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Dynamic personalized risk prediction in chronic heart failure patients: a longitudinal, clinical investigation of 92 biomarkers (Bio-SHiFT study).
Klimczak-Tomaniak, D, de Bakker, M, Bouwens, E, Akkerhuis, KM, Baart, S, Rizopoulos, D, Mouthaan, H, van Ramshorst, J, Germans, T, Constantinescu, A, et al
Scientific reports. 2022;(1):2795
Abstract
The aim of our observational study was to derive a small set out of 92 repeatedly measured biomarkers with optimal predictive capacity for adverse clinical events in heart failure, which could be used for dynamic, individual risk assessment in clinical practice. In 250 chronic HFrEF (CHF) patients, we collected trimonthly blood samples during a median of 2.2 years. We selected 537 samples for repeated measurement of 92 biomarkers with the Cardiovascular Panel III (Olink Proteomics AB). We applied Least Absolute Shrinkage and Selection Operator (LASSO) penalization to select the optimal set of predictors of the primary endpoint (PE). The association between repeatedly measured levels of selected biomarkers and the PE was evaluated by multivariable joint models (mvJM) with stratified fivefold cross validation of the area under the curve (cvAUC). The PE occurred in 66(27%) patients. The optimal set of biomarkers selected by LASSO included 9 proteins: NT-proBNP, ST2, vWF, FABP4, IGFBP-1, PAI-1, PON-3, transferrin receptor protein-1, and chitotriosidase-1, that yielded a cvAUC of 0.88, outperforming the discriminative ability of models consisting of standard biomarkers (NT-proBNP, hs-TnT, eGFR clinically adjusted) - 0.82 and performing equally well as an extended literature-based set of acknowledged biomarkers (NT-proBNP, hs-TnT, hs-CRP, GDF-15, ST2, PAI-1, Galectin 3) - 0.88. Nine out of 92 serially measured circulating proteins provided a multivariable model for adverse clinical events in CHF patients with high discriminative ability. These proteins reflect wall stress, remodelling, endothelial dysfunction, iron deficiency, haemostasis/fibrinolysis and innate immunity activation. A panel containing these proteins could contribute to dynamic, personalized risk assessment.Clinical Trial Registration: 10/05/2013 https://clinicaltrials.gov/ct2/show/NCT01851538?term=nCT01851538&draw=2&rank=1 .
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BCG revaccination of health workers in Brazil to improve innate immune responses against COVID-19: A structured summary of a study protocol for a randomised controlled trial.
Junqueira-Kipnis, AP, Dos Anjos, LRB, Barbosa, LCS, da Costa, AC, Borges, KCM, Cardoso, ADRO, Ribeiro, KM, Rosa, SBA, Souza, CC, das Neves, RC, et al
Trials. 2020;(1):881
Abstract
OBJECTIVES The BCG vaccine, widely used in Brazil in new-borns, induces adjuvant protection for several diseases, including childhood virus infections. BCG activates monocytes and innate memory NK cells which are crucial for the antiviral immune response. Therefore, strategies to prevent COVID-19 in health workers (HW) should be carried out to prevent them becoming unwell so that they can continue to work during the pandemic. The hypothesis is that BCG will improve the innate immune response and prevent symptomatic infection or COVID-19 severity. The primary objective is to verify the effectiveness and safety of the BCG vaccine to prevent or reduce incidence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the city of Goiânia (Brazil) among HW previously vaccinated with BCG and also its severity and mortality during the pandemic of the disease. Secondary objectives are to estimate the incidence of COVID-19 among these professionals and the innate immune response elicited to BCG. TRIAL DESIGN This a phase II trial for repositioning BCG as a preventive strategy against COVID-19. The trial is an open-label, parallel-group randomised clinical trial, comparing HW vaccinated with BCG and HW not vaccinated. PARTICIPANTS The trial will recruit 800 HW of Goiânia - Goiás, Brazil to reach a total of 400 HW included after comorbidities questioning and laboratorial evaluation. Eligibility criteria: Any HW presenting BCG vaccination scar with direct contact with suspected COVID-19 patients for at least 8 hours per week, whether in hospital beds, ICU, or in transportation or admission (nurses, doctors, physiotherapists, nutritionists, receptionists, etc.) who have negative IgM and IgG COVID-19 test. Participants with any of the following characteristics will be excluded: - Have had in the last fifteen days any signs or symptoms of virus infection, including COVID-19; - Have had fever in the last fifteen days; - Have been vaccinated fifteen days before the inclusion; - Have a history or confirmation of any immunosuppressive disease such as HIV, presented solid tumour in the last two years or autoimmune diseases; - Are under preventive medication with antibiotics, steroid anti-inflammatories, or chemotherapy; - Have less than 500 neutrophils per mL of blood; - Have previously been diagnosed with tuberculosis; - Are breastfeeding or pregnant; - Are younger than 18 years old; - Are participating as an investigator in this clinical trial. INTERVENTION AND COMPARATOR HW will be randomized into the BCG vaccinated group or the BCG unvaccinated control group. The BCG vaccinated group will receive in the right arm, intradermally, a one off dose of 0.1 mL corresponding to approximately 2 x105 to 8 x105 CFU of live, freeze-dried, attenuated BCG Moscow 361-I, Bacillus Calmette Guerin vaccine (Serum Institute of India PVT. LTD.). The unvaccinated control group will not be vaccinated. The HW allocated in both groups will be followed up at specific times points until 180 days post inclusion. The vaccinated and control groups will be compared according to COVID-19 related outcomes. MAIN OUTCOMES The primary outcomes are the incidence coefficient of infection by SARS-CoV-2 determined by RT-PCR of naso-oropharyngeal swab specimen or rapid lateral flow IgG and IgM test, and presence of general COVID-19 symptoms, disease severity and admission to hospital during the 180 days of follow up. The secondary outcome is the innate immune response elicited 15-20 days after vaccination. RANDOMISATION The vaccine vial contains approximately 10 doses. In order to optimize the vaccine use, the randomisation was performed in blocks of 20 participants using the platform randomization.com [ http://www.jerrydallal.com/random/permute.htm ]. The randomization was prepared before any HW inclusion. The results were printed and inserted in sealed envelopes that were numbered with BCG-001 to BCG-400. The printed results as well the envelopes had the same numbers. At the time of the randomisation, each participant that meets the inclusion criteria will receive a consecutive participant number [BCG-001-BCG-400]. The sealed envelope with the assigned number, blinded to the researchers, will be opened in front of the participant and the arm allocation will be known. BLINDING (MASKING): There is no masking for the participants or for the healthcare providers. The study will be blinded to the laboratory researchers and to those who will be evaluating the outcomes and performing the statistical analyses. In this case, only the participant identification number will be available. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Four hundred heath workers will be randomised in two groups. Two hundred participants will be vaccinated, and 200 participants will not be vaccinated. TRIAL STATUS The protocol approved by the Brazilian Ethical Committee is the seventh version, number CAAE 31783720.0.0000.5078. The trial has been recruiting since September 20th, 2020. The clinical trial protocol was registered on August 5th, 2020. It is estimated that recruitment will finish by March 2021. TRIAL REGISTRATION The protocol number was registered on August 5th, 2020 at REBEC (Registro Brasileiro de Ensaios Clínicos). Register number: RBR-4kjqtg and WHO trial registration number UTN: U1111-1256-3892. FULL PROTOCOL The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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Rationale and design of the allogeneiC human mesenchymal stem cells (hMSC) in patients with aging fRAilTy via intravenoUS delivery (CRATUS) study: A phase I/II, randomized, blinded and placebo controlled trial to evaluate the safety and potential efficacy of allogeneic human mesenchymal stem cell infusion in patients with aging frailty.
Golpanian, S, DiFede, DL, Pujol, MV, Lowery, MH, Levis-Dusseau, S, Goldstein, BJ, Schulman, IH, Longsomboon, B, Wolf, A, Khan, A, et al
Oncotarget. 2016;(11):11899-912
Abstract
Frailty is a syndrome associated with reduced physiological reserves that increases an individual's vulnerability for developing increased morbidity and/or mortality. While most clinical trials have focused on exercise, nutrition, pharmacologic agents, or a multifactorial approach for the prevention and attenuation of frailty, none have studied the use of cell-based therapies. We hypothesize that the application of allogeneic human mesenchymal stem cells (allo-hMSCs) as a therapeutic agent for individuals with frailty is safe and efficacious. The CRATUS trial comprises an initial non-blinded phase I study, followed by a blinded, randomized phase I/II study (with an optional follow-up phase) that will address the safety and pre-specified beneficial effects in patients with the aging frailty syndrome. In the initial phase I protocol, allo-hMSCs will be administered in escalating doses via peripheral intravenous infusion (n=15) to patients allocated to three treatment groups: Group 1 (n=5, 20 million allo-hMSCs), Group 2 (n=5, 100 million allo-hMSCs), and Group 3 (n=5, 200 million allo-hMSCs). Subsequently, in the randomized phase, allo-hMSCs or matched placebo will be administered to patients (n=30) randomly allocated in a 1:1:1 ratio to one of two doses of MSCs versus placebo: Group A (n=10, 100 million allo-hMSCs), Group B (n=10, 200 million allo-hMSCs), and Group C (n=10, placebo). Primary and secondary objectives are, respectively, to demonstrate the safety and efficacy of allo-hMSCs administered in frail older individuals. This study will determine the safety of intravenous infusion of stem cells and compare phenotypic outcomes in patients with aging frailty.
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25-hydroxyvitamin D3 status is associated with developing adaptive and innate immune responses in the first 6 months of life.
Jones, AP, D'Vaz, N, Meldrum, S, Palmer, DJ, Zhang, G, Prescott, SL
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2015;(1):220-31
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Abstract
BACKGROUND Vitamin D (25[OH]D3) status in early life has been linked to the risk of allergic disease in multiple observational studies. While immunomodulating properties are well recognized, there are few longitudinal studies of 25(OH)D3 status, immune function and allergic disease in infants. OBJECTIVE To investigate 25(OH)D3 levels at birth [cord blood (CB)] and at 6 months of age in relation to immune function at 6 months of age, and clinical outcomes up to 30 months of age in infants with a maternal history of atopy. METHODS In a subset of infants (n = 225) enrolled in a RCT (ACTRN12606000281594), 25(OH)D3 levels were assessed in relation to peripheral blood mononuclear cell cytokine responses to house dust mite (HDM), ovalbumin (OVA) and β-lactoglobulin allergens, or Toll-like receptor (TLR) ligands (lipopolysaccharide, lipoteichoic acid, polyinosinic : polycytidylic acid and CpG oligonucleotide) at 6 months of age, in addition to clinical outcomes (eczema, wheeze and allergen sensitisation) up to 30 months of age. RESULTS Infants with higher 25(OH)D3 at birth (≥ 75 nmol/L, compared with < 50 nmol/L) had lower IL-5 and IL-13 responses to HDM by 6 months (P < 0.001 and P = 0.003, respectively). This was also reflected in strong inverse correlations between CB 25(OH)D3 levels and HDM IL-13 (ρ = -0.57; P = 0.0002) and IL-5 (ρ = -0.59, P = 0.0001) responses, with a similar trend for IL-5 (ρ = -0.29; P = 0.009) responses to OVA. For innate stimulations, higher 25(OH)D3 levels at 6 months were associated with greater responses to TLR ligands. Additionally, higher CB 25(OH)D3 was associated with reduced risk eczema at 6 months (P = 0.011) and 12 months (P = 0.034). CONCLUSION This suggests that improving 25(OH)D3 status in pregnancy or early infancy may reduce the development of allergic disease in high-risk infants by inhibiting cytokine profiles associated with allergy. Results of clinical trials are awaited to determine the efficacy of vitamin D supplementation in allergy prevention.
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The effect of iron loading and iron chelation on the innate immune response and subclinical organ injury during human endotoxemia: a randomized trial.
van Eijk, LT, Heemskerk, S, van der Pluijm, RW, van Wijk, SM, Peters, WH, van der Hoeven, JG, Kox, M, Swinkels, DW, Pickkers, P
Haematologica. 2014;(3):579-87
Abstract
In this double-blind randomized placebo-controlled trial involving 30 healthy male volunteers we investigated the acute effects of iron loading (single dose of 1.25 mg/kg iron sucrose) and iron chelation therapy (single dose of 30 mg/kg deferasirox) on iron parameters, oxidative stress, the innate immune response, and subclinical organ injury during experimental human endotoxemia. The administration of iron sucrose induced a profound increase in plasma malondialdehyde 1 h after administration (433±37% of baseline; P<0.0001), but did not potentiate the endotoxemia-induced increase in malondialdehyde, as was seen 3 h after endotoxin administration in the placebo group (P=0.34) and the iron chelation group (P=0.008). Endotoxemia resulted in an initial increase in serum iron levels and transferrin saturation that was accompanied by an increase in labile plasma iron, especially when transferrin saturation reached levels above 90%. Thereafter, serum iron decreased to 51.6±9.7% of baseline at T=8 h in the placebo group versus 84±15% and 60.4±8.9% of baseline at 24 h in the groups treated with iron sucrose and deferasirox, respectively. No significant differences in the endotoxemia-induced cytokine response (TNF-α, IL-6, IL-10 and IL-1RA), subclinical vascular injury and kidney injury were observed between groups. However, vascular reactivity to noradrenalin was impaired in the 6 subjects in whom labile plasma iron was elevated during endotoxemia as opposed to those in whom no labile plasma iron was detected (P=0.029). In conclusion, a single dose of iron sucrose does not affect the innate immune response in a model of experimental human endotoxemia, but may impair vascular reactivity when labile plasma iron is formed. (Clinicaltrials.gov identifier:01349699).
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Two strategies for response to 14 °C cold-water immersion: is there a difference in the response of motor, cognitive, immune and stress markers?
Brazaitis, M, Eimantas, N, Daniuseviciute, L, Mickeviciene, D, Steponaviciute, R, Skurvydas, A
PloS one. 2014;(9):e109020
Abstract
Here, we address the question of why some people have a greater chance of surviving and/or better resistance to cold-related-injuries in prolonged exposure to acute cold environments than do others, despite similar physical characteristics. The main aim of this study was to compare physiological and psychological reactions between people who exhibited fast cooling (FC; n = 20) or slow cooling (SC; n = 20) responses to cold water immersion. Individuals in whom the T(re) decreased to a set point of 35.5 °C before the end of the 170-min cooling time were indicated as the FC group; individuals in whom the T(re) did not decrease to the set point of 35.5 °C before the end of the 170-min cooling time were classified as the SC group. Cold stress was induced using intermittent immersion in bath water at 14 °C. Motor (spinal and supraspinal reflexes, voluntary and electrically induced skeletal muscle contraction force) and cognitive (executive function, short term memory, short term spatial recognition) performance, immune variables (neutrophils, leucocytes, lymphocytes, monocytes, IL-6, TNF-α), markers of hypothalamic-pituitary-adrenal axis activity (cortisol, corticosterone) and autonomic nervous system activity (epinephrine, norepinephrine) were monitored. The data obtained in this study suggest that the response of the FC group to cooling vs the SC group response was more likely an insulative-hypothermic response and that the SC vs the FC group displayed a metabolic-insulative response. The observations that an exposure time to 14 °C cold water--which was nearly twice as short (96-min vs 170-min) with a greater rectal temperature decrease (35.5 °C vs 36.2 °C) in the FC group compared with the SC group--induces similar responses of motor, cognitive, and blood stress markers were novel. The most important finding is that subjects with a lower cold-strain-index (SC group) showed stimulation of some markers of innate immunity and suppression of markers of specific immunity.
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Randomized controlled trial of exercise and blood immune function in postmenopausal breast cancer survivors.
Fairey, AS, Courneya, KS, Field, CJ, Bell, GJ, Jones, LW, Mackey, JR
Journal of applied physiology (Bethesda, Md. : 1985). 2005;(4):1534-40
Abstract
The objective was to determine the effects of exercise training on changes in blood immune function in postmenopausal breast cancer survivors. Fifty-three postmenopausal breast cancer survivors were randomly assigned to an exercise (n=25) or control group (n=28). The exercise group trained on cycle ergometers three times per week for 15 wk. The control group did not train. The primary end point was change in natural killer cell cytotoxic activity in isolated peripheral blood mononuclear cells. Secondary end points were changes in standard hematological variables, whole blood neutrophil function, the phenotypes of isolated mononuclear cells, estimations of unstimulated and phytohemaglutinin-stimulated mononuclear cell function (rate of [3H]thymidine uptake), and the production of proinflammatory [interleukin (IL)-1alpha, tumor necrosis factor-alpha, IL-6] and anti-inflammatory cytokines (IL-4, IL-10, transforming growth factor-beta1). Statistical tests were two-sided (alpha <0.05). Fifty-two participants completed the trial. Intention-to-treat analyses, which included the baseline value as a covariate, showed significant differences between groups for change in percent specific lysis of a target natural killer cell at all five effector-to-target ratios (adjusted mean between-group change over all 5 effector-to-target ratios = +6.34%; P <0.05 for all comparisons), the lytic activity per cell (adjusted mean between-group change = -2.72 lytic units; P=0.035), and unstimulated [3H]thymidine uptake by peripheral blood lymphocytes (adjusted mean between-group change = +218 per dpm x 10(6) cells; P = 0.007). There were no significant differences between groups for change in any other end point. Exercise training increased natural killer cell cytotoxic activity and unstimulated [3H]thymidine uptake by peripheral blood lymphocytes in postmenopausal breast cancer survivors.