Early Exclusion of Major Adverse Cardiac Events in Emergency Department Chest Pain Patients: A Prospective Observational Study.

BACKGROUND: The current evaluation of patients with chest pain presenting to an emergency department (ED) with suspected acute coronary syndrome (ACS) is a lengthy process involving serial measurements of troponin. OBJECTIVE: We aimed to validate the diagnostic accuracy of a Thrombolysis in Myocardial Infarction (TIMI) score with single high-sensitive cardiac troponin T (hs-cTnT) for early rule out of 30-day major adverse cardiac events (MACE), and to compare the TIMI score with combinations of heart-type fatty acid binding protein (H-FABP) and a modified HEART (history, electrocardiogram, age, risk factors, troponin) score. METHODS: We recruited 602 consecutive adult patients with chest pain and suspected ACS in the ED. Each patient had TIMI and HEART scores, and a point-of-care H-FABP test. RESULTS: MACE occurred in 42 (7.0%) patients within 30 days. A low risk for 30-day MACE was identified by a modified TIMI score of 0 in 65 (11%) patients, and by a HEART score ≤ 2 in 96 (16%) patients. No MACE occurred in these groups, giving both scores a sensitivity of 100% (95% confidence interval [CI] 91.6-100%), and specificity of 11.6% (95% CI 9.2-14.5%) and 17.1% (95% CI 14.2-20.5%), respectively. Use of combined TIMI and HEART scores improved the specificity further to 22.0% (95% CI 18.7-25.6%) without lowering sensitivity. Early H-FABP measurement > 7 µg/L had a sensitivity of 41.5% (95% CI 27.8-56.6%) and a specificity of 91.1% (95% CI 88.4-93.2%) for predicting 30-day MACE. CONCLUSIONS: A modified TIMI score of 0 or a HEART score of ≤ 2, incorporating a single hs-cTnT level, will identify patients with low risk of 30-day MACE for early discharge within 2 h of ED arrival.

Validating a pragmatic definition of shock in adult patients presenting to the ED.

OBJECTIVE: The importance of the early recognition of shock in patients presenting to emergency departments is well recognized, but at present, there is no agreed practical definition for undifferentiated shock. The main aim of this study was to validate an a priori clinical definition of shock against 28-day mortality. DESIGN, SETTING AND SUBJECTS: This prospective, observational, cross-sectional, single-center study was conducted in Hong Kong, China. Data were collected between July 1, 2012, and January 31, 2013. An a priori definition of shock was designed, whereby patients admitted to the resuscitation room or high dependency area of the emergency department were divided into 1 of 3 groups-no shock, possible shock, and shock. The primary outcome was 28-day mortality. Secondary outcomes were in-hospital mortality or admission to the intensive or coronary care unit. MEASUREMENTS AND MAIN RESULTS: A total of 111 patients (mean age, 67.2 ± 17.1 years; male = 69 [62%]) were recruited, of which 22 were classified as no shock, 54 as possible shock, and 35 as shock. Systolic blood pressure, mean arterial pressure, lactate, and base deficit correlated well with shock classifications (P < .05). Patients who had 3 or more positively defined shock variables had a 100% poor composite outcome rate (5 of 5). Patients with 2 shock variables had a 66.7% (4 of 6) poor composite outcome rate. CONCLUSIONS: A simple, practical definition of undifferentiated shock has been proposed and validated in a group of patients presenting to an emergency department in Hong Kong. This definition needs further validation in a larger population and other settings.

A one-step immunotest for rapid detection of heart-type fatty acid-binding protein in patients with acute coronary syndromes.

Using heart-type fatty acid-binding protein (H-FABP) as an early cardiac marker for diagnosis of acute myocardial infarction (AMI) soon after the onset of symptoms requires a rapid assay. A one-step test called, CardioDetect, is used for detection of H-FABP in whole blood sample. Thirty patients suspected of AMI presenting to the emergency department within 12 hours after onset were enrolled in this study. The diagnostic performance of CardioDetect was compared with different cardiac markers. There were 59.1% of patients with positive H-FABP within 6 hours after onset, while there were only 18.2% with positive cardiac troponin I (cTnI). Results indicated the diagnostic power of H-FABP for AMI was significantly higher than that of cTnI. The sensitivity of H-FABP was 81.8%, which was higher than those of the other cardiac markers, while the specificity was comparable. The area under the receiver operating characteristic curve for H-FABP was 0.909, which was significantly larger than the others. With this rapid and sensitive immunotest, H-FABP could be soon introduced in clinical practice in combination with well-established markers like troponins.

Development of a creatinine enzyme-based bar-code-style lateral-flow assay.

A lateral-flow, enzyme-based, bar-code assay for creatinine employing the concept of combination of diffusion and kinetics controlled has been developed. Unlike the traditional bar-code version of immunochromatographic assay, which depends on the stepwise capture of colorimetric tracer-labeled antibody-antigen complex by the immobilized antibody on each successive line, the principle of our proposed assay is based on the delay in TMB release and its diffusion in combination with horseradish peroxidase kinetics. Hydrogen peroxide (H(2)O(2)) produced from enzymatic reactions acts as a limiting factor, which controls the rate of conversion of TMB to blue color complex. The assay takes advantage of giving ladder bar result therefore without the need of any reading device. Depending on the amount of enzymes used, the assay can be one (9 min) or two steps (19 min). The strip assay semiquantitatively measures creatinine concentrations ranging from 0 to 400 microM. Thirty urine samples and thirty serum samples were tested, and the assay showed 90.0% and 86.7% agreement compared with conventional Jaffé method, respectively. This assay provides a tool for quick identification of creatinine for patients without the requirement of any instrument.

Plasma miR-124-3p and miR-16 concentrations as prognostic markers in acute stroke.

OBJECTIVES: This study aimed to investigate plasma concentrations of miR-124-3p and miR-16 as prognostic markers in emergency department patients with acute stroke. DESIGN AND METHODS: Plasma concentrations of miR-124-3p and miR-16 of 84 stroke patients (presenting to the emergency department within 24h from onset of symptoms) were determined by RT-qPCR. The primary outcome measure was 3-month mortality and the secondary outcome measure was post-stroke modified Rankin Score (mRS). RESULTS: Twelve patients (14.3%) died within 3months of hospital admission and forty-one (48.8%) patients as achieved a 3-month mRS>2. Median plasma miR-124-3p concentrations were elevated in patients who died compared to patients who survived (p=0.0052), and its levels were found to be higher in patients with a 3-month mRS>2 compared with patients with mRS≤2 (p=0.0312). Higher plasma miR-16 concentrations were observed in patients who survived than in patients who died (p=0.0394), while its concentrations were lower in patients achieving mRS>2 than in patients with mRS≤2 (p=0.0124). For a subgroup of cases presenting to the emergency department within 6h from time of symptom onset (n=36), plasma miR-124-3p concentrations predicted 3-month mortality with an area under the ROC curve of 0.87 (95%CI: 0.72-0.96). CONCLUSIONS: Plasma miR-124-3p and miR-16 are molecular markers which could be useful for the early prediction of mortality and mRS.

Prognostic values of 4 risk scores in Chinese patients with chest pain: Prospective 2-centre cohort study.

Four risk scores for stratifying patients with chest pain presenting to emergency departments (EDs) (namely Thrombolysis in myocardial infarction [TIMI], Global registry for acute coronary events [GRACE], Banach and HEART) have been developed in Western settings but have never been compared and validated in Chinese patients. We aimed to find out to the number of MACE within 7 days, 30 days, and 6 months after initial ED presentation, and also to compare the prognostic performance of these scores in Chinese patients with suspected cardiac chest pain (CCP) to predict 7-day, 30-day, and 6-month major adverse cardiac events (MACE).A prospective 2-center observational cohort study of consecutive patients presenting with chest pain to the EDs of 2 university hospitals in Guangdong and Hong Kong from 17 March 2012 to 14 August 2013 was conducted. Patients aged ≥18 years with suspected CCP but without ST-segment elevation myocardial infarction (STEMI) were recruited.Of 833 enrolled patients (mean age 65.1 years, SD14.5; 55.6% males), 121 (14.5%) experienced MACE within 6 months (4.8% with safety outcomes and 10.3% with effectiveness outcomes). The HEART score had the largest area under the receiver operating characteristic (ROC) curve for predicting MACE at 7-day, 30-day, and 6-month follow-up [area under curve (AUC) = 0.731, 0.726, and 0.747, respectively. The HEART score also had the largest AUC for predicting effectiveness outcome (AUC = 0.715, 0.704, and 0.721, respectively). However, there was no significant difference in AUC between HEART and TIMI scores. Banach had the largest AUC for predicting safety outcome (AUC = 0.856, 0.837, and 0.850, respectively).The HEART score performed better than the GRACE and Banach scores to predict total MACE and effectiveness outcome in Chinese patients with suspected CCP, whereas the Banach score best predicted safety outcomes.

Silole nanocrystals as novel biolabels.

A novel class of biofunctional silole nanocrystals with the potential to create highly sensitive immunoassay was firstly demonstrated. Biolabels were constructed by encapsulating nanocrystalline hexaphenylsilole [Ph2Si(CPh)4HPS] within ultrathin polyelectrolyte layers via the layer-by-layer (LbL) technique that provided an "interface" for the attachment of antibodies. A high ratio of fluorescent dyes to biomolecules (F/P ratio; 2.4 x 10(3)) was achieved without self-quenching problem. The aggregation-induced emission (AIE) feature offered silole biolabels the sensitivity 40- to 140-fold higher than that of a start-of-the-art immunoassay using directly fluorescent-labeled antibodies.

Evaluation of the Recognition of Stroke in the Emergency Room (ROSIER) scale in Chinese patients in Hong Kong.

BACKGROUND AND PURPOSE: The objective of this study was to determine the performance of the Recognition Of Stroke In the Emergency Room (ROSIER) scale in risk-stratifying Chinese patients with suspected stroke in Hong Kong. METHODS: This was a prospective cohort study in an urban academic emergency department (ED) over a 7-month period. Patients over 18 years of age with suspected stroke were recruited between June 2011 and December 2011. ROSIER scale assessment was performed in the ED triage area. Logistic regression analysis was used to estimate the impacts of diagnostic variables, including ROSIER scale, past history and ED characteristics. FINDINGS: 715 suspected stroke patients were recruited for assessment, of whom 371 (52%) had acute cerebrovascular disease (302 ischaemic strokes, 24 transient ischaemic attacks (TIA), 45 intracerebral haemorrhages), and 344 (48%) had other illnesses i.e. stroke mimics. Common stroke mimics were spinal neuropathy, dementia, labyrinthitis and sepsis. The suggested cut-off score of>0 for the ROSIER scale for stroke diagnosis gave a sensitivity of 87% (95%CI 83-90), a specificity of 41% (95%CI 36-47), a positive predictive value of 62% (95%CI 57-66), and a negative predictive value of 75% (95%CI 68-81), and the AUC was 0.723. The overall accuracy at cut off>0 was 65% i.e. (323+141)/715. INTERPRETATION: The ROSIER scale was not as effective at differentiating acute stroke from stroke mimics in Chinese patients in Hong Kong as it was in the original studies, primarily due to a much lower specificity. If the ROSIER scale is to be clinically useful in Chinese suspected stroke patients, it requires further refinement.

Age-specific non-invasive transcutaneous Doppler ultrasound derived haemodynamic reference ranges in elderly Chinese adults.

BACKGROUND: Whilst there is a presumption in medicine that ageing adversely affects cardiovascular function, it is unknown if resting haemodynamics are compromised in the elderly, and if so, to what degree. This study was intended to answer several questions; whether age-related changes in haemodynamics occur; whether there was a difference between the haemodynamics of ageing subjects with and without mild chronic disease; whether there was a difference in haemodynamics as measured from either the aortic or the pulmonary valve; and to establish reference ranges for this population. METHODS: Chinese adults aged over 60 years were divided into three age bands of 61-70, 71-80 and over 80 years. The haemodynamic parameters were measured using a non-invasive Doppler ultrasound-based instrument, the Ultrasonic Cardiac Output Monitor (USCOM). RESULTS: One hundred and sixty-five subjects (48.5% males) were recruited. 78 (47.3%) had no known disease whilst 87 (52.7%) had mild chronic illness. A total of 21 individual haemodynamic parameters were measured or calculated for each subject. There were no significant differences in stroke volume (SV), cardiac output (CO), systemic vascular resistance (SVR) or in body surface area (BSA)-indexed parameters, SV index (SVI), cardiac index (CI) and SVR index (SVRI) across age groups, or in other indexed haemodynamic parameters. No significant differences in indexed haemodynamics were found between those subjects with and those without mild chronic disease. Small, statistically significant, but clinically insignificant, differences (< 5%) were found between the aortic and pulmonary valve measurements for SV, SVI and heart rate. CONCLUSIONS: Ageing does not have any significant effect on resting haemodynamics in the elderly population studied. Mild chronic disease does not adversely affect resting haemodynamics in this population. GENERAL SIGNIFICANCE: Reference ranges were established for 21 haemodynamic parameters, as measured by USCOM, for an elderly Chinese population but not for non-Chinese populations.

Comparison of miR-124-3p and miR-16 for early diagnosis of hemorrhagic and ischemic stroke.

BACKGROUND: The present study aimed to investigate and compare plasma concentrations of miR-124-3p and miR-16 as diagnostic markers in acute stroke. METHODS: miR-124-3p and miR-16 concentrations in 93 stroke patients were analyzed using real-time polymerase chain reaction. The primary outcome was the differentiation of hemorrhagic and ischemic stroke. RESULTS: Of 93 patients, 74 (79.6%) were diagnosed as ischemic stroke (IS) and 19 (20.4%) were diagnosed as hemorrhagic stroke (HS). Median plasma 124-3p concentrations taken within 24h of symptom onset were higher in HS patients than that in IS patients (3.8×10(5) vs 2.0×10(5) copies/ml plasma, p=0.0109), while median miR-16 concentration in IS patients were higher than that in HS patients (1.6×10(9) vs 1.3×10(9) copies/ml plasma, p=0.0399). The odds ratio (OR) for discriminating HS and IS with miR-124-3p and miR-16 was 5.37 and 9.75 respectively. CONCLUSION: Both miR-124-3p and miR-16 are diagnostic markers to discriminate HS and IS.

Pathophysiological roles and clinical importance of biomarkers in acute coronary syndrome.

Early diagnosis of acute coronary syndrome (ACS) is important to guide appropriate therapy at a time when it is most likely to be of value. Accurate prognostic and risk stratification will facilitate high-risk patients to have early advanced diagnostic investigations and early appropriate interventions in a cost-effective and efficient manner, while those patients at low risk of ACS complications do not need such costly diagnostic tests and unnecessary hospital admission. Recent investigations have demonstrated that elevation of biomarkers upstream from acute-phase biomarkers, biomarkers of plaque destabilization and rupture, biomarkers of myocardial ischemia, necrosis, and dysfunction may provide an earlier assessment of patient risk and identify patients with higher risk of having an adverse event. This review provides an overview of the pathophysiology and clinical characteristics of several well-established biomarkers as well as emerging biomarkers that may have potential clinical utility in patients with ACS. Such emerging biomarkers hold promise and need to be more thoroughly evaluated before utilization in routine clinical practice.

Evidence-based point-of-care diagnostics: current status and emerging technologies.

Point-of-care (POC) diagnostics brings tests nearer to the site of patient care. The turnaround time is short, and minimal manual interference enables quick clinical management decisions. Growth in POC diagnostics is being continuously fueled by the global burden of cardiovascular and infectious diseases. Early diagnosis and rapid initiation of treatment are crucial in the management of such patients. This review provides the rationale for the use of POC tests in acute coronary syndrome, heart failure, human immunodeficiency virus, and tuberculosis. We also consider emerging technologies that are based on advanced nanomaterials and microfluidics, improved assay sensitivity, miniaturization in device design, reduced costs, and high-throughput multiplex detection, all of which may shape the future development of POC diagnostics.

Influence of different positions on hemodynamics derived from noninvasive transcutaneous Doppler ultrasound.

A proper alignment of the ultrasound beam to the aortic or pulmonary outflow tracts is essential to acquire accurate signals. This study aimed to investigate the influence of different positions on the acquisition of Doppler signals using a noninvasive transcutaneous Doppler ultrasound. This was a prospective observational crossover study. Two operators performed hemodynamics measurements on each subject in supine, sitting, semirecumbent, passive leg raising (PLR) 20°, and PLR 60° positions using both aortic and pulmonary approaches. All Doppler flow profile images were assessed using the Fremantle and Prince of Wales Hospital criteria. Time required to obtain Doppler signals was recorded. A total of 60 subjects (50% males) aged 18-60 years old were investigated. In both sitting and semirecumbent positions, aortic stroke volume indexes (SVIs) and cardiac indexes (CIs) were significantly lower than those in the other three positions while the pulmonary CIs were comparable to that in the supine position. In the sitting position, the aortic signal qualities were lower and the time to obtain the pulmonary Doppler signals was prolonged. Instead, the signal quality and the time to obtain the Doppler signals in the semirecumbent position were similar to those in the other three positions using the pulmonary approach. PLR did not cause a significant increase in SVI regardless of the degree of leg elevation. These data show that it is feasible to perform the noninvasive transcutaneous Doppler ultrasound using the pulmonary approach in the semirecumbent position for patients unable to maintain the supine position. The aortic approach in the sitting and semirecumbent positions is not suitable as it is not sufficiently reliable.

Multiple atherosclerosis-related biomarkers associated with short- and long-term mortality after stroke.

OBJECTIVES: We investigated the relationships of biomarkers of various pathophysiologic pathways including high-sensitivity C-reactive protein (hs-CRP), lipocalin-2 (LCN2), myeloperoxidase (MPO) and matrix metalloproteinases 9 (MMP9) with mortality in stroke patients. DESIGN AND METHODS: hs-CRP, LCN2 and MPO concentrations in 92 patients were determined using enzyme-linked immunosorbent assays. MMP9 mRNA concentrations were determined using real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: Twelve patients (13.0%) died at 6 months and 34 patients (37.0%) died at 5 years. The independent predictors for 6-month mortality were hs-CRP (adjusted OR=16.0) and LCN2 (adjusted OR=16.9), while for 5-year mortality was hs-CRP (adjusted OR=5.56). For patients with hs-CRP >3.4 mg/L, an increase in LCN2 was associated with 2.5-fold higher 6-month mortality, while an increase in normalized MMP9 mRNA was associated with 5.8-fold higher 6-month and 1.5-fold higher 5-year mortality. CONCLUSION: hs-CRP was the most significant independent predictor of both short- and long-term mortality after stroke, with LCN2 and MMP9 mRNA each adding further to the risk stratification.

Diagnostic utility of an anti-CCP point-of-care immunotest in Chinese patients with rheumatoid arthritis.

BACKGROUND: Early and accurate diagnosis of rheumatoid arthritis (RA) has become increasingly important. The clinical significance of anti-cyclic citrullinated peptide (CCP) antibody in Chinese RA adults was studied using an anti-CCP2 rapid test. METHODS: Anti-CCP antibody and rheumatoid factor (RF) were determined in 95 RA patients and 140 patients with rheumatic diseases other than RA. RESULTS: Two hundred and thirty five subjects were enrolled in this study. Both sensitivity and specificity of anti-CCP2 ELISA (78.9% & 95.7%) were higher than those of RF (67.4% & 84.3%). The area under the receiver operating characteristic curve for anti-CCP2 ELISA was 0.852 (95% CI: 0.792-0.913) which was larger than that for RF 0.775 (95% CI: 0.710-0.840). Both sensitivity and specificity (75.8% and 92.9%) of the anti-CCP2 rapid test were comparable to the ELISA. However, the sensitivity (62.1%) of a combined strategy by measuring anti-CCP antibody and RF was even lower than either marker alone although the specificity (98.6%) was slightly improved. CONCLUSIONS: Anti-CCP antibody is a valuable tool for diagnosis of RA in Chinese patients. With the use of the reliable and user-friendly anti-CCP rapid test, it may have an important role in the design of therapeutic strategies in RA patients.

Ingenious nanoprobes in bioassays.

This article has a special focus on the broad range of innovative nanoprobes for signal amplification and new generations of bioassays. Advances in functionalizing gold nanoparticles with oligonucleotides speed up the development of a series of new nucleic acid assays. A biobarcode assay allows signal amplification by utilizing antibody-coated magnetic beads to concentrate the analytes and antibody-coated gold nanoparticle probes to carry a large number of oligonucleotides. Novel signal-amplification technologies, based on either new classes of nanoprobes consisting of releasable fluorophores or with aggregation-induced emission features, can also improve the sensitivity of bioassays. Advances in synthesis and biofunctionalization of quantum dots with unique properties have generated increasingly widespread applications in DNA sorting, multiplexing bioassays and fluorescence resonance energy transfer-based sensing. Ingenious nanoprobes in bioassays can offer PCR-like sensitivity, high selectivity, capacity for massive multiplexing, time efficiency and, most importantly, the ability to be performed at the point- of-care.

Development of enzyme-based bar code-style lateral-flow assay for hydrogen peroxide determination.

A unique approach of developing a bar code version of lateral-flow enzymatic-based assay for the semi-quantification of hydrogen peroxide is described. The proposed assay system is mainly composed of a goat anti-mouse IgG-horseradish peroxidase conjugate (Gt anti-M IgG-HRP)-coated nitrocellulose (NC) membrane and a peroxidase substrate pad. Unlike the bar code immunochromatographic assay which depends on the stepwise capture of analyte, the principle of enzyme-based bar code lateral-flow assay is based on the different reaction time on successive lines due to the delay in 3,3',5,5'-tetramethylbenzidine (TMB) release. Hydrogen peroxide (H(2)O(2)) acts as a limiting factor which controls the rate of the enzymatic conversion of TMB to blue color complex. The system expresses the concentration of H(2)O(2) in micromole range as three distinct ladder bars in 9 min therefore without the need of any reading device. The major advantages of this assay are its easily readable result, and also its simplicity and low-cost in production offers a cheaper alternative for testing those expensive biosensors might not be available to the third world countries. By incorporating with H(2)O(2)-generating oxidoreductases, the assay can be further extended to detect a variety of analytes with clinical and environmental importance. Glucose was chosen to be the model analyte where the proposed system gave signal response at between 5 microM and 100 microM.

Human heart-type fatty acid-binding protein for on-site diagnosis of early acute myocardial infarction.

Human heart-type fatty acid-binding protein (H-FABP) has a high potential as an early marker for acute myocardial infarction (AMI) being more sensitive than current routine cardiac markers. Seventy-four patients presenting to hospital with a median symptom onset of 2.2 h (IQR 1.5-2.9 h) were enrolled in this study and 54 (73%) had AMI. At presentation, H-FABP gave the highest sensitivity of 83.3% (95% CI: 70.7-92.1) and troponin I (cTnI) gave the highest specificity of 50.0% (95% CI: 27.2-72.8). This study demonstrated that H-FABP immunotest gave a better diagnostic classification at the early stage. Also, AMI was identified significantly earlier by H-FABP than cTnI (17 vs. 6 patients, p<0.05).

New trends in immunoassays.

This article takes a special focus on signal amplification technologies in immunoassays and new generations of lateral-flow assays. Novel signal amplification technologies based either on new classes of biofunctional nanocrystals consisting of releasable fluorophores or on aggregation-induced emission (AIE) can improve the sensitivity and the limits of detection in immunoassays. A bio-barcode assay also allows signal amplification by utilizing antibody-coated magnetic beads to concentrate the analytes and antibody-coated gold nanoparticle probes to carry with a large number of oligonucleotides. These innovative technologies boost the development of immunoassays. Growth in rapid immunoassay is fueled by the increasing number of diabetics, the globalization of infectious diseases and the surge in cardiovascular and other chronic diseases as well as other chronic conditions. Rapid, near patient, decentralized, point-of-care (POC) tests are emerging as a tool for more efficient diagnosis and patient evaluation. Technological innovations in lateral-flow assays have enabled a move to bring testing closer to the patient. A novel "digital-style" lateral-flow assay provides semi-quantitative results by simply counting the number of red lines in the test without any expensive reading instrument. An immuno-threshold-based assay can give a signal directly proportional to the concentration of a hapten to prevent confusion on interpretation of the test results. In addition, POC tests become more meaningful to healthcare professionals by combining the benefits of new technologies to provide quantitative results. A molecular compact disc provides a high-resolution imaging capability that can identify and quantify many different antigens simultaneously in highly complex immunoassays. Further advances in immunoassays will bring diagnostic testing even closer to the patient, and can help physicians to monitor diseases that require immediate test results, thereby enhancing the quality of patient care.