Surgical site infections and other postoperative complications following prophylactic anticoagulation in total joint arthroplasty
BACKGROUND: Anticoagulants reduce the risk of venous thromboembolism (VTE) after total joint replacement. However, concern remains that pharmacologic VTE prophylaxis can lead to bleeding, which may impact on postoperative complications such as infections and reoperations.
METHODS AND FINDINGS: From the Global Orthopedic Registry (GLORY), we reviewed 3,755 patients in US who elected for primary total hip or knee arthroplasty, received either warfarin or low molecular weight heparin (LMWH) as VTE prophylactics, and had up-to-90-day follow-up after discharge. We compared incidence rates of VTE, infections and other complications between LMWH and warfarin groups, and used multivariate analyses with propensity score weighting to generate the odds ratio (OR). Patients receiving LMWH tended to be older and higher in the American Society of Anesthesiologists grade scores. In contrast, warfarin was used more frequently for hip arthroplasty with longer duration among patients with more pre-existing comorbidity (all P < 0.02). A weight variable was created with propensity score to account for differences in covariate distributions. Propensity score-weighted analyses showed no differences in VTE complications. However, compared to warfarin, LMWH was associated with significantly higher rates of bleeding (6.2% vs. 2.1%; OR = 3.82, 95% confidence interval [CI], 2.64 to 5.52), blood transfusion (29.4% vs. 22.0%; OR = 1.75, 95% CI, 1.51 to 2.04), reoperations (2.4% vs. 1.3%; OR = 1.77, 95% CI, 1.07 to 2.93) and infections (1.6% vs. 0.6%; OR = 2.79, 95% CI, 1.42 to 5.45). Similar results were obtained from compliant uses of warfarin (26%) and LMWH (62%) according to clinical guidelines. While surgical site infections were mostly superficial, current study was underpowered to compare incidence rates of deep infections ( < 1.0%).
CONCLUSIONS: Surgical site infections and reoperations in 3 months following primary total joint arthroplasty may be associated with anticoagulant use that exhibited higher bleeding risk. Long-term complications and deep wound infections remain to be studied.
Irisin, secreted by skeletal muscle and possibly fat, is hypothesized to play an important role in modulating energy expenditure, obesity and metabolism. Coffee consumption also increases energy expenditure and leads to positive metabolic effects, but whether these effects are mediated by irisin remains unknown. The objective of this study was to determine the association between baseline irisin levels and the metabolic profile in humans and to investigate whether consumption of caffeinated coffee alters irisin levels. To this end, a secondary analysis was performed investigating irisin levels at baseline and after eight weeks in 32 healthy, overweight coffee drinkers who were randomized to consumption of 5 cups per day of instant caffeinated coffee, decaffeinated coffee, or water. Spearman correlation and analysis of covariance analyses were performed to identify possible associations. Irisin levels were positively correlated with waist circumference (r = 0.41, p = 0.02), fat mass (r = 0.44, p = 0.01) and CRP (r = 0.47, p = 0.007). Though there was a trend towards increased levels of irisin over time in the caffeinated coffee group (+1.8%) when compared to the placebo group (24%) this did not reach statistical significance (p = 0.75 for the trend). This first randomized trial failed to reveal any effects of coffee consumption on irisin levels, but a larger trial, appropriately sized on the basis of data provided by this study, is needed to conclusively investigate such a relationship. TRIAL REGISTRATION: Clinicaltrials.gov NCT00305097.
Metalloproteinase-dependent TLR2 ectodomain shedding is involved in soluble toll-like receptor 2 (sTLR2) production
Toll-like receptor (TLR) 2, a type I membrane receptor that plays a key role in innate immunity, recognizes conserved molecules in pathogens, and triggering an inflammatory response. It has been associated with inflammatory and autoimmune diseases. Soluble TLR2 (sTLR2) variants have been identified in human body fluids, and the TLR2 ectodomain can negatively regulate TLR2 activation by behaving as a decoy receptor. sTLR2 generation does not involve alternative splicing mechanisms, indicating that this process might involve a post-translational modification of the full-length receptor; however, the specific mechanism has not been studied. Using CD14+ peripheral human monocytes and the THP-1 monocytic leukemia-derived cell line, we confirm that sTLR2 generation increases upon treatment with pro-inflammatory agents and requires a post-translational mechanism. We also find that the constitutive and ligand-induced release of sTLR2 is sensitive to pharmacological metalloproteinase activator and inhibitors leading us to conclude that metalloproteinase TLR2 shedding contributes to soluble receptor production. By expressing human TLR2 in ADAM10- or ADAM17-deficient MEF cells, we find both enzymes to be implicated in TLR2 ectodomain shedding. Moreover, using a deletion mutant of the TLR2 juxtamembrane region, we demonstrate that this domain is required for sTLR2 generation. Functional analysis suggests that sTLR2 generated by metalloproteinase activation inhibitsTLR2-induced cytokine production by this monocytic leukemia-derived cell line. The identification of the mechanisms involved in regulating the availability of soluble TLR2 ectodomain and cell surface receptors may contribute further research on TLR2-mediated processes in innate immunity and inflammatory disorders.
A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy
Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC) associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd) carrying sequences of amastigote surface protein-2 (rAdASP2) and trans-sialidase (rAdTS) T. cruzi antigens. For prophylactic vaccination, naive C57BL/6 mice were immunized with rAdASP2+rAdTS (rAdVax) using a homologous prime/boost protocol before challenge with the Colombian strain. For therapeutic vaccination, rAdVax administration was initiated at 120 days post-infection (dpi), when mice were afflicted by CCC. Mice were analyzed for electrical abnormalities, immune response and cardiac parasitism and tissue damage. Prophylactic immunization with rAdVax induced antibodies and H-2Kb-restricted cytotoxic and interferon (IFN)gamma-producing CD8+ T-cells, reduced acute heart parasitism and electrical abnormalities in the chronic phase. Therapeutic vaccination increased survival and reduced electrical abnormalities after the prime (analysis at 160 dpi) and the boost (analysis at 180 and 230 dpi). Post-therapy mice exhibited less heart injury and electrical abnormalities compared with pre-therapy mice. rAdVax therapeutic vaccination preserved specific IFNgamma-mediated immunity but reduced the response to polyclonal stimuli (anti-CD3 plus anti-CD28), CD107a+ CD8+ T-cell frequency and plasma nitric oxide (NO) levels. Moreover, therapeutic rAdVax reshaped immunity in the heart tissue as reduced the number of perforin+ cells, preserved the number of IFNgamma+ cells, increased the expression of IFNgamma mRNA but reduced inducible NO synthase mRNA. Vaccine-based immunostimulation with rAd might offer a rational alternative for re-programming the immune response to preserve and, moreover, recover tissue injury in Chagas' heart disease.
Biomedical literature incorporates millions of figures, which are a rich and important knowledge resource for biomedical researchers. Scientists need access to the figures and the knowledge they represent in order to validate research findings and to generate new hypotheses. By themselves, these figures are nearly always incomprehensible to both humans and machines and their associated texts are therefore essential for full comprehension. The associated text of a figure, however, is scattered throughout its full-text article and contains redundant information content. In this paper, we report the continued development and evaluation of several figure summarization systems, the FigSum+ systems, that automatically identify associated texts, remove redundant information, and generate a text summary for every figure in an article. Using a set of 94 annotated figures selected from 19 different journals, we conducted an intrinsic evaluation of FigSum+. We evaluate the performance by precision, recall, F1, and ROUGE scores. The best FigSum+ system is based on an unsupervised method, achieving F1 score of 0.66 and ROUGE-1 score of 0.97. The annotated data is available at figshare.com (http://figshare.com/articles/Figure_Associated_Text_Summarization_and_Evaluation /858903).
FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1)
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1.
Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps
Plasmacytoid dendritic cells (pDCs) were initially considered as critical for innate immunity to viruses. However, our group has shown that pDCs bind to and inhibit the growth of Aspergillus fumigatus hyphae and that depletion of pDCs renders mice hypersusceptible to experimental aspergillosis. In this study, we examined pDC receptors contributing to hyphal recognition and downstream events in pDCs stimulated by A. fumigatus hyphae. Our data show that Dectin-2, but not Dectin-1, participates in A. fumigatus hyphal recognition, TNF-alpha and IFN-alpha release, and antifungal activity. Moreover, Dectin-2 acts in cooperation with the FcRgamma chain to trigger signaling responses. In addition, using confocal and electron microscopy we demonstrated that the interaction between pDCs and A. fumigatus induced the formation of pDC extracellular traps (pETs) containing DNA and citrullinated histone H3. These structures closely resembled those of neutrophil extracellular traps (NETs). The microarray analysis of the pDC transcriptome upon A. fumigatus infection also demonstrated up-regulated expression of genes associated with apoptosis as well as type I interferon-induced genes. Thus, human pDCs directly recognize A. fumigatus hyphae via Dectin-2; this interaction results in cytokine release and antifungal activity. Moreover, hyphal stimulation of pDCs triggers a distinct pattern of pDC gene expression and leads to pET formation.
Declining Long-term Risk of Adverse Events after First-time Community-presenting Venous Thromboembolism: The Population-based Worcester VTE Study (1999 to 2009)
INTRODUCTION: Contemporary trends in health-care delivery are shifting the management of venous thromboembolism (VTE) events (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) from the hospital to the community, which may have implications for its prevention, treatment, and outcomes.
MATERIALS AND METHODS: Population-based surveillance study monitoring trends in clinical epidemiology among residents of the Worcester, Massachusetts, metropolitan statistical area (WMSA) diagnosed with an acute VTE in all 12 WMSA hospitals. Patients were followed for up to 3years after their index event. Total of 2334 WMSA residents diagnosed with first-time community-presenting VTE (occurring in an ambulatory setting or diagnosed within 24hours of hospitalization) from 1999 through 2009.
RESULTS: While PE patients were consistently admitted to the hospital for treatment over time, the proportion diagnosed with DVT-alone admitted to the hospital decreased from 67% in 1999 to 37% in 2009 (p value for trend
CONCLUSIONS: A decade of change in VTE management was accompanied by improved long-term outcomes. However, rates of adverse events remained fairly high in our population-based surveillance study, implying that new risk-assessment tools to identify individuals at increased risk for developing major adverse outcomes over the long term are needed.
Background: Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated inflammatory conditions of the gastrointestinal tract, which have increasingly been linked to dysbiosis, or an imbalance in the gut microbiome. Standard of care for IBD involves an often-evolving combination of anti-inflammatory, antibiotic, and immunomodulatory medications; however, the pharmacological approach is never curative, and medications routinely become ineffective for individual patients. Partially fueled by the increasing inadequacy of pharmacologic treatment regimens, there is emerging interest from patients regarding diet and its role in the pathogenesis and treatment of inflammatory diseases, demanding more in-depth and substantiating research from the medical community.
The Anti-Inflammatory Diet for IBD (IBD-AID), which is derived and augmented from The Specific Carbohydrate Diet (SCD), is a nutritional regimen that restricts the intake of pro-inflammatory carbohydrates such as refined sugar, lactose, and most grains, while maximizing anti-inflammatory foods including those with prebiotic and probiotic properties. We have previous results from a case series of 11 patients with IBD showing symptomatic improvement (by Harvey Bradshaw Index scores) and downscaling of medication regimens in all 11 patients after 4 weeks on the IBD-AID.
Objectives: The purpose of this small prospective study was to further assess the efficacy and feasibility of the IBD-AID intervention for the treatment of CD, and to provide pilot data for a larger application.
Methods: The sample included 17 patients with biopsy-confirmed Crohn’s disease. Participants were offered the treatment diet (IBD-AID) (n=12) or standard medical care alone (control) (n=5). Patients in the IBD-AID group were required to attend one individual nutrition counseling session and three IBD-AID-specific cooking classes at the University of Massachusetts Medical School’s Shaw Building teaching kitchen. The control group continued with usual care. For all participants, demographic, clinical, and symptom data were obtained from baseline and follow-up questionnaires; dietary composition was monitored by weekly dietary recalls and food journals. All participants continued to follow with their gastroenterologists throughout the study duration. Study duration was 2 months after 70% adherence to the diet for IBD-AID participants, and 2 months after baseline for control participants.
Consistent with the goals for any treatment used for CD, efficacy measures included: 1) reduction in symptomology, as measured by the validated Harvey Bradshaw Index (HBI); 2) reduction in the need of immunomodulatory and anti-inflammatory medications; and 3) normalizing trend in circulating inflammatory markers (i.e., CRP and ESR), albumin, and hematocrit. Feasibility measures included participant retention, dietary compliance, and participants’ self-assessments of difficulty in maintaining the diet.
Results: A total of 15 enrolled patients with confirmed diagnosis of Crohn’s Disease, 5 in observation arm, 10 in intervention arm. Significant trends in dietary composition included significant increases in prebiotic and favorable dietary components, and decrease in adverse foods for the group as a whole (paired t-test values 0.0016, 0.0344, 0.0085, and 0.0014, respectively). For those patients on medication at baseline and with complete follow-up (n=9), one-third were able to decrease doses of or discontinue these medications. In addition, lab values reflected symptomatic improvements in two of our intervention patients, with changes in CRP, ESR, and hematocrit levels of -55.9 and -1.4, -30.0 and -15.0, and +5.4 and +0.3, respectively, with corresponding symptomatic improvements (HBI scores 1à7 and 8à0, respectively). No significance can be assigned, however, due to low sample size and loss to follow-up. Feasibility measures include a significant loss to follow-up rate of 33.3%, as well as an average “difficulty score” of 3.1, reflecting participants’ views on the difficult nature of “sticking with” the IBD-AID (scored on scale of 1-5, very easy to very difficult).
Conclusion: Despite the study’s limitations, as well as because of them, several conclusions can be drawn. The trends noticed in the participants’ dietary component reports, and supported by participants’ self-evaluation, reveal that it is relatively easy to eliminate problem foods from the diet, but adding unfamiliar foods, particularly from the probiotic category such as plain yogurt, kimchi, miso, sauerkraut, etc., is a huge barrier to maintaining compliance. This trend may be a partial reflection of the Western food and dieting culture in which our daily meals are relatively homogenous. We are also brought up from a young age learning that “dieting” and “healthy eating” means cutting out the bad, but not necessarily bringing in the good and/or new. Despite lack of statistical significance, the two patients who exhibited normalizing lab values, in combination with their improved HBI scores, suggest the possibility of a real and meaningful benefit from IBD-AID for those able to comply with the dietary and lifestyle changes.
In terms of the diet’s feasibility, the considerable loss to follow-up in this study may reflect a variety of issues, one of which may be the well-established medical and psychosocial complexity of IBD patients. This element is important for clinicians to keep in mind, and reflects the need for additional support and close follow-up when it comes to facilitating lifestyle change in this population. It also has implications for the diet itself, which should be re-examined to simplify or reframe in order to maximize generalizability and access for a greater percentage of IBD patients. Overall, this small study highlights the need for larger-scale research to draft clinical nutrition guidelines and further legitimize the utility of preventive clinical nutrition in Western medicine.
Regression of lymphoproliferative disorder after treatment for hepatitis C virus infection in a patient with partial trisomy 3, Bcl-2 overexpression, and type II cryoglobulinemia
A patient with type II cryoglobulinemic vasculitis and hepatitis C virus (HCV) infection presented with a leukemiclike proliferation of B cells bearing marginal zone B-cell phenotypic markers. A partial trisomy 3 (bands 3q11-29) and overexpression of Bcl-2 without t(14;18) translocation was detected in the monoclonal B cells that were classic rheumatoid factor-producing B cells bearing the WA cross-idiotype. Treatment with interferon-alpha produced a complete clinical remission and synchronous marked decreases in viremia and monoclonal B-cell prevalence. This is the first report of partial trisomy 3 and Bcl-2 overexpression in type II cryoglobulinemic vasculitis associated with HCV infection. Further studies of HCV-infected patients with and without type II cryoglobulinemia are required to determine the prevalence and possible physiologic and/or pathophysiologic significance of these findings.
Nephrogenic systemic fibrosis (NSF) is an iatrogenic fibrosing disorder that primarily affects individuals with chronic kidney disease (CKD) following exposure to gadolinium-based contrast agents (GBCAs) during imaging procedures. NSF is characterised by skin thickening, tethering and hyperpigmentation; flexion contractures of joints; and extracutaneous fibrosis. This article reviews the history, clinical manifestations, epidemiology, histopathology and pathophysiology of this disabling disease.
How is the concept of “treating to a target” relevant to rheumatology in general, and to the management of rheumatoid arthritis (RA) in particular? In this article, we employ a question and answer approach to address the importance of treating RA to target, review the seminal studies supporting a treat to target approach in the management of RA, describe ongoing international treat to target initiatives, and discuss the practical issues related to using a treat to target approach in clinical practice.
DM is associated with various musculoskeletal manifestations. The strength of this relationship varies among the various musculoskeletal disorders; the associations are based mostly on epidemiologic data. For most of these conditions, definitive pathophysiologic correlates are lacking.Hand and shoulder disorders occur more frequently than other musculoskeletal manifestations of DM. Recognition of the association between DM and shoulder adhesive capsulitis, DD, and stenosing flexor tenosynovitis facilitates their correct diagnosis in the setting of DM and prompt initiation of appropriate treatment, which may include optimizing glycemic control. Conversely, awareness and identification of the characteristic musculoskeletal manifestations of DM may facilitate earlier diagnosis of DM and initiation of glucose-lowering therapy to retard the development of diabetic complications.Much less has been published about the musculoskeletal complications of DM than about its micro- and macrovascular complications. Prospective case-control cohort studies are needed to establish the true prevalence of musculoskeletal complications of DM and the metabolic syndrome, especially in this era of tighter glycemic control.The potential relationship between DM and the development of OA needs to be clarified in large, prospective, case-control cohort studies. The effect on musculoskeletal manifestations of various therapeutic regimens to manage DM should be studied prospectively. Treatment regimens for some musculoskeletal conditions associated with DM, such as DISH, should be studied in larger prospective, randomized,controlled clinical trials.At the molecular level, further studies are warranted to clarify the potential contribution of AGEs and adipokines to the development of OA and diabetic musculoskeletal syndromes, such as shoulder adhesive capsulitis, DD, stenosing flexor tenosynovitis, and LJM. Identification of such molecular targets for therapy would promote the development of additional treatments for these and other rheumatic diseases.