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I would like to welcome breast cancer research community to the first editorial of our newest journal "Breast Cancer: Basic and Clinical Research". In pursuit of breast cancer culprits, we have come a long way since the early 90's when the first breast cancer susceptibility gene BRCA1 was mapped and cloned. In the past few years, several new loci associated with the various degree of breast cancer risk have been identified using "Candidate Gene Association Study (CGAS) and Genome-Wide Association Study (GWAS)" approaches. This editorial is meant to quickly glance over recent findings of these population-based association studies.
17,187 patients entering 417 hospitals up to 24 hours (median 5 hours) after the onset of suspected acute myocardial infarction were randomised, with placebo control, between: (i) a 1-hour intravenous infusion of 1.5 MU of streptokinase; (ii) one month of 160 mg/day enteric-coated aspirin; (iii) both active treatments; or (iv) neither. Streptokinase alone and aspirin alone each produced a highly significant reduction in 5-week vascular mortality: 791/8592 (9.2%) among patients allocated streptokinase infusion vs 1029/8595 (12.0%) among those allocated placebo infusion (odds reduction: 25% SD 4; 2p less than 0.00001); 804/8587 (9.4%) vascular deaths among patients allocated aspirin tablets vs 1016/8600 (11.8%) among those allocated placebo tablets (odds reduction: 23% SD 4; 2p less than 0.00001). The combination of streptokinase and aspirin was significantly (2p less than 0.0001) better than either agent alone. Their separate effects on vascular deaths appeared to be additive: 343/4292 (8.0%) among patients allocated both active agents vs 568/4300 (13.2%) among those allocated neither (odds reduction: 42% SD 5; 95% confidence limits 34-50%). There was evidence of benefit from each agent even for patients treated late after pain onset (odds reductions at 0-4, 5-12, and 13-24 hours: 35% SD 6, 16% SD 7, and 21% SD 12 for streptokinase alone; 25% SD 7, 21% SD 7, and 21% SD 12 for aspirin alone; and 53% SD 8, 32% SD 9, and 38% SD 15 for the combination of streptokinase and aspirin). Streptokinase was associated with an excess of bleeds requiring transfusion (0.5% vs 0.2%) and of confirmed cerebral haemorrhage (0.1% vs 0.0%), but with fewer other strokes (0.6% vs 0.8%). These "other" strokes may have included a few undiagnosed cerebral haemorrhages, but still there was no increase in total strokes (0.7% streptokinase vs 0.8% placebo infusion). Aspirin significantly reduced non-fatal reinfarction (1.0% vs 2.0%) and non-fatal stroke (0.3% vs 0.6%), and was not associated with any significant increase in cerebral haemorrhage or in bleeds requiring transfusion. An excess of non-fatal reinfarction was reported when streptokinase was used alone, but this appeared to be entirely avoided by the addition of aspirin. Those allocated the combination of streptokinase and aspirin had significantly fewer reinfarctions (1.8% vs 2.9%), strokes (0.6% vs 1.1%), and deaths (8.0% vs 13.2%) than those allocated neither. The differences in vascular and in all-cause mortality produced by streptokinase and by aspirin remain highly significant (2p less than 0.001 for each) after the median of 15 months of follow-up thus far available.
BACKGROUND: The diagnostic evaluation of patients presenting with possible lung cancer is often complex and time consuming. A rapid outpatient diagnostic program (RODP) including (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contrast-enhanced computed tomography (CT) as a routine diagnostic tool may improve timeliness, however the diagnostic performance of such a combined approach of RODP remains unclear. OBJECTIVES: We evaluated timeliness of care and diagnostic performance of FDG-PET and contrast-enhanced CT (FDG-PET/CT) in an RODP for all patients referred with a chest X-ray suspicious of lung cancer. METHODS: Charts of patients referred to the 2-day RODP of our tertiary care university clinic after an abnormal chest X-ray between 1999 and 2009 were reviewed. Between 1999 and 2005 co-registered FDG-PET and CT imaging took place; from September 2005 onwards, a hybrid system was used. We analyzed timeliness of care and diagnostic performance of FDG-PET/CT to differentiate malignant from benign lesions. RESULTS: In 386 patients available for analysis, 260 were diagnosed with lung cancer and 23 had another type of malignancy; in 78 patients benign disease was confirmed, and in another 45 the diagnosis was not pathologically confirmed but a median 24.5-month follow-up confirmed a benign outcome. Sensitivity, specificity, negative and positive predictive values and accuracy of FDG-PET/CT to differentiate lung cancer from benign disease were 97.7, 60.2, 92.5, 84.0 and 85.8%, respectively. Lung cancer patients had a median referral, diagnostic and therapeutic delay of 7, 2 and 19 days, respectively. CONCLUSIONS: FDG-PET/CT in an RODP setting for suspected lung cancer has high performance in detecting cancer and facilitates timely care.
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BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) is elevated in pregnant women before the clinical onset of preeclampsia, but its predictive value in women with suspected preeclampsia is unclear. METHODS: We performed a prospective, multicenter, observational study to derive and validate a ratio of serum sFlt-1 to PlGF that would be predictive of the absence or presence of preeclampsia in the short term in women with singleton pregnancies in whom preeclampsia was suspected (24 weeks 0 days to 36 weeks 6 days of gestation). Primary objectives were to assess whether low sFlt-1:PlGF ratios (at or below a derived cutoff) predict the absence of preeclampsia within 1 week after the first visit and whether high ratios (above the cutoff) predict the presence of preeclampsia within 4 weeks. RESULTS: In the development cohort (500 women), we identified an sFlt-1:PlGF ratio cutoff of 38 as having important predictive value. In a subsequent validation study among an additional 550 women, an sFlt-1:PlGF ratio of 38 or lower had a negative predictive value (i.e., no preeclampsia in the subsequent week) of 99.3% (95% confidence interval [CI], 97.9 to 99.9), with 80.0% sensitivity (95% CI, 51.9 to 95.7) and 78.3% specificity (95% CI, 74.6 to 81.7). The positive predictive value of an sFlt-1:PlGF ratio above 38 for a diagnosis of preeclampsia within 4 weeks was 36.7% (95% CI, 28.4 to 45.7), with 66.2% sensitivity (95% CI, 54.0 to 77.0) and 83.1% specificity (95% CI, 79.4 to 86.3). CONCLUSIONS: An sFlt-1:PlGF ratio of 38 or lower can be used to predict the short-term absence of preeclampsia in women in whom the syndrome is suspected clinically. (Funded by Roche Diagnostics.).
BACKGROUND: Several diagnostic strategies using ultrasound imaging, measurement of D-dimer, and assessment of clinical probability of disease have proved safe in patients with suspected deep-vein thrombosis, but they have not been compared in randomized trials. METHODS: Outpatients presenting with suspected lower-extremity deep-vein thrombosis were potentially eligible. Using a clinical model, physicians evaluated the patients and categorized them as likely or unlikely to have deep-vein thrombosis. The patients were then randomly assigned to undergo ultrasound imaging alone (control group) or to undergo D-dimer testing (D-dimer group) followed by ultrasound imaging unless the D-dimer test was negative and the patient was considered clinically unlikely to have deep-vein thrombosis, in which case ultrasound imaging was not performed. RESULTS: Five hundred thirty patients were randomly assigned to the control group, and 566 to the D-dimer group. The overall prevalence of deep-vein thrombosis or pulmonary embolism was 15.7 percent. Among patients for whom deep-vein thrombosis had been ruled out by the initial diagnostic strategy, there were two confirmed venous thromboembolic events in the D-dimer group (0.4 percent; 95 percent confidence interval, 0.05 to 1.5 percent) and six events in the control group (1.4 percent; 95 percent confidence interval, 0.5 to 2.9 percent; P=0.16) during three months of follow-up. The use of D-dimer testing resulted in a significant reduction in the use of ultrasonography, from a mean of 1.34 tests per patient in the control group to 0.78 in the D-dimer group (P=0.008). Two hundred eighteen patients (39 percent) in the D-dimer group did not require ultrasound imaging. CONCLUSIONS: Deep-vein thrombosis can be ruled out in a patient who is judged clinically unlikely to have deep-vein thrombosis and who has a negative D-dimer test. Ultrasound testing can be safely omitted in such patients.
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BACKGROUND: The limitations of the current diagnostic standard, ventilation-perfusion lung scanning, complicate the management of patients with suspected pulmonary embolism. We previously demonstrated that determining the pretest probability can assist with management and that the high negative predictive value of certain D -dimer assays may simplify the diagnostic process. OBJECTIVE: To determine the safety of using a simple clinical model combined with D -dimer assay to manage patients presenting to the emergency department with suspected pulmonary embolism. DESIGN: Prospective cohort study. SETTING: Emergency departments at four tertiary care hospitals in Canada. PATIENTS: 930 consecutive patients with suspected pulmonary embolism. INTERVENTIONS: Physicians first used a clinical model to determine patients' pretest probability of pulmonary embolism and then performed a D -dimer test. Patients with low pretest probability and a negative D -dimer result had no further tests and were considered to have a diagnosis of pulmonary embolism excluded. All other patients underwent ventilation-perfusion lung scanning. If the scan was nondiagnostic, bilateral deep venous ultrasonography was done. Whether further testing (by serial ultrasonography or angiography) was done depended on the patients' pretest probability and the lung scanning results. MEASUREMENTS: Patients received a diagnosis of pulmonary embolism if they had a high-probability ventilation-perfusion scan, an abnormal result on ultrasonography or pulmonary angiography, or a venous thromboembolic event during follow-up. Patients for whom the diagnosis was considered excluded were followed up for 3 months for the development of thromboembolic events. RESULTS: The pretest probability of pulmonary embolism was low, moderate, and high in 527, 339, and 64 patients (1.3%, 16.2%, and 37.5% had pulmonary embolism), respectively. Of 849 patients in whom a diagnosis of pulmonary-embolism had initially been excluded, 5 (0.6% [95% CI, 0.2% to 1.4%]) developed pulmonary embolism or deep venous thrombosis during follow-up. However, 4 of these patients had not undergone the proper diagnostic testing protocol. In 7 of the patients who received a diagnosis of pulmonary embolism, the physician had performed more diagnostic tests than were called for by the algorithm. In 759 of the 849 patients in whom pulmonary embolism was not found on initial evaluation, the diagnostic protocol was followed correctly. Only 1 (0.1% [CI, 0.0% to 0.7%]) of these 759 patients developed thromboembolic events during follow-up. Of the 437 patients with a negative D -dimer result and low clinical probability, only 1 developed pulmonary embolism during follow-up; thus, the negative predictive value for the combined strategy of using the clinical model with D -dimer testing in these patients was 99.5% (CI, 99.1% to 100%). CONCLUSION: Managing patients for suspected pulmonary embolism on the basis of pretest probability and D -dimer result is safe and decreases the need for diagnostic imaging.
T his is the second edition (version 1.2) of this document, which was originally adapted from Clinical management of severe acute respiratory infection when MERS-CoV infection is suspected (WHO, 2019).
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Importance: The Sepsis-3 Criteria emphasized the value of a change of 2 or more points in the Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, introduced quick SOFA (qSOFA), and removed the systemic inflammatory response syndrome (SIRS) criteria from the sepsis definition. Objective: Externally validate and assess the discriminatory capacities of an increase in SOFA score by 2 or more points, 2 or more SIRS criteria, or a qSOFA score of 2 or more points for outcomes among patients who are critically ill with suspected infection. Design, Setting, and Participants: Retrospective cohort analysis of 184 875 patients with an infection-related primary admission diagnosis in 182 Australian and New Zealand intensive care units (ICUs) from 2000 through 2015. Exposures: SOFA, qSOFA, and SIRS criteria applied to data collected within 24 hours of ICU admission. Main Outcomes and Measures: The primary outcome was in-hospital mortality. In-hospital mortality or ICU length of stay (LOS) of 3 days or more was a composite secondary outcome. Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC). Adjusted analyses were performed using a model of baseline risk determined using variables independent of the scoring systems. Results: Among 184 875 patients (mean age, 62.9 years [SD, 17.4]; women, 82 540 [44.6%]; most common diagnosis bacterial pneumonia, 32 634 [17.7%]), a total of 34 578 patients (18.7%) died in the hospital, and 102 976 patients (55.7%) died or experienced an ICU LOS of 3 days or more. SOFA score increased by 2 or more points in 90.1%; 86.7% manifested 2 or more SIRS criteria, and 54.4% had a qSOFA score of 2 or more points. SOFA demonstrated significantly greater discrimination for in-hospital mortality (crude AUROC, 0.753 [99% CI, 0.750-0.757]) than SIRS criteria (crude AUROC, 0.589 [99% CI, 0.585-0.593]) or qSOFA (crude AUROC, 0.607 [99% CI, 0.603-0.611]). Incremental improvements were 0.164 (99% CI, 0.159-0.169) for SOFA vs SIRS criteria and 0.146 (99% CI, 0.142-0.151) for SOFA vs qSOFA (P <.001). SOFA (AUROC, 0.736 [99% CI, 0.733-0.739]) outperformed the other scores for the secondary end point (SIRS criteria: AUROC, 0.609 [99% CI, 0.606-0.612]; qSOFA: AUROC, 0.606 [99% CI, 0.602-0.609]). Incremental improvements were 0.127 (99% CI, 0.123-0.131) for SOFA vs SIRS criteria and 0.131 (99% CI, 0.127-0.134) for SOFA vs qSOFA (P <.001). Findings were consistent for both outcomes in multiple sensitivity analyses. Conclusions and Relevance: Among adults with suspected infection admitted to an ICU, an increase in SOFA score of 2 or more had greater prognostic accuracy for in-hospital mortality than SIRS criteria or the qSOFA score. These findings suggest that SIRS criteria and qSOFA may have limited utility for predicting mortality in an ICU setting.
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The role of human cytochrome P-450 IIE1 (P-450 IIE1) in the oxidation of a number of suspect carcinogens was examined by using a variety of approaches, including (1) selective inhibition of catalytic activity in human liver microsomes by diethyldithiocarbamate, which was found to be a selective mechanism-based inactivator of P-450 IIE1, (2) correlation of rates of different catalytic activities with each other and with chlorzoxazone 6-hydroxylation, an indicator of P-450 IIE1, in human liver microsomes, (3) demonstration of catalytic activity in reconstituted systems containing purified human P-450 IIE1, and (4) immunoinhibition of catalytic activity in human liver microsomes with rabbit anti-human P-450 IIE1. The results collectively indicate that P-450 IIE1 is a major catalyst of the oxidation of benzene, styrene, CCl4, CHCl3, CH2Cl2, CH3Cl, CH3CCl3, 1,2-dichloropropane, ethylene dichloride, ethylene dibromide, vinyl chloride, vinyl bromide, acrylonitrile, vinyl carbamate, ethyl carbamate, and trichloroethylene. Levels of P-450 IIE1 can vary considerably among individual humans--the availability of chlorzoxazone as a noninvasive probe of human P-450 IIE1 and of disulfiram (oxidized diethyldithiocarbamate) as an inhibitor may facilitate discernment of the in vivo significance of human P-450 IIE1 as a factor in the bioactivation and detoxication of these cancer suspects. Further, many investigations with diethyldithiocarbamate, disulfiram, and ethanol in humans and experimental animals may be interpreted in light of mechanisms involving P-450 IIE1.
CONTEXT: Previous studies have evaluated the safety of relatively complex combinations of clinical decision rules and diagnostic tests in patients with suspected pulmonary embolism. OBJECTIVE: To assess the clinical effectiveness of a simplified algorithm using a dichotomized clinical decision rule, D-dimer testing, and computed tomography (CT) in patients with suspected pulmonary embolism. DESIGN, SETTING, AND PATIENTS: Prospective cohort study of consecutive patients with clinically suspected acute pulmonary embolism, conducted in 12 centers in the Netherlands from November 2002 through December 2004. The study population of 3306 patients included 82% outpatients and 57% women. INTERVENTIONS: Patients were categorized as "pulmonary embolism unlikely" or "pulmonary embolism likely" using a dichotomized version of the Wells clinical decision rule. Patients classified as unlikely had D-dimer testing, and pulmonary embolism was considered excluded if the D-dimer test result was normal. All other patients underwent CT, and pulmonary embolism was considered present or excluded based on the results. Anticoagulants were withheld from patients classified as excluded, and all patients were followed up for 3 months. MAIN OUTCOME MEASURE: Symptomatic or fatal venous thromboembolism (VTE) during 3-month follow-up. RESULTS: Pulmonary embolism was classified as unlikely in 2206 patients (66.7%). The combination of pulmonary embolism unlikely and a normal D-dimer test result occurred in 1057 patients (32.0%), of whom 1028 were not treated with anticoagulants; subsequent nonfatal VTE occurred in 5 patients (0.5% [95% confidence interval {CI}, 0.2%-1.1%]). Computed tomography showed pulmonary embolism in 674 patients (20.4%). Computed tomography excluded pulmonary embolism in 1505 patients, of whom 1436 patients were not treated with anticoagulants; in these patients the 3-month incidence of VTE was 1.3% (95% CI, 0.7%-2.0%). Pulmonary embolism was considered a possible cause of death in 7 patients after a negative CT scan (0.5% [95% CI, 0.2%-1.0%]). The algorithm was completed and allowed a management decision in 97.9% of patients. CONCLUSIONS: A diagnostic management strategy using a simple clinical decision rule, D-dimer testing, and CT is effective in the evaluation and management of patients with clinically suspected pulmonary embolism. Its use is associated with low risk for subsequent fatal and nonfatal VTE.
BACKGROUND: The benefit of CT coronary angiography (CTCA) in patients presenting with stable chest pain has not been systematically studied. We aimed to assess the effect of CTCA on the diagnosis, management, and outcome of patients referred to the cardiology clinic with suspected angina due to coronary heart disease. METHODS: In this prospective open-label, parallel-group, multicentre trial, we recruited patients aged 18-75 years referred for the assessment of suspected angina due to coronary heart disease from 12 cardiology chest pain clinics across Scotland. We randomly assigned (1:1) participants to standard care plus CTCA or standard care alone. Randomisation was done with a web-based service to ensure allocation concealment. The primary endpoint was certainty of the diagnosis of angina secondary to coronary heart disease at 6 weeks. All analyses were intention to treat, and patients were analysed in the group they were allocated to, irrespective of compliance with scanning. This study is registered with ClinicalTrials.gov, number NCT01149590. FINDINGS: Between Nov 18, 2010, and Sept 24, 2014, we randomly assigned 4146 (42%) of 9849 patients who had been referred for assessment of suspected angina due to coronary heart disease. 47% of participants had a baseline clinic diagnosis of coronary heart disease and 36% had angina due to coronary heart disease. At 6 weeks, CTCA reclassified the diagnosis of coronary heart disease in 558 (27%) patients and the diagnosis of angina due to coronary heart disease in 481 (23%) patients (standard care 22 [1%] and 23 [1%]; p<0·0001). Although both the certainty (relative risk [RR] 2·56, 95% CI 2·33-2·79; p<0·0001) and frequency of coronary heart disease increased (1·09, 1·02-1·17; p=0·0172), the certainty increased (1·79, 1·62-1·96; p<0·0001) and frequency seemed to decrease (0·93, 0·85-1·02; p=0·1289) for the diagnosis of angina due to coronary heart disease. This changed planned investigations (15% vs 1%; p<0·0001) and treatments (23% vs 5%; p<0·0001) but did not affect 6-week symptom severity or subsequent admittances to hospital for chest pain. After 1·7 years, CTCA was associated with a 38% reduction in fatal and non-fatal myocardial infarction (26 vs 42, HR 0·62, 95% CI 0·38-1·01; p=0·0527), but this was not significant. INTERPRETATION: In patients with suspected angina due to coronary heart disease, CTCA clarifies the diagnosis, enables targeting of interventions, and might reduce the future risk of myocardial infarction. FUNDING: The Chief Scientist Office of the Scottish Government Health and Social Care Directorates funded the trial with supplementary awards from Edinburgh and Lothian's Health Foundation Trust and the Heart Diseases Research Fund.
The removal of the acute appendix is one of the most frequently performed surgical procedures. Open surgery associated with therapeutic efficacy has been the treatment of choice for acute appendicitis. However, in consequence of the evolution of endoscopic surgery, the operation can also be performed with minimally invasive surgery. Due to smaller incisions, the laparoscopic approach may be associated with reduced postoperative pain, reduced wound infection rate, and shorter time until return to normal activity.This is an update of the review published in 2010.
BACKGROUND: The low specificity of ventilation-perfusion lung scanning complicates the management of patients with suspected pulmonary embolism. OBJECTIVE: To determine the safety of a clinical model for patients with suspected pulmonary embolism. DESIGN: Prospective cohort study. SETTING: Five tertiary care hospitals. PATIENTS: 1239 inpatients and outpatients with suspected pulmonary embolism. INTERVENTIONS: A clinical model categorized pretest probability of pulmonary embolism as low, moderate, or high, and ventilation-perfusion scanning and bilateral deep venous ultrasonography were done. Testing by serial ultrasonography, venography, or angiography depended on pretest probability and lung scans. MEASUREMENTS: Patients were considered positive for pulmonary embolism if they had an abnormal pulmonary angiogram, abnormal ultrasonogram or venogram, high-probability ventilation-perfusion scan plus moderate or high pretest probability, or venous thromboembolic event during the 3-month follow-up. All other patients were considered negative for pulmonary embolism. Rates of pulmonary embolism during follow-up in patients who had a normal lung scan and those with a non-high-probability scan and normal serial ultrasonogram were compared. RESULTS: Pretest probability was low in 734 patients (3.4% with pulmonary embolism), moderate in 403 (27.8% with pulmonary embolism), and high in 102 (78.4% with pulmonary embolism). Three of the 665 patients (0.5% [95% CI, 0.1% to 1.3%]) with low or moderate pretest probability and a non-high-probability scan who were considered negative for pulmonary embolism had pulmonary embolism or deep venous thrombosis during 90-day follow-up; this rate did not differ from that in patients with a normal scan (0.6% [CI, 0.1% to 1.8%]; P > 0.2). CONCLUSION: Management of patients with suspected pulmonary embolism on the basis of pretest probability and results of ventilation-perfusion scanning is safe.
BACKGROUND: Myocardial infarction with nonobstructive coronary arteries (MINOCA) is a puzzling clinical entity with no previous evaluation of the literature. This systematic review aims to (1) quantify the prevalence, risk factors, and 12-month prognosis in patients with MINOCA, and (2) evaluate potential pathophysiological mechanisms underlying this disorder. METHODS AND RESULTS: Quantitative assessment of 28 publications using a meta-analytic approach evaluated the prevalence, clinical features, and prognosis of MINOCA. The prevalence of MINOCA was 6% [95% confidence interval, 5%-7%] with a median patient age of 55 years (95% confidence interval, 51-59 years) and 40% women. However, in comparison with those with myocardial infarction associated with obstructive coronary artery disease, the patients with MINOCA were more likely to be younger and female but less likely to have hyperlipidemia, although other cardiovascular risk factors were similar. All-cause mortality at 12 months was lower in MINOCA (4.7%; 95% confidence interval, 2.6%-6.9%) compared with myocardial infarction associated with obstructive coronary artery disease (6.7%, 95% confidence interval, 4.3%-9.0%). Qualitative assessment of 46 publications evaluating the underlying pathophysiology responsible for MINOCA revealed the presence of a typical myocardial infarct on cardiac magnetic resonance imaging in only 24% of patients, with myocarditis occurring in 33% and no significant abnormality in 26%. Coronary artery spasm was inducible in 27% of MINOCA patients, and thrombophilia disorders were detected in 14%. CONCLUSIONS: MINOCA should be considered as a working diagnosis with multiple potential causes that require evaluation so that directed therapies may improve its guarded prognosis.