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Abstract Background Leukocytes commonly infiltrate solid tumors, and have been implicated in the mechanism of spontaneous regression in some cancers. Conventional techniques for the quantitative estimation of leukocyte infiltrates in tumors rely on light microscopy of immunostained thin tissue sections, in which an arbitrary assessment (based on low, medium or high levels of infiltration) of antigen density is made by the pathologist. These estimates are relatively subjective and often require the opinion of a second pathologist. In addition, since thin tissue sections are cut, no data regarding the three-dimensional distribution of antigen can be obtained. Results To overcome these problems, we have designed a method to enumerate leukocyte infiltration into tumors, using confocal laser scanning microscopy of fluorescently immunostained leukocytes in thick tissue sections. Using image analysis software, a threshold was applied to eliminate unstained tissue and residual noise. The total antigen volume in the scanned tissue was calculated and divided by the mean cell volume (calculated by "seeding" ten individual cells) to obtain the cell count. Using this method, we compared the calculated leukocyte counts with those obtained manually by ten laboratory personnel. There was no significant difference (P > 0.05) between the cell counts obtained by either method. We then compared leukocyte infiltration into seven tumors and matched non-malignant tissue obtained from the periphery of the resected tissue. There was a significant increase in the infiltration of all leukocyte subsets into the tumors compared to minimal numbers in the non-malignant tissue. Conclusion From these results we conclude that this method may be of considerable use for the enumeration of cells in tissues. Furthermore, since it can be performed by laboratory technical staff, less time input is required by the pathologist in assessing the degree of leukocyte infiltration into tumors.

BACKGROUND: Patients with heparin-platelet factor 4 (PF4) antibodies, particularly platelet-activating ones, are at risk for heparin-induced thrombocytopenia if administered heparin. We determined the heparin-PF4 antibody prevalence in emergency department (ED) patients presenting with chest pain or symptoms of thrombosis. METHODS: Admission samples from 324 ED patients with chest pain or symptoms of thrombosis were tested for heparin-PF4 antibodies and, if positive, platelet-activating antibodies. RESULTS: Twenty-four (7.4%; 95% confidence interval, 4.8%-10.8%) patients had heparin-PF4 antibodies. Seropositivity occurred in 18 (9.2%) of 196 patients recently (< or =6 months) hospitalized vs 6 (4.7%) of 128 not recently hospitalized (P = .19), and in 16/231 (6.9%) patients with chest pain vs 8/93 (8.6%) with other thrombosis (P = .64). Of 22 seropositive patients retested, 8 (7 recently hospitalized) had platelet-activating antibodies. CONCLUSION: Heparin-PF4 antibody prevalence is 7.4% in ED patients with chest pain or thrombosis, with approximately 1 in 3 seropositive patients having platelet-activating antibodies. Alternative, nonheparin anticoagulation would be prudent in these at-risk patients. Copyright © 2007 by Elsevier Inc. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine the relationship of anger and hostility to angiographic coronary artery disease (CAD), symptoms, and functional status among women with suspected CAD. METHODS: Data were collected from 636 women with suspected CAD referred for diagnostic angiography in the Women's Ischemia Syndrome Evaluation (WISE) Study. CAD was assessed as angiographic presence/absence of disease (> or =50% stenosis in any epicardial coronary artery). Hostility/anger, angina, symptoms, and functional status were assessed by the Cook-Medley Hostility Inventory, Spielberger Anger Expression Scale, cardiovascular symptom history, and the Duke Activity Status Index. RESULTS: Logistic regression revealed that anger-out (i.e., aggressive behavior in response to angry feelings) was independently associated with the presence/absence of angiographic CAD (OR = 1.09, CI 1.01-1.17). Anger and hostility were higher among women reporting increased cardiovascular symptoms. In women without angiographic CAD, those with nonanginal cardiac symptoms had the highest anger-out, anger expression, hostile affect, and aggressive responding scores, and those with typical angina reported the lowest functional status. Among women with CAD, functional status was lowest in women with atypical angina. CONCLUSIONS: Among women with suspected CAD, anger-out scores were associated with the presence of angiographic CAD. Anger/hostility traits were associated with increased symptoms, particularly with nonanginal chest pain in women without angiographic CAD. Relationships among psychosocial factors, cardiac symptoms, and angiographic CAD are potentially important in the management of women with suspected CAD. [ABSTRACT FROM AUTHOR]

This immune reaction to a common anticoagulant can have devastating consequences. Learn how to recognize who's at risk and how to intervene if trouble hits. [ABSTRACT FROM AUTHOR]

PURPOSE: This study examined the nature of the variability in salivary immunoglobulin and albumin concentrations within an individual, between individuals, and between populations with differing levels of habitual physical activity. METHODS: Fourteen elite swimmers, and 21 active and 18 sedentary individuals provided 12 saliva samples over a 30-d period. Group classifications were based on interviews, anthropometric measurements, and physical activity records. Symptoms of illness and physical activity data were recorded daily. Salivary IgA, IgG, and IgM were measured by ELISA, and albumin concentrations were measured by nephelometry. Variability was assessed using ANOVA procedures. RESULTS: Elite swimmers, compared with active and sedentary individuals, had higher concentrations of salivary IgA (geometric mean=65 vs 32 and 40 mg.L, P=0.002) and greater variability in salivary IgA concentrations as individuals (P=0.007) and as a group (P=0.03). Salivary IgG variability in swimmers was also twofold greater than the other two groups (P=0.008). Salivary IgM and albumin variability were not significantly different between groups, but individual variability differed for swimmers and active individuals. The intraclass correlations for salivary IgA and IgG (but not for IgM or albumin) were 50% lower for swimmers than the other two groups (ICC for IgA: 20% swimmers vs 54% active and 46% sedentary individuals; ICC for IgG: 36 vs 59 and 57%). CONCLUSION: The variability and fluctuation of salivary immunoglobulin concentrations were consistently greater in the elite swimmers, but multiple samples from individual swimmers were less correlated compared with participants with lower physical activity levels. These findings have implications for monitoring mucosal immune status within individuals and when comparing salivary immunoglobulin concentrations between groups with differing levels of physical fitness and activity. [ABSTRACT FROM AUTHOR]

Background.We have previously explored the clinical significance of urinary tissue factor (uTF) in patients with glomerulonephritis (GN) and malignancy. However, the functional and structural properties and putative cell of origin of uTF are poorly documented. In these studies we investigate these aspects of uTF. [ABSTRACT FROM PUBLISHER]

1. Whole blood platelet aggregation was measured by electrical impedance in 28 controls and 28 patients with primary Raynaud's phenomenon. 2. The patients were entered into a double-blind, placebo- controlled cross-over trial of the calcium antagonist nisoldipine, in which they received, in random order, three, 4 week treatments with placebo and nisoldipine (5 and 10 mg day-1). 3. Platelet aggregation responses to two concentrations (5.0 and 0.5 micrograms ml-1) of collagen were determined before treatment and at the end of each treatment phase. 4. There were no differences in aggregation response to either collagen concentration between controls and patients with primary Raynaud's phenomenon, or between placebo and active treatment phases. 5. These data do not support the suggestion that nisoldipine has a significant anti-platelet effect. [ABSTRACT FROM AUTHOR]

Objective To examine the level of stated compliance with public health pandemic influenza control measures and explore factors influencing cooperation for pandemic influenza control in Australia. Methods A computer-assisted telephone interview survey was conducted by professional interviewers to collect information on the Australian public's knowledge of pandemic influenza and willingness to comply with public health control measures. The sample was randomly selected using an electronic database and printed telephone directories to ensure sample representativeness from all Australian states and territories. After we described pandemic influenza to the respondents to ensure they understood the significance of the issue, the questions on compliance were repeated and changes in responses were analysed with McNemar's test for paired data. Findings Only 23% of the 1166 respondents demonstrated a clear understanding of the term 'pandemic influenza'. Of those interviewed, 94.1% reported being willing to comply with home quarantine; 94.2%, to avoid public events; and 90.7%, to postpone social gatherings. After we explained the meaning of 'pandemic' to interviewees, stated compliance increased significantly (to 97.5%, 98.3% and 97.2% respectively). Those who reported being unfamiliar with the term 'pandemic influenza,' male respondents and employed people not able to work from home were less willing to comply. Conclusion In Australia, should the threat arise, compliance with containment measures against pandemic influenza is likely to be high, yet it could be further enhanced through a public education programme conveying just a few key messages. A basic understanding of pandemic influenza is associated with stated willingness to comply with containment measures. Investing now in promoting measures to prepare for a pandemic or other health emergency will have considerable value. Copyright © 2009 World Health Organization [ABSTRACT FROM AUTHOR]

Objective: Although strategies exist to minimize alcohol-related harms associated with establishments licensed to serve alcohol, such establishments are associated with a disproportionate level of harm. To date, understanding the association between such establishments and alcohol-related harms, and hence the opportunities for reducing harm, has been limited by inadequate information regarding incidents of alcohol-related crime. To address this deficiency, this study was undertaken to describe the association between such establishments and incidents of crime using enhanced police-recorded, alcohol-related crime intelligence.Method: A descriptive analysis was undertaken of intoxicated people who had last consumed alcohol in establishments licensed to serve alcohol (841 bars, 551 licensed social clubs, 11 nightclubs, and 18 other locations) preceding their involvement in police-recorded incidents of violence, disorder, or motor vehicle crashes. The study area encompassed 21 nonmetropolitan police commands in the state of New South Wales, Australia.Results: Among intoxicated persons involved in incidents of violence, disorder, or motor vehicle crashes, the risk of being recorded as having last consumed alcohol in a bar or nightclub before the incident was at least twice that of licensed social clubs and other establishments. Approximately 20% of establishments accounted for 80% of intoxicated persons involved in such incidents, and 6% of establishments were in the top 20% of establishments for all three offense types.Conclusions: The disproportionate burden of alcohol-related crime associated with establishments licensed to serve alcohol may be reduced if harm-reduction strategies address the specific risks posed by bars and nightclubs, and individual high-risk establishments. [ABSTRACT FROM AUTHOR]

Objective: To examine changes in glomerular hyperfiltration and other measures of kidney function in youth with type 2 diabetes treated with dulaglutide or placebo., Research Design and Methods: Post hoc analysis was performed on kidney laboratory data from 154 youths (age 10-18 years) with type 2 diabetes enrolled in a completed placebo-controlled glycemic control trial of dulaglutide., Results: Mean estimated glomerular filtration rate (eGFR) decreased from baseline to 26 weeks in participants treated with dulaglutide versus placebo (-5.8 vs. -0.1 mL/min/1.73 m2; P = 0.016). Decreases in eGFR were observed primarily in participants with baseline glomerular hyperfiltration. At 26 weeks, the prevalence of both glomerular hyperfiltration and proteinuria increased with placebo but decreased with dulaglutide (P = 0.014 and 0.004 vs. placebo, respectively)., Conclusions: Dulaglutide was associated with attenuated glomerular hyperfiltration and proteinuria in youth with type 2 diabetes. The impact of these changes on the risk of diabetic kidney disease is unclear., (© 2024 by the American Diabetes Association.)

Background: Borderline personality disorder (BPD) is increasingly diagnosed in perinatal and infant settings, and research suggests that as well as an escalation of BPD symptoms in this period, these symptoms may also be detrimental to infant development. Providing tailored treatments during the postnatal period may help women and prevent an intergenerational cycle of emotional and interpersonal symptoms in infants. Mother-infant dialectical behavior therapy (MI-DBT) has produced promising, yet inconsistent, improvements on quantitative scales of maternal mental health and the mother-infant relationship. The qualitative evaluation may provide complementary information., Aims: This study aimed to explore the subjective experiences of women who had completed MI-DBT., Material and Methods: Thematic analysis of semistructured interviews conducted on 13 women undertaking MI-DBT before, post, and 12 months after MI-DBT were analyzed for themes., Results: Five major themes were identified. Overall, the women expressed that their emotional literacy and regulation improved after MI-DBT, subsequently addressing key risks and challenges such as uncertainty around their child's cues, and low self-esteem, and potentially improving the women's mentalization capability., Discussion and Conclusions: This study consolidates previous research on maternal BPD, and provides qualitative evidence of the benefits of MI-DBT for mothers as both individuals and as parents with likely flow-on effects for infants. Lived experience input for future adaptations was a valuable gain., (© 2022 The Authors. Journal of Clinical Psychology published by Wiley Periodicals LLC.)

Background: Heparin-induced thrombocytopenia (HIT) is a common differential diagnosis in cardiothoracic surgery. The latex immunoturbidimetric assay (LIA) is an enhanced immunoassay that has recently been introduced for the detection of total HIT immunoglobulin and retains a higher specificity of 95% compared to the enzyme-linked immunosorbent assay., Objectives: To investigate if a semiquantitative relationship exists between increasing LIA levels beyond the current positivity threshold and its correlation to positive serotonin release assay results in cardiothoracic surgery., Methods: This was a multicenter, observational cohort of cardiothoracic surgery patients initiated on anticoagulation with heparin-based products. To conduct sensitivity and specificity analysis of LIA values, HIT positive was defined as a LIA value ≥1 unit/mL and HIT negative was defined as a LIA level <1 unit/mL. A receiver operating characteristic (ROC) analysis was utilized to evaluate the predictive performance of the LIA., Results: At manufactures' cutoffs of ≥1.0 unit/mL, LIA sensitivity and specificity was 93.8% and 22%, respectively, yielding a false positive rate of 78%. At a higher cutoff of 4.5 units/mL, LIA sensitivity and specificity was 75% and 71%, respectively, yielding a false positive rate of 29% and an area under the ROC curve of 0.75 ( P  = .01; 95% confidence interval: 0.621-0.889). Bivalirudin was initiated in 84.6% of false positive LIA results., Conclusion: This study suggests that the diagnostic accuracy of the LIA can be optimized by increasing the LIA positivity threshold. Proposing a higher LIA cutoff, may mitigate unwarranted anticoagulation and bleeding outcomes.

Aims: Fractures of the distal radius are common, and form a considerable proportion of the trauma workload. We conducted a study to examine the patterns of injury and treatment for adult patients presenting with distal radius fractures to a major trauma centre serving an urban population., Methods: We undertook a retrospective cohort study to identify all patients treated at our major trauma centre for a distal radius fracture between 1 June 2018 and 1 May 2021. We reviewed the medical records and imaging for each patient to examine patterns of injury and treatment. We undertook a binomial logistic regression to produce a predictive model for operative fixation or inpatient admission., Results: Overall, 571 fractures of the distal radius were treated at our centre during the study period. A total of 146 (26%) patients required an inpatient admission, and 385 surgical procedures for fractures of the distal radius were recorded between June 2018 and May 2021. The most common mechanism of injury was a fall from a height of one metre or less. Of the total fractures, 59% (n = 337) were treated nonoperatively, and of those patients treated with surgery, locked anterior-plate fixation was the preferred technique (79%; n = 180)., Conclusion: The epidemiology of distal radius fractures treated at our major trauma centre replicated the classical bimodal distribution described in the literature. Patient age, open fractures, and fracture classification were factors correlated with the decision to treat the fracture operatively. While most fractures were treated nonoperatively, locked anterior-plate fixation remains the predominant method of fixation for fractures of the distal radius; this is despite questions and continued debate about the best method of surgical fixation for these injuries.Cite this article: Bone Jt Open  2022;3(8):623-627.

Introduction: Heparin-induced thrombocytopenia (HIT) is a potentially life-threatening adverse reaction of heparin. Laboratory evaluation of HIT is often not available within a reasonable time. We evaluated the HemosIL ® HIT-Ab (PF4-H) (Instrumentation Laboratory), a rapid, on-demand, fully automated, latex immunoturbidimetric assay (LIA)., Materials and Methods: Following determination of the LIA's reference interval and cutoff values, a multicenter study was conducted between March 2013 and June 2015. Plasma samples of HIT-suspected patients (n = 632) were collected and evaluated by LIA on the ACL TOP ® Family systems (Instrumentation Laboratory), enzyme-linked immunosorbent assays (EIA), and serotonin release assay (SRA). Patient characteristics, medical conditions, comorbidities, laboratory results, and medications were collected via medical chart review. The pretest clinical probability of HIT was also calculated for each patient., Results: Based on the 95% reference interval for healthy donors and HIT-negative patients, a LIA value ≥1.0 U/mL was interpreted positive. The overall agreement of LIA versus EIA and SRA results were 90% (95% CI 88%-92%) and 79% (95% CI 75%-82%), respectively. The negative predictive value for LIA and EIA was comparable (87%) with SRA. The positive and negative percent agreements with the clinical probability were 89% (95% CI 69%-97%) and 86% (95% CI 83%-89%), respectively, with a negative predictive value of 99.6% (95% CI 98%-100%)., Discussion: Overall, the LIA results were comparable to those of EIA and SRA. This fully automated assay with a remarkable short analytical turnaround time of <20 minutes can be performed on-demand, which would greatly facilitate more prompt management of HIT., (© 2019 The Authors. International Journal of Laboratory Hematology published by John Wiley & Sons Ltd.)

Objective: To evaluate the association between intermittent phosphodiesterase type 5 inhibitor (PDE5i) exposure and risk of acute nonarteritic anterior ischemic optic neuropathy (NAION) using a case-crossover design., Methods: Male adults with suspected NAION were enrolled at 41 US ophthalmology sites from 2010 to 2015 and were interviewed regarding risk factors for NAION, medical history, and PDE5i use before NAION onset (index date of onset [IDO]). An adjudication committee confirmed the NAION cases. The primary analysis, using the person-time method, examined the rate of PDE5i exposure within 5 half-lives of NAION onset relative to PDE5i exposure over a 30-day study period preceding the IDO in men exposed to PDE5i intermittently as a measure of NAION risk associated with PDE5i exposure. Rate ratios were estimated using the Mantel-Haenszel estimator. Secondary analyses included person-time analyses over the 12-months preceding the IDO and matched-interval analyses over 42 days preceding the IDO., Results: Of 279 men with confirmed NAION, 22 were exposed to PDE5i intermittently within 30 days of IDO. The Mantel-Haenszel rate ratio for risk of NAION associated with PDE5i exposure within 5 half-lives of IDO was 2.27 (95% confidence interval [CI]: 0.99-5.20) over the 30-day period (n = 22) and 3.52 (95% CI: 1.59-7.79) over the 12-month period (n = 26). Sensitivity analyses showed similar results and were statistically significant. The matched-interval method found no association (hazard ratio = 1.64 [95% CI: 0.60-4.51])., Conclusion: Overall, the study suggests an increased risk of NAION associated with PDE5i use. Patients and health-care providers should continue to weigh the risks and benefits of PDE5i use, including the potential for NAION., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Aim: The aim of the study was to assess the utility of blood cultures in children admitted to hospital with community-acquired pneumonia. The primary outcome was the number of positive blood culture results, and secondary outcomes included the effect of positive blood culture results on management, and the identification of other clinical/biochemical variables that could predict blood culture results or the course of illness., Methods: A retrospective data analysis was carried out on all children admitted to Gosford Hospital during the 2-year period from July 2013 to June 2015. Included were patients under 16 years old who had a diagnosis-related group code of pneumonia. A review of blood culture results, chest X-ray, serology, C-reactive protein and white cell count and clinical outcomes were analysed., Results: There were 215 paediatric admissions with a diagnosis of pneumonia during the 2-year study period. A blood culture was collected in 82.3% (177/215). Although seven had a positive blood culture, only two of these were finally reported as true positives and both were Streptococcus pneumoniae. Both patients were treated with a cephalosporin and demonstrated clinical improvement. No changes were made to their treatment based on the blood culture results., Conclusion: Blood cultures have a low yield and do not appear to be helpful when collected in all patients admitted to hospital with community-acquired pneumonia., (© 2016 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Previous studies have shown that some lipoglycopeptide and lipopeptide antimicrobial agents may cause falsely elevated values for some phospholipid-dependent coagulation tests. The effect of oritavancin, a lipoglycopeptide antibiotic, on coagulation test results was explored using pooled human plasma samples spiked with drug and in a clinical study after an infusion of a single 1,200-mg intravenous dose of oritavancin in normal healthy volunteers. Pooled plasma with oritavancin added ex vivo showed concentration-dependent prolongation of prothrombin time/international normalized ratio (PT/INR), activated partial thromboplastin time (aPTT), and dilute Russell viper venom time (DRVVT) test results. In contrast, oritavancin had no effect on the activated protein C resistance assay, chromogenic anti-factor Xa assay (anti-FXa), thrombin time, and an immunoassay for the laboratory diagnosis of heparin-induced thrombocytopenia. In participants that received a single dose of oritavancin, elevations in PT/INR result, aPTT, DRVVT, activated clotting time, and silica clotting time occurred, with the maximum times to resolution of test interference determined to be 12, 120, 72, 24, and 18 h, respectively. The anti-FXa assay was unaffected, whereas transient elevations in D dimer levels were observed in 30% of participants, with a maximum time to resolution of 72 h. Although oritavancin has no impact on the coagulation system in vivo, a single dose of oritavancin can produce falsely elevated values of some coagulation tests used to monitor hemostasis. The interference of oritavancin on affected tests is transient, and the test results revert to normal ranges within specified times after dosing., (Copyright © 2017 American Society for Microbiology.)

Objective: The objective of this study was to examine the presentations of patients by ambulance, under Section 20 of the NSW Mental Health Act of 2007, to a hospital emergency department (ED) with a 24-hour Mental Health Team., Methods: Patient records between December 2013 and December 2014 were audited and analysed in Excel., Results: There were 47 such presentations: 51% required a mental health admission. Patients required management for up to six of the nine identified mental health and physical problems. As the number of clinical problems in these patients increased, the length of their stay and the likelihood of discharge to home increased. The need for psychiatric admission did not appear to prolong their length of stay, though chemical sedation did. The availability of an ED mental health team did assist in achieving a length of stay that was in keeping with Australian National Emergency Access Target guidelines., Conclusions: A 24-hour ED mental health team provided specialised assessment and management for patients, alongside the necessary emergency medical intervention. This team assisted in easing the increasing pressure on the ED and minimising the patients' length of stay. The team redirected patients requiring admission, facilitated timely discharge of others and revoked Section 20 when less restrictive care was appropriate., (© The Royal Australian and New Zealand College of Psychiatrists 2016.)

Background: Tissue factor (TF) is involved in tumor growth and metastasis and contributes to venous thromboembolism (VTE) in cancer, including gynecological malignancies. The diagnostic value of microvesicle-associated TF procoagulant activity (MV TF PCA) in women with suspected ovarian cancer, however, has not been studied., Objective: To evaluate MV TF PCA as a diagnostic tool in women with an ovarian mass of unknown etiology and as a predictive biomarker for perioperative VTE., Methods: Plasma MVs were isolated by high-speed centrifugation and analyzed for TF-specific PCA by single-stage clotting assay. In addition, plasma TF antigen and soluble P-selectin (sCD62P) were measured by ELISA., Results: D-Dimer, MV TF PCA, and sCD62P, but not the tumor marker, CA-125, significantly differentiated patients with malignant (n=40) from those with benign tumors (n=15) and healthy controls (n=34). In cancer patients, only D-Dimer and CA-125 correlated with the FIGO stage. An abnormal D-dimer had the highest sensitivity for the diagnosis of cancer, while MV TF PCA above the ROC curve-derived cut-off value of 182U/mL had the highest specificity. By multivariate logistic regression analysis, addition of MV TF PCA conferred diagnostic benefit to the single variables, CA-125 (p=0.052) and D-dimer (p=0.019). Perioperative VTE occurred in 16% of cancer patients and was associated with an advanced FIGO stage, but not MV TF PCA. There was no difference in plasma TF antigen levels between study groups., Conclusions: MV TF PCA, but not plasma TF antigen, may provide valuable additional information for the diagnostic work-up of women with suspected ovarian cancer., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The CD32a immunoglobulin G (IgG) receptor (Fcγ receptor IIa) is a potential therapeutic target for diseases in which IgG immune complexes (ICs) mediate inflammation, such as heparin-induced thrombocytopenia, rheumatoid arthritis, and systemic lupus erythematosus. Monoclonal antibodies (mAbs) are a promising strategy for treating such diseases. However, IV.3, perhaps the best characterized CD32a-blocking mAb, was recently shown to induce anaphylaxis in immunocompromised "3KO" mice. This anaphylactic reaction required a human CD32a transgene because mice lack an equivalent of this gene. The finding that IV.3 induces anaphylaxis in CD32a-transgenic mice was surprising because IV.3 had long been thought to lack the intrinsic capacity to trigger cellular activation via CD32a. Such an anaphylactic reaction would also limit potential therapeutic applications of IV.3. In the present study, we examine the molecular mechanisms by which IV.3 induces anaphylaxis. We now report that IV.3 induces anaphylaxis in immunocompetent CD32a-transgenic "FCGR2A" mice, along with the novel finding that IV.3 and 2 other well-characterized CD32a-blocking mAbs, AT-10 and MDE-8, also induce severe thrombocytopenia in FCGR2A mice. Using recombinant variants of these same mAbs, we show that IgG "Fc" effector function is necessary for the induction of anaphylaxis and thrombocytopenia in FCGR2A mice. Variants of these mAbs lacking the capacity to activate mouse IgG receptors not only failed to induce anaphylaxis or thrombocytopenia, but also very potently protected FCGR2A mice from near lethal doses of IgG ICs. Our findings show that effector-deficient IV.3, AT-10, and MDE-8 are promising candidates for developing therapeutic mAbs to treat CD32a-mediated diseases., (© 2015 by The American Society of Hematology.)

Background: In acute myeloid leukemia (AML), disseminated intravascular coagulation (DIC) contributes to morbidity and mortality, but the underlying pathomechanisms remain incompletely understood., Methods: We conducted a prospective study on 69 patients with newly diagnosed AML to further define the correlates of systemic coagulation activation in this hematological malignancy. Tissue factor procoagulant activity (TF PCA) of isolated peripheral blood mononuclear cells (PBMCs) and TF expression by circulating microparticles (MPs) were assessed by single-stage clotting and thrombin generation assay, respectively. Soluble plasma TF antigen and secretion of vascular endothelial growth factor (VEGF) by cultured PBMCs were measured by ELISA. Cell-free plasma DNA was quantified by staining with a fluorescent dye., Result: TF PCA of PBMCs was significantly increased in AML patients as compared to healthy controls. Furthermore, TF PCA was significantly associated with decompensated DIC at presentation, as defined by a plasma fibrinogen level of ≤1 g/L (n = 11). In addition to TF PCA and circulating blasts, serum lactate dehydrogenase, a surrogate marker for leukemic cell turnover, correlated with plasma D-Dimer in the total patient cohort and was significantly increased in DIC patients, suggesting a role for myeloblast apoptosis/necrosis in activation of the TF-dependent coagulation pathway. Consistently, TF-bearing plasma MPs were more frequently detected and levels of soluble TF antigen were significantly higher in DIC vs. non-DIC patients. No association was found between TF PCA expression and VEGF secretion by isolated PBMCs, but significantly increased levels of cell-free plasma DNA pointed to a contribution of the intrinsic contact pathway to systemic coagulation activation in the total patient cohort and in patients with lower TF PCA expression. While PBMC-associated TF PCA had no effect on long-term survival, DIC occurrence at presentation increased the risk of early mortality., Conclusion: In newly diagnosed AML, TF expression by PBMCs and shedding of TF-bearing plasma MPs are central to the pathogenesis of DIC, but additional pathways, such as DNA liberation, may contribute to systemic coagulation activation.

Objective: To determine the impact of an implementation intervention designed to introduce policies and practices supportive of healthy eating in centre-based child-care services. Intervention strategies included staff training, resources, incentives, follow-up support, and performance monitoring and feedback., Design: A quasi-experimental design was used to assess change over 20 months in healthy eating policy and practice in intervention and comparison child-care services., Setting: The Hunter New England (HNE) region of New South Wales (NSW), Australia., Subjects: All centre-based child-care services (n 287) in the intervention region (HNE) were invited and 240 (91% response rate) participated. Two hundred and ninety-six services in the rest of NSW were randomly selected as a comparison region and 191 participated (76% response rate). A sub-analysis was conducted on those services that provided children food (n 196 at baseline and n 190 at follow-up). Ninety-six provided menus for analysis at baseline (HNE, n 36; NSW, n 50) and 102 provided menus at follow-up (HNE, n 50; NSW, n 52)., Results: Services in the intervention region were significantly more likely to provide only plain milk and water for children (P = 0.018) and to engage parents in nutrition policy or programmes (P = 0.002). They were also more likely (P = 0.056) to have nutrition policy on home packed food. In addition, menus of services that provided lunch were significantly more likely to comply with healthy eating guidelines for sweetened drinks (P < 0.001), fruit (P < 0.001) and vegetables (P = 0.01)., Conclusions: An implementation intervention was able to modify policy and practice in a large number of child-care services so that they were more supportive of healthy eating.

We examined older women's qualitative experiences of stroke with the World Health Organization's 18-item Brief International Classification of Functioning, Disability and Health Core Set for Stroke. Women were participants of the Australian Longitudinal Study on Women's Health, born between 1921 and 1926, who had experienced a stroke in the previous 3 years. An inductive thematic analysis was conducted of women's qualitative experiences of stroke, which were then examined with the 18-item Brief Core Set for Stroke for congruency. Our analysis showed that for older Australian women, their concerns of poststroke living were not adequately classified, potentially impeding a full recovery.

Background: Although many people survive an initial stroke, little is known about long-term impacts of stroke on survival., Methods: Data from the Australian Longitudinal Study on Women's Health were used to compare 12-year survival rates in older women with prevalent stroke, incident stroke, and no stroke. Cox regression models were fitted to assess the effect of lifestyle and demographic characteristics on the relationship between stroke and all-cause mortality. The "no stroke" group was used as the reference category in all statistical models., Results: At baseline, 4% of the women reported a previous stroke (prevalent stroke). At survey 2 in 1999, a further 3% reported having a stroke between 1996 and 1999 (incident stroke). Stroke was significantly associated with reduced long-term survival. Age-adjusted hazards ratios (HRs) were: 1.64 (1.43-1.89) for the "prevalent stroke" group and 2.29 (1.97-2.66) for the "incident stroke" group. Adjusting for comorbidities reduced the HRs, but the risk of death was still significantly higher in the 2 stroke groups. Adjusting for demographic and lifestyle factors did not make any further difference to the relationship between stroke and survival. However, obesity and past smoking were also risk factors for mortality., Conclusions: This study highlights the long-term impacts of stroke on life expectancy and the importance of comorbidities and other lifestyle factors in affecting poststroke survival., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Introduction: Platelet activation via the Fcγ receptor IIa (FcγRIIa) is implicated in the pathogenesis of immune complex (IC)-mediated thrombocytopenia and thrombosis (ITT). We previously showed that ICs composed of antigen and antibodies targeting CD40 ligand (CD40L) or β2 Glycoprotein I (β2GPI) induce ITT in mice transgenic for human FcγRIIa (hFcR) but not wild-type controls (which lack FcγRIIa). Here we evaluated the contribution of the guanine nucleotide exchange factor, CalDAG-GEFI, and P2Y12, key regulators of Rap1 signaling in platelets, to ITT induced by these clinically relevant ICs., Methods: Pre-formed anti-CD40L or anti-β2GPI ICs were injected into hFcR/Caldaggef1(+/+) or hFcR/Caldaggef1(-/-) mice, with or without clopidogrel pretreatment. Animals were observed for symptoms of shock for 30 min, during which time core body temperature was monitored. Platelet counts were obtained before and 30 min after IC injection. Lungs were assessed for thrombosis by histology or near-infrared imaging., Results: Both CD40L and β2GPI ICs rapidly induced severe thrombocytopenia, shock and a reduction in body temperature in hFcR/Caldaggef1(+/+) mice. hFcR/Caldaggef1(-/-) mice were protected from CD40L and β2GPI IC-induced thrombocytopenia and shock, whereas P2Y12 inhibition had only a modest effect on IC-induced ITT. Consistent with these findings, IC-induced integrin activation in vitro and the accumulation of activated platelets in the lungs of IC-challenged mice was strongly dependent on CalDAG-GEFI., Conclusions: Our studies demonstrate that CalDAG-GEFI plays a critical role in platelet activation, thrombocytopenia and thrombosis induced by clinically relevant ICs in mice. Thus, CalDAG-GEFI may be a promising target for the intervention of IC-associated, FcγRIIa-mediated thrombotic conditions., (© 2014 International Society on Thrombosis and Haemostasis.)

Objective: To describe the impact of a training and support intervention to encourage completion of the Healthy Kids Check (HKC) by general practitioners (GP) or practice nurses (PN) and provision of brief advice on diet and physical activity., Methods: The intervention (June 2008 to July 2010) was delivered by Divisions of General Practice (DGP) in the Hunter New England (HNE) region of NSW, Australia, to members in 300 practices. Intervention impact was evaluated using Medicare data on the number of HKCs completed and a post-intervention telephone survey of randomly selected parents in HNE and rest of NSW., Results: Training reached 31% of GPs (n∼ 216/700) and 71% of PNs (n∼320/450); 31% of four-year-olds received a HKC in HNE compared to 15% in NSW; 27% of HNE parents (n=162) reported a GP or PN had provided advice during their child's vaccinations visit compared to 15% of parents (n=154) in NSW (p=0.002). There was no significant difference in proportion of children who had weight or height assessed (55.6% in HNE and 54.6% in NSW)., Conclusions: Boosting HKC claims and healthy eating and physical activity messages in general practice is feasible. More intensive strategies are required if obesity prevention and management benefits are to be achieved., Implications: General practice is an important but under-utilised source of advice for parents and data for policy makers on childhood obesity in Australia., (© 2014 The Authors. ANZJPH © 2014 Public Health Association of Australia.)

Background: Tumor-derived tissue factor (TF) activates coagulation in vitro and in vivo in an orthotopic model of human pancreatic cancer. Here, we further characterized tumor-derived TF in this model., Methods: Conditioned medium (CM) of L3.6pl human pancreatic tumor cells and plasma from nude mice bearing L3.6pl tumors were ultracentrifuged, and the pellets were filtered through membranes with different pore sizes. The size distribution of particles was analyzed in CM or plasma fractions with nanoparticle tracking and dynamic light scattering. Human TF antigen and activity were measured in pellets and supernatants with ELISA and clotting or thrombin generation assays, respectively. Human alternatively spliced TF (asTF) was measured with ELISA. Human TF and thrombin-antithrombin complex (TAT) concentrations were assessed in plasma of mice injected with filtered fractions of CM., Results: Particles in both CM and plasma were < 0.4 μm. TF antigen and activity in the CM were mainly associated with microparticles (MP). Approximately 50% of antigen and 20% of activity were associated with particles of < 0.1 μm. Injection of < 0.1 μm particles into mice caused a 30% drop in platelet counts and an increase in TAT levels. In contrast, ~ 90% of TF antigen in tumor-bearing mice plasmas was non-sedimentable, whereas TF activity was exclusively associated with MP. Particles of < 0.1 μm and the supernatants of both CM and plasma gained TF activity after addition of exogenous phospholipids. Although asTF was found in MP-free CM supernatants, it was also present in CM and plasma pellets., Conclusions: Tumor-derived particles of < 0.1 μm and non-sedimentable TF are or can become procoagulant in the presence of phospholipids, and may contribute to the procoagulant potential of circulating TF., (© 2013 International Society on Thrombosis and Haemostasis.)