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.

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.

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.

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.

Long-term prognostic value of stress echocardiography in patients presenting to the ED with spontaneous chest pain.

PURPOSE: The aims of this study were to evaluate the long-term prognostic value of stress echocardiography (SE) in patients evaluated in emergency department (ED) and to determine SE parameters that best predicted outcome. METHODS: Between June 2008 and July 2012, 626 patients with an episode of spontaneous chest pain underwent SE (exercise stress echocardiography or dobutamine stress echocardiography [DSE]). Between December 2012 and January 2013, all patients were contacted to verify the occurrence of cardiac events. Patients were divided in 3 subgroups according to peak stress Wall Motion Score Index (pWMSI): normal peak wall motion (pWMSI, 1; group A1), mild to moderate peak asynergy (pWMSI, 1.1-1.7; group A2), and severe peak asynergy (pWMSI, >1.7; group A3). RESULTS: Stress echocardiography showed inducible ischemia in 159 patients (25%); it was negative in 425 (68%) and inconclusive in 42 (7%). Patients with cardiac events more frequently showed inducible ischemia (50% vs 26%; P = .015) compared with patients with good prognosis; a normal SE (14% vs 61%) was significantly less common. At a multivariate regression analysis, an increased pWMSI (relative risk: 9.816, 95% confidence interval: 3.665-26.290; P < .0001) was independently associated with a bad outcome. Cumulative event-free survival was significantly worse with an increasing degree of peak wall motion asynergy (99% in group A1; 96%, group A2; and 88% in group A3; P = .011 between A1 and A2 groups, P = .012 between A2 and A3 groups, and P < .0001 between A1 and A3 groups). CONCLUSIONS: Stress echocardiography showed an optimal prognostic value among ED patients evaluated for chest pain. The presence of an extensive asynergic area at peak stress was associated with an adverse prognosis.

Reversal or Repletion Treatment Strategies and Outcomes of Patients With Major Bleeding Events Managed in the Emergency Department: Large Real-Life Investigation in the Northwestern Healthcare District of Tuscany.

OBJECTIVE: To verify the incidence of bleeding events in patients on ongoing anticoagulant treatment in the real world and compare the results of different reversal or repletion strategies currently available for pharmacological treatment. METHODS: Patients managed in the emergency department (ED) with major bleeding events, on ongoing anticoagulation were stratified according to bleeding site and reversal or repletion therapy with andexanet alfa (ADX), idarucizumab (IDA), prothrombin complex concentrate (PCC), and vitamin K (Vit-K). ENDPOINT: Death at 30 days was compared in the subgroups with cerebral hemorrhage (CH) and gastrointestinal (GI) bleeding. RESULTS: Of the 809,397 visits in the years 2022-2023 at 6 EDs in the northwestern health district of Tuscany, 5372 patients with bleeding events were considered; 3740 were excluded due to minor bleeding or propensity score matching. Of the remaining 1632 patients with major bleeding, 548 on ongoing anticoagulation were enrolled; 334 received reversal or repletion agents. Patients with CH (n = 176) and GI bleeding (n = 108) represented the primary analysis cohorts in the study's strategic treatment assessment. Overall, 30-day survival of patients on ongoing aFXa treatment receiving on-label ADX versus off-label PCC showed a relative increase of 71%, while 30-day survival of patients on ongoing aFII receiving on-label IDA versus off-label PCC showed a relative increase of 30%; no substantial difference was found when comparing on-label PCC combined with Vit-K versus off-label Vit-K alone. Indeed, patients undergoing on-label ADX or IDA showed a statistically significant difference over off-label PCC (ADX vs. PCC: n = 15, events = 4, mean ± SD 82.50 ± 18.9, vs. 49, 13, 98.82 ± 27, respectively; analysis of variance [ANOVA] variance 8627; P < 0.001; posthoc test diff 32, 95% confidence interval: 28-35; P < 001; IDA vs. PCC: 20, 5, 32.29 ± 15.0 vs. 2, 1, 28.00 ± 0.0, respectively; ANOVA 1484; P < 0.001; posthoc test -29, -29 -29, respectively; P = n.d.). On-label PCC combined with Vit-K showed overall a slight statistically significant difference versus off-label Vit-K alone (52, 16, 100.58 ± 22.6 vs. 53, 11, 154.62 ± 29.8, respectively; ANOVA 310; P < 0.02; posthoc test 4, 0.7-7.2, respectively; P < 0.02). Data were confirmed in the group of patients with CH (ADX vs. PCC: n = 13, events = 3, mean ± SD 91.55 ± 18.6 vs. 78, 21, 108.91 ± 20.9, respectively; ANOVA variance 10,091, F = 261; P < 0.001; posthoc difference test 36, 95% confidence interval: 30-41; P < 0.001; IDA vs. PCC: 10, 2, 4.50 ± 2.5 vs. 78, 21, 108.91 ± 20.9, respectively; ANOVA 16,876,303, respectively; P < 0.001; posthoc test 41, 34-47, respectively; P < 0.001). On-label PCC combined with Vit-K showed an overall slight statistically significant difference compared with off-label Vit-K alone (P < 0.01 and P < 0.001 in the subgroups of CH and GI bleeding). CONCLUSIONS: Patients undergoing specific reversal therapy with on-label ADX or IDA, when treated with aFXa or aFII anticoagulants, respectively, showed statistically elevated differences in 30-day death compared with off-label repletion therapy with PCC. Overall, 30-day survival of patients on ongoing aFXa or aFII receiving on-label reversal therapy with ADX or IDA compared with off-label PCC repletion agents showed an increase of 71% and 30%, respectively.

IFNγ Production by Functionally Reprogrammed Tregs Promotes Antitumor Efficacy of OX40/CD137 Bispecific Agonist Therapy.

Regulatory T cells (Treg) are highly enriched within many tumors and suppress immune responses to cancer. There is intense interest in reprogramming Tregs to contribute to antitumor immunity. OX40 and CD137 are expressed highly on Tregs, activated and memory T cells, and NK cells. In this study, using a novel bispecific antibody targeting mouse OX40 and CD137 (FS120m), we show that OX40/CD137 bispecific agonism induces potent antitumor immunity partially dependent upon IFNγ production by functionally reprogrammed Tregs. Treatment of tumor-bearing animals with OX40/CD137 bispecific agonists reprograms Tregs into both fragile Foxp3+ IFNγ+ Tregs with decreased suppressive function and lineage-instable Foxp3- IFNγ+ ex-Tregs. Treg fragility is partially driven by IFNγ signaling, whereas Treg instability is associated with reduced IL2 responsiveness upon treatment with OX40/CD137 bispecific agonists. Importantly, conditional deletion of Ifng in Foxp3+ Tregs and their progeny partially reverses the antitumor efficacy of OX40/CD137 bispecific agonist therapy, revealing that reprogramming of Tregs into IFNγ-producing cells contributes to the anti-tumor efficacy of OX40/CD137 bispecific agonists. These findings provide insights into mechanisms by which bispecific agonist therapies targeting costimulatory receptors highly expressed by Tregs potentiate antitumor immunity in mouse models. SIGNIFICANCE: The bispecific antibody FS120, an immunotherapy currently being tested in the clinic, partially functions by inducing anti-tumor activity of Tregs, which results in tumor rejection.

Stress echocardiography in the ED: diagnostic performance in high-risk subgroups.

PURPOSE: To assess stress-echo (SE) diagnostic performance in patients presenting to the emergency department (ED) with spontaneous chest pain, especially in subgroups in which exercise ECG diagnostic performance has been questioned (women, elderly, history of coronary artery disease). METHODS: Between June 2008 and May 2011, 474 patients with an episode of spontaneous chest pain, non-diagnostic electrocardiogram and negative cardiac necrosis markers underwent SE. Patients with inducible ischemia (Isch) were asked to undergo coronary angiography. Patients with negative SE were discharged and contacted by telephone at least 6 months after discharge, to ascertain the occurrence of new cardiac events. MAIN FINDINGS: Exercise stress-echo (ESE) was employed in 270 patients and dobutamine (DSE) in 218 (including 14 with inconclusive ESE); a diagnosis of coronary artery disease (CAD) was confirmed or excluded in 434 (92%) patients. SE was negative for Isch in 318 patients (206 ESE and 112 DSE) and positive in 132. During follow-up, patients with negative SE had 4 cardiac events. SE showed: sensitivity 90%, specificity 92%, positive predictive value 78% and negative predictive value 97%. Sensitivity was comparable between patients aged < or ≥70 years (84 vs 94%) and between gender (89 vs 96%), but lower in patients with known CAD (88 vs 94%, P < .05); specificity was comparable regardless of age (94 vs 99%) and presence of CAD (97 vs 91%), but was lower among women (87 vs 96%, P < .05). CONCLUSIONS: SE had a very good diagnostic performance in ED patients with suspected Isch, both overall and in selected high-risk groups.

Abnormal troponin level as short-term predictor of poor outcome in acute atrial fibrillation.

BACKGROUND: The link between minor troponin (cardiac troponin I [cTnI]) elevations and atrial fibrillation (AF) is still debated. METHODS: A total of 948 patients with AF lasting less than 48 hours participated in the study and were required to undergo 1-month and 12-month follow-up. The exclusion criteria were represented by younger than 18 years, the presence of hemodynamic instability, or severe comorbidity. Primary end point was the composite of ischemic vascular events inclusive of stroke, acute coronary syndrome, revascularization, and death. RESULTS: In the short term, 4 patients (5%) of 78 with abnormal cTnI reached the primary end point (P = .001 vs others). Conversely, in the long term, 13 patients (17%) with abnormal cTnI, 21 (10%) with known ischemic vascular disease, and 50 (5%) aged patients (75 ± 10 years) reached the primary end point (P < .001, P < .001, and P = .002, respectively). At multivariate analysis, abnormal cTnI (hazard ratio [HR], 2.84; 95% confidence interval, 1.38-5.84; P = .005), known ischemic vascular disease (HR, 2.03; 95% confidence interval, 1.11-3.70; P = .021), and age (HR, 1.05; 95 confidence interval, 1.02-1.08; P = .002) were predictors of the primary end point. Minimal or minor cTnI elevation (<0.45 or ≥ 0.45 ng/mL, respectively) showed no differences when associated with the primary end point. The C-statistic demonstrated the significant prognostic value of older age and known ischemic vascular disease, beyond troponin. Clinical parameters inclusive of heart rate, blood pressure, and risk factors for arteriosclerosis showed no relationship with adverse events. Readmission rate did not differ between groups. CONCLUSIONS: In patients with acute AF, minor cTnI elevations link to short-term adverse events. Known ischemic vascular disease and older age showed prognostic value only in the long term.

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.

Usefulness of chest ultrasonography in detecting pulmonary embolism in patient with chronic obstructive pulmonary disease and chronic renal failure: a case report.

We describe the case of a 75-year-old man affected by a chronic obstructive pulmonary disease and chronic renal failure admitted to our emergency department for dyspnea and interscapular stabbing pain. Chest radiography showed diffuse parenchymal consolidation in the lower right lung with bronchiectasis, but the treatment for infection disease did not improve the clinical conditions of the patient. According to Wells score indicating an intermediate risk for pulmonary embolism, we performed a chest ultrasonography that showed ultrasonographic patterns of thromboembolism. Because the presence of chronic renal failure limited the execution of a helical computed tomographic pulmonary angiography, a pulmonary scintigraphy was performed confirming the diagnosis of pulmonary embolism. Our case suggested that chest ultrasonography can be a valuable tool for early detection of pulmonary embolism and to establish immediately an appropriate therapy.

Short- and long-term cardiac events in patients with chest pain with or without known existing coronary disease presenting normal electrocardiogram.

AIM: The aim of this study is to evaluate incidence of adverse cardiac events in patients with chest pain with or without known existing coronary disease presenting normal electrocardiogram (ECG) and initial troponin. METHODS: Prospective, nonrandomized study enrolled low-risk patients with normal ECG and troponin on admission who underwent observation and/or stress testing by unstandardized clinical judgment. Patients who experienced recurrent angina or positive ECGs or positive troponins during observation or patients with positive stress testing were admitted; otherwise, they were discharged. END POINT: The end points are cardiac events at short- and long-term follow-up including cardiovascular death, myocardial infarction, unstable angina, and revascularization. RESULTS: Of 5656 patients considered, 1732 with ischemic ECG were initially admitted and, therefore, excluded from the analysis; 2860 with pleuritic chest pain and normal ECG were discharged; 1064 with visceral chest pain and normal ECG were enrolled. Patients with known coronary disease (45%) were older and likely presented known vascular disease. Patients with known vascular disease, older age, female sex, diabetes mellitus, and lower chest pain score were likely managed with observation. In patients with known coronary disease as compared with patients without, overall cardiac events account for 35% vs 14%, respectively (P < .001), as follows: in-hospital, 23% vs 10%, (P < .001); 1 month, 4% vs 2% (P = .133); and 9.9 ± 4.9 months, 8% vs 2%, respectively (P < .001). CONCLUSIONS: One-third of patients with chest pain with known coronary disease, negative ECG, and biomarkers were subsequently found to have adverse cardiac events. The value of this research for an emergency medicine audience could be extended to all clinicians and general practitioners beyond cardiologists.

Risk scores prognostic implementation in patients with chest pain and nondiagnostic electrocardiograms.

BACKGROUND: Several risk scores are available for prognostic purpose in patients presenting with chest pain. AIM: The aim of this study was to compare Grace, Pursuit, Thrombolysis in Myocardial Infarction (TIMI), Goldman, Sanchis, and Florence Prediction Rule (FPR) to exercise electrocardiogram (ECG), decision making, and outcome in the emergency setting. METHODS: Patients with nondiagnostic ECGs and normal troponins and without history of coronary disease underwent exercise ECG. Patients with positive testing underwent coronary angiography; otherwise, they were discharged. End point was the composite of coronary stenosis at angiography or cardiovascular death, myocardial infarction, angina, and revascularization at 12-month follow-up. RESULTS: Of 508 patients considered, 320 had no history of coronary disease: 29 were unable to perform exercise testing, and finally, 291 were enrolled. Areas under the receiver operating characteristic curves for Grace, Pursuit, TIMI, Goldman, Sanchis, and FPR were 0.59, 0.68, 0.69, 0.543, 0.66, and 0.74, respectively (P < .05 FPR vs Goldman and Grace). In patients with negative exercise ECG and overall low risk score, only the FPR effectively succeeded in recognizing those who achieved the end point; in patients with high risk score, the additional presence of carotid stenosis and recurrent angina predicted the end point (odds ratio, 12 and 5, respectively). Overall, logistic regression analysis including exercise ECG, coronary risk factors, and risk scores showed that exercise ECG was an independent predictor of coronary events (P < .001). CONCLUSIONS: The FPR effectively succeeds in ruling out coronary events in patients categorized with overall low risk score. Exercise ECG, nonetheless being an independent predictor of coronary events could be considered questionable in this subset of patients.

Clinical management of atrial fibrillation: early interventions, observation, and structured follow-up reduce hospitalizations.

BACKGROUND: Novel facilities such as an intensive observation unit and an outpatient clinic could result in improving management of patients presenting with atrial fibrillation (AF). METHODS: This observational study enrolled 3475 patients. Group 1 (1120 patients; years 2004-2005) was managed with standard approach; group 2 (992 patients; years 2006-2007) was managed with additional intensive observation; group 3 (1363 patients; years 2008-2009) was managed with additional intensive observation and outpatient clinic. Primary end point was admission to hospital. Secondary end points included modalities of rhythm conversion and administration of class IC vs class III antiarrhythmic drugs in patients with AF lasting less than 48 hours. RESULTS: Lack of rhythm control, comorbidities, diabetes, and age were independent predictors of hospitalization. Admissions significantly decreased from group 1 (50%) to 2 (38%) and to 3 (24%) (P < .001). Interestingly, more than a quarter of patients in group 3 were referred to the outpatient clinic for short-term follow-up, eventually avoiding admission. Patients with AF lasting less than 48 hours (n = 2189) and without structural heart disease (n = 1685) achieved sinus rhythm in 89% of cases and were discharged. In these patients, early administration of antiarrhythmic drugs of class IC and III gained sinus rhythm in 80% and 20%, respectively (P < .001). Spontaneous conversion occurred in 26%; electrical, 17%; and pharmacological, 57%. CONCLUSIONS: In patients with AF, beyond the standard approach, the novel organization with an additional intensive observation unit for early pharmacological interventions and an outpatient clinic for elective treatment and short-term follow-up significantly reduced admission irrespective of independent predictors of hospitalizations. Patients without structural heart disease treated with antiarrhythmic drugs achieved sinus rhythm in 89% of cases, mostly with class IC drugs.

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.

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.

A new simple risk score in patients with acute chest pain without existing known coronary disease.

OBJECTIVE: To derive and validate a prediction rule in patients with acute chest pain (CP) without existing known coronary disease. METHODS: Cohort study including 2233 patients with CP. Based on clinical judgment, 1435 were discharged as very low risk and the remaining 798 underwent exercise tolerance test (ETT). END POINT: 6-month composite of cardiovascular death, nonfatal myocardial infarction, and revascularization. The prediction rule was derived from a randomly selected test cohort (n = 1106) summing factors of variables selected by multivariate regression analysis: CP score higher than 6 (factor of 3), male gender, age older than 50 years, metabolic syndrome, and diabetes mellitus (factor of 1, for each). The prediction rule was validated in the remaining cohort (n = 1127). All patients with CP were categorized into 3 groups: group A (prediction rule 0-1), B (2-4), or C (5-6). Outcomes and prognostic yield of ETT were compared among each group. RESULTS: In the test cohort, 55 patients (5%) reached the composite end point. Event rate increased as the prediction rule increased: 1% for group A, 6% for B, and 25% for C (P < .001). This pattern was confirmed in the validation cohort (P < .001). A normal ETT did not significantly improve the high (99%) negative predictive value in group A and did not succeed in excluding the composite end point (17%) in group C. CONCLUSIONS: In patients with acute CP without existing coronary disease, a prediction rule based on clinical characteristics provided a useful method for prognostication with possible implication in decision making.

Management of patients with acute atrial fibrillation in the ED.

BACKGROUND: Patients with acute atrial fibrillation with a history of mild structural heart disease could be considered for rhythm conversion. METHODS: Patients received intravenous flecainide, propafenone, or amiodarone on presentation and a second dose after 6 hours if atrial fibrillation persisted. No randomization was used, and drugs were given at the discretion of the treating physician. Primary end point was rhythm conversion within the first 6 hours from presentation. Secondary end points included rhythm conversion, time to rhythm conversion, and adverse drug effects within 24 hours. RESULTS: Among the 378 patients enrolled, 37 (10%) recovered sinus rhythm before therapy was given. Of the remaining 341 patients, 43 (13%) received flecainide, 187 (55%) received propafenone, and 111 (32%) received amiodarone. Baseline clinical characteristics were homogeneous among groups. Rhythm conversion was obtained in 87% of treated patients overall. Within 6 hours, the primary end point was achieved in a higher proportion in the flecainide and propafenone groups (72% and 55%, respectively) as compared with the amiodarone group (30%; P < .001). The mean time to the end point overall was shorter in the flecainide and propafenone groups (178 ± 227 and 292 ± 285 minutes, respectively) as compared with the amiodarone group (472 ± 269 minutes; P < .001). Length of in-hospital stay in the amiodarone group was significantly higher (26.1 ± 22.4 hours) compared with the flecainide and propafenone groups (8.9 ± 10.3 and 11.0 ± 13.8 hours; respectively; P = .001). No significant differences were found in adverse drug effects. CONCLUSIONS: Flecainide and propafenone achieve rhythm control in a higher proportion of patients as compared with amiodarone within a 6-hour management.