Derivation and External Validation of the Ottawa Bloodstream Infection Model for Acutely Ill Adults.

BACKGROUND: Knowing the probability that patients have a bloodstream infection (BSI) could influence the ordering of blood cultures and interpretation of their preliminary results. Many previous BSI probability models have limited applicability and accuracy. This study used currently recommended modeling techniques and a large sample to derive and validate the Ottawa BSI Model. METHODS: At a tertiary care teaching hospital, we retrieved a random sample of 4180 adults having blood cultures in our emergency department or during the initial 48 h of the encounter. Variable selection was based on clinical experience and a systematic review of previous model performance. Model performance was measured in a temporal external validation group of 4680 patients. RESULTS: A total of 327 derivation patients had a BSI (8.0%). BSI risk increased with increased number of culture sets (2 sets: adjusted odds ratio [aOR] 1.52 [1.10-2.11]; 3 sets: 1.99 [0.86-4.58]); with indwelling catheter (aOR 2.07 [1.34-3.20); with increasing temperature, heart rate, and neutrophil-lymphocyte ratio; and with decreasing systolic blood pressure, platelet count, urea-creatinine ratio, and estimated glomerular filtration rate. In the temporal external validation group, model discrimination was good (c-statistic 0.71 [0.69-0.74]) and calibration was very good (integrated calibration index .016 [.010-.024]). Exclusion of validation patients with acute SARS-CoV-2 infection improved discrimination slightly (c-statistic 0.73 [0.69-0.76]). CONCLUSIONS: The Ottawa BSI Model uses commonly available data to return an expected BSI probability for acutely ill patients. However, it cannot exclude BSI and its complexity requires computational assistance to use.

Concurrent external validation of bloodstream infection probability models.

OBJECTIVE: Accurately estimating the likelihood of bloodstream infection (BSI) can help clinicians make diagnostic and therapeutic decisions. Many multivariate models predicting BSI probability have been published. This study measured the performance of BSI probability models within the same patient sample. METHODS: We retrieved validated BSI probability models included in a recently published systematic review that returned a patient-level BSI probability for adults. Model applicability, discrimination, and accuracy was measured in a simple random sample of 4485 admitted adults having blood cultures ordered in the emergency department or the initial 48 hours of hospitalization. RESULTS: Ten models were included (publication years 1991-2015). Common methodological threats to model performance included overfitting and continuous variable categorization. Restrictive inclusion criteria caused seven models to apply to <15% of validation patients. Model discrimination was less than originally reported in derivation groups (median c-statistic 60%, range 48-69). The observed BSI risk frequently deviated from expected (median integrated calibration index 4.0%, range 0.8-12.4). Notable disagreement in expected BSI probabilities was seen between models (median (25th-75th percentile) relative difference between expected risks 68.0% (28.6-113.6%)). DISCUSSION: In a large randomly selected external validation population, many published BSI probability models had restricted applicability, limited discrimination and calibration, and extensive inter-model disagreement. Direct comparison of model performance is hampered by dissimilarities between model-specific validation groups.

Quantifying Utilitarian Outcomes to Inform Triage Ethics: Simulated Performance of a Ventilator Triage Protocol under Sars-CoV-2 Pandemic Surge Conditions.

BACKGROUND: Equitable protocols to triage life-saving resources must be specified prior to shortages in order to promote transparency, trust and consistency. How well proposed utilitarian protocols perform to maximize lives saved is unknown. We aimed to estimate the survival rates that would be associated with implementation of the New York State 2015 guidelines for ventilator triage, and to compare them to a first-come-first-served triage method. METHODS: We constructed a simulation model based on a modified version of the New York State 2015 guidelines compared to a first-come-first-served method under various hypothetical ventilator shortages. We included patients with SARs-CoV-2 infection admitted with respiratory failure requiring mechanical ventilation to three acute care hospitals in New York from 3/01/2020 and 5/27/2020. We estimated (1) survival rates, (2) number of excess deaths, (3) number of patients extubated early or not allocated a ventilator due to capacity constraints, (4) survival rates among patients not allocated a ventilator at triage or extubated early due to capacity constraints. RESULTS: 807 patients were included in the study. The simulation model based on a modified New York State policy did not decrease mortality, excess death or exclusion from ventilators compared to the first-come-first-served policy at every ventilator capacity we tested using COVID-19 surge cohort patients. Survival rates were similar at all the survival probabilities estimated. At the lowest ventilator capacity, the modified New York State policy has an estimated survival of 28.5% (CI: 28.4-28.6), compared to 28.1% (CI: 27.7-28.5) for the first-come-first-served policy. CONCLUSIONS: This simulation of a modified New York State guideline-based triage protocol revealed limitations in achieving the utilitarian goals these protocols are designed to fulfill. Quantifying these outcomes can inform a better balance among competing moral aims.

Evaluation of Vaccine Safety After the First Public Sector Introduction of Typhoid Conjugate Vaccine-Navi Mumbai, India, 2018.

BACKGROUND: In December 2017, the World Health Organization (WHO) prequalified the first typhoid conjugate vaccine (TCV; Typbar-TCV). While no safety concerns were identified in pre- and postlicensure studies, WHO's Global Advisory Committee on Vaccine Safety recommended robust safety evaluation with large-scale TCV introductions. During July-August 2018, the Navi Mumbai Municipal Corporation (NMMC) launched the world's first public sector TCV introduction. Per administrative reports, 113 420 children 9 months-14 years old received TCV. METHODS: We evaluated adverse events following immunization (AEFIs) using passive and active surveillance via (1) reports from the passive NMMC AEFI surveillance system, (2) telephone interviews with 5% of caregivers of vaccine recipients 48 hours and 7 days postvaccination, and (3) chart abstraction for adverse events of special interest (AESIs) among patients admitted to 5 hospitals using the Brighton Collaboration criteria followed by ascertainment of vaccination status. RESULTS: We identified 222/113 420 (0.2%) vaccine recipients with AEFIs through the NMMC AEFI surveillance system: 211 (0.19%) experienced minor AEFIs, 2 (0.002%) severe, and 9 serious (0.008%). At 48 hours postvaccination, 1852/5605 (33%) caregivers reported ≥1 AEFI, including injection site pain (n = 1452, 26%), swelling (n = 419, 7.5%), and fever (n = 416, 7.4%). Of the 4728 interviews completed at 7 days postvaccination, the most reported AEFIs included fever (n = 200, 4%), pain (n = 52, 1%), and headache (n = 42, 1%). Among 525 hospitalized children diagnosed with an AESI, 60 were vaccinated; no AESIs were causally associated with TCV. CONCLUSIONS: No unexpected safety signals were identified with TCV introduction. This provides further reassurance for the large-scale use of Typbar-TCV among children 9 months-14 years old.

Scleraxis as a prognostic marker of myocardial fibrosis in hypertrophic cardiomyopathy (SPARC) study.

Interstitial fibrosis is a histopathological hallmark of hypertrophic cardiomyopathy (HCM). Although extracellular matrix (ECM) biomarkers, including matrix metalloproteinases, are overexpressed in HCM patients, they do not correlate with sudden cardiac death (SCD) risk. The objective of this study was to determine whether scleraxis, a transcription factor that regulates collagen gene expression, is detectable in HCM patients and correlates with disease burden. Between 2017 and 2018, a total of 46 HCM patients were enrolled (58 ± 14 years (31 males, 15 females)) with a mean 5 year SCD risk of 2.3% ± 1.3%. Cardiac MRI confirmed HCM in all patients with a mean interventricular septal thickness of 20 ± 2 mm. Late gadolinium enhancement (LGE) was present in 32 (70%) study participants occupying 18% ± 7% of the left ventricular (LV) myocardium. Serum scleraxis levels were significantly higher in the HCM patients by approximately twofold as compared to controls (0.76 ± 0.06 versus 0.32 ± 0.02 ng/mL, p < 0.05). No correlation was demonstrated between serum scleraxis levels and markers of disease severity in HCM patients, including maximum LV wall thickness, %LGE, and SCD risk factors. Serum scleraxis is elevated in the HCM population. Future studies are warranted to evaluate the prognostic value of scleraxis in identifying high-risk HCM patients who require aggressive management for prevention of SCD.

Role of renin-angiotensin system antagonists in the prevention of bevacizumab- and sunitinib-mediated cardiac dysfunction.

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg-1·wk-1), or 3) SNT (40 mg·kg-1·day-1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

The Cardioprotective Role of N-Acetyl Cysteine Amide in the Prevention of Doxorubicin and Trastuzumab-Mediated Cardiac Dysfunction.

BACKGROUND: In the breast cancer setting, anticancer therapies including doxorubicin (DOX) and trastuzumab (TRZ) are associated with a significantly increased risk of cardiotoxicity. Despite the increasing support for the role of oxidative stress (OS) in its pathophysiology, we still do not have an optimal antioxidant for the prevention of DOX + TRZ-mediated cardiac dysfunction. The objective of this study was to investigate whether the novel antioxidant N-acetylcysteine amide (NACA) can attenuate DOX + TRZ-induced heart failure in a murine model. METHODS: A total of 100 C57Bl/6 female mice received 1 of the following drug regimens: (1) saline, (2) NACA, (3) DOX, (4) TRZ, (5) DOX + TRZ, (6) NACA + DOX, (7) NACA + TRZ, and (8) NACA + DOX + TRZ. Serial echocardiography was performed over a 10-day study period, after which the mice were killed for histologic and biochemical analyses. RESULTS: In mice receiving DOX, the left ventricular ejection fraction (LVEF) decreased from 73% ± 4% to 43% ± 2% on day 10. In mice receiving DOX + TRZ, the LVEF decreased from 72% ± 3% to 32% ± 2% on day 10. Prophylactic administration of NACA to mice receiving DOX or DOX + TRZ was cardioprotective, with an LVEF of 62% ± 3% and 55% ± 3% on day 10, respectively. Histologic and biochemical analyses demonstrated a loss of cellular integrity, increased OS, and increased cardiac apoptosis in mice treated with DOX + TRZ, which was attenuated by the prophylactic administration of NACA. CONCLUSIONS: NACA attenuated the cardiotoxic side effects of DOX + TRZ in a murine model of chemotherapy-induced cardiac dysfunction by decreasing OS and apoptosis.

Pathophysiology and prevention of sudden cardiac death.

Sudden cardiac death (SCD) is known to occur in individuals with diverse diseases. Each disease state has a specific etiology and pathophysiology, and is diagnosed and treated differently. Etiologies for SCD include cardiac arrhythmias, coronary artery disease, congenital coronary artery anomalies, hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, and aortic valve stenosis. A potential unifying mechanism of SCD in these diseases involves a massive stimulation of the sympathetic nervous system's stress response and the subsequent elevation of circulating catecholamines. The diagnosis of cardiac diseases that contribute to an increased risk for SCD is accomplished by a combination of different techniques including electrocardiography, echocardiography, magnetic resonance imaging, and invasive cardiac catheterization. Several therapies including anti-arrhythmic drugs, ß-blockers, and antiplatelet agents may be used as medical treatment in patients for the prevention of SCD. Invasive therapies including percutaneous angioplasty, coronary artery bypass surgery, and implantable cardioverter-defibrillators are also used in the clinical management of SCD.

The utility of cardiac biomarkers and echocardiography for the early detection of bevacizumab- and sunitinib-mediated cardiotoxicity.

The recent introduction of novel anticancer therapies, including bevacizumab (BVZ) and sunitinib (SNT), is associated with an increased risk of cardiotoxicity. However, early identification of left ventricular (LV) systolic dysfunction may facilitate dose modification and avoid the development of advanced heart failure. Using a murine model of BVZ- and SNT-mediated cardiotoxicity, we investigated whether cardiac biomarkers and/or tissue velocity imaging (TVI) using echocardiography can detect early changes in cardiac function, before a decrease in LV ejection fraction is identified. A total of 75 wild-type C57Bl/6 male mice were treated with either 0.9% saline, BVZ, or SNT. Serial monitoring of blood pressure, high-sensitivity troponin I, and echocardiographic indexes were performed over a 14-day study period, after which the mice were euthanized for histological and biochemical analyses. Mice treated with either BVZ or SNT developed systemic hypertension as early as day 7, which increased by day 14. Cardiac biomarkers, specifically high-sensitivity troponin I, were not predictive of early LV systolic dysfunction. Although conventional LV ejection fraction values decreased at day 13 in mice treated with either BVZ or SNT, TVI confirmed early LV systolic dysfunction at day 8. Histological and biochemical analysis demonstrated loss of cellular integrity, increased oxidative stress, and increased cardiac apoptosis in mice treated with BVZ or SNT therapy at day 14. In a murine model of BVZ- or SNT-mediated cardiomyopathy, noninvasive assessment by TVI detected early LV systolic dysfunction before alterations in conventional echocardiographic indexes.

The role of renin angiotensin system antagonists in the prevention of doxorubicin and trastuzumab induced cardiotoxicity.

BACKGROUND: Cardio-Oncology is an evolving discipline that focuses on the management of cancer patients who develop cardiovascular complications as a result of their treatment. Although the current combination of surgical resection, radiation, and chemotherapy may lead to a cure in cancer patients, the administration of anti-cancer drugs, in particular Doxorubicin (DOX) and Trastuzumab (TRZ), is associated with an increased risk of cardiotoxicity. Little is known on the potential cardioprotective role of renin angiotensin system (RAS) antagonists in the prevention of DOX+TRZ mediated cardiotoxicity. OBJECTIVE: The aim of the study was to determine whether RAS antagonists would be useful in attenuating DOX+TRZ induced cardiotoxicity. METHODS: A total of 240 C57Bl/6 mice were randomized to prophylactic treatment with placebo, Aliskiren, Perindopril, or Valsartan for a total of 13 weeks. Within each arm, mice received treatment with either DOX, TRZ, or the combination of both drugs. Serial murine echocardiography was performed weekly to characterize the degree of cardiovascular remodeling within each group. RESULTS: In wild-type (WT) mice treated with DOX+TRZ, LV end diastolic internal diameter (LVID) increased from 3.1 ± 0.2 mm at baseline to 4.6 ± 0.3 mm at week 13 (p < 0.05) and the LV fractional shortening (FS) decreased from 52 ± 2% at baseline to 26 ± 2% at week 13 (p < 0.05). Prophylactic treatment with Aliskiren, Perindopril, or Valsartan attenuated the degree of LV cavity dilatation with LVID dimensions of 3.9 ± 0.2 mm, 4.1 ± 0.2 mm, and 4.2 ± 0.1 mm at week 13, respectively (p < 0.05). Similarly, prophylactic treatment with Aliskiren, Perindopril, or Valsartan was partially cardioprotective with FS of 40 ± 1%, 32 ± 1%, and 33 ± 2% at week 13, respectively (p < 0.05). As compared to WT mice receiving DOX+TRZ, prophylactic treatment with RAS inhibition was also associated with improved survival, corroborating the echocardiographic findings. CONCLUSION: The cardiotoxic effects of DOX+TRZ were partially attenuated by the prophylactic administration of RAS antagonists in a chronic murine model of chemotherapy induced cardiac dysfunction.

Multimodality cardiac imaging of a left ventricular thrombus: a case report.

BACKGROUND: Left ventricular thrombus (LVT) formation occasionally complicates patient recovery post myocardial infarction, conveying a significant risk of systemic embolism. Accordingly, thrombus detection and subsequent anticoagulation is imperative in order to minimize patient morbidity and mortality. Transthoracic echocardiography (TTE) is the imaging modality most widely used to screen for thrombus formation despite its suboptimal sensitivity and specificity. CASE PRESENTATION: This report describes the discordant imaging findings of a LVT in a 56 year old Caucasian male with an anterior ST elevation myocardial infarction. Left ventriculography revealed a filling defect, suggestive of a potential left ventricular (LV) thrombus, which could not be confirmed by TTE. Cardiac magnetic resonance imaging (MRI) demonstrated evidence of a full thickness scar involving the mid to distal anterior wall and apical regions, with confirmation of a small LV apical thrombus. CONCLUSIONS: This case illustrates the limitations of TTE when used as a tool to screen for thrombus formation. It highlights the importance of multimodality cardiac imaging for the detection of post myocardial infarction (MI) complications, in the context of a high clinical suspicion.

Catching broken hearts: pre-clinical detection of doxorubicin and trastuzumab mediated cardiac dysfunction in the breast cancer setting.

Although breast cancer is one of the leading causes of death in women worldwide, there is an overall improvement in the survival of this patient population. This is likely due to a combination of early detection through screening and awareness, improved targeted biological therapy, and an overall improvement in disease management. Despite the beneficial effects of the 2 anti-cancer drugs doxorubicin (DOX) and trastuzumab (TRZ) in women with breast cancer, development of cardiotoxicity is a major concern. The occurrence of left ventricular systolic dysfunction is unacceptably high in nearly 1 in 4 women treated with DOX+TRZ in the breast cancer setting. In this review, we explore the use of non-invasive cardiac imaging for the early detection of chemotherapy-mediated cardiotoxicity in women with breast cancer, in the hope of preventing end-stage heart disease in this cancer population.

Clinical-Epidemiological Profile of Influenza A H1N1 Cases at a Tertiary Care Institute of India.

INTRODUCTION: Influenza virus is a common human pathogen that has caused serious respiratory illness and death over the past century. In April 2009, a new strain of Influenza virus A H1N1, commonly referred to as "swine flu", began to spread in several countries around the world, and India confirmed its first case on 16 May 16 2009. AIM: To study the clinical and epidemiological profile of Influenza A H1N1 cases at the Government Medical College and Hospital, Chandigarh. MATERIALS AND METHODS: Clinical epidemiological characteristics of Influenza A H1N1 cases from May 2009 to April 2010 were retrospectively, descriptively analyzed using data from the Influenza A H1N1 screening center and isolation ward at the Government Medical College and Hospital, Chandigarh. Data were Analyzed using MS Excel software. RESULTS: At GMCH, till April 2010, a total of 4379 patients were screened for Influenza A H1N1, of which 365 patients were tested. The most common symptoms were fever (87.6%), cough (49.77%), sore throat (27%) and breathlessness (23.9%). The most common presentation (42.30%) of Influenza A H1N1 cases was fever and cold-like features, not cough. 29.58% (108) of the tested patients were found to be positive for the disease. Maximum cases were detected in the month of December, and the patients less than 40 years of age accounted for 81.4% (44 cases) of the cases. Influenza A H1N1 resulted in death of 54.9% (28) of the admitted cases, of which 46% (12) deaths occurred within 48 h of admission. CONCLUSION: On the basis of these findings, it can be safely hypothesized that prevalence of Influenza A H1N1 is high in the younger population, and fever, cough and sore throat are the most common symptoms with which the patients usually present.