Acquisition of suppressive function by conventional T cells limits antitumor immunity upon Treg depletion.

Regulatory T (Treg) cells contribute to immune homeostasis but suppress immune responses to cancer. Strategies to disrupt Treg cell-mediated cancer immunosuppression have been met with limited clinical success, but the underlying mechanisms for treatment failure are poorly understood. By modeling Treg cell-targeted immunotherapy in mice, we find that CD4+ Foxp3- conventional T (Tconv) cells acquire suppressive function upon depletion of Foxp3+ Treg cells, limiting therapeutic efficacy. Foxp3- Tconv cells within tumors adopt a Treg cell-like transcriptional profile upon ablation of Treg cells and acquire the ability to suppress T cell activation and proliferation ex vivo. Suppressive activity is enriched among CD4+ Tconv cells marked by expression of C-C motif receptor 8 (CCR8), which are found in mouse and human tumors. Upon Treg cell depletion, CCR8+ Tconv cells undergo systemic and intratumoral activation and expansion, and mediate IL-10-dependent suppression of antitumor immunity. Consequently, conditional deletion of Il10 within T cells augments antitumor immunity upon Treg cell depletion in mice, and antibody blockade of IL-10 signaling synergizes with Treg cell depletion to overcome treatment resistance. These findings reveal a secondary layer of immunosuppression by Tconv cells released upon therapeutic Treg cell depletion and suggest that broader consideration of suppressive function within the T cell lineage is required for development of effective Treg cell-targeted therapies.

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.

Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Rα with higher affinity, triggers STAT5 activation, and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.

Clinical and Virological Response to Convalescent Plasma in a Chronic Lymphocytic Leukemia Patient with COVID-19 Pneumonia.

The burden of COVID-19 remains unchanged for immunocompromised patients who do not respond to vaccines. Unfortunately, Omicron sublineages are resistant to monoclonal antibodies authorized in Europe so far, and small chemical antivirals have contraindications and toxicities that have not been studied in these patients. We report here the successful treatment of COVID-19 pneumonia lasting for 4 months after the transfusion of COVID-19 convalescent plasma (CCP) in a patient with severe immunosuppression due to both chronic lymphocytic leukemia and venetoclax treatment. The patient achieved a complete clinical, radiological and virological response after six transfusions (600 mL each) of high-titer CCP collected from triple-vaccinated and convalescent donors. This dramatic case adds to the mounting evidence of CCP efficacy in immunocompromised patients, provided that high-titer and large volumes are infused.

CCR8 marks highly suppressive Treg cells within tumours but is dispensable for their accumulation and suppressive function.

CD4+ regulatory T (Treg) cells, dependent upon the transcription factor Foxp3, contribute to tumour immunosuppression but are also required for immune homeostasis. There is interest in developing therapies that selectively target the immunosuppressive function of Treg cells within tumours without disrupting their systemic anti-inflammatory function. High levels of expression of chemokine (C-C motif) receptor 8 (CCR8) discriminate Treg cells within tumours from those found in systemic lymphoid tissues. It has recently been proposed that disruption of CCR8 function using blocking anti-CCR8 antibodies results in reduced accumulation of Treg cells within tumours and disruption of their immunosuppressive function. Here, using Ccr8-/- mice, we show that CCR8 function is not required for Treg cell accumulation or immunosuppression in the context of syngeneic MC38 colorectal adenocarcinoma and B16 melanoma tumours. We observed high levels of CCR8 expression on tumour-infiltrating Treg cells which were abolished in Ccr8-/- mice. High levels of CCR8 marked cells with high levels of suppressive function. However, whereas systemic ablation of Treg cells resulted in strikingly diminished tumour burden, growth of subcutaneously implanted tumours was unaffected by systemic CCR8 loss. Consistently, we observed minimal impact of systemic CCR8 ablation on the frequency, phenotype and function of tumour-infiltrating Treg cells and conventional T (Tconv) function. These findings suggest that CCR8 is not required for Treg cell accumulation and immunosuppressive function within tumours and that depletion of CCR8+ Treg cells rather than blockade of CCR8 function is a more promising avenue for selective immunotherapy.

Definition of major bleeding: Prognostic classification.

BACKGROUND: In patients on anticoagulant treatment, the major bleeding (MB) definition released by the International Society of Thrombosis and Haemostasis (ISTH) is widely accepted. However, this definition identifies MBs with highly variable short-term risk of death. OBJECTIVES: The study aims were to derive and validate a classification of ISTH-defined MBs for the risk of short-term death. METHODS: Consecutive patients admitted for ISTH-defined MB occurring while on treatment with oral anticoagulants were included in the study and divided into a derivation and a validation cohort. Death within 30 days was the primary study outcome. RESULTS: Among 1077 patients with MB, 64/517 and 63/560 patients in the derivation and validation cohort died, respectively. In the derivation cohort, Glasgow coma scale (GCS) <14 and shock were predictors of death; critical site bleeding and hemoglobin decrease ≥2 g/dL, or transfusion ≥ 2 units were not. GCS <14 (hazard ratio [HR], 8.67; 95% confidence interval [CI], 3.93-19.13) was predictor of death in intracranial hemorrhage (ICH) and shock at admission (HR, 4.84; 95% CI, 2.01-11.70) and pericardial bleeding (HR, 11.37; 95% CI, 1.33-97.31) in non-ICH MBs. The predictive value of GCS <14 in ICH and shock and pericardial bleeding in non-ICH MBs was confirmed in the validation cohort. None of the patients with isolated ocular or articular bleeding died. A prognostic classification of ISTH-defined MBs for the risk of short-term death is proposed as "serious," "severe," and "life-threatening" (ICH with GCS <14 or non-ICH with shock) MBs. CONCLUSION: According to our study, ISTH-defined MBs can be stratified for the risk of death within 30 days.

Bleeding Events in Patients 75 Years of Age and Older Under Long-term Anticoagulant Therapy: A Real-life Study.

OBJECTIVE: To investigate the risk of bleeding events in older patients under oral anticoagulant with a 4-year survey of a catchment area with 197,722 inhabitants of whom 15,267 were on warfarin and 10,397 on direct oral anticoagulants (DOACs). METHODS: Patients presented to the Emergency Department with major bleeding were enrolled and stratified according to age ≥75 years and ongoing warfarin or DOACs. Primary endpoint was 1-month death. RESULTS: Out of 1919 major bleeding, those of patients ≥75 years of age were 1127 (59%) versus 792 (41%) <75 years of age, P < 0.0001. In patients ≥75 years of age, brain hemorrhage accounted for 612 (54%) patients, gastrointestinal hemorrhage for 301 (27%), hematuria for 104 (9%), and other hemorrhage for 108 (10%). In patients ≥75 years of age, those on warfarin accounted for 175 versus 53 on DOACs, without difference of Charlson Comorbidity Index (5.25 ± 1.92 versus 5.09 ± 1.61; P = 0.5824). One-month death in patients ≥75 of age versus <75 years of age accounted for 77 (4.0%) versus 20 (1.0%); P < 0.0001. One-month death in patients ≥75 of age on DOACs was very low, without difference versus <75 years and within DOACs. Among DOACs, absolute bleeding events showed differences as follows: 3 bleeding events for edoxaban versus 21 for dabigatran; P < 0.001; versus 16 for rivaroxaban, P = 0.006; and versus 13 for apixaban, P = 0.02. CONCLUSIONS: Major bleeding and 1-month death accounted for higher percentage in patients ≥75 years of age and in patients receiving warfarin. Among DOACs, edoxaban presented the lowest absolute rate of hemorrhage among the 4 available DOACs, without difference in mortality.

Role of Hypertension and Other Clinical Variables in Prognostication of Patients Presenting to the Emergency Department With Major Bleeding Events.

BACKGROUND: Clinical variables including hypertension could be linked with major bleeding events and death beyond vitamin K antagonist (warfarin) or direct oral anti-coagulants (DOACs) treatment strategy. METHODS: Subgroup analysis of major bleeding (primary endpoint) associated with clinical variables, site of bleeding, ongoing antithrombotics, reversal treatment or blood transfusion, outcomes (secondary endpoints) was performed in patients with bleeding events submitted to hard 5:1 propensity-score matching for hypertension. RESULTS: Enrolled patients were 2,792 (mean age, 65.6 ± 19.9 years) during 2-year survey including 166,000 visits, of 200,000 inhabitants catchment area; 8,239 patients received warfarin and 3,797 DOACs. Hypertension account for 1,077 (39%) patients; major bleeding for 474 (17%); death for 29 (1%), and 72 (3%) on 1-month and 1-year, respectively. Hypertension, age, glucose, cancer, ischemic vascular disease, and CHA2D2VASc score were more likely to link with major bleeding. On multivariate analysis, only age (odds ratio [OR], 1.02; P < 0.001), CHA2DS2VASc score ≥ 2 (OR, 2.14; P = 0.001), and glucose (OR, 1.01; P = 0.005) were predictors of major bleeding. Kaplan-Meier analysis demonstrated patients with hypertension as compared with patients without showed 60% versus 20% death on 1-month (P < 0.001). Warfarin compared with DOACs was more likely to present with major bleeding (0.7% versus 0.2%; OR, 2.8; P = 0.005). Receiver operator characteristics analysis showed high value (0.61) of age and glucose over creatinine and systolic arterial pressure (P = NS). CONCLUSIONS: Four in 10 patients with major bleeding showed hypertension; of these 8 in 10 will die within 1 month. Warfarin compared with DOACs was more likely to present with major bleeding.

SOFA score in septic patients: incremental prognostic value over age, comorbidities, and parameters of sepsis severity.

Several widely used scoring systems for septic patients have been validated in an ICU setting, and may not be appropriate for other settings like Emergency Departments (ED) or High-Dependency Units (HDU), where a relevant number of these patients are managed. The purpose of this study is to find reliable tools for prognostic assessment of septic patients managed in an ED-HDU. In 742 patients diagnosed with sepsis/severe sepsis/septic shock, not-intubated, admitted in ED between June 2008 and April 2016, SOFA, qSOFA, PIRO, MEWS, Charlson Comorbidity Index, MEDS, and APACHE II were calculated at ED admission (T0); SOFA and MEWS were also calculated after 24 h of ED-High-Dependency Unit stay (T1). Discrimination and incremental prognostic value of SOFA score over demographic data and parameters of sepsis severity were tested. Primary outcome is 28-day mortality. Twenty-eight day mortality rate is 31%. The different scores show a modest-to-moderate discrimination (T0 SOFA 0.695; T1 SOFA 0.741; qSOFA 0.625; T0 MEWS 0.662; T1 MEWS 0.729; PIRO: 0.646; APACHE II 0.756; Charlson Comorbidity Index 0.596; MEDS 0.674, all p < 0.001). At a multivariate stepwise Cox analysis, including age, Charlson Comorbidity Index, MEWS, and lactates, SOFA shows an incremental prognostic ability both at T0 (RR 1.165, IC 95% 1.009-1.224, p < 0.0001) and T1 (RR 1.168, IC 95% 1.104-1.234, p < 0.0001). SOFA score shows a moderate prognostic stratification ability, and demonstrates an incremental prognostic value over the previous medical conditions and clinical parameters in septic patients.

Short and long-term mortality of patients presenting with bleeding events to the Emergency Department.

BACKGROUND: Death of patients presenting with bleeding events to the Emergency Department still represent a major problem. We sought to analyze clinical characteristics associated with worse outcomes including short- and long-term death, beyond antithombotic treatment strategy. METHODS: Patients presenting with any bleeding events during 2016-2017years were enrolled. Clinical parameters, site of bleeding, major bleeding, ongoing anti-thrombotic treatment strategy and death were collected. Hard 5:1 propensity score matching was performed to adjust dead patients in baseline characteristics. Endpoints were one-month and one-year death. RESULTS: Out of 166,000 visits to the Emergency Department, 3.050 patients (1.8%) were enrolled and eventually 429 were analyzed after propensity. Overall, anticoagulants or antiplatelets were given to 234(54%). Major bleeding account for 111(26%) patients, without differences between those taking anticoagulants or antiplatelets versus others. Death at one-month and one-year was 26(6%) and 72(17%), respectively. Independent predictors of one-month death were major bleeding (Odds Ratio, OR 26, p<0.001), female gender (OR 7, p<0.001) and white blood cells (OR 1.2, p=0.01); of one-year were major bleeding (OR 7, p<0.001), age (OR 1.1, p<0.001) and female gender (OR 2.3, p=0.043). Of note, death rate of gastrointestinal and intracranial bleeding where higher than others (p<0.001). Overall mortality was approximately 40% on one-month; 60% in older patients and 80% in female gender with CHA2D2VASC-score≥2. Receiver operator characteristics analysis showed larger areas for major bleeding and age (0.75 and 0.72, respectively) over others; p<0.05 on C-statistic. CONCLUSIONS: In patients with bleeding events, death rate was driven by major bleeding on short-term and older age on long-term. Among dead patients mortality was approximately 40% on one-month; 60% in older patients, and 80% in female gender.

Point-of-Care Ultrasonography for Evaluation of Acute Dyspnea in the ED.

BACKGROUND: Acute dyspnea is a common symptom in the ED. The standard approach to dyspnea often relies on radiologic and laboratory results, causing excessive delay before adequate therapy is started. Use of an integrated point-of-care ultrasonography (PoCUS) approach can shorten the time needed to formulate a diagnosis, while maintaining an acceptable safety profile. METHODS: Consecutive adult patients presenting with dyspnea and admitted after ED evaluation were prospectively enrolled. The gold standard was the final diagnosis assessed by two expert reviewers. Two physicians independently evaluated the patient; a sonographer performed an ultrasound evaluation of the lung, heart, and inferior vena cava, while the treating physician requested traditional tests as needed. Time needed to formulate the ultrasound and the ED diagnoses was recorded and compared. Accuracy and concordance of the ultrasound and the ED diagnoses were calculated. RESULTS: A total of 2,683 patients were enrolled. The average time needed to formulate the ultrasound diagnosis was significantly lower than that required for ED diagnosis (24 ± 10 min vs 186 ± 72 min; P = .025). The ultrasound and the ED diagnoses showed good overall concordance (κ = 0.71). There were no statistically significant differences in the accuracy of PoCUS and the standard ED evaluation for the diagnosis of acute coronary syndrome, pneumonia, pleural effusion, pericardial effusion, pneumothorax, and dyspnea from other causes. PoCUS was significantly more sensitive for the diagnosis of heart failure, whereas a standard ED evaluation performed better in the diagnosis of COPD/asthma and pulmonary embolism. CONCLUSIONS: PoCUS represents a feasible and reliable diagnostic approach to the patient with dyspnea, allowing a reduction in time to diagnosis. This protocol could help to stratify patients who should undergo a more detailed evaluation.

Utility of repeat head computed tomography after mild head trauma: influence on short- and long-term prognosis and health-related quality of life.

The aim of this study was to investigate the utility of repeat head CT in a large population of patients with non-isolated blunt mild head trauma (MTBI), especially in the presence of intracranial injury. This is a study of a cohort of 478 non-isolated MTBI patients admitted to the High Dependency Unit of the Emergency Department of the University-Hospital of Florence from July 2008 to December 2013. Results of initial and subsequent head CT scans, and indications for repeat head CT scan (routine vs. neurologic change) were recorded. The study population was divided into two subgroups: 28 (6 %) patients with neurological change or persistently reduced GCS (group GCS-) and 450 (94 %) patients with normal or improving GCS (group GCS+). After 6 months from the event, a telephone interview using SF12 questionnaire was conducted. Among GCS- patients, the admission CT scan showed intracranial lesions (ICI) in 16 (57 %) patients; only two patients had a TBI-related neurosurgical intervention. Among GCS+ patients, the first CT scan showed an ICI in 133 patients; in a significant proportion of patients with ICI at the first CT scan, the injury worsened (40/133, 30 %, p < 0.0001). However, no GCS+ patient had any neurosurgical intervention. We observed a significant reduction in both MCS and PCS scores after the injury compared with the previous period. The number of repeat CT scan was high in patients who presented ICI at the first CT scan; however, no patient with ICI and normal or improving GCS score needed a neurosurgical intervention.

Can non-invasive ventilation modify central venous pressure? Comparison between invasive measurement and ultrasonographic evaluation.

Central venous pressure (CVP) is primarily measured to assess intravascular volume status and heart preload. In clinical practice, the measuring device most commonly used in emergency departments and intensive care units, is an electronic transducer that interconnects a central venous catheter (CVC) with a monitoring system. Non-invasive ventilation (NIV) consists in a breathing support that supplies a positive pressure in airways through a mask or a cask though not using an endotracheal prosthesis. In emergency settings, non-invasive ultrasonography evaluation of CVP, and hence of intravascular volume status entail the measurement by a subxiphoid approach of inferior vena cava diameter and its variations in relation to respiratory activity. In the literature, there are many studies analyzing the ability to estimate CVP through ultrasonography, rating inspiratory and expiratory vena cava diameters and their ratio, defined as inferior vena cava collapsibility index (IVC-CI). At the same time, the effects of invasive mechanical ventilation on blood volume and the correlation during ventilation between hemodynamic invasive measurement of CVP and inferior vena cava diameters have already been demonstrated. Nevertheless, there are no available data regarding the hemodynamic effects of NIV and the potential correlations during this kind of ventilation between invasive and non-invasive CVP measurements. Therefore, this study aims to understand whether there exists or not an interrelationship between the values of CVP assessed invasively through a CVC and non-invasively through the IVC-CI in patients with severe respiratory distress, and above all to evaluate if these means of assessment can be influenced using NIV.

High-frequency QRS analysis superior to conventional ST-segment analysis of women with chest pain.

BACKGROUND: The novel analysis of high-frequency QRS components (HF/QRS) has been proposed in patients with chest pain (CP) referred for exercise tolerance test (ex-ECG). We sought to evaluate the prognostic role of exercise high-frequency QRS-analysis (ex-HF/QRS) in patients with recent-onset stable CP, in the emergency setting. METHODS: Patients with CP underwent ex-ECG. A decrease greater than or equal to 50% of the signal of HF/QRS intensity was considered as index of ischemia as ST-segment depression greater than or equal to 2 mm or greater than or equal to 1 mm associated with CP. Exclusion criteria were QRS duration greater than or equal to 120 milliseconds and inability to exercise. Baseline characteristics were adjusted with the propensity score matching specifying nearest-neighbor matching in cardiovascular risk factors and risk scores. The primary end point was the composite of coronary stenosis greater than or equal to 70% or acute coronary syndrome, revascularization, and cardiac death on the 6-month follow-up. RESULTS: Of 589 patients, 22 achieved the end point. On the univariate analysis, known cardiovascular disease, GRACE score, and ex-HF/QRS were predictors of the end point. On the multivariate analysis, only ex-HF/QRS was predictor of the end point (odd ratio, 28; 95% confidence interval [CI], 6-120; P < .001). Overall, the ex-HF/QRS when compared to ex-ECG showed higher sensitivity (91% vs 27%; P = .02), lower specificity (74% vs 86%; P = .09), and comparable negative predictive value (99% vs 97%; P = .78). Receiver operating characteristic curve analysis showed the larger area of ex-HF/QRS (0.83; 95% CI, 0.75-0.90) over ex-ECG (0.57; CI, 0.44-0.70) and GRACE score (0.65; CI, 0.54-0.76); P < .03 on C-statistic. Women showed the largest area (0.89; CI, 0.83-0.95; P < .03) vs the other clinical data. CONCLUSIONS: In patients with CP, the novel ex-HF/QRS analysis has a valuable incremental prognostic role over ex-ECG, especially in women.

Coronary atherosclerosis and adverse outcomes in patients with recent-onset atrial fibrillation and troponin rise.

BACKGROUND: The relationship between troponin and atrial fibrillation (AF) without acute coronary syndrome is still unclear. We sought to investigate the presence of coronary atherosclerosis and adverse outcomes in patients with AF. METHODS: Consecutive patients with recent-onset AF and without severe comorbidities were enrolled between 2004 and 2013. Patients with a troponin rise or with adverse outcomes were considered for coronary angiography and revascularization when "critical" stenosis (≥70%) was recognized. Propensity score matching was performed to adjust for baseline characteristics; after matching, no differences existed between the groups of patients with or without troponin rise. The primary end point was the composite of acute coronary syndrome, revascularization, and cardiac death at 1- and 12-month follow-ups. RESULTS: Of 3627 patients enrolled, 3541 completed the study; 202 (6%) showed troponin rise; and 91 (3%), an adverse outcome. In the entire cohort, on multivariate analysis, the odds ratio for the occurrence of the primary end point of troponin rise was 14 (95% confidence interval [CI], 10-23; P<.001), and that of known coronary artery disease was 3 (CI, 2-5; P=.001). In the matching cohort, the odds ratio of troponin rise was 10 (CI, 4-22; P<.001), and that of TIMI score greater than 2 was 4 (CI, 2-9; P≤.001). In the entire cohort, patients with or without troponin rise achieved the primary end point in 38 (19%) and 43 (1%) patients, respectively (P<.001). Stroke occurred in 4 (2%) and 20 (1%), respectively (P=.018). Critical stenosis and revascularization account for 23 (12%) and 15 (1%), respectively (P<.001). In the matching cohort, results were confirmed, but incidence of stroke was comparable. CONCLUSIONS: Patients with recent-onset AF and troponin rise showed higher prevalence of coronary atherosclerosis and adverse cardiac events. Stroke per se did not succeed in justifying the high morbidity. Thus, beyond stroke, coronary atherosclerosis might have a pivotal role in poor outcomes.

High-frequency QRS analysis compared to conventional ST-segment analysis in patients with chest pain and normal ECG referred for exercise tolerance test.

BACKGROUND: The novel analysis of high-frequency QRS components (HFQRS-analysis) has been proposed in patients with chest pain (CP) and normal electrocardiography (ECG) referred for exercise tolerance test (ex-ECG). The aim of the study was to compare the diagnostic value of ex-ECG with ex-HFQRS-analysis. METHODS: Patients with CP and normal ECG, troponin, and echocardiography were considered. All patients underwent ex-ECG for conventional ST-segment-analysis and ex-HFQRS-analysis. A decrease ≥ 50% of the HFQRS signal intensity recorded in at least 2 contiguous leads was considered an index of ischemia, as ST-segment depression ≥ 2 mm or ≥ 1 mm and CP on ex-ECG. Exclusion criteria were: QRS duration ≥ 120 ms and inability to exercise. End-point: The composite of coronary stenosis ≥ 70% or acute coronary syndrome, revascularization, cardiovascular death at 3-month follow-up. RESULTS: Three-hundred thirty-seven patients were enrolled (age 60 ± 15 years). The percent-age of age-adjusted maximal predicted heart rate was 89 ± 10 beat per minute and the maximal systolic blood pressure was 169 ± 23 mm Hg. Nineteen patients achieved the end-point. In multivariate analysis, both ex-ECG and ex-HFQRS were predictors of the end-point. The ex-HFQRS-analysis showed higher sensitivity (63% vs. 26%; p < 0.05), lower specificity (68% vs. 95%; p < 0.001), and comparable negative predictive value (97% vs. 96%; p = 0.502) when compared to ex-ECG-analysis. Receiver operator characteristics analysis showed the incremental diagnostic value of HFQRS (area: 0.655, 95% CI 0.60-0.71) over conventional ex-ECG (0.608, CI 0.55-0.66) and CP score (0.530, CI 0.48-0.59), however without statistical significance in pairwise comparison by C-statistic. CONCLUSIONS: In patients with CP submitted to ex-ECG, the novel ex-HFQRS-analysis shows a valuable incremental diagnostic value over ST-segment-analysis.

Comparison of exercise electrocardiogram and exercise echocardiography in intermediate-risk chest pain patients.

BACKGROUND: The novel exercise computer-assisted high-frequency QRS analysis (HF/QRS) has demonstrated improved sensitivity and specificity over the conventional ST/electrocardiogram-segment analysis (ST/ECG) in the detection of myocardial ischemia. The aim of the present study was to compare the diagnostic value of the validated exercise echocardiography (ex-Echo) with the novel exercise ECG (ex-ECG) including HF/QRS and ST/ECG analysis. METHODS: A prospective cohort study was conducted in the emergency department of a tertiary care teaching Hospital. Patients with chest pain (CP), normal resting ECGs, troponins, and echocardiography, labeled as "intermediate-risk" for adverse coronary events, underwent the novel ex-ECG and ex-Echo. An ST-segment depression of at least 2 mV or at least 1 mV when associated with CP was considered as an index of ischemia, as well as a decrease of at least 50% in HF/QRS intensity, or new wall motion abnormalities on ex-Echo. Exclusion criteria were QRS duration of at least 120 milliseconds, poor echo-acoustic window, and inability to exercise. Patients were followed up to 3 months. The end point was the composite of coronary stenoses of 50% or greater at angiography or acute coronary syndrome, revascularization, and cardiovascular death on the 3-month follow-up. RESULTS: Of 188 patients enrolled, 18 achieved the end point. The novel ex-ECG and ex-Echo showed comparable negative predictive value (97% vs 96%; P = .930); however, sensitivity was 83% vs 61%, respectively (P = .612), and specificity was 64% vs 92%, respectively,(P = .026). The areas on receiver operating characteristic analysis were comparable (ex-ECG: 0.734 [95% confidence interval, or CI, 0.62-0.85] vs ex-Echo: 0.767 [CI, 0.63-0.91]; C statistic, P = .167). On multivariate analysis, both ex-ECG (hazard ratio, 5; CI, 1-20; P = .017) and ex-Echo (HR, 12; CI, 4-40; P < .001) were predictors of the end point. CONCLUSIONS: In intermediate-risk CP patients, the novel ex-ECG including HF/QRS added to ST/ECG analysis was a valuable diagnostic tool and might be proposed to avoid additional imaging. However, the novel test needs additional study before it can be recommended as a replacement for current techniques.

Quality of life after mild to moderate trauma.

INTRODUCTION: To evaluate potential reduction in health-related quality of life (HRQOL) after a mild to moderate trauma. MATERIALS AND METHODS: Follow-up study of a cohort of 153 trauma patients admitted to the High Dependency Unit of the Emergency Department of the University-Hospital of Florence from July 2008 to February 2012. After 6 months from the event, a telephone interview using the Physical (PCS) and Mental (MCS) Health Composite Score (SF12) was conducted. Patients reported their HRQOL both at present and before trauma. Scores ≥ 50 represent no disability; 40-49, mild disability; 30-39, moderate disability; and below 30, severe disability. RESULTS: Before the event 143 (93%) subjects reported a normal PCS and MCS. After the events, a significantly lower proportion of patients maintained a normal PCS and MCS values (52 and 68%, all p<0.01). One, two, three and four PCS items worsened in 14%, 15%, 18% and 38% of the study population, while one, two, three or four MCS dimensions worsened in 12%, 19%, 19% and 24%. We identified 109 subjects (N+), which showed normal PCS and MCS values before trauma, in the absence of any pre-existing medical condition. After the event, we observed a significant PCS (before: 54, standard deviation, SD 6; after 43, SD 11, p<0.0001) and MCS (before: 55, SD 7; after 47, SD 11, p<0.0001) worsening among N+ subjects. Distribution across the four disability categories was 52, 24, 17 and 6% for MCS score and 38, 25, 27 and 11% for PCS score: overall 8 (7%) patients reported a moderate disability and 5 (5%) reported a severe disability in both dimensions. Compared with subjects with preserved values, patients with an abnormal (<39) HRQOL were older, showed a higher prevalence of female gender and pre-existing medical conditions and a worst Sequential Organ Failure Assessment score. An advanced age (OR 1.033, 95% CI 1.010-1.057, p=0.005) and a higher SOFA T1 score (OR 1.500, 95% CI 1.027-2.190, p=0.036) were independently associated with a worsening PCS. CONCLUSIONS: After a mild trauma, we evidenced a relevant reduction in HRQOL; an advanced age and a higher degree of organ dysfunction were independently associated with HRQOL deterioration.

Role of masked coronary heart disease in patients with recent-onset atrial fibrillation and troponin elevations.

BACKGROUND: Patients with recent-onset atrial fibrillation (AF) and cardiac troponin I (cTnI) elevations show poor outcomes. Coronary heart disease might be a cause, consequence, or an innocent bystander. OBJECTIVE: The aim of this study was to recognize and treat coronary heart disease to avoid adverse events. METHODS: Patients with recent-onset AF participated in the study. The exclusion criteria were acute coronary syndrome and severe comorbidities. Patients managed with standard care (group 1, n=1086, years 2010-2011) were compared with patients managed with tailored care inclusive of echocardiography and stress testing when required (group 2, n=1055, years 2012-2013). ENDPOINT: The endpoint was a composite of ischemic vascular events including stroke, acute coronary syndrome, revascularization and cardiovascular death at 6 months of follow-up. RESULTS: Of 4008 patients considered, 2141 were enrolled; 183 showed cTnI elevations, 92 in group 1 and 91 in group 2. cTnI elevations, known ischemic heart disease and age were predictors of the endpoint on multivariate analysis. Overall, two versus seven patients (P=0.033) in groups 1 and 2, respectively, underwent revascularization. Eventually, 16 patients in group 1 versus five patients in group 2 reached the endpoint (P=0.019). Patients of group 2 were managed as follow: 35 were admitted, 15 with positive stress testing and 20 with high cTnI values (mean values: 0.64±1.01 ng/ml). Fifty-six patients were discharged with negative stress testing results (n=13) or very low cTnI values (n=43, mean values 0.29±0.30 ng/ml). CONCLUSION: In patients with AF and cTnI elevations, tailored care inclusive of echocardiography and stress testing succeeded in recognizing and treating masked 'critical' coronary heart disease, avoiding adverse events.