A common TLR1 polymorphism is associated with higher parasitaemia in a Southeast Asian population with Plasmodium falciparum malaria

Abstract Background The factors leading to poor outcomes in malaria infection are incompletely understood. Common genetic variation exists in the human genes for Toll like receptors (TLRs) that alter host responses to pathogen-associated molecular patterns. Genetic variation in TLR1 and TLR6 could alter the risk of development of complicated malaria and ability of the host to control the parasite burden during acute Plasmodium falciparum infection. Methods Five single nucleotide polymorphisms in TLR1 and TLR6 in 432 patients with clinical P. falciparum monoinfection acquired on the Thai-Myanmar border were genotyped. Using logistic regression, associations with the development of complicated malaria and the percentage of infected erythrocytes (parasitaemia) on the day of presentation to clinical care (day zero) were tested. Results Genotypes carrying the T (major) allele of TLR1 rs5743551—an allele associated with improved outcomes in sepsis—were associated with higher parasitaemia measured on day zero (p = 0.03). Discussion Since malaria exerts strong genetic pressure on the human genome, protection from parasitaemia associated with TLR1 rs5743551 may account for the maintenance of an allele associated with poor outcomes in Caucasians with sepsis. Conclusion These data suggest that genetic variation in TLR1 has effects on the host response to Plasmodium falciparum malaria in Asian populations. Genotypes from TLR6 showed no evidence of association with either complicated malaria or parasite burden

Oral neutrophils are an independent marker of the systemic inflammatory response after cardiac bypass

Abstract Background Cardiopulmonary bypass (CPB) is an immuno-reactive state where neutrophils are activated and accumulate in different tissues. Edema and tissue necrosis are the most common sequelae observed, predominantly in the lungs, kidneys, and heart, heralding significant risk for postoperative complications. No method exists to noninvasively assess in vivo neutrophil activity. The objective of this study was to determine if neutrophil recruitment to the oral cavity would correlate with specific biomarkers after coronary bypass surgery (CPB). Methods We conducted a single site prospective observational study including non-consecutive adult patients undergoing elective, on-pump CPB. Blood and either oral cavity rinses or swabs were collected pre- and post-CPB. Absolute neutrophil counts from oral samples and serum biomarkers were measured. The association between neutrophil recruitment to the oral cavity, biomarkers and outcomes after CPB were analyzed. Results CPB was associated with statistically significant increases in oral and blood neutrophil counts, as well as an increase in certain biomarkers over preoperative baseline. Peripheral blood neutrophil count were increased at all time points however statistically significant differences in median oral neutrophil counts were observed only at the time point immediately postoperative, and in what seems to be two unique patient populations (p < 0.001; group 1, median: 1.6×105, Interquartile range [IQR], 1.1×105 - 4.8×105, and group 2, median: 1.9×106, IQR, 8.7×105 - 4.0×106). Conclusions CPB is associated with a transient increase in oral neutrophils that may correlate with the systemic inflammatory response; oral neutrophils may have the ability to discriminate and identify unique patient populations based on their tissue migration

Oral neutrophils are an independent marker of the systemic inflammatory response after cardiac bypass

Background Cardiopulmonary bypass (CPB) is an immuno-reactive state where neutrophils are activated and accumulate in different tissues. Edema and tissue necrosis are the most common sequelae observed, predominantly in the lungs, kidneys, and heart, heralding significant risk for postoperative complications. No method exists to noninvasively assess in vivo neutrophil activity. The objective of this study was to determine if neutrophil recruitment to the oral cavity would correlate with specific biomarkers after coronary bypass surgery (CPB). Methods We conducted a single site prospective observational study including non-consecutive adult patients undergoing elective, on-pump CPB. Blood and either oral cavity rinses or swabs were collected pre- and post-CPB. Absolute neutrophil counts from oral samples and serum biomarkers were measured. The association between neutrophil recruitment to the oral cavity, biomarkers and outcomes after CPB were analyzed. Results CPB was associated with statistically significant increases in oral and blood neutrophil counts, as well as an increase in certain biomarkers over preoperative baseline. Peripheral blood neutrophil count were increased at all time points however statistically significant differences in median oral neutrophil counts were observed only at the time point immediately postoperative, and in what seems to be two unique patient populations (p < 0.001; group 1, median: 1.6×105, Interquartile range [IQR], 1.1×105 - 4.8×105, and group 2, median: 1.9×106, IQR, 8.7×105 - 4.0×106). Conclusions CPB is associated with a transient increase in oral neutrophils that may correlate with the systemic inflammatory response; oral neutrophils may have the ability to discriminate and identify unique patient populations based on their tissue migration

Sipuleucel‐T associated inflammatory cardiomyopathy: a case report and observations from a large pharmacovigilance database

International audienceAims: The major cardiovascular (CV) adverse effects observed with sipuleucel-T from large multi-institutional clinical trials included thromboembolic events, myocardial infarction, and congestive heart failure in up to 0.3% of patients with CV risk factors. The incidence, outcomes, and mechanisms in real-world clinical settings of these CV adverse effects to date have not been fully elucidated. Our study identified a patient with sipuleucel-T-induced inflammatory cardiomyopathy, which led to the identification of CV adverse effects associated with sipuleucel-T from a large pharmacovigilance database and elucidation of its potential mechanisms.Methods and results: Using the MedDRA term 'cardiac disorders' (System Organ Class level), CV adverse events associated with sipuleucel-T versus all other drugs were reviewed from VigiBase, a large pharmacovigilance database. Disproportionality analysis was calculated by the information component (IC), a Bayesian disproportionality indicator. A positive IC025 (IC 95% lower end credibility interval) value (>0) is the traditional threshold used in statistical signal detection at the Uppsala Monitoring Centre. From VigiBase, the total number of CV adverse drug reaction reported with sipuleucel-T was 306 out of a total of 22 980 104 adverse drug reactions in VigiBase on 10/25/2020. MedDRA preferred terms levels were grouped into major CV adverse drug reaction categories where we observed significant reports of myocardial ischaemia, supraventricular tachycardia (particularly atrial fibrillation/atrial flutter), congestive heart failure, and valvular disorders. Myocardial ischemia included acute myocardial infarction (IC025 2.3) with n = 4/26 (15%) of these individual case safety reports considered fatal. Among patients with 'cardiac failure congestive' (IC025 1.5), 11 of these 43 cases (26%) were fatal with 42 (98%) of these cases considered to be solely due to sipuleucel-T.Conclusions: Patients with CV risk factors who are receiving sipuleucel-T may be at higher risk for congestive heart failure, myocardial ischemia, and supraventricular tachycardia. Electrocardiograms during weekly sipuleucel-T infusions and left ventricular function monitoring with echocardiogram should be considered in these patients. Our findings are suggestive of another rare presentation of T-cell-mediated CV toxicity with cancer immunotherapy

Κορώνη -- Μοσχάτον

A joint measurement is presented of the branching fractions $B^0_s\to\mu^+\mu^-$ and $B^0\to\mu^+\mu^-$ in proton-proton collisions at the LHC by the CMS and LHCb experiments. The data samples were collected in 2011 at a centre-of-mass energy of 7 TeV, and in 2012 at 8 TeV. The combined analysis produces the first observation of the $B^0_s\to\mu^+\mu^-$ decay, with a statistical significance exceeding six standard deviations, and the best measurement of its branching fraction so far, and three standard deviation evidence for the $B^0\to\mu^+\mu^-$ decay. The measurements are statistically compatible with SM predictions and impose stringent constraints on several theories beyond the SM