Coagulation Profile in Neonates with Congenital Heart Disease: A Pilot Study.

Background and Objectives: congenital heart disease (CHD), cyanotic and, to a lesser degree, acyanotic, often are accompanied by coagulation abnormalities, impacting substantially morbidity and mortality. Until now, no consistent hemostatic patterns have been demonstrated in neonates and children with CHD because they represent a variable and heterogenous population. The aim of the present study is to investigate the hemostatic profile, as well as the role of ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type-1 motives), the cleaving protein of von Willebrand factor (VWF) in neonates with CHD and compare them to healthy age-matched controls. Materials and Methods: twenty neonates with a mean gestational age of 37.1 ± 2.5 weeks were included in the CHD group, and 18 healthy neonates with a mean gestational age of 38.2 ± 1.5 weeks were in the control group. Results: prothrombin time was significantly prolonged, and accordingly, factor VII (FVII) levels were significantly decreased in the CHD group in comparison to controls. Factor VIII (FVIII), VWF, and ristocetin cofactor activity (Rcof) levels were significantly higher in the study vs. control group. Concentrations of ADAMTS-13 were decreased in the CHD vs. control group, but the difference was not statistically significant. Our results, in combination, indicate a balanced hemostatic mechanism, although with greater variability in neonates with CHD, while developmental aspects of coagulation are evident in the specific patient population. Conclusions: the coagulation profile is moderately impaired early in the course of CHD, though increased thrombogenicity is already present and should not be ignored.

Longitudinal Analysis of Antibody Response Following SARS-CoV-2 Infection Depending on Disease Severity: A Prospective Cohort Study.

OBJECTIVE: Severe coronavirus disease 19 (COVID-19) is characterized by a dysregulated inflammatory response, with humoral immunity playing a central role in the disease course. The objective of this study was to assess the immune response and the effects of vaccination in recovered individuals with variable disease severity up to one year following natural infection. METHODS: A prospective cohort study was conducted including patients with laboratory-confirmed COVID-19. Disease severity was classified as mild, moderate, and severe based on clinical presentation and outcomes. Anti-RBD (receptor binding domain) and neutralizing antibodies were evaluated at multiple timepoints during the first year after COVID-19 diagnosis. RESULTS: A total of 106 patients were included; of them, 28 were diagnosed with mild, 38 with moderate, and 40 with severe disease. At least one vaccine dose was administered in 58 individuals during the follow-up. Participants with mild disease presented significantly lower anti-RBD and neutralizing antibodies compared to those with moderate and severe disease up to the 3rd and 6th months after the infection, respectively. After adjusting for covariates, in the third month, severe COVID-19 was associated with significantly higher anti-RBD (ß: 563.09; 95% confidence intervals (CI): 257.02 to 869.17) and neutralizing (ß: 21.47; 95% CI: 12.04 to 30.90) antibodies. Among vaccinated individuals, at the 12th month, a history of moderate disease was associated with significantly higher anti-RBD levels (ß: 5615.19; 95% CI: 657.92 to 10,572.46). CONCLUSIONS: Severe COVID-19 is associated with higher anti-RBD and neutralizing antibodies up to 6 months after the infection. Vaccination of recovered patients is associated with a remarkable augmentation of antibody titers up to one year after COVID-19 diagnosis, regardless of disease severity.

A Global Assessment of Coagulation Profile and a Novel Insight into Adamts-13 Implication in Neonatal Sepsis.

Neonatal sepsis is a life-threatening condition associated with significant morbidity and mortality. Sepsis-induced coagulopathy is a well-recognized entity, signifying the strong cross-talk between inflammation and coagulation. The aim of the present study was to compare the coagulation profile between the acute phase of sepsis and recovery in term and preterm neonates. Additional comparisons to healthy neonates were undertaken. Levels of clotting, anti-clotting factors and ADAMTS-13 (A disintegrin and metalloprotease with thrombospondin type-1 motives), the cleaving protein of von Willebrand factor (VWF), were measured in 16 term and preterm neonates in the acute phase of infection and following recovery, as well as in 18 healthy neonates. Clotting times were prolonged, while levels of particular clotting factors were lower in the acute phase of infection compared to controls and recovery. On the other hand, levels of fibrinogen, factor VIII (FVIII) and VWF were significantly higher in the acute phase in comparison to controls and recovery, while they remained persistently higher in the infection group compared to controls. In regard to the anticlotting mechanism, a clear suppression was observed in septic neonates. ADAMTS-13 levels were significantly lower in the acute phase of infection in comparison to controls and recovery (p = 0.015 and 0.004, respectively), while a trend toward superimposed normalization was demonstrated post infection, as higher ADAMTS-13 levels were measured in recovered neonates compared to controls (p = 0.002). The coagulation profile is considerably deranged in neonatal sepsis. ADAMTS-13 deficiency in septic neonates is a novel finding with promising future implications, as ADAMTS-13 substitution may serve as a useful therapeutic option in neonatal sepsis, prompting further investigation in future studies.

Evidence that platelets from transfusion-dependent ß-thalassemia patients induce T cell activation.

A hypercoagulable state leading to increased risk for thrombotic events represents one of the most common complications observed in transfusion-dependent ß-thalassemia (TDT) patients. TDT patients have increased frequencies of circulating activated platelets. However, there is no information so far if platelets from TDT patients can activate T cells. In the present study we showed that T cells treated with platelets from TDT patients showed significant increased surface expression of CD69 compared to the T cells treated with platelets from healthy individuals. Patients with splenectomy showed increased T cell activation compared to patients with intact spleen. No T cell activation was observed following incubation with plasma alone, nor with platelets from healthy subjects. The percentages of regulatory T cells (Tregs) were also examined. TDT patients showed statistically significant increased percentages of Tregs compared to healthy controls. Additionally, we observed a positive statistically significant correlation between the percentages of Tregs and the platelet-induced activated T cells in patients who were not treated with aspirin. TDT patients showed increased levels of sP-selectin, suPAR and GDF-15, molecules implicated in platelet activation. We show that platelets from TDT patients can activate T cells in vitro. This activation correlates with markers of platelet activation and increased numbers of Tregs, perhaps in an effort to eliminate immune dysregulation, conceivably secondary to platelet activation.

Acute iv CRH administration significantly increases serum active ghrelin in postmenopausal PCOS women compared to postmenopausal controls.

PURPOSE: In women with Polycystic Ovarian Syndrome (PCOS), an increased risk of disordered eating has been described. There is growing interest regarding a possible interconnection between psychological states and increased appetite in women with PCOS. Acute stress is characterized by increased Corticotropin Releasing Hormone (CRH) secretion. The aim was to estimate the ghrelin concentrations during CRH test. METHODS: Twenty postmenopausal women with PCOS and twenty age- and BMI- matched postmenopausal control women were recruited at Aretaieion University Hospital. In the morning (9 am) all subjects had anthropometric measurements (weight, height, waist circumference) and a fasting sample for hormonal measurements. An intravenous (iv) CRH stimulation test conducted over 1 min. Serum active ghrelin levels were measured at 0, 15, 30, 60, 90, 120 min after iv CRH administration. RESULTS: The postmenopausal PCOS group had a higher waist circumference compared to postmenopausal controls. Active ghrelin concentrations increased significantly from 0 to 15 min, to 30 min, to 60 min, to 90 min and then decreased to 120 min. However, within the postmenopausal control group there were no significant changes in serum active ghrelin levels. Serum active ghrelin concentrations were significantly greater in the postmenopausal control group at 0, 15 and 120 min compared to the postmenopausal PCOS group. At 90 min active ghrelin concentrations were significantly greater in the postmenopausal PCOS group. Delta Area Under the Curve of active ghrelin (ΔAUCghr) was significantly greater in the postmenopausal PCOS group compared to controls. CONCLUSIONS: In postmenopausal PCOS, but not in postmenopausal controls, iv CRH administration induces increased serum active ghrelin secretion, suggesting a possible anti-stress adaptive mechanism. An increase in serum active ghrelin may induce hunger as a side-effect of this presumed adaptive mechanism.

Serum YKL-40 as a Potential Biomarker for Sepsis in Term Neonates-A Pilot Study.

Although YKL-40 is a promising diagnostic biomarker of sepsis in adults, its value in neonatal sepsis is not known. The study objectives included assessing the levels and diagnostic value of serum YKL-40 in term neonates with sepsis and comparing YKL-40 with other commonly used inflammatory biomarkers. In this pilot case-control study, 45 term neonates (30 septic and 15 non-septic, as controls), 4 to 28 days old, were prospectively studied. The International Pediatric Sepsis Consensus Conference criteria were applied to diagnose sepsis. During the acute phase (admission) and remission of sepsis, blood samples were collected from cases (while from controls they were only collected once) for routine laboratory tests, cultures, and the measurement of serum YKL-40 levels via Elisa. In the acute phase of sepsis, YKL-40 levels were significantly elevated in comparison with remission (p = 0.004) and controls (p = 0.003). YKL-40 levels did not differ significantly between patients in remission and controls (p = 0.431). Upon admission, YKL-40 levels correlated positively with white blood count, absolute neutrophil count, and CRP levels. Via ROC analysis, it was shown that YKL-40 levels upon admission were a significant indicator of sepsis (AUC = 0.771; 95% CI 0.632-0.911; p = 0.003). Serum YKL-40 might be considered as an adjuvant biomarker of sepsis in term neonates.

Soluble Urokinase-Type Plasminogen Activator Receptor (suPAR) and Growth Differentiation Factor-15 (GDF-15) Levels Are Significantly Associated with Endothelial Injury Indices in Adult Allogeneic Hematopoietic Cell Transplantation Recipients.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) and graft-versus-host disease (GvHD) represent life-threatening syndromes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In both conditions, endothelial dysfunction is a common denominator, and development of relevant biomarkers is of high importance for both diagnosis and prognosis. Despite the fact that soluble urokinase plasminogen activator receptor (suPAR) and growth differentiation factor-15 (GDF-15) have been determined as endothelial injury indices in various clinical settings, their role in HSCT-related complications remains unexplored. In this context, we used immunoenzymatic methods to measure suPAR and GDF-15 levels in HSCT-TMA, acute and/or chronic GVHD, control HSCT recipients, and apparently healthy individuals of similar age and gender. We found considerably greater SuPAR and GDF-15 levels in HSCT-TMA and GVHD patients compared to allo-HSCT and healthy patients. Both GDF-15 and suPAR concentrations were linked to EASIX at day 100 and last follow-up. SuPAR was associated with creatinine and platelets at day 100 and last follow-up, while GDF-15 was associated only with platelets, suggesting that laboratory values do not drive EASIX. SuPAR, but not GDF-15, was related to soluble C5b-9 levels, a sign of increased HSCT-TMA risk. Our study shows for the first time that suPAR and GDF-15 indicate endothelial damage in allo-HSCT recipients. Rigorous validation of these biomarkers in many cohorts may provide utility for their usefulness in identifying and stratifying allo-HSCT recipients with endothelial cell impairment.

Circulating FGF21 vs. Stress Markers in Girls during Childhood and Adolescence, and in Their Caregivers: Intriguing Inter-Relations between Overweight/Obesity, Emotions, Behavior, and the Cared-Caregiver Relationship.

Fibroblast growth factor-21 (FGF21) acts on several brain regions, including the hypothalamic paraventricular nucleus, which is involved in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The purpose of this study was to investigate the interrelations between FGF21 and stress indices in girls, as well as in their caregivers. 78 girls, aged between 5 and 15 years, were studied; 50 of them were overweight and obese (OB) and 28 in the control group (C). Serum FGF21 and hair and diurnal salivary cortisol were measured. Children participants filled in the Children's Depression Inventory (CDI) and the State-Trait Anxiety Inventory for Children (STAIC), while their caregivers filled in the State-Trait Anxiety Inventory (STAI), the Perceived Stress Scale (PSS), and the Holmes-Rahe Stress Events Scale (HRSES). The OB group girls had significantly higher levels of FGF21 than the C group (p < 0.001). In contrast to the C group, in whom FGF21 levels were positively correlated with both hair and salivary AUCg cortisol concentrations (p = 0.045 and p = 0.007, respectively), no such correlations were observed in the OB group. In the caregivers of the OB group, STAI-state (r = 0.388, p = 0.008), STAI-trait (r = 0.4, p = 0.006), PSS (r = 0.388, p = 0.008), and HRSES (r = 0.358, p = 0.015) scores, all correlated positively with the FGF21 levels of the children under their care. FGF21 concentrations positively correlated with hair and salivary cortisol levels in the C group only. These findings may represent an interesting correlation dictated by bi-directional empathy links between the primary caregivers and the children under their care.

Immune response and adverse events after vaccination against SARS-CoV-2 in adult patients with transfusion-dependent thalassaemia.

Patients with transfusion-dependent thalassaemia (TDT) are considered an at increased-risk population for severe and/or morbid coronavirus disease 2019 (COVID-19) infection. Timely vaccination is the main preventive method for severe COVID-19. Different adverse events and reactions after vaccination have been reported, with severe ones being extremely rare. Patients with TDT may have altered immunity due to chronic transfusions, iron overload and chelation therapy, and splenic dysfunction. Here, we show that adult patients with TDT following vaccination with the novel messenger RNA vaccines have mild adverse events and can produce protective antibodies comparable to the healthy population.

Oxidant/Antioxidant Status Is Impaired in Sepsis and Is Related to Anti-Apoptotic, Inflammatory, and Innate Immunity Alterations.

Oxidative stress is considered pivotal in the pathophysiology of sepsis. Oxidants modulate heat shock proteins (Hsp), interleukins (IL), and cell death pathways, including apoptosis. This multicenter prospective observational study was designed to ascertain whether an oxidant/antioxidant imbalance is an independent sepsis discriminator and mortality predictor in intensive care unit (ICU) patients with sepsis (n = 145), compared to non-infectious critically ill patients (n = 112) and healthy individuals (n = 89). Serum total oxidative status (TOS) and total antioxidant capacity (TAC) were measured by photometric testing. IL-6, -8, -10, -27, Hsp72/90 (ELISA), and selected antioxidant biomolecules (Ζn, glutathione) were correlated with apoptotic mediators (caspase-3, capsase-9) and the central anti-apoptotic survivin protein (ELISA, real-time PCR). A wide scattering of TOS, TAC, and TOS/TAC in all three groups was demonstrated. Septic patients had an elevated TOS/TAC, compared to non-infectious critically ill patients and healthy individuals (p = 0.001). TOS/TAC was associated with severity scores, procalcitonin, IL-6, -10, -27, IFN-γ, Hsp72, Hsp90, survivin protein, and survivin isoforms -2B, -ΔΕx3, -WT (p < 0.001). In a propensity probability (age-sex-adjusted) logistic regression model, only sepsis was independently associated with TOS/TAC (Exp(B) 25.4, p < 0.001). The AUCTOS/TAC (0.96 (95% CI = 0.93-0.99)) was higher than AUCTAC (z = 20, p < 0.001) or AUCTOS (z = 3.1, p = 0.002) in distinguishing sepsis. TOS/TAC, TOS, survivin isoforms -WT and -2B, Hsp90, IL-6, survivin protein, and repressed TAC were strong predictors of mortality (p < 0.01). Oxidant/antioxidant status is impaired in septic compared to critically ill patients with trauma or surgery and is related to anti-apoptotic, inflammatory, and innate immunity alterations. The unpredicted TOS/TAC imbalance might be related to undefined phenotypes in patients and healthy individuals.

Stress, Inflammation and Metabolic Biomarkers Are Associated with Body Composition Measures in Lean, Overweight, and Obese Children and Adolescents.

The aim of this study was to examine the associations between multiple indices of stress, inflammation and metabolism vs. body composition parameters in 121 (43 boys, 78 girls) children and adolescents, aged 5-15 y. Subjects were divided into two groups: normal weight (N) (N = 40, BMI z-score = -0.1923 ± 0.6), and overweight/obese (OB) (N = 81, BMI z-score = 2.1947 ± 1.4). All subjects completed the State-Trait Anxiety Inventory for Children (STAIC) and Children's Depression Inventory, and underwent cortisol measurements in hair, diurnal series of saliva, and morning serum. Circulating concentrations of high sensitivity C-reactive protein (hsCRP) and other inflammation biomarkers were also obtained. Body composition analysis was performed with a clinically validated, advanced bioimpedance apparatus (BIA), while heart rate variability (HRV) was measured as a stress biomarker by photoplethysmography (PPG). The OB group had a higher STAIC-state score, waist-to-hip ratio, skeletal muscle mass, and total and abdominal fat mass, and a lower percent fat-free mass (FFM) and bone density than the N group. HRV did not differ between the groups. In the entire population, percent fat mass correlated strongly with circulating hsCRP (r = 0.397, p = 0.001), ferritin, and other inflammatory biomarkers, as well as with indices of insulin resistance. A strong correlation between serum hsCRP and hair cortisol was also observed (r = 0.777, p < 0.001), suggesting interrelation of chronic stress and inflammation. Thus, body fat accumulation in children and adolescents was associated with an elevation in clinical and laboratory biomarkers of stress, inflammation, and insulin resistance. BIA-ACC and PPG can be utilized as a direct screening tool for assessing overweight- and obesity -related health risks in children and adolescents.

Seroepidemiology of SARS-CoV-2 in pediatric population during a 16-month period prior to vaccination.

Limited prospective serosurveillance data in children regarding severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. We prospectively investigated SARS-CoV-2 seropositivity in children during a 16-month period of the coronavirus disease 2019 (COVID-19) pandemic, including the four waves of the pandemic, before SARS-CoV-2 adolescents' vaccination. Serum samples from children admitted to the major tertiary Greek pediatric hospital for any cause, except for COVID-19 infection, were randomly collected from 05/2020 to 08/2021. The study period was divided into four 4-month periods representing relevant epidemic waves. Total SARS-CoV-2 antibodies for nucleocapsid protein were determined using the Elecsys® Anti-SARS-CoV-2 reagent. A total of 3099 children (0-16 years) were included in the study. A total of 344 (11.1%) seropositive children were detected (males: 205 [59.5%]; median age [interquartile range [IQR]]: 3 years [0.6-10]). Seropositivity rates (%) increased during the four 4-month periods: 1.4%, 8.6%, 17.2%, and 17.6%, respectively. A correlation of seropositivity rates in children with new diagnosed SARS-CoV-2 cases in the community was detected. No significant differences were detected between males and females. Seropositivity was significantly higher in hospitalized than in nonhospitalized children and in non-Greek compared to Greek children (p < 0.001). The lowest seropositivity rate before school opening (9/2021) was detected in the age groups 6-12 years (14.4%) and 12-16 years (16.1%). However, compared with the other age groups, the lowest median antibody titers were observed in children 0-1 year (median [IQR]: 13.9 cut-off index: [4.5-53.9] [p < 0.001]). Although the seropositivity of children was related to the community epidemic waves, the exposure was limited. Low seropositivity rates in school-age children support the need for SARS-CoV-2 immunization.

Elevated circulating endothelial microparticles (EMPs) in prepubertal children born preterm.

BACKGROUND: Endothelial microparticles (EMPs) act as early biomarkers of endothelial activation and damage. No studies have investigated EMPs in preterm-born individuals. METHODS: Sixty-three preterm-born children and 52 children born full-term (controls) were studied. Circulating CD62E(+), CD144(+), and CD31(+)/CD42b(-) EMPs were measured in preterm-born children compared to controls; possible associations with cardiovascular risk factors and endothelial function parameters were also assessed. RESULTS: Circulating CD62E(+), CD144(+), and CD31(+)/CD42b(-) EMPs were significantly higher in preterm-born children compared to controls (p = 0.003, p < 0.001, and p < 0.001, respectively). Preterm birth was recognized as an independent predictor of each EMP subpopulation studied; moreover, the mean pressure and velocity of pulmonary artery were independently correlated with CD62E(+) (ß = 0.20, p = 0.04) and CD144(+) EMPs (ß = 0.22, p = 0.02), respectively, whereas age (ß = 0.21, p = 0.03) and being born SGA (ß = 0.26, p = 0.01) correlated independently with CD31(+)/CD42b(-) EMPs in the study population. Furthermore, diastolic blood pressure (ß = 0.24, p = 0.04), being born SGA (ß = 0.24, p = 0.04) and the hyperemic peak velocity of the brachial artery (ß = -0.65, p = 0.02) were independently associated with CD31(+)/CD42b(-) EMPs in the preterm-born group. CONCLUSION: Circulating EMPs were higher in preterm-born children compared to children born full-term. Whether EMPs could act, in clinical practice, as a complementary tool for non-invasive evaluation of endothelium in preterm-born children, remains under investigation. IMPACT: Circulating endothelial microparticles (EMPs) are small membrane vesicles released from endothelial cells and they act as novel biomarkers of endothelial activation and damage. No studies have investigated circulating EMPs in preterm-born individuals. Circulating EMPs were significantly higher in prepubertal preterm-born children compared to children born at term. In the preterm-born group, the hyperemic peak velocity of the brachial artery was independently associated with CD31(+)/CD42b(-) EMPs. Whether assessment of circulating EMPs could act, in clinical practice, as a complementary tool for non-invasive evaluation of endothelium in preterm-born children, remains to be defined in future investigations.

Sustained but Declining Humoral Immunity Against SARS-CoV-2 at 9 Months Postvaccination With BNT162b2: A Prospective Evaluation in 309 Healthy Individuals.

The sustainability of coronavirus 19 (COVID-19) vaccine-induced immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to be determined to inform public health decisions on vaccination programs and prevention measures against COVID-19. The aim of the present study was to prospectively evaluate the kinetics of neutralizing antibodies (NAbs) and anti-S-receptor binding domain (RBD IgGs) against SARS-CoV-2 after full vaccination with the BNT162b2 mRNA vaccine for up to 9 months in healthy individuals (NCT04743388). The assessments were performed at the following time points after the second vaccination: 2 weeks, 1 month, 3 months, 6 months, and 9 months. The measurements were performed with the GenScript's cPassTM SARS-CoV-2 NAbs Detection Kit (GenScript, Inc.; Piscataway, NJ) and the Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics GmbH; Mannheim, Germany). Three hundred nine participants with a median age of 48 years were included. A gradual decline in both NAbs and anti-S-RBD IgGs became evident from 2 weeks to 9 months postvaccination. Both NAbs and anti-S-RBD IgGs levels were significantly lower at 9 months compared with the previous timepoints. Interestingly, age was found to exert a statistically significant effect on NAbs elimination only during the first-trimester postvaccination, as older age was associated with a more rapid clearance of NAbs. Furthermore, simulation studies predicted that the median NAb value would fall from 66% at 9 months to 59% and 45% at 12 and 18 months postvaccination, respectively. This finding may reflect a declining degree of immune protection against COVID-19 and advocates for the administration of booster vaccine shots especially in areas with emerging outbreaks.

Low-Grade Systemic Inflammation Interferes with Anabolic and Catabolic Characteristics of the Aged Human Skeletal Muscle.

Aging is associated with the development of chronic low-grade systemic inflammation (LGSI) characterized by increased circulating levels of proinflammatory cytokines and acute phase proteins such as C-reactive protein (CRP). Collective evidence suggests that elevated levels of inflammatory mediators such as CRP, interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) are correlated with deteriorated skeletal muscle mass and function, though the molecular footprint of this observation in the aged human skeletal muscle remains obscure. Based on animal models showing impaired protein synthesis and enhanced degradation in response to LGSI, we compared here the response of proteolysis- and protein synthesis-related signaling proteins as well as the satellite cell and amino acid transporter protein content between healthy older adults with increased versus physiological blood hs-CRP levels in the fasted (basal) state and after an anabolic stimulus comprised of acute resistance exercise (RE) and protein feeding. Our main findings indicate that older adults with increased hs-CRP levels demonstrate (i) increased proteasome activity, accompanied by increased protein carbonylation and IKKα/ß phosphorylation; (ii) reduced Pax7+ satellite cells; (iii) increased insulin resistance, at the basal state; and (iv) impaired S6 ribosomal protein phosphorylation accompanied by hyperinsulinemia following an acute RE bout combined with protein ingestion. Collectively, these data provide support to the concept that age-related chronic LGSI may upregulate proteasome activity via induction of the NF-κB signaling and protein oxidation and impair the insulin-dependent anabolic potential of human skeletal muscle.

Comparative kinetics of SARS-CoV-2 anti-spike protein RBD IgGs and neutralizing antibodies in convalescent and naïve recipients of the BNT162b2 mRNA vaccine versus COVID-19 patients.

BACKGROUND: Coronavirus SARS-CoV-2, the causative agent of COVID-19, has caused a still evolving global pandemic. Given the worldwide vaccination campaign, the understanding of the vaccine-induced versus COVID-19-induced immunity will contribute to adjusting vaccine dosing strategies and speeding-up vaccination efforts. METHODS: Anti-spike-RBD IgGs and neutralizing antibodies (NAbs) titers were measured in BNT162b2 mRNA vaccinated participants (n = 250); we also investigated humoral and cellular immune responses in vaccinated individuals (n = 21) of this cohort 5 months post-vaccination and assayed NAbs levels in COVID-19 hospitalized patients (n = 60) with moderate or severe disease, as well as in COVID-19 recovered patients (n = 34). RESULTS: We found that one (boosting) dose of the BNT162b2 vaccine triggers robust immune (i.e., anti-spike-RBD IgGs and NAbs) responses in COVID-19 convalescent healthy recipients, while naïve recipients require both priming and boosting shots to acquire high antibody titers. Severe COVID-19 triggers an earlier and more intense (versus moderate disease) immune response in hospitalized patients; in all cases, however, antibody titers remain at high levels in COVID-19 recovered patients. Although virus infection promotes an earlier and more intense, versus priming vaccination, immune response, boosting vaccination induces antibody titers significantly higher and likely more durable versus COVID-19. In support, high anti-spike-RBD IgGs/NAbs titers along with spike (vaccine encoded antigen) specific T cell clones were found in the serum and peripheral blood mononuclear cells, respectively, of vaccinated individuals 5 months post-vaccination. CONCLUSIONS: These findings support vaccination efficacy, also suggesting that vaccination likely offers more protection than natural infection.

Kinetics of Anti-SARS-CoV-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2; A Prospective Study in 283 Health Workers.

The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111) (NCT04743388). 283 health workers were included in this study. NAbs showed a rapid increase from D8 to D36 at a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50, a slight decrease in NAbs values was detected and it became more prominent between D50 and D111 when the rate of decline was determined at -0.11 per day. The median (SD) NAbs value at D111 was 92.7% (11.8). A similar pattern was also observed for anti-S-RBD antibodies. Anti-S-RBDs showed a steeper increase during D22-D36 and a lower decline rate during D36-D111. Prior COVID-19 infection and younger age were associated with superior antibody responses over time. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals.

Novel Therapeutic Advances in ß-Thalassemia.

The main characteristic of the pathophysiology of ß-thalassemia is reduced ß-globin chain production. The inevitable imbalance in the α/ß-globin ratio and α-globin accumulation lead to oxidative stress in the erythroid lineage, apoptosis, and ineffective erythropoiesis. The result is compensatory hematopoietic expansion and impaired hepcidin production that causes increased intestinal iron absorption and progressive iron overload. Chronic hemolysis and red blood cell transfusions also contribute to iron tissue deposition. A better understanding of the underlying mechanisms led to the detection of new curative or "disease-modifying" therapeutic options. Substantial evolvement has been made in allogeneic hematopoietic stem cell transplantation with current clinical trials investigating new condition regimens as well as different donors and stem cell source options. Gene therapy has also moved forward, and phase 2 clinical trials with the use of ß-globin insertion techniques have recently been successfully completed leading to approval for use in transfusion-dependent patients. Genetic and epigenetic manipulation of the γ- or ß-globin gene have entered the clinical trial setting. Agents such as TGF-ß ligand traps and pyruvate kinase activators, which reduce the ineffective erythropoiesis, have been tested in clinical trials with favorable results. One TGF-ß ligand trap, luspatercept, has been approved for use in adults with transfusion-dependent ß-thalassemia. The induction of HbF with the phosphodiesterase 9 inhibitor IMR-687, which increase cyclic guanosine monophosphate, is currently being tested. Another therapeutic approach is to target the dysregulation of iron homeostasis, using, for example, hepcidin agonists (inhibitors of TMPRSS6 and minihepcidins) or ferroportin inhibitors (VIT-2763). This review provides an update on the novel therapeutic options that are presently in development at the clinical level in ß-thalassemia.

Increased Serum Concentrations of High Mobility Group Box 1 (HMGB1) Protein in Children with Autism Spectrum Disorder.

High mobility group box 1 protein (HMGB1) has been suggested to be involved in the immune dysfunction and inflammation reported in autism spectrum disorder (ASD). We aimed to assess HMGB1 serum concentrations (SCs) in high-functioning ASD children compared to typically developing (TD) controls and to explore their associations with the autism spectrum quotient (AQ), the empathy quotient (EQ), and the systemizing quotient (SQ). The study involved 42 ASD children and 38 TD children, all-male, aged between 6.1 and 13.3 years old. HMGB1 SCs were measured by enzyme-linked immunosorbent assay (ELISA). Groups were comparable regarding age, general IQ, birth weight, and maternal age at birth. ASD children showed significantly higher HMGB1 SCs compared to TD children (1.25 ± 0.84 ng/mL versus 1.13 ± 0.79 ng/mL, respectively, p = 0.039). The Spearman's rho revealed that HMGB1 SCs were positively correlated with the AQ attention to detail subscale (rs = 0.46, p = 0.045) and with the SQ total score (rs = 0.42, p = 0.04) in the ASD group. These results show that HMGB1 serum concentrations are altered in ASD children, and suggest that inflammatory processes mediated by HMGB1 may be associated with specific cognitive features observed in ASD.