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Introduction C-reactive protein (CRP) is a marker commonly used in clinical practice as a reference for the inflammatory activity in vivo. Low levels are often associated with good health and lower risk for adverse outcomes. Patients and methods We examined medical records of the last 6 years, of all patients admitted for hospitalization in internal medicine wards who had the first CRP measurement below ≤ 0.03 mg/L (detection limit). Diagnosis criteria and 7 days’ survival were reviewed. Results Out of 61,590 total admissions to internal medicine wards, three hundred and thirteen patients had CRP equal to or lower than 0.03 mg/L (0.5%). Second CRP measurement revealed gradual increment up to 10.8 ± 35.4 mg/L. Four patients died within 7 days from admission. Discussion Presentation to the internal medicine department with a very low concentration of CRP is highly unusual, but it does not exclude the existence of significant acute morbidities. Clinicians should take additional CRP tests before any conclusion is considered regarding the presence or absence of an inflammatory response.

Introduction: Patients with diabetes are prone to infections. An elevated C-reactive protein (CRP) level indicates an underlying infection/inflammation; hence, a reliable point-of-care (POC) CRP measurement, independent of glucose level, would be advantageous in rapid detection of an inflammatory process and allowing for appropriate therapy in a timely manner. Methods: A validation study of patients with type 2 diabetes mellitus diagnosed with an inflammatory condition either infectious or non-infectious underwent a capillary CRP measurement on the same blood drop used for the measurement of capillary glucose level. Results: 154 samples from patients with diabetes across a broad range of CRP levels that underwent capillary CRP measurement, demonstrating a linear profile of the dynamic range compared with the wide range CRP assay, with significant correlation of R2 = 0.9 and a slope of 0.98 (95% C.I: 0.91–1). Bland Altman analysis, presents a positive bias profile; the total difference between assays is 6.6 mg/L. The mean bias between methods is 13.34% (C.I 95% 9.8–17.5%). The total agreement between the methods is 89%, the observed Kappa index is: 0.71 with confidence interval of 0.57–0.84 indicating substantial agreement between the methods. C-reactive protein level is independent of glucose concentration. Conclusion: Point-of-care capillary CRP testing is a useful mean of early detection of infection/inflammation in patients with diabetes and enables the treating physician to rapidly assess and treat the patients underlying inflammatory process.

Background COVID-19 infection is associated with a hypercoagulable state. Severe COVID-19 patients present with high plasma fibrinogen levels, continuous deposition of fibrin and the presence of microthrombi in their lungs, accompanied by significant fibrinolysis, resulting in high D-dimer levels. Due to the role of FXIII in fibrin crosslinking and clot stabilization, we analyzed its activity levels and dynamics in COVID-19 patients hospitalized in the intensive care unit (ICU). Methods FXIII levels were measured in thirty four COVID-19 patients hospitalized in the ICU and in fourteen non-severe COVID-19 patients. FVIII levels were measured for comparison. Laboratory data and clinical variables were recorded. Results The average FXIII activity level in 34 ICU hospitalized COVID-19 patients was 69.9±33 %, significantly lower compared to an average of 120±20.9 % FXIII activity in 14 non-severe COVID-19 patients. FXIII activity levels were below the low normal value (< 79 % FXIII activity) in 74 % of the ICU hospitalized COVID-19 patients. In contrast, high FVIII activity was measured among all severe COVID-19 patients. Consecutive measurements, performed in fourteen ICU hospitalized COVID-19 patients, pointed to a significant decrease in FXIII activity from the average of 85.7±28.2 %, (which is in the normal range), to an average of 68.0±20.4 %, below the low normal range, within 6.4±3.4 days of ICU hospitalization. Liver functions did not differentiate between patients with low and normal FXIII activity. No inhibitor to FXIII activity was found in the plasma of severe COVID-19 patients. Levels of FXIII-A antigen correlated with FXIII activity, and were low in severe COVID-19 patients. Conclusions Low FXIII activity levels were found in COVID-19 patients hospitalized in the ICU, with gradual decline during their hospitalization. A mechanism of consumption may account for the low FXIII activity in these patients.

Background/Aims The aims of the present study were to elucidate whether oxidative stress has a role in Con A-induced hepatitis and to examine if antioxidants may protect against liver damage in this model. Methods Hepatitis was induced in Balb/c mice by administration of Con A (18 mg/kg) to the tail vein. Liver enzymes and histology were determined 24 h after Con A injection. Tumor necrosis factor alpha (TNFα) and interleukin-10 (IL-10) levels were assayed 2 h after Con A injection. Hepatic malondialdehyde levels were measured at 1, 3, 8, 12, 18, and 24 h after Con A injection in order to examine the timing of free-radicals formation. Nuclear factor kappa B (NF-κβ) activation was determined by electrophoresis mobility shift assay (EMSA) 1 and 2 h after Con A injection. In separate experiments, mice were pretreated with either dimethylsulfoxide or dimethylthiourea before Con A inoculation. The antioxidant and NF-κβ inhibitor pyrrolidine dithiocarbamate (PDTC) was used as positive control. Results Hepatic malondialdehyde levels increased 12, 18, and 24 h after Con A inoculation but not earlier. Serum levels of liver enzymes and TNFα, hepatic malondialdehyde, and protein carbonyls and the histologic necroinflammatory score were significantly reduced in the antioxidants-treated mice, while IL-10 levels were increased. Dimethylsulfoxide, dimethylthiourea, and PDTC inhibited oxidative stress, but only PDTC inhibited Con A-induced NF-κB activation. Conclusions Reactive oxygen species play a role in immune-mediated Con A-induced hepatitis probably secondary to immune-mediated liver damage. Scavenging of reactive oxygen species by antioxidants prevents hepatitis independently of NF-κB inhibition and may be a new therapeutic target in this experimental model.

Background Several reports suggested that compliance with acute kidney injury care bundles among hospitalized patients resulted in improved kidney and patient outcomes. We investigated the effect of acute kidney injury care bundle utilization on the incidence of acute kidney injury and renal outcomes in a large cohort of myocardial infarction patients treated with percutaneous coronary intervention. Methods We included patients with myocardial infarction admitted following percutaneous coronary intervention between January 2008 and December 2020. From January 2016, acute kidney injury care bundle was implemented in our cardiac intensive care unit. Acute kidney injury care bundle consisted of simple standardized investigations and interventions, including strict monitoring of serum creatinine and urine analysis, planning investigations, treatment, and guidance about seeking nephrologist advice. Patients' records were evaluated for the occurrence of acute kidney injury, its severity, and recovery, before and after the implementation of acute kidney injury care bundle. Results We included 2646 patients (1941 patients in the years 2008–2015 and 705 patients in the years 2016–2020). Implementation of care bundles resulted in a significant decrease in the occurrence of acute kidney injury from 190/1945 to 42/705 (10–6%; p  < 0.001), with a trend for lower acute kidney injury score > 1 (20% vs. 25%; p  = 0.07) and higher acute kidney injury recovery (62% vs. 45%, p  = 0.001). Using a multivariable regression model, the use of care bundles resulted in a 45% decrease in the relative risk for acute kidney injury (HR 0.55, 95% CI 0.37–0.82, p  < 0.001). Conclusion Among patients with ST-elevation myocardial infarction, treated with percutaneous coronary intervention and admitted to our cardiac intensive care unit over the period January 2008–December 2020, compliance with acute kidney injury care bundle was independently associated with a significant decrease in occurrence of acute kidney injury and with better renal outcomes following acute kidney injury. Further interventions, such as e-alert systems for acute kidney injury, could improve utilization of the acute kidney injury care bundle and optimize its clinical benefits. Graphical abstract

Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium. Each had a homozygous null variant in CORIN , the gene encoding atrial natriuretic peptide (ANP)–converting enzyme. A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested. These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis. Findings from a study involving two siblings homozygous for a null variant in CORIN have implications for understanding the extent to which the BNP and ANP pathways overlap.

Introduction The C‐reactive protein (CRP)‐troponin‐test (CTT) comprises simultaneous serial measurements of CRP and cardiac troponin and might reflect the systemic inflammatory response in patients with acute coronary syndrome. We sought to test its ability to stratify the short‐ and long‐term mortality risk in patients with non‐ST elevation myocardial infarction (NSTEMI). Methods We examined 1,675 patients diagnosed with NSTEMI on discharge who had at least two successive measurements of combined CRP and cardiac troponin within 48 h of admission. A tree classifier model determined which measurements and cutoffs could be used to best predict mortality during a median follow‐up of 3 years [IQR 1.8–4.3]. Results Patients with high CRP levels ( > 90th percentile, >54 mg/L) had a higher 30‐day mortality rate regardless of their troponin test findings (16.7% vs. 2.9%, p < 0.01). However, among patients with “normal” CRP levels ( < 54 mg/L), those who had high troponin levels ( > 80th percentile, 4,918 ng/L) had a higher 30‐day mortality rate than patients with normal CRP and troponin concentrations (7% vs. 2%, p < 0.01). The CTT test result was an independent predictor for overall mortality even after adjusting for age, sex, and comorbidities (HR = 2.28 [95% CI 1.56‐3.37], p < 0.01 for patients with high troponin and high CRP levels). Conclusions Early serial CTT results may stratify mortality risk in patients with NSTEMI, especially those with “normal” CRP levels. The CTT could potentially assess the impact of inflammation during myocardial necrosis on the outcomes of patients with NSTEMI and identify patients who could benefit from novel anti‐inflammatory therapies. We examined 1,675 patients diagnosed with NSTEMI who had at least two successive measurements of CRP and cardiac troponin within 48 h of admission. A tree classifier model determined which cutoffs could be used to best predict mortality. The CRP‐Troponin‐Test (CTT) might identify inflammatory‐prone patients with worse outcomes following NSTEMI.

Ferritin is an acute phase response protein, which may not rise as expected in acute bacterial infections. This could be due to the time required for its production or to a lack of response of ferritin to the bacterial inflammatory process. Medical records of hospitalized patients with acute hyper inflammation were retrieved and studied, looking closely at two acute phase proteins: C-reactive protein (CRP) and ferritin. The estimated time between symptom onset and the procurement of blood tests was also measured. 225 patients had a median ferritin level of 109.9 ng/mL [IQR 85.1, 131.7] and a median CRP level of 248.4 mg/L [IQR 221, 277.5]. An infectious inflammatory process was identified in 195 patients. Ferritin levels were relatively low in comparison with the CRP in each group, divided according to time from symptom onset until the procurement of blood tests. The discrepancy between high CRP and low ferritin suggests that these two acute phase response proteins utilize different pathways, resulting in a failure to increase ferritin concentrations in a documented state of hyperinflammation. A new entity of normoferremic inflammation accounts for a significant percentage of patients with acute bacterial infections, which enables bacteria to better survive the inflammation and serves as a new “inflammatory stamp”.

Although a fourth dose of SARS-CoV-2 vaccine was shown to be effective, the immunogenicity of a fifth dose in immunocompetent individuals had not been well described. This was a prospective observational cohort study of previously vaccinated healthcare workers at a single tertiary hospital in Israel. Individuals were administered up to three booster doses of the BNT162b2 mRNA vaccine (i.e., up to five overall doses), during the period between July 2021 and January 2023. Immunogenicity was assessed using the SARS-CoV-2 IgG (sCOVG) semi-quantitative assay, performed at several time points. The cohort consisted of 162 individuals (median age 69 years, 62% female). Of these, 104 (64%) received four doses and 58 (36%) received five doses. Anti-SARS-CoV-2 antibody levels increased in all cases, regardless of the baseline levels. The fold-change increase in the mean sCOVG index was 29.2 (SD 2.6) after the third vaccine, 3.8 (SD 2.4) after the fourth vaccine, and 3.6 (SD 3.0) after the fifth vaccine. A waning effect over time was seen in 78% and 43% of participants for the third and fourth doses, respectively. Adverse events following the fifth dose were limited and mild. Similar to previous booster vaccines, a fifth dose of BNT162b2 is immunogenic and safe in healthy individuals, although the clinical implications remain unclear.

Abstract Background Immune checkpoint inhibitors (ICIs) may lead to immune-related adverse events, including potentially life-threatening cardiovascular (CV) complications. Despite guideline-recommended troponin monitoring, limited data exist on evaluating its predictive significance. Objective We aimed to assess the predictive value of serial high-sensitivity troponin I (hs-TnI) monitoring in patients treated with ICIs. Methods A retrospective, single-center, observational study including patients treated with ICIs and performing serial hs-TnI measurements. The primary endpoint was all-cause mortality, and the secondary endpoint was CV events, defined as the composite of myocarditis, pericarditis, acute coronary syndrome, heart failure, or arrhythmias. A tree classifier model identified the most predictive hs-TnI concentration for the main study endpoints. Results Overall, 455 patients performed baseline (T1) and follow-up hs-TnI (T2) assessments and were included in the cohort. During a mean follow-up of 25 months (IQR [12-36]), 253 (56%) patients died, and 70 (15%) developed CV events. T2 > 8 ng/L was significantly associated with increased all-cause mortality (64% vs 48%, P < .001) and CV events (22% vs 9%, P < .001), notably HF (12% vs 4%, P = .003) and myocarditis (3% vs 0%, P = .038). A multivariable analysis confirmed that T2 > 8 ng/L was an independent predictor for all-cause mortality (HR 1.67, 95% CI: 1.29-2.17, P < .001) and CV events (HR 2.59, 95% CI: 1.50-4.46, P = .001). Conclusions Our study emphasizes the significant role of serial troponin monitoring during ICIs therapy as an independent predictor of all-cause mortality and CV events, and suggests an optimal lower hs-TnI cutoff of >8 ng/L for risk stratification. Large prospective trials are needed to confirm these findings.