Depth of anesthesia, temperature, and postoperative delirium in children and adolescents undergoing cardiac surgery.

BACKGROUND: After pediatric cardiosurgical interventions, postoperative delirium can occur, which can be associated with undesirable consequences during and after the hospital stay. It is therefore important to avoid any factors causing delirium as far as possible. Electroencephalogram (EEG) monitoring can be used during anesthesia to individually adjust dosages of hypnotically acting drugs. It is necessary to gain knowledge about the relationship between intraoperative EEG and postoperative delirium in children. METHODS: In a dataset comprising 89 children (53 male, 36 female; median age: 0.99 (interquartile range: 0.51, 4.89) years) undergoing cardiac surgery involving use of a heart-lung machine, relationships between depth of anesthesia as measured by EEG (EEG index: Narcotrend Index (NI)), sevoflurane dosage, and body temperature were analyzed. A Cornell Assessment of Pediatric Delirium (CAP-D) score ≥ 9 indicated delirium. RESULTS: The EEG could be used in patients of all age groups for patient monitoring during anesthesia. In the context of induced hypothermia, EEG monitoring supported individually adjusted sevoflurane dosing. The NI was significantly correlated with the body temperature; decreasing temperature was accompanied by a decreasing NI. A CAP-D score ≥ 9 was documented in 61 patients (68.5%); 28 patients (31.5%) had a CAP-D < 9. Delirious patients with an intubation time ≤ 24 h showed a moderate negative correlation between minimum NI (NImin) and CAP-D (rho = -0.41, 95% CI: -0.70 - -0.01, p = 0.046), i.e., CAP-D decreased with increasing NImin. In the analysis of all patients' data, NImin and CAP-D showed a weak negative correlation (rho = -0.21, 95% CI: -0.40 - 0.01, p = 0.064). On average, the youngest patients had the highest CAP-D scores (p = 0.002). Patients with burst suppression / suppression EEG had a longer median intubation time in the intensive care unit than patients without such EEG (p = 0.023). There was no relationship between minimum temperature and CAP-D score. CONCLUSIONS: The EEG can be used to individually adjust sevoflurane dosing during hypothermia. Of the patients extubated within 24 h and classified as delirious, patients with deeper levels of anesthesia had more severe delirium symptoms than patients with lighter levels of anesthesia.

Safety and Immunogenicity of an Inactivated Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine in a Subgroup of Healthy Adults in Chile.

BACKGROUND: The development of effective vaccines against coronavirus disease 2019 is a global priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 years in a phase 3 clinical trial. METHODS: Volunteers randomly received 2 doses of CoronaVac or placebo, separated by 2 weeks. A total of 434 volunteers were enrolled, 397 aged 18-59 years and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity. RESULTS: The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-receptor binding domain (RBD) immunoglobulin G (IgG) were 82.22% and 84.44% in the 18-59 year age group and 62.69% and 70.37% in the ≥60 year age group, 2 and 4 weeks after the second dose, respectively. A significant increase in circulating neutralizing antibodies was detected 2 and 4 weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T-cell responses characterized by the secretion of interferon-γ (IFN-γ) upon stimulation with Mega Pools of peptides from SARS-CoV-2. CONCLUSIONS: Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 years is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γ upon stimulation with SARS-CoV-2 antigens.

EEG monitoring during anesthesia in children aged 0 to 18 months: amplitude-integrated EEG and age effects.

BACKGROUND: The amplitude-integrated EEG (aEEG) is a widely used monitoring tool in neonatology / pediatric intensive care. It takes into account the amplitudes, but not the frequency composition, of the EEG. Advantages of the aEEG are clear criteria for interpretation and time compression. During the first year of life, the electroencephalogram (EEG) during sedation / anesthesia changes from a low-differentiated to a differentiated EEG; higher-frequency waves develop increasingly. There are few studies on the use of aEEG during pediatric anesthesia. A systematic evaluation of the aEEG in defined EEG stages during anesthesia / sedation is not yet available. Parameters of pediatric EEGs (power, median frequency, spectral edge frequency) recorded during anesthesia and of the corresponding aEEGs (upper and lower value of the aEEG trace) should be examined for age-related changes. Furthermore, it should be examined whether the aEEG can distinguish EEG stages of sedation / anesthesia in differentiated EEGs. METHODS: In a secondary analysis of a prospective observational study EEGs and aEEGs (1-channel recordings, electrode positions on forehead) of 50 children (age: 0-18 months) were evaluated. EEG stages: A (awake), Slow EEG, E2, F0, and F1 in low-differentiated EEGs and A (awake), B0-2, C0-2, D0-2, E0-2, F0-1 in differentiated EEGs. RESULTS: Median and spectral edge frequency increased significantly with age (p < 0.001 each). In low-differentiated EEGs, the power of the Slow EEG increased significantly with age (p < 0.001). In differentiated EEGs, the power increased significantly with age in each of the EEG stages B1 to E1 (p = 0.04, or less), and the upper and lower values of the aEEG trace increased with age (p < 0.001). A discriminant analysis using the upper and lower values of the aEEG showed that EEG epochs from the stages B1 to E1 were assigned to the original EEG stage in only 19.3% of the cases. When age was added as the third variable, the rate of correct reclassifications was 28.5%. CONCLUSIONS: The aEEG was not suitable for distinguishing EEG stages above the burst suppression range. For this purpose, the frequency composition of the EEG should be taken into account.

Pathogenicity island excision during an infection by Salmonella enterica serovar Enteritidis is required for crossing the intestinal epithelial barrier in mice to cause systemic infection.

Pathogenicity island excision is a phenomenon that occurs in several Salmonella enterica serovars and other members of the family Enterobacteriaceae. ROD21 is an excisable pathogenicity island found in the chromosome of S. Enteritidis, S. Dublin and S. Typhi among others, which contain several genes encoding virulence-associated proteins. Excision of ROD21 may play a role in the ability of S. Enteritidis to cause a systemic infection in mice. Our previous studies have shown that Salmonella strains unable to excise ROD21 display a reduced ability to colonize the liver and spleen. In this work, we determined the kinetics of ROD21 excision in vivo in C57BL/6 mice and its effect on virulence. We quantified bacterial burden and excision frequency in different portions of the digestive tract and internal organs throughout the infection. We observed that the frequency of ROD21 excision was significantly increased in the bacterial population colonizing mesenteric lymph nodes at early stages of the infective cycle, before 48 hours post-infection. In contrast, excision frequency remained very low in the liver and spleen at these stages. Interestingly, excision increased drastically after 48 h post infection, when intestinal re-infection and mortality begun. Moreover, we observed that the inability to excise ROD21 had a negative effect on S. Enteritidis capacity to translocate from the intestine to deeper organs, which correlates with an abnormal transcription of invA in the S. Enteritidis strain unable to excise ROD21. These results suggest that excision of ROD21 is a genetic mechanism required by S. Enteritidis to produce a successful invasion of the intestinal epithelium, a step required to generate systemic infection in mice.

Effect of age on Narcotrend Index monitoring during sevoflurane anesthesia in children below 2 years of age.

BACKGROUND: In older children, different electroencephalogram-based algorithms for measuring depth of anesthesia displayed a similar performance as in adults, but in infants they have not displayed the same reliability so far. According to the individual developmental state, the Narcotrend distinguishes "differentiated" electroencephalograms, which can be classified using the full Narcotrend Index scale, from "undifferentiated" electroencephalograms, which are classified using a scale with fewer stages. OBJECTIVE: The objective of this prospective clinical observational study was to assess the feasibility and performance of the Narcotrend monitor in children <2 years within a clinical setting. METHODS: Sixty-one children aged 0-24 months undergoing general anesthesia with sevoflurane and remifentanil for elective pediatric surgery were studied. We investigated the percentage of differentiated electroencephalograms and the correlation between multiples of minimal alveolar sevoflurane concentration and the Narcotrend Index according to age groups. Prediction probability was used to evaluate the performance of the Narcotrend Index for differentiation between consciousness and unconsciousness and between different sevoflurane concentrations. RESULTS: The percentage of differentiated electroencephalograms increased with increasing age (0-3 months: 23.8%, 4-5 months: 87.5%, 6-11 months: 92.3%, 12-24 months: 100%). The overall prediction probability of Narcotrend Index was 1.0 (SE 0.05) for differentiation between awake and loss of consciousness and 1.0 (SE 0.01) for differentiation between anesthetized and return of consciousness. Spearman correlation analysis revealed a significant negative correlation between sevoflurane concentration and the Narcotrend Index (r = -0.78, P < .0001, 95%CI: -0.81 to -0.74). Overall prediction probability of Narcotrend Index to sevoflurane concentration was 0.8 (95%CI: 0.78-0.82). CONCLUSION: The Narcotrend monitor indicated a Narcotrend Index in most infants and young children starting from 4 months with significant correlation to and acceptable prediction probability for minimal alveolar sevoflurane concentration.

Optimization of initial propofol bolus dose for EEG Narcotrend Index-guided transition from sevoflurane induction to intravenous anesthesia in children.

BACKGROUND: Sevoflurane induction followed by intravenous anesthesia is a widely used technique to combine the benefits of an easier and less traumatic venipuncture after sevoflurane inhalation with a recovery with less agitation, nausea, and vomiting after total intravenous anesthesia (TIVA). Combination of two different anesthetics may lead to unwanted burst suppression in the electroencephalogram (EEG) during the transition phase. OBJECTIVE: The objective of this prospective clinical observational study was to identify the optimal initial propofol bolus dose for a smooth transition from sevoflurane induction to TIVA using the EEG Narcotrend Index (NI). METHODS: Fifty children aged 1-8 years scheduled for elective pediatric surgery were studied. After sevoflurane induction and establishing of an intravenous access, a propofol bolus dose range 0-5 mg·kg-1 was administered at the attending anesthetist's discretion to maintain a NI between 20 and 64, and sevoflurane was stopped. Anesthesia was continued as TIVA with a propofol infusion dose of 15 mg·kg-1 ·h-1 for the first 15 min, followed by stepwise reduction according to McFarlan's pediatric infusion regime, and remifentanil 0.25 µg·kg-1 ·min-1 . Endtidal concentration of sevoflurane, NI, and hemodynamic data were recorded during the whole study period using a standardized case report form. Propofol plasma concentrations were calculated using the paedfusor dataset and a TIVA simulation program. RESULTS: Median endtidal concentration of sevoflurane at the time of administration of the propofol bolus was 5.1 [IQR 4.7-5.9] Vol%. The median propofol bolus dose was 1.2 [IQR 0.9-2.5] mg·kg-1 and median NI thereafter was 33 [IQR 23-40]. Nine children presented with a NI 13-20 and three children with burst suppression in the EEG (NI 0-12); all of them received an initial propofol bolus dose >2 mg·kg-1 . Regression equation demonstrated that NI 20-64 was achieved with a 95% probability when using a propofol bolus dose of 1 mg·kg-1 after sevoflurane induction. Decrease in mean arterial blood pressure correlated significantly with propofol bolus dose (P = 0.038). After 25 min of TIVA, children younger than 2 years had a higher NI (median difference 14.0, 95%CI: 6.0-20.0, P = 0.001), higher deviations from the expected Narcotend Index (median difference 4.1, 95%CI: 3.9-4.2, P < 0.001) and lower calculated propofol plasma concentrations (median difference 0.2 µg·ml-1 , 95% CI: 0.1-0.3 µg·ml-1 , P < 0.001) than older children. CONCLUSION: After sevoflurane induction, a reduced propofol bolus dose of 1 mg·kg-1 followed by TIVA according to McFarlan's regime resulted in a NI within the recommended range in children aged 1-8 years. During the course of TIVA, children younger than 2 years displayed higher NI values and more pronounced interindividual variation. Processed EEG monitoring is recommended to find adequate individual age-dependent doses.

Women awaken faster than men after electroencephalogram-monitored propofol sedation for colonoscopy: A prospective observational study.

BACKGROUND: Sedation for colonoscopy using intravenous propofol has become standard in many Western countries. OBJECTIVE: Gender-specific differences have been shown for general anaesthesia in dentistry, but no such data existed for gastrointestinal endoscopy. DESIGN: A prospective observational study. SETTING: An academic teaching hospital of Hannover Medical School. PATIENTS: A total of 219 patients (108 women and 111 men) scheduled for colonoscopy. INTERVENTION: Propofol sedation using electroencephalogram monitoring during a constant level of sedation depth (D0 to D2) performed by trained nurses or physicians after a body-weight-adjusted loading dose. MAIN OUTCOME MEASURES: The primary end-point was the presence of gender-specific differences in awakening time (time from end of sedation to eye-opening and complete orientation); secondary outcome parameters analysed were total dose of propofol, sedation-associated complications (bradycardia, hypotension, hypoxaemia and apnoea), patient cooperation and patient satisfaction. Multivariate analysis was performed to correct confounding factors such as age and BMI. RESULTS: Women awakened significantly faster than men, with a time to eye-opening of 7.3 ±â€Š3.7 versus 8.4 ±â€Š3.4 min (P = 0.005) and time until complete orientation of 9.1 ±â€Š3.9 versus 10.4 ±â€Š13.7 min (P = 0.008). The propofol dosage was not significantly different, with some trend towards more propofol per kg body weight in women (3.98 ±â€Š1.81 mg versus 3.72 ±â€Š1.75 mg, P = 0.232). CONCLUSION: The effect of gender aspects should be considered when propofol is used as sedation for gastrointestinal endoscopy. That includes adequate dosing for women as well as caution regarding potential overdosing of male patients. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02687568).

How an acute care hospital reduced workplace violence injuries by more than 50 percent in a single year.

The formation of well trained, organized, and supervised clinical staff working in collaboration with security officers, has resulted in a reduction of work-place violence injuries to staff, according to the authors. In addition, the rate of restraint deployment for disruptive patients has also been reduced.

[Neuromonitoring in children - how deep does my patient sleep?]. / Neuromonitoring bei Kindern - Wie tief schläft mein Patient?

The electroencephalogram (EEG) of wakefulness, sleep, and anaesthesia changes during childhood. Especially marked are the changes during the first year of life. In the second half of the first year, in most children EEG stages can be classified visually and automatically during anaesthesia which are similar to those observed in older children. In the first months of life, the EEG of anaesthesia is less differentiated, but it is still useful in patient monitoring during anaesthesia.

Humoral and cellular response induced by a second booster of an inactivated SARS-CoV-2 vaccine in adults.

BACKGROUND: The Omicron variant has challenged the control of the COVID-19 pandemic due to its immuno-evasive properties. The administration of a booster dose of a SARS-CoV-2 vaccine showed positive effects in the immunogenicity against SARS-CoV-2, effect that is even enhanced after the administration of a second booster. METHODS: During a phase-3 clinical trial, we evaluated the effect of a second booster of CoronaVac®, an inactivated vaccine administered 6 months after the first booster, in the neutralization of SARS-CoV-2 (n = 87). In parallel, cellular immunity (n = 45) was analyzed in stimulated peripheral mononuclear cells by flow cytometry and ELISPOT. FINDINGS: Although a 2.5-fold increase in neutralization of the ancestral SARS-CoV-2 was observed after the second booster when compared with prior its administration (Geometric mean units p < 0.0001; Geometric mean titer p = 0.0002), a poor neutralization against the Omicron variant was detected. Additionally, the activation of specific CD4+ T lymphocytes remained stable after the second booster and, importantly, equivalent activation of CD4+ T lymphocytes against the Omicron variant and the ancestral SARS-CoV-2 were found. INTERPRETATION: Although the neutralizing response against the Omicron variant after the second booster of CoronaVac® was slightly increased, these levels are far from those observed against the ancestral SARS-CoV-2 and could most likely fail to neutralize the virus. In contrast, a robust CD4+T cell response may confer protection against the Omicron variant. FUNDING: The Ministry of Health, Government of Chile, the Confederation of Production and Commerce, Chile and SINOVAC Biotech.NIHNIAID. The Millennium Institute on Immunology and Immunotherapy.

Role of Extracellular Trap Release During Bacterial and Viral Infection.

Neutrophils are innate immune cells that play an essential role during the clearance of pathogens that can release chromatin structures coated by several cytoplasmatic and granular antibacterial proteins, called neutrophil extracellular traps (NETs). These supra-molecular structures are produced to kill or immobilize several types of microorganisms, including bacteria and viruses. The contribution of the NET release process (or NETosis) to acute inflammation or the prevention of pathogen spreading depends on the specific microorganism involved in triggering this response. Furthermore, studies highlight the role of innate cells different from neutrophils in triggering the release of extracellular traps during bacterial infection. This review summarizes the contribution of NETs during bacterial and viral infections, explaining the molecular mechanisms involved in their formation and the relationship with different components of such pathogens.

Distal Consequences of Mucosal Infections in Intestinal and Lung Inflammation.

Infectious diseases are one of the leading causes of morbidity and mortality worldwide, affecting high-risk populations such as children and the elderly. Pathogens usually activate local immune responses at the site of infection, resulting in both protective and inflammatory responses, which may lead to local changes in the microbiota, metabolites, and the cytokine environment. Although some pathogens can disseminate and cause systemic disease, increasing evidence suggests that local infections can affect tissues not directly invaded. In particular, diseases occurring at distal mucosal barriers such as the lung and the intestine seem to be linked, as shown by epidemiological studies in humans. These mucosal barriers have bidirectional interactions based mainly on multiple signals derived from the microbiota, which has been termed as the gut-lung axis. However, the effects observed in such distal places are still incompletely understood. Most of the current research focuses on the systemic impact of changes in microbiota and bacterial metabolites during infection, which could further modulate immune responses at distal tissue sites. Here, we describe how the gut microbiota and associated metabolites play key roles in maintaining local homeostasis and preventing enteric infection by direct and indirect mechanisms. Subsequently, we discuss recent murine and human studies linking infectious diseases with changes occurring at distal mucosal barriers, with particular emphasis on bacterial and viral infections affecting the lung and the gastrointestinal tract. Further, we discuss the potential mechanisms by which pathogens may cause such effects, promoting either protection or susceptibility to secondary infection.

Pre- and intraoperative cerebral near-infrared spectroscopy and postoperative delirium: Results of a prospective cross-sectional trial.

Postoperative delirium (PODE) is a serious complication that can occur during the first few days after surgery. A number of causes can make delirium more likely; one factor to consider is hypoxia during anesthesia. In this study, the pre- and intraoperative cerebral regional oxygen saturation (rSO2) as measured by near-infrared spectroscopy (NIRS) was to be examined with regard to an association with the occurrence of PODE in patients undergoing major abdominal procedures. Data from 80 patients (33 women, 47 men) was examined. The mean age was 66.31 ± 10.55 years (between 42 and 84 years). Thirteen patients developed PODE. The preoperative rSO2 values (P = .10) and the rSO2 values during the steady state of anesthesia (P = .06) tended to be lower in the delirium group than in the non-delirium group. There was a significant correlation between the preoperative rSO2 and the preoperative hemoglobin values (P < .001). The variance of rSO2 during the steady state of anesthesia was significantly greater in the delirium group compared to the non-delirium group (P = .03). In two patients from the delirium group, rSO2 dropped below 50%; they also had a minimum mean arterial pressure below 50 mm Hg, which could have disturbed cerebral autoregulation. The duration of rSO2 decreases (>10%, >15%, >20%) and increases (>10%) compared to the preoperative values was not significantly different between patients with and without PODE. The results suggest that NIRS could be a useful monitoring method for patients undergoing abdominal surgical procedures, on the one hand to recognize patients with low pre- or intraoperative rSO2 values, and on the other hand to detect changes in rSO2 values during anesthesia.

Limited Heme Oxygenase Contribution to Modulating the Severity of Salmonella enterica serovar Typhimurium Infection.

An important virulence trait of Salmonella enterica serovar Typhimurium (S. Typhimurium) is the ability to avoid the host immune response, generating systemic and persistent infections. Host cells play a crucial role in bacterial clearance by expressing the enzyme heme oxygenase 1 (Hmox1), which catalyzes the degradation of heme groups into Fe2+, biliverdin, and carbon monoxide (CO). The role of Hmox1 activity during S. Typhimurium infection is not clear and previous studies have shown contradictory results. We evaluated the effect of pharmacologic modulation of Hmox1 in a mouse model of acute and persistent S. Typhimurium infection by administering the Hmox1 activity inductor cobalt protoporphyrin-IX (CoPP) or inhibitor tin protoporphyrin-IX (SnPP) before infection. To evaluate the molecular mechanism involved, we measured the colocalization of S. Typhimurium and autophagosome and lysosomal markers in macrophages. Administering CoPP reduced the bacterial burden in organs of mice 5 days post-infection, while SnPP-treated mice showed bacterial loads similar to vehicle-treated mice. Furthermore, CoPP reduced bacterial loads when administered after infection in macrophages in vitro and in a persistent infection model of S. Typhimurium in vivo, while tin protoporphyrin-IX (SnPP) treatment resulted in a bacterial burden similar to vehicle-treated controls. However, we did not observe significant differences in co-localization of green fluorescent protein (GFP)-labeled S. Typhimurium with the autophagic vesicles marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and the lysosomal marker lysosomal-associated membrane protein 1 (LAMP-1) in macrophages treated with CoPP. Our results suggest that CoPP can enhance antimicrobial activity in response to Salmonella infection, reducing bacterial dissemination and persistence in mice, in a CO and autophagy- independent manner.

A booster dose of an inactivated SARS-CoV-2 vaccine increases neutralizing antibodies and T cells that recognize Delta and Omicron variants of concern.

Background: CoronaVac ® is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization. Previous studies reported increased levels of neutralizing antibodies and specific T cells two- and four-weeks after two doses of CoronaVac ® , but the levels of neutralizing antibodies are reduced at six to eight months after two doses. Here we report the effect of a booster dose of CoronaVac ® on the anti-SARS-CoV-2 immune response generated against variants of concern (VOC) Delta and Omicron in adults participating in a phase 3 clinical trial in Chile. Methods: Volunteers immunized with two doses of CoronaVac ® in a four-week interval received a booster dose of the same vaccine between twenty-four and thirty weeks after the 2nd dose. Four weeks after the booster dose, neutralizing antibodies and T cell responses were measured. Neutralization capacities and T cell activation against VOC Delta and Omicron were detected at four weeks after the booster dose. Findings: We observed a significant increase in neutralizing antibodies at four weeks after the booster dose. We also observed an increase in CD4 + T cells numbers over time, reaching a peak at four weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2 specific T cells induced by the booster showed activity against VOC Delta and Omicron. Interpretation: Our results show that a booster dose of CoronaVac ® increases the anti-SARS-CoV-2 humoral and cellular immune responses in adults. Immunity induced by a booster dose of CoronaVac ® is active against VOC, suggesting an effective protection.

Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial.

Background: The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. Methods: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac separated by 2 (0-14 schedule) or 4 weeks (0-28 schedule); 2302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured. Results: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4+ T cells for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion. Conclusions: Immunization with CoronaVac in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule. Funding: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. Clinical trial number: NCT04651790.

Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children.

Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4+ T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4+ T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4+ T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4+ T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.

A Booster Dose of CoronaVac Increases Neutralizing Antibodies and T Cells that Recognize Delta and Omicron Variants of Concern.

CoronaVac is an inactivated SARS-CoV-2 vaccine approved by the World Health Organization (WHO). Previous studies reported increased levels of neutralizing antibodies and specific T cells 2 and 4 weeks after two doses of CoronaVac; these levels were significantly reduced at 6 to 8 months after the two doses. Here, we report the effect of a booster dose of CoronaVac on the anti-SARS-CoV-2 immune response generated against the variants of concern (VOCs), Delta and Omicron, in adults participating in a phase III clinical trial in Chile. Volunteers immunized with two doses of CoronaVac in a 4-week interval received a booster dose of the same vaccine between 24 and 30 weeks after the second dose. Neutralization capacities and T cell activation against VOCs Delta and Omicron were assessed 4 weeks after the booster dose. We observed a significant increase in neutralizing antibodies 4 weeks after the booster dose. We also observed a rise in anti-SARS-CoV-2-specific CD4+ T cells over time, and these cells reached a peak 4 weeks after the booster dose. Furthermore, neutralizing antibodies and SARS-CoV-2-specific T cells induced by the booster showed activity against VOCs Delta and Omicron. Our results show that a booster dose of CoronaVac increases adults' humoral and cellular anti-SARS-CoV-2 immune responses. In addition, immunity induced by a booster dose of CoronaVac is active against VOCs, suggesting adequate protection. IMPORTANCE CoronaVac is an inactivated vaccine against SARS-CoV-2 that has been approved by WHO for emergency use. Phase III clinical trials are in progress in several countries, including China, Brazil, Turkey, and Chile, and have shown safety and immunogenicity after two doses of the vaccine. This report characterizes immune responses induced by two doses of CoronaVac followed by a booster dose 5 months after the second dose in healthy Chilean adults. The data reported here show that a booster dose increased the immune responses against SARS-CoV-2, enhancing levels of neutralizing antibodies against the ancestral strain and VOCs. Similarly, anti-SARS-CoV-2 CD4+ T cell responses were increased following the booster dose. In contrast, levels of gamma interferon secretion and T cell activation against the VOCs Delta and Omicron were not significantly different from those for the ancestral strain. Therefore, a third dose of CoronaVac in a homologous vaccination schedule improves its immunogenicity in healthy volunteers.

Intraoperative monitoring parameters and postoperative delirium: Results of a prospective cross-sectional trial.

ABSTRACT: Postoperative delirium (PODE) can be associated with severe clinical complications; therefore, preventive measures are important. The objective of this trial was to elucidate whether haemodynamic or electroencephalographic (EEG) monitoring parameters during general anaesthesia or sevoflurane dosage correlate with the incidence of PODE. In addition, sevoflurane dosages and EEG stages during the steady state of anaesthesia were analyzed in patients of different ages.Eighty adult patients undergoing elective abdominal surgery received anaesthesia with sevoflurane and sufentanil according to the clinical routine. Anaesthesiologists were blinded to the EEG. Haemodynamic parameters, EEG parameters, sevoflurane dosage, and occurrence of PODE were analyzed.Thirteen patients (4 out of 33 women, 9 out of 47 men) developed PODE. Patients with PODE had a greater mean arterial pressure (MAP) variance (267.26 (139.40) vs 192.56 (99.64) mmHg2, P = .04), had a longer duration of EEG burst suppression or suppression (27.09 (45.32) vs 5.23 (10.80) minutes, P = .03), and received higher minimum alveolar sevoflurane concentrations (MAC) (1.22 (0.22) vs 1.09 (0.17), P = .03) than patients without PODE. MAC values were associated with wide ranges of EEG index values representing different levels of hypnosis.The results suggest that, in order to prevent PODE, a great variance of MAP, higher doses of sevoflurane, and deep levels of anaesthesia should be avoided. Titrating sevoflurane according to end-tidal gas monitoring and vital signs can lead to unnecessarily deep or light hypnosis. Intraoperative EEG monitoring may help to prevent PODE.