Gap and stepoff measurements provide information about fracture displacement and are used for clinical decision-making when choosing either operative or nonoperative management of tibial plateau ...fractures. However, there is no consensus about the maximum size of gaps and stepoffs on CT images and their relation to functional outcome in skeletally mature patients with tibial plateau fractures who were treated without surgery. Because this is important for patient counseling regarding treatment and prognosis, it is critical to identify the limits of gaps and stepoffs that are well tolerated.
(1) In patients treated nonoperatively for tibial plateau fractures, what is the association between initial fracture displacement, as measured by gaps and stepoffs at the articular surface on a CT image, and functional outcome? (2) What is the survivorship of the native joint, free from conversion to a total knee prosthesis, among patients with tibial plateau fractures who were treated without surgery?
A multicenter cross-sectional study was performed in all patients who were treated nonoperatively for a tibial plateau fracture between 2003 and 2018 in four trauma centers. All patients had a diagnostic CT scan, and a gap and/or stepoff more than 2 mm was an indication for recommending surgery. Some patients with gaps and/or stepoffs exceeding 2 mm might not have had surgery based on shared decision-making. Between 2003 and 2018, 530 patients were treated nonoperatively for tibial plateau fractures, of which 45 had died at follow-up, 30 were younger than 18 years at the time of injury, and 10 had isolated tibial eminence avulsions, leaving 445 patients for follow-up analysis. All patients were asked to complete the validated Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaire consisting of five subscales: symptoms, pain, activities of daily living (ADL), function in sports and recreation, and knee-related quality of life (QOL). The score for each subscale ranged from 0 to 100, with higher scores indicating better function. A total of 46% (203 of 445) of patients participated at a mean follow-up of 6 ± 3 years since injury. All knee radiographs and CT images were reassessed, fractures were classified, and gap and stepoff measurements were taken. Nonresponders did not differ much from responders in terms of age (53 ± 16 years versus 54 ± 20 years; p = 0.89), gender (70% 142 of 203 women versus 59% 142 of 242 women; p = 0.01), fracture classifications (Schatzker types and three-column concept), gaps (2.1 ± 1.3 mm versus 1.7 ± 1.6 mm; p = 0.02), and stepoffs (2.1 ± 2.2 mm versus 1.9 ± 1.7 mm; p = 0.13). In our study population, the mean gap was 2.1 ± 1.3 mm and stepoff was 2.1 ± 2.2 mm. The participating patients divided into groups with increasing fracture displacement based on gap and/or stepoff (< 2 mm, 2 to 4 mm, or > 4 mm), as measured on CT images. ANOVA was used to assess whether an increase in the initial fracture displacement was associated with poorer functional outcome. We estimated the survivorship of the knee free from conversion to total knee prosthesis at a mean follow-up of 5 years using a Kaplan-Meier survivorship estimator.
KOOS scores in patients with a less than 2 mm, 2 to 4 mm, or greater than 4 mm gap did not differ (symptoms: 83 versus 83 versus 82; p = 0.98, pain: 85 versus 83 versus 86; p = 0.69, ADL: 87 versus 84 versus 89; p = 0.44, sport: 65 versus 64 versus 66; p = 0.95, QOL: 70 versus 71 versus 74; p = 0.85). The KOOS scores in patients with a less than 2 mm, 2 to 4 mm, or greater than 4 mm stepoff did not differ (symptoms: 84 versus 83 versus 77; p = 0.32, pain: 85 versus 85 versus 81; p = 0.66, ADL: 86 versus 87 versus 82; p = 0.54, sport: 65 versus 68 versus 56; p = 0.43, QOL: 71 versus 73 versus 61; p = 0.19). Survivorship of the knee free from conversion to total knee prosthesis at mean follow-up of 5 years was 97% (95% CI 94% to 99%).
Patients with minimally displaced tibial plateau fractures who opt for nonoperative fracture treatment should be told that fracture gaps or stepoffs up to 4 mm, as measured on CT images, could result in good functional outcome. Therefore, the arbitrary 2-mm limit of gaps and stepoffs for tibial plateau fractures could be revisited. The survivorship of the native knee free from conversion to a total knee prosthesis was high. Large prospective cohort studies with high response rates are needed to learn more about the relationship between the degree of fracture displacement and functional recovery after tibial plateau fractures.
Level III, prognostic study.
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease, where patients often suffer from fatigue. Biological pathways underlying fatigue are unknown. In this study aptamer-based SOMAscan ...technology is used to identify potential biomarkers and treatment targets for fatigue in pSS.
SOMAscan® Assay 1.3k was performed on serum samples of healthy controls (HCs) and pSS patients characterized for interferon upregulation and fatigue. Differentially expressed proteins (DEPs) between pSS patients and HC or fatigued and non-fatigued pSS patients were validated and discriminatory capacity of markers was tested using independent technology.
Serum concentrations of over 1,300 proteins were compared between 63 pSS patients and 20 HCs resulting in 58 upregulated and 46 downregulated proteins. Additionally, serum concentrations of 30 interferon positive (IFNpos) and 30 interferon negative (IFNneg) pSS patients were compared resulting in 25 upregulated and 13 downregulated proteins. ELISAs were performed for several DEPs between pSS patients and HCs or IFNpos and IFNneg all showing a good correlation between protein levels measured by ELISA and relative fluorescence units (RFU) measured by the SOMAscan. Comparing 22 fatigued and 23 non-fatigued pSS patients, 16 serum proteins were differentially expressed, of which 14 were upregulated and 2 were downregulated. Top upregulated DEPs included neuroactive synaptosomal-associated protein 25 (SNAP-25), alpha-enolase (ENO1) and ubiquitin carboxyl-terminal hydrolase isozyme L1 (UCHL1). Furthermore, the proinflammatory mediator IL36a and several complement factors were upregulated in fatigued compared to non-fatigued pSS patients. ROC analysis indicated that DEPs showed good capacity to discriminate fatigued and non-fatigued pSS patients.
In this study we validated the use of aptamer-based proteomics and identified a novel set of proteins which were able to distinguish fatigued from non-fatigued pSS patients and identified a so-called "fatigue signature."
Background
Trained immunity – or innate immune memory – can be described as the long-term reprogramming of innate immune cells towards a hyperresponsive state which involves intracellular metabolic ...changes. Trained immunity has been linked to atherosclerosis. A subgroup of patients with primary Sjögren’s syndrome (pSS) exhibits systemic type I interferon (IFN) pathway activation, indicating innate immune hyperactivation. Here, we studied the link between type I IFNs and trained immunity in an
in vitro
monocytic cell model and peripheral blood mononuclear cells (PBMCs) from pSS patients.
Methods
The training stimuli heat killed
Candida albicans
, muramyl dipeptide, IFNβ, and patient serum were added to THP-1 cells for 24 hours, after which the cells were washed, rested for 48 hours and subsequently re-stimulated with LPS, Pam3Cys, poly I:C, IFNβ or oxLDL for 4-24 hours. PBMCs from pSS patients and healthy controls were stimulated with LPS, Pam3Cys, poly I:C or IFNβ for 0.5-24 hours.
Results
Training with IFNβ induced elevated production of pro-atherogenic cytokines IL-6, TNFα and
CCL2
, differential cholesterol- and glycolysis-related gene expression, and increased glucose consumption and oxLDL uptake upon re-stimulation. Type I IFN production was increased in
Candida albicans
- and IFNβ-trained cells after LPS re-stimulation, but was reduced after poly I:C re-stimulation. Training with muramyl dipeptide and IFNβ, but not
Candida albicans
, affected the IFN-stimulated gene expression response to IFNβ re-stimulation. PBMCs from pSS patients consumed more glucose compared with healthy control PBMCs and tended to produce more TNFα and type I IFNs upon LPS stimulation, but less type I IFNs upon poly I:C stimulation.
Conclusions
Type I IFN is a trainer inducing a trained immunity phenotype with pro-atherogenic properties in monocytes. Conversely, trained immunity also affects the production of type I IFNs and transcriptional response to type I IFN receptor re-stimulation. The phenotype of pSS PBMCs is consistent with trained immunity. This connection between type I IFN, trained immunity and cholesterol metabolism may have important implications for pSS and the pathogenesis of (subclinical) atherosclerosis in these patients.
43 cerebrospinal fluid (CSF) specimens obtained from 20 children with tuberculous meningitis (TBM) at varying times during the first month of treatment were examined by polymerase chain reaction ...(PCR) for the presence of M. tuberculosis DNA. Overall 27 CSF specimens (63%) from 16 patients (80%) gave > or = 1 positive results and positive results were obtained from CSF specimens throughout the first 4 weeks of therapy. Nine CSF specimens (21%) gave a doubtful result (only 1 of duplicate determinations positive) and 7 (16%) a negative result. CSF from patients with suspected TBM should be submitted for PCR evaluation and positive results may be obtained up to at least 4 weeks after the start of treatment.
Functional and structural effects of histones H1 and H1(0) were studied on isolated chromatin and nuclei from embryonic skeletal muscle as well as on cultured cells. The results showed that: H1 was ...responsible for a greater compaction of chromatin than H1(0) as evidenced by sedimentation. In contrast, H1(0) inhibited DNA synthesis in chromatin and cells to a greater extent than H1. No significant difference between the two histones on RNA synthesis inhibition was observed. histones H1 and H1(0) evidenced a quantitative increase in developing muscle cells. The results indicate that H1(0) may not be the inducer of the differentiated cell state, but rather assists in the maintenance of that state.
Upregulation of type I interferons (IFN-I) is a hallmark of systemic autoimmune diseases like primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). ...Expression of IFN-I is induced by three different receptor families: Toll-like receptors (TLRs), RIG-like receptors (RLRs) and DNA-sensing receptors (DSRs). TANK-binding kinase (TBK1) is an important signaling hub downstream of RLRs and DSRs. TBK1 activates IRF3 and IRF7, leading to IFN-I production and subsequent induction of interferon stimulated genes (ISGs). The objective of this study was to explore the potential of BX795, an inhibitor of TBK1, to downregulate IFN-I activation in pSS, SLE and SSc.
TBK1, IRF3, IRF7 and STAT1 were determined by RT-PCR in PAXgene samples and phosphorylated-TBK1 (pTBK1) was analyzed by flowcytometry in plasmacytoid dendritic cells (pDCs) from IFN-I positive (IFNpos) patients. Peripheral blood mononuclear cells (PBMCs) of pSS, SLE and SSc patients and TLR7 stimulated PBMCs of healthy controls (HCs) were cultured with the TBK1 inhibitor BX795, followed by analysis of ISGs.
Increased gene expression of TBK1, IRF3, IRF7 and STAT1 in whole blood and pTBK1 in pDCs was observed in IFNpos pSS, SLE and SSc patients compared to HCs. Upon treatment with BX795, PBMCs from IFNpos pSS, SLE, SSc and TLR7-stimulated HCs downregulated the expression of the ISGs MxA, IFI44, IFI44L, IFIT1 and IFIT3.
TBK1 inhibition reduced expression of ISGs in PBMCs from IFNpos patients with systemic autoimmune diseases indicating TBK1 as a potential treatment target.
•Phosphorylated TBK1 is upregulated in plasmacytoid dendritic cells of patients with interferon-I positive pSS, SLE and SSc.•TBK1, IRF3, IRF7 and STAT1 gene-expression is upregulated in interferon-I positive patients with systemic autoimmunity.•A TBK1 inhibitor downregulates interferon-I activation in TLR7-stimulated PBMCs.•In PBMCs of patients with systemic autoimmunity interferon-I activation is downregulated by TBK1 inhibitors.•Targeting TBK1 in interferon-I positive systemic autoimmune diseases is a promising treatment strategy.
Abstract
The green peach aphid, Myzus persicae (Sulzer) (Homoptera: Aphididae), is a major pest of brassica plants, with the ability to transmit > 100 viruses. Although the adoption of Integrated ...Pest Management is increasing, chemical treatment remains the predominant method used to control M. persicae globally. Insecticide seed treatments, typically with neonicotinoid active ingredients, have become commonplace in canola crops, and are viewed as a “softer” alternative to foliar sprays but may nevertheless impact natural enemies of M. persicae. In this study, the effects of canola seed treatments, containing imidacloprid, thiamethoxam, and a mixture of thiamethoxam + lambda-cyhalothrin, were investigated on the parasitoid wasp, Aphidius colemani Viereck (Hymenoptera: Braconidae) and the green lacewing, Mallada signatus (Schneider) (Neuroptera: Chrysopidae), both important natural enemies of M. persicae. Laboratory trials were undertaken using whole plants, with lethal and sublethal effects assessed by measuring several traits. Compared with untreated plants, more aphid mummies were produced and more A. colemani were reared on plants treated with thiamethoxam + lambda-cyhalothrin and more aphid mummies were produced on imidacloprid plants. Imidacloprid reduced the time A. colemani spent searching for M. persicae and thiamethoxam reduced its cleaning time. However, after A. colemani were removed from treated plants, there were no such effects observed, suggesting these impacts were relatively short-lived. We found no significant effects of seed treatments on M. signatus. These results point to the complexity of ecotoxicology studies involving multiple trophic levels and indicate that seed treatments may have variable impacts on key fitness traits of natural enemies.
Graphical Abstract
Graphical Abstract
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