstrate anti-PD-1 and anti-CTLA-4 therapy induces a novel subset of effector T cells, and support administration of induction chemotherapy immediately prior to immune checkpoint blockade in children with high-risk neuroblastoma.
In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors ...(UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P < .0001) in mortality (hazard ratio HR = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches.
•Mismatches in alleles C*03:03/C*03:04 were most frequent (68.7%) among the transplants with a single allele level mismatch in HLA-C.•The 7/8 C*03:03/C*03:04 mismatch group was not significantly different from the 8/8 HLA matched transplants in any transplant outcome.
Summary Background Acute kidney injury often goes unrecognised in its early stages when effective treatment options might be available. We aimed to determine whether an automated electronic alert for ...acute kidney injury would reduce the severity of such injury and improve clinical outcomes in patients in hospital. Methods In this investigator-masked, parallel-group, randomised controlled trial, patients were recruited from the hospital of the University of Pennsylvania in Philadelphia, PA, USA. Eligible participants were adults aged 18 years or older who were in hospital with stage 1 or greater acute kidney injury as defined by Kidney Disease Improving Global Outcomes creatinine-based criteria. Exclusion criteria were initial hospital creatinine 4·0 mg/dL (to convert to μmol/L, multiply by 88·4) or greater, fewer than two creatinine values measured, inability to determine the covering provider, admission to hospice or the observation unit, previous randomisation, or end-stage renal disease. Patients were randomly assigned (1:1) via a computer-generated sequence to receive an acute kidney injury alert (a text-based alert sent to the covering provider and unit pharmacist indicating new acute kidney injury) or usual care, stratified by medical versus surgical admission and intensive care unit versus non-intensive care unit location in blocks of 4–8 participants. The primary outcome was a composite of relative maximum change in creatinine, dialysis, and death at 7 days after randomisation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01862419. Findings Between Sept 17, 2013, and April 14, 2014, 23 664 patients were screened. 1201 eligible participants were assigned to the acute kidney injury alert group and 1192 were assigned to the usual care group. Composite relative maximum change in creatinine, dialysis, and death at 7 days did not differ between the alert group and the usual care group (p=0·88), or within any of the four randomisation strata (all p>0·05). At 7 days after randomisation, median maximum relative change in creatinine concentrations was 0·0% (IQR 0·0–18·4) in the alert group and 0·6% (0·0–17·5) in the usual care group (p=0·81); 87 (7·2%) patients in the alert group and 70 (5·9%) patients in usual care group had received dialysis (odds ratio 1·25 95% CI 0·90–1·74; p=0·18); and 71 (5·9%) patients in the alert group and 61 (5·1%) patients in the usual care group had died (1·16 0·81–1·68; p=0·40). Interpretation An electronic alert system for acute kidney injury did not improve clinical outcomes among patients in hospital. Funding Penn Center for Healthcare Improvement and Patient Safety.
It has been suggested that Earth’s current supply of water was delivered by asteroids, some time after the collision that produced the Moon (which would have vaporized any of the pre-existing water). ...So far, no measurements of water ice on asteroids have been made, but its presence has been inferred from the comet-like activity of several small asteroids, including two members of the Themis dynamical family. Here we report infrared spectra of the asteroid 24 Themis which show that ice and organic compounds are not only present on its surface but also prevalent. Infrared spectral differences between it and other asteroids make 24 Themis unique so far, and our identification of ice and organics agrees with independent results that rule out other compounds as possible sources of the observed spectral structure. The widespread presence of surface ice on 24 Themis is somewhat unexpected because of the relatively short lifetime of exposed ice at this distance (∼3.2 au) from the Sun. Nevertheless, there are several plausible sources, such as a subsurface reservoir that brings water to the surface through ‘impact gardening’ and/or sublimation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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