The size of the adaptive immune system is considered to be kept constant by the attrition of pre-existing memory. However, recently it was shown that the CD8 memory compartment can grow in size and the number of pre-existing memory is largely preserved, predicting that pre-existing immunity should be maintained (Vezys et al.; Nature 457: 196-199). Experimental proof for this assumption is still lacking. We address this question in the Listeria monocytogenes (L.m.) infection model and confirm the growth of size of the memory compartment by subsequent vaccination with modified vaccinia virus Ankara. We also find only modest attrition of pre-existing L.m.-specific memory CD8 T cells. However, pre-existing protective immunity toward L.m. is not preserved. Pre-existing L.m.-specific effector-memory cells, in contrast to central memory cells, become altered, and this results in a significant loss of pre-existing protective immunity. Our findings are clinically relevant for vaccines introducing new CD8 memory cells in high numbers, as this might influence pre-existing immunity.
Mortality rates in females who survived acute myocardial infarction (AMI) exceed those in males. Differences between sexes in age, cardiovascular risk factors and revascularization therapy have been proposed as possible reasons.To select sets of female and male patients comparable in respect of relevant risk factors in order to compare the sex-specific risk in a systematic manner.Data of the ISAR-RISK and ART studies were investigated. Patients were enrolled between 1996 and 2005 and suffered from AMI within 4 weeks prior to enrolment. Patients of each sex were selected with 1:1 equivalent age, previous AMI history, sinus-rhythm presence, hypertension, diabetes mellitus, smoking status, left ventricular ejection fraction (LVEF), and revascularization therapy. Survival times were compared between sex groups in the whole study cohort and in the matched cohort.Of 3840 consecutive AMI survivors, 994 (25.9%) were females and 2846 (74.1%) were males. Females were older and suffered more frequently from hypertension and diabetes mellitus. In the whole cohort, females showed an increased mortality with a hazard ratio (HR) of 1.54 compared to males (p<0.0001). The matched cohort comprised 802 patients of each sex and revealed a trend towards poorer survival in females (HR for female sex 1.14; p = 0.359). However, significant mortality differences with a higher risk in matched females was observed during the first year after AMI (HR = 1.61; p = 0.045) but not during the subsequent years.Matched sub-groups of post-AMI patients showed a comparable long-term mortality. However, a female excess mortality remained during first year after AMI and cannot be explained by differences in age, cardiovascular risk factors, and modes of acute treatment. Other causal factors, including clinical as well as psychological and social aspects, need to be considered. Female post-AMI patients should be followed more actively particularly during the first year after AMI.
Single-stranded RNA stimulates immune cells and induces the secretion of pro-inflammatory cytokines and type I IFN. As adjuvant RNA can induce a T(h)2 type of humoral response, however, its potency in the induction of cytotoxic T cells in vivo has not been analyzed. Here we show that immunization with the antigen ovalbumin (OVA) and the adjuvant phosphodiester RNA complexed to the cationic lipid N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methylsulfate (DOTAP) induced a Toll-like receptor-7-dependent cytotoxic T cell and humoral response. Staining with SIINFEKL-K(b) tetramers demonstrated the induction of antigen-specific T cells that were functional in in vivo cytotoxic T cell assays against SIINFEKL-loaded target cells. In infection experiments with OVA-secreting Listeria monocytogenes, the cytotoxic T cell response strongly reduced the bacterial load in liver and spleen. The RNA-driven humoral response was characterized by OVA-specific antibodies of the IgG1 isotype whereas CpG-DNA induced antigen-specific antibodies of the IgG2a (BALB/c) or IgG2c (C57BL/6) isotype. Furthermore, stimulation with RNA did not induce splenomegaly, a common feature of CpG-DNA-driven immune activation in mice. Taken together, our data confirm that RNA can be used as a safe adjuvant and induces a strong antibody response of the IgG1 isotype. Additionally, we demonstrate that RNA induces an antigen-specific immunity characterized by a potent cytotoxic T cell response to infection.
Background If a COVID-19 patient develops a so-called severe course, he or she must be taken to hospital as soon as possible. This proves difficult in domestic isolation, as patients are not continuously monitored. The aim of our study was to establish a telemonitoring system in this setting. Methods Oxygen saturation, respiratory rate, heart rate and temperature were measured every 15 minutes using an in-ear device. The data was transmitted to the Telecovid Centre via mobile network or internet and monitored 24/7 by a trained team. The data were supplemented by daily telephone calls. The patients´ individual risk was assessed using a modified National Early Warning Score. In case of a deterioration, a physician initiated the appropriate measures. Covid-19 Patients were included if they were older than 60 years or fulfilled at least one of the following conditions: pre-existing disease (cardiovascular, pulmonary, immunologic), obesity (BMI >35), diabetes mellitus, hypertension, active malignancy, or pregnancy. Findings 153 patients (median age 59 years, 77 female) were included. Patients were monitored for 9 days (median, IQR 6–13 days) with a daily monitoring time of 13.3 hours (median, IQR 9.4–17.0 hours). 20 patients were referred to the clinic by the Telecovid team. 3 of these required intensive care without invasive ventilation, 4 with invasive ventilation, 1 of the latter died. All patients agreed that the device was easy to use. About 90% of hospitalised patients indicated that they would have delayed hospitalisation further if they had not been part of the study. Interpretation Our study demonstrates the successful implementation of a remote monitoring system in a pandemic situation. All clinically necessary information was obtained and adequate measures were derived from it without delay.
Seit Einführung der Proteaseinhibitoren (PI)in die Therapie der HIV-Infektion haben Morbidität und Mortalität signifikant abgenommen. Proteaseinhibitoren sind jedoch relativ nebenwirkungsreich. Als Komplikationen können Lipodystrophie, Hyperlipidämie und Insulinresistenz auftreten, deren klinische Bedeutung bisher nicht klar ist. Die Therapie mit Proteaseinhibitoren erfordert wegen der zum Teil schwierigen Einnahmemodalitäten eine gute Patientenführung. Aufgrund von Interaktionen können die Einnahmemodalitäten durch Kombination mehrerer Proteaseinhibitoren vereinfacht werden.
Abstract Monitoring of QTc interval is mandated in different clinical conditions. Nevertheless, intra-subject variability of QTc intervals reduces the clinical utility of QTc monitoring strategies. Since this variability is partly related to QT heart rate correction, 10 different heart rate corrections (Bazett, Fridericia, Dmitrienko, Framingham, Schlamowitz, Hodges, Ashman, Rautaharju, Sarma, and Rabkin) were applied to 452,440 ECG measurements made in 539 healthy volunteers (259 females, mean age 33.3 ± 8.4 years). For each correction formula, the short term (5-min time-points) and long-term (day-time hours) variability of rate corrected QT values (QTc) was investigated together with the comparisons of the QTc values with individually corrected QTcI values obtained by subject-specific modelling of the QT/RR relationship and hysteresis. The results showed that (a) both in terms of short-term and long-term QTc variability, Bazett correction led to QTc values that were more variable than the results of other corrections ( p < 0.00001 for all), (b) the QTc variability by Fridericia and Framingham corrections were not systematically different from each other but were lower than the results of other corrections ( p -value between 0.033 and < 0.00001), and (c) on average, Bazett QTc values departed from QTcI intervals more than the QTc values of other corrections. The study concludes that (a) previous suggestions that Bazett correction should no longer be used in clinical practice are fully justified, (b) replacing Bazett correction with Fridericia and/or Framingham corrections would improve clinical QTc monitoring, (c) heart rate stability is needed for valid QTc assessment, and (d) development of further QTc corrections for day-to-day use is not warranted.
Diabetic postinfarction patients are at increased mortality risk compared with nondiabetic postinfarction patients. In a substantial number of these patients, diabetic cardiac neuropathy already preexists at the time of the infarction. In the current study we investigated if markers of autonomic dysfunction can further discriminate diabetic postinfarction patients into low- and high-risk groups.We prospectively enrolled 481 patients with type 2 diabetes who survived acute myocardial infarction (MI), were aged ≤ 80 years, and presented in sinus rhythm. Primary end point was total mortality at 5 years of follow-up. Severe autonomic failure (SAF) was defined as coincidence of abnormal autonomic reflex function (assessed by means of heart rate turbulence) and of abnormal autonomic tonic activity (assessed by means of deceleration capacity of heart rate). Multivariable risk analyses considered SAF and standard risk predictors including history of previous MI, arrhythmia on Holter monitoring, insulin treatment, and impaired left ventricular ejection fraction (LVEF) ≤ 30%.During follow-up, 83 of the 481 patients (17.3%) died. Of these, 24 deaths were sudden cardiac deaths and 21 nonsudden cardiac deaths. SAF identified a high-risk group of 58 patients with a 5-year mortality rate of 64.0% at a sensitivity level of 38.0%. Multivariately, SAF was the strongest predictor of mortality (hazard ratio 4.9 [95% CI 2.4-9.9]), followed by age ≥65 years (3.4 [1.9-5.8]), and LVEF ≤ 30% (2.6 [1.5-4.4]).Combined abnormalities of autonomic reflex function and autonomic tonic activity identifies diabetic postinfarction patients with very poor prognoses.
It has been known for a long time that memory CD8+ T cells are the main players in conferring long-lasting and effective protection against infection with intracellular pathogens. The generation of instantly protective memory cells, so-called effector memory T cells, represents the basic principle of T cell-based vaccination strategies. Therefore, the understanding of the exact mechanisms required for in vivo generation of distinct CD8+ memory T cell subtypes will become the crucial rationale for enhancing the efficiency and quality of vaccine-induced protective immunity.
