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Abstract Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

Objective: Non-contact respiratory rate estimation (RR) is highly desirable for infants because of their sensitive skin. We propose a novel RGB video-based RR estimation method for infants in the neonatal intensive care unit (NICU) that can accurately measure the RR contact-less.Methods and Procedures: We utilize Eulerian video magnification (EVM) method and develop an adaptive peak prominence threshold value estimation method to address challenges of RR estimation (e.g., dark environments, shallow breathing, babies swaddled or under blankets). We recruited 13 infants recorded for 4 consecutive hours per case. We then evaluate the performance of the algorithm for several (i.e., 19 to 25) randomly selected videos, each lasting 1 minute, for each case.Results: Intraclass correlation coefficients of the proposed method over manually and automatically selected ROIs are 0.91 (95%CI: $0.89-0.93$ ) and 0.88 (95%CI: $0.85-0.9$ ), indicating excellent and good reliability, respectively. The Bland-Altman analysis of the proposed algorithm shows higher agreement between the estimated values via the proposed method and visually counted RR than the agreement between the RR obtained from the impedance sensors and reference RR, and agreement between a former EVM-based method and reference RR values.Conclusion: Our algorithm shows promising results for RR estimation in a real-life NICU environment under various conditions that can confound the estimation.Clinical impact: We present a robust algorithm for non-contact neonatal respiratory rate monitoring, capable of performing well under various environmental lighting conditions in NICU, even when the infant is clothed or covered.

In many low-income countries, over five percent of hospitalized children die following hospital discharge. The lack of available tools to identify those at risk of post-discharge mortality has limited the ability to make progress towards improving outcomes. We aimed to develop algorithms designed to predict post-discharge mortality among children admitted with suspected sepsis. Four prospective cohort studies of children in two age groups (0-6 and 6-60 months) were conducted between 2012-2021 in six Ugandan hospitals. Prediction models were derived for six-months post-discharge mortality, based on candidate predictors collected at admission, each with a maximum of eight variables, and internally validated using 10-fold cross-validation. 8,810 children were enrolled: 470 (5.3%) died in hospital; 257 (7.7%) and 233 (4.8%) post-discharge deaths occurred in the 0-6-month and 6-60-month age groups, respectively. The primary models had an area under the receiver operating characteristic curve (AUROC) of 0.77 (95%CI 0.74-0.80) for 0-6-month-olds and 0.75 (95%CI 0.72-0.79) for 6-60-month-olds; mean AUROCs among the 10 cross-validation folds were 0.75 and 0.73, respectively. Calibration across risk strata was good: Brier scores were 0.07 and 0.04, respectively. The most important variables included anthropometry and oxygen saturation. Additional variables included: illness duration, jaundice-age interaction, and a bulging fontanelle among 0-6-month-olds; and prior admissions, coma score, temperature, age-respiratory rate interaction, and HIV status among 6-60-month-olds. Simple prediction models at admission with suspected sepsis can identify children at risk of post-discharge mortality. Further external validation is recommended for different contexts. Models can be digitally integrated into existing processes to improve peri-discharge care as children transition from the hospital to the community.

Sub-Saharan Africa accounts for two-thirds of the global burden of maternal and newborn deaths. Adverse outcomes among postpartum women and newborns occurring in the first six weeks of life are often related, though data co-examining patients are limited. This study is an exploratory analysis describing the epidemiology of postnatal complications among postpartum women and newborns following facility birth and discharge in Mbarara, Uganda. This single-site prospective cohort observational study enrolled postpartum women following facility-based delivery. To capture health information about both the postpartum women and newborns, data was collected and categorized according to domains within the continuum of care including (1) social and demographic, (2) pregnancy history and antenatal care, (3) delivery, (4) maternal discharge, and (5) newborn discharge. The primary outcomes were readmission and mortality within the six-week postnatal period as defined by the WHO. Multivariable logistic regression was used to identify risk factors. Among 2930 discharged dyads, 2.8% and 9.0% of women and newborns received three or more postnatal visits respectively. Readmission and deaths occurred among 108(3.6%) and 25(0.8%) newborns and in 80(2.7%) and 0(0%) women, respectively. Readmissions were related to sepsis/infection in 70(88%) women and 68(63%) newborns. Adjusted analysis found that caesarean delivery (OR:2.91; 95%CI:1.5-6.04), longer travel time to the facility (OR:1.54; 95%CI:1.24-1.91) and higher maternal heart rate at discharge (OR:1.02; 95%CI:1.00-1.01) were significantly associated with maternal readmission. Discharge taken on all patients including maternal haemoglobin (per g/dL) (OR:0.90; 95%CI:0.82-0.99), maternal symptoms (OR:1.76; 95%CI:1.02-2.91), newborn temperature (OR:1.66; 95%CI:1.28-2.13) and newborn heart rate at (OR:1.94; 95%CI:1.19-3.09) were risk factors among newborns. Readmission and death following delivery and discharge from healthcare facilities is still a problem in settings with low rates of postnatal care visits for both women and newborns. Strategies to identify vulnerable dyads and provide better access to follow-up care, are urgently required.

The aim of this study was to examine the factors associated with mental health outcomes in school staff during the second year of the COVID-19 pandemic. Adapting the Transactional Model of Stress and Coping, we tested whether school staff who lived with others and adopted healthier behaviours (e.g., diet, physical activity) would be more likely to manage pandemic stressors, altering mental health outcomes. The current study included 2,343 school staff (60% teachers) from the greater Vancouver area in British Columbia, Canada, who completed the online questionnaire between February 3 and June 18, 2021 as part of a longitudinal study of COVID-19 impacts on schools. Results showed that participants’ perceived risk of getting COVID-19 was associated with poorer mental health among both male and female school staff. Furthermore, when perceived risk of COVID-19 was low, living with others reduced the negative impact of pandemic stressors on anxiety symptoms and dispositional optimism among female school staff. We detected no influence of health behaviours on the associations between stressors and mental health. Favorable health behaviours were also associated with lower anxiety and psychological distress among female school staff. These findings underlie the importance of proactive prevention and intervention strategies to address the mental health of school staff.

IntroductionIn low-income country settings, the first six weeks after birth remain a critical period of vulnerability for both mother and newborn. Despite recommendations for routine follow-up after delivery and facility discharge, few mothers and newborns receive guideline recommended care during this period. Prediction modelling of post-delivery outcomes has the potential to improve outcomes for both mother and newborn by identifying high-risk dyads, improving risk communication, and informing a patient-centered approach to postnatal care interventions. This study aims to derive post-discharge risk prediction algorithms that identify mother-newborn dyads who are at risk of re-admission or death in the first six weeks after delivery at a health facility.MethodsThis prospective observational study will enroll 7,000 mother-newborn dyads from two regional referral hospitals in southwestern and eastern Uganda. Women and adolescent girls aged 12 and above delivering singletons and twins at the study hospitals will be eligible to participate. Candidate predictor variables will be collected prospectively by research nurses. Outcomes will be captured six weeks following delivery through a follow-up phone call, or an in-person visit if not reachable by phone. Two separate sets of prediction models will be built, one set of models for newborn outcomes and one set for maternal outcomes. Derivation of models will be based on optimization of the area under the receiver operator curve (AUROC) and specificity using an elastic net regression modelling approach. Internal validation will be conducted using 10-fold cross-validation. Our focus will be on the development of parsimonious models (5–10 predictor variables) with high sensitivity (>80%). AUROC, sensitivity, and specificity will be reported for each model, along with positive and negative predictive values.DiscussionThe current recommendations for routine postnatal care are largely absent of benefit to most mothers and newborns due to poor adherence. Data-driven improvements to postnatal care can facilitate a more patient-centered approach to such care. Increasing digitization of facility care across low-income settings can further facilitate the integration of prediction algorithms as decision support tools for routine care, leading to improved quality and efficiency. Such strategies are urgently required to improve newborn and maternal postnatal outcomes. Clinical trial registrationhttps://clinicaltrials.gov/, identifier (NCT05730387).

Summary: Background: The COVID-19 pandemic has perturbed the seasonality of respiratory syncytial virus (RSV) infections. However, we lack data on how this impacted the severity of paediatric RSV cases. The objective of this study was to describe the clinical severity of RSV cases before, during and after pandemic measures in British Columbia (BC), Canada. Methods: Retrospective study of RSV cases from September 1st, 2017 to May 15th, 2023, with a review of RSV outcomes in children below 18 years old at BC's paediatric hospital. Temporal changes in RSV cases and hospitalisations were quantified using interrupted time series. Findings: BC experienced only 11 RSV cases (from 95,266 tests) between September 2020 and August 2021. This was followed by a resurgence of 9,529 RSV cases (219,566 tests [4.3% positive tests]) in 2021–22 and 8,215 cases (124,449 tests [6.6% positive tests]) in 2022–23, increased compared to 1,750 cases (48,664 tests [3.6% positive tests]) per corresponding yearly period in 2017–20. From September 2017 to May 2023, the median age of children with RSV at BC Children's Hospital increased from 8.7 [IQR: 2.0–26.0] to 19.6 [3.9–43.7] months per yearly period. More children were hospitalised in 2022–23 (n = 360), compared to 2017–20 (n = 168 per period) and 2021–22 (n = 172). However, we detected no increase in hospitalisations or ICU admissions in children born prematurely or with chronic cardiorespiratory conditions. Interpretation: The increased detection of symptomatic RSV cases in older children in 2021–22 and increased RSV-related hospitalisations in 2022–23 suggest a gradual increase in the pool of immunologically vulnerable children due to a prolonged lack of viral exposure. Funding: Government of Canada via its COVID-19 Immunity Task Force.

Introduction Severe bronchopulmonary dysplasia (BPD) is a well-known factor consistently associated with impaired cognitive outcomes. Regarding reported benefits on long-term neurodevelopmental outcomes, the potential adverse effects of high-dose docosahexaenoic acid (DHA) supplementation on this short-term neonatal morbidity need further investigations in infants born very preterm. This study will determine whether high-dose DHA enteral supplementation during the neonatal period is associated with the risk of severe BPD at 36 weeks’ postmenstrual age (PMA) compared with control, in contemporary cohorts of preterm infants born at less than 29 weeks of gestation.Methods and analysis As part of an Australian–Canadian collaboration, we will conduct an individual participant data (IPD) meta-analysis of randomised controlled trials targeting infants born at less than 29 weeks of gestation and evaluating the effect of high-dose DHA enteral supplementation in the neonatal period compared with a control. Primary outcome will be severe grades of BPD (yes/no) at 36 weeks’ PMA harmonised according to a recent definition that predicts early childhood morbidities. Other outcomes will be survival without severe BPD, death, BPD severity grades, serious brain injury, severe retinopathy of prematurity, patent ductus arteriosus and necrotising enterocolitis requiring surgery, sepsis, combined neonatal morbidities and growth. Severe BPD will be compared between groups using a multivariate generalised estimating equations log-binomial regression model. Subgroup analyses are planned for gestational age, sex, small-for-gestational age, presence of maternal chorioamnionitis and mode of delivery.Ethics and dissemination The conduct of each trial was approved by institutional research ethics boards and written informed consent was obtained from participating parents. A collaboration and data sharing agreement will be signed between participating authors and institutions. This IPD meta-analysis will document the role of DHA in nutritional management of BPD. Findings will be disseminated through conferences, media interviews and publications to peer-reviewed journals.PROSPERO registration number CRD42023431063.Trial registration number NCT05915806.

Background: Increasing the interval between the first and second SARS-CoV-2 vaccine doses enhances vaccine immunogenicity, however the optimal timing of the third vaccine is unknown. In this study, we investigated how the time interval between the first and second (V1–V2), or second and third (V2–V3) doses affects immunogenicity after three doses of the BNT162b2 (Comirnaty, Pfizer-BioNTech) vaccine. Methods: This is an observational cohort consisting of 360 participants enrolled in the COVID-19 Occupational Risks, Seroprevalence, and Immunity among Paramedics in Canada (CORSIP) study. Immune responses to BA.1 and other variants were measured from serum using an ACE2 competitive binding assay for surrogate SARS-CoV-2 neutralization. We fit a multiple linear regression model to estimate the independent association between both the V1–V2 and V2–V3 intervals and serum SARS-CoV-2 neutralization, while adjusting for age, sex, and the V3-to-blood collection interval. We examined vaccine dosing intervals as continuous variables and categorized them into quartiles. Results: The mean age was 40 years, 45% were female sex (at birth), and the median BA.1 surrogate neutralization was 61% (IQR 38–77%). The multivariate analysis indicated that longer V1–V2 (β = 0.1292, 95% CI: 0.04807–0.2104) and V2–V3 (β = 0.2653, 95% CI: 0.2291–0.3015) intervals were associated with increased surrogate neutralization of BA.1. These results were consistent when examining responses against Spike from other SARS-CoV-2 strains. When categorized into V2–V3 quartiles, the first (56–231 days), and second (231–266 days) quartiles demonstrated decreased BA.1 surrogate neutralization compared to the longest V2–V3 quartile (282–329 days). There was no significant difference in surrogate neutralization between the long (266–282 days) and longest (282–329 days) V2–V3 intervals. Conclusion: Longer intervals between first, second and third doses are independently associated with increased immunogenicity for all tested SARS-CoV-2 strains. Increasing the intervals between the second and third vaccine doses up to 8.9 months provided additive benefits increasing the immunogenicity of BNT162b2 vaccine schedules.

Objective To determine the SARS-CoV-2 seroprevalence among school workers within the Greater Vancouver area, British Columbia, Canada, after the first Omicron wave.Design Cross-sectional study by online questionnaire, with blood serology testing.Setting Three main school districts (Vancouver, Richmond and Delta) in the Vancouver metropolitan area.Participants Active school staff enrolled from January to April 2022, with serology testing between 27 January and 8 April 2022. Seroprevalence estimates were compared with data obtained from Canadian blood donors weighted over the same sampling period, age, sex and postal code distribution.Primary and secondary outcomes SARS-CoV-2 nucleocapsid antibody testing results adjusted for test sensitivity and specificity, and regional variation across school districts using Bayesian models.Results Of 1850 school staff enrolled, 65.8% (1214/1845) reported close contact with a COVID-19 case outside the household. Of those close contacts, 51.5% (625/1214) were a student and 54.9% (666/1214) were a coworker. Cumulative incidence of COVID-19 positive testing by self-reported nucleic acid or rapid antigen testing since the beginning of the pandemic was 15.8% (291/1845). In a representative sample of 1620 school staff who completed serology testing (87.6%), the adjusted seroprevalence was 26.5% (95% CrI 23.9% to 29.3%), compared with 32.4% (95% CrI 30.6% to 34.5%) among 7164 blood donors.Conclusion Despite frequent COVID-19 exposures reported, SARS-CoV-2 seroprevalence among school staff in this setting remained no greater than the community reference group. Results are consistent with the premise that many infections were acquired outside the school setting, even with Omicron.

Abstract Preterm infants are deficient in long-chain polyunsaturated fatty acids, especially docosahexaenoic acid (DHA), a fatty acid (FA) associated with an increase in bronchopulmonary dysplasia (BPD). In two previous randomized control trials, DHA supplementation did not reduce the risk of BPD. We examined the breast milk FA profile, collected 14 days after birth, of mothers who delivered before 29 weeks of gestation and who were supplemented with DHA-rich algae oil or a placebo within 72 h after birth as part of the MOBYDIck trial. Milk FA were analyzed by gas chromatography. The total amount of FA (mg/mL) was similar in both groups but the supplementation increased DHA (expressed as % of total FA, mean ± SD, treatment vs placebo, 0.95 ± 0.44% vs 0.34 ± 0.20%; P

ABSTRACT SARS-CoV-2 anti-spike antibody concentrations and angiotensin converting enzyme-2 (ACE-2) inhibition have been used as surrogates to live viral neutralizing antibody titers; however, validity among vaccinated individuals is unclear. We tested the correlation of these measures among vaccinated participants, and examined subgroups based on duration since vaccination and vaccine dosing intervals. We analyzed 120 samples from two-dose mRNA vaccinees without previous COVID-19. We calculated Spearman correlation coefficients between wild-type viral neutralizing antibody titers and: anti-spike (total and IgG), anti-receptor-binding-domain (RBD), and anti-N-terminal-domain (NTD) antibodies; and ACE-2 binding by RBD. We performed three secondary analyses, dichotomizing samples by the first vaccination-to-blood collection interval, second vaccination-to-blood collection interval, and by the vaccine dosing interval (all groups divided by the median), and compared correlation coefficients (Fisher’s Z test). Of 120 participants, 63 (53%) were women, 91 (76%) and 29 (24%) received BNT162b2 and mRNA-1273 vaccines, respectively. Overall, live viral neutralization was correlated with anti-spike total antibody (correlation coefficient = 0.80), anti-spike IgG (0.63), anti-RBD IgG (0.62), anti-NTD IgG (0.64), and RBD ACE2 binding (0.65). Samples with long (>158 days) first vaccination-to-blood collection and long (>71 days) second vaccination-to-blood collection intervals demonstrated higher correlation coefficients, compared with short groups. When comparing cases divided by short (≤39 days) versus long vaccine dosing intervals, only correlation with RBD-ACE-2 binding inhibition was higher in the long group. Among COVID-negative mRNA vaccinees, anti-spike antibody and ACE-2 inhibition concentrations are correlated with live viral neutralizing antibody titers. Correlation was stronger among samples collected at later durations from vaccination. IMPORTANCE Live viral neutralizing antibody titers are an accepted measure of immunity; however, testing procedures are labor-intensive. COVID-19 antibody and angiotensin converting enzyme-2 (ACE-2) levels have been used as surrogates to live viral neutralizing antibody titers; however, validity among vaccinated individuals is unclear. Using samples from 120 two-dose mRNA vaccinees without previous COVID-19, we found that live viral neutralization was correlated with COVID-19 antibody and ACE2 binding levels. When grouping samples by the time interval between vaccination and sample blood collection, samples collected over 158 days after the first vaccine and over 71 days from the second vaccine demonstrated stronger correlation between live viral neutralization titers and both antibody and ACE2 levels, in comparison to those collected earlier.

Abstract Intestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37 is an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1β) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1β. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NFκB signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by suppressing inflammatory signaling.

ABSTRACT We prospectively studied SARS-CoV-2 transmission at schools in an era of variants of concern, offering all close contacts serial viral asymptomatic testing up to 14 days. From the 69 primary cases detected in schools, 392 close contacts were identified and offered asymptomatic testing. A total of 229 (58%) were close school contacts, and of these, 3 tested positive (1.3%), 2 of which were detected through asymptomatic testing. This is in contrast to the 117 household contacts, where 43 (37%) went on to become secondary cases. Routine asymptomatic testing of close contacts should be examined in the context of local testing rates, preventive measures, programmatic costs, and health impacts of asymptomatic transmission. IMPORTANCE There is concern that schools may be a setting where asymptomatic infections might result in significant “silent” transmission of SARS-CoV-2, particularly after the emergence of more transmissible variants of concern. After the programmatic implementation of a strategy of asymptomatic testing of close COVID-19 contacts as part of contact tracing in the school setting, the majority of the secondary cases were still found to have occurred in home or social contacts. However, for the 6.2% of secondary cases that occurred in close school contacts, the majority were detected through asymptomatic testing. The potential added yield of this approach needs to be considered within the overall setting, including consideration of the local epidemiology, ongoing goals of case and contact management, additional costs, logistical challenges for families, and possible health impacts of asymptomatic transmission.

Background: The aim of this study was to: 1) assess mental health symptoms in Canadian school staff during the second year of the pandemic (Spring 2021) and compare these same outcomes to national representative samples, and 2: examine whether the number of hours of direct contact with students was a significant predictor of anxiety symptoms. Methods: Online data on anxiety symptoms, psychological distress, overall mental health, and demographic information was collected from 2,305 school staff in the greater Vancouver area between February 3 and June 18, 2021, as part of a seroprevalence study. Results: School staff reported significantly higher anxiety symptoms than a national representative survey in Spring 2021 and higher exposure contact time with students was significantly associated with anxiety symptoms, in addition to sex and age, but not level of education and ethnicity. School staff also reported poorer mental health and higher levels of psychological distress compared to pre-pandemic population measures. Limitations: Cross-sectional design, self-report measures. Conclusions: These results show that priorities to reduce mental health challenges are critical during a public health crisis, not only at the beginning, but also one year later. Ongoing proactive prevention and intervention strategies for school staff are warranted.

BackgroundThe purpose of this study was to explore factors associated with COVID-19 vaccine intentions among school staff as high vaccine uptake is essential to ensure schools return to normal activities.MethodsStaff (e.g., teachers, administrators, student support workers) from three urban school districts in the Greater Vancouver Area of British Columbia, Canada completed a survey between February and June 2021 (n = 2,393) on COVID-19 vaccine intentions and perceptions (i.e., acceptance of routine vaccines, benefits and risks of vaccination, susceptibility to, and severity of COVID-19, recommendation by authority figures, information mistrust and conspiracy beliefs) as part of a COVID-19 seroprevalence study. Confirmatory factor analysis followed by multiple logistic regression models adjusting for relevant covariates were used to identify vaccine perceptions uniquely associated with (a) intention to get the COVID-19 vaccine (intention), and (b) intention to get vaccinated right away (urgency).ResultsIn total, 95.4% of participants of the seroprevalence study completed the vaccine questionnaire, corresponding to 17.7% of the target population. Vaccine intention was associated with staff who valued expert recommendations (AOR = 10.5, 95% CI = 7.39–14.90) accepted routine vaccines (AOR = 1.94, 95% CI = 1.26–2.98) and perceived higher benefits (AOR = 1.29, 95% CI = 1.01–1.65) and lower safety risks of vaccination (AOR = 0.40, 95% CI = 0.29–0.54). Comparable associations were found with vaccine urgency. Perceived susceptibility to the COVID-19 virus was uniquely associated with vaccine urgency (AOR = 1.30, 95% CI = 1.05–1.61). A significant interaction effect (p = 0.01) revealed that staff who expressed mistrust in COVID-19 information intended to get vaccinated only if they also perceived high benefits of vaccination.ConclusionsEducation about the risks and benefits of COVID-19 vaccines from a trusted source had the strongest relationship with vaccine intentions among this occupational group. Notably, those who expressed mistrust in information still intended to get vaccinated if they also perceived strong benefits of the vaccine.

ABSTRACT While mRNA vaccines are highly efficacious against short-term COVID-19, long-term immunogenicity is less clear. We compared humoral immunogenicity between BNT162b2 and mRNA-1273 vaccines 6 months after the first vaccine dose, examining the wild-type strain and multiple Delta-variant lineages. Using samples from a prospective observational cohort study of adult paramedics, we included COVID-19-negative participants who received two BNT162b2 or mRNA-1273 vaccines, and provided a blood sample 170 to 190 days post first vaccine dose. We compared wild-type spike IgG concentrations using the Mann-Whitney U test. We also compared secondary outcomes of: receptor binding domain (RBD) wild-type antibody concentrations, and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to spike proteins from the wild-type strain and five Delta-variant lineages. We included 571 adults: 475 BNT162b2 (83%) and 96 mRNA-1273 (17%) vaccinees, with a mean age of 39 (SD = 10) and 43 (SD = 10) years, respectively. Spike IgG antibody concentrations were significantly higher (P

Objectives Few studies reported COVID-19 cases in schools during the 2020/21 academic year in a setting of uninterrupted in-person schooling. The main objective was to determine the SARS-CoV-2 seroprevalence among school staff in Vancouver public schools.Design Cumulative incident COVID-19 cases among all students and school staff based on public health data, with an embedded cross-sectional serosurvey among a school staff sample that was compared to period, age, sex and geographical location-weighted data from blood donors.Setting Vancouver School District (British Columbia, Canada) from kindergarten to grade 12.Participants Active school staff enrolled from 3 February to 23 April 2021 with serology testing from 10 February to 15 May 2021.Main outcome measures SARS-CoV-2 seroprevalence among school staff, based on spike (S)-based (unvaccinated staff) or N-based serology testing (vaccinated staff).Results Public health data showed the cumulative incidence of COVID-19 among students attending in-person was 9.8 per 1000 students (n=47 280), and 13 per 1000 among school staff (n=7071). In a representative sample of 1689 school staff, 78.2% had classroom responsibilities, and spent a median of 17.6 hours in class per week (IQR: 5.0–25 hours). Although 21.5% (363/1686) of surveyed staff self-reported close contact with a COVID-19 case outside of their household (16.5% contacts were school-based), 5 cases likely acquired the infection at school based on viral testing. Sensitivity/Specificity-adjusted seroprevalence in 1556/1689 staff (92.1%) was 2.3% (95% CI: 1.6% to 3.2%), comparable to a sex, age, date and residency area-weighted seroprevalence of 2.6% (95% CI: 2.2% to 3.1%) among 5417 blood donors.Conclusion Seroprevalence among staff was comparable to a reference group of blood donors from the same community. These data show that in-person schooling could be safely maintained during the 2020/21 school year with mitigation measures, in a large school district in Vancouver, Canada.

ABSTRACT SARS-CoV-2 seroprevalence studies may be complicated by vaccination efforts. It is important to characterize the ability of serology methods to correctly distinguish prior infection from postvaccination seroreactivity. We report the performance of the Meso Scale Discovery (MSD) V-PLEX COVID-19 Coronavirus Panel 2 IgG assay. Using serum samples from a prospective cohort of paramedics, we calculated the performance of the V-PLEX nucleocapsid (“N”) assay to classify prior SARS-CoV-2 infections, defined as a (i) history of a positive SARS-CoV-2 PCR test or (ii) positive serology results using the Roche Elecsys total nucleocapsid anti-SARS-Cov-2 assay. We calculated sensitivity and specificity at the optimal threshold (defined by the highest Youden index). We compared subgroups based on vaccination status, and between models that excluded prior infections 3 to 12 months before sample collection. Of 1119 participants, 914 (81.7%) were vaccinated and 60 (5.4%) had evidence of a preceding SARS-CoV-2 infection. Overall and within vaccinated and unvaccinated subgroups, the optimal thresholds were 828 AU/mL, 827 AU/mL, and 1324 AU/mL; with sensitivities of 0.95 (95% CI: 0.94 to 0.96), 0.95 (0.94 to 0.96), 0.94 (0.92 to 0.96) and specificities of 0.88 (0.86 to 0.90), 0.87 (0.85 to 0.89), and 0.94 (0.89 to 0.98), respectively. N-assay specificity was significantly better in unvaccinated (versus vaccinated) individuals (P = 0.005). Overall optimal thresholds based on the AUC values were higher for samples from unvaccinated participants, especially when examining infections within the preceding 9 months (5855 versus 1704 AU/mL). Overall, V-PLEX nucleocapsid assay cutoff values were higher among unvaccinated individuals. Specificity was also significantly higher among unvaccinated individuals. Different thresholds were required to achieve optimal test performance, especially for detecting SARS-CoV-2 infections within the preceding 9 months. IMPORTANCE Among a cohort of adult paramedics in Canada, we investigated the performance of nucleocapsid (N) antibody detection (measured with a V-PLEX assay) to identify previous COVID-19 infections and compared differences among vaccinated and unvaccinated. Our data indicate that vaccinated and unvaccinated groups require different thresholds to achieve optimal test performance, especially for detecting COVID-19 within the preceding 9 months. Overall, specificity was significantly higher among unvaccinated, compared to vaccinated individuals.

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1.Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G > A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts.Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Newborns are frequently affected by mucocutaneous candidiasis. Th17 cells essentially limit mucosal invasion by commensal Candida spp. Here, we sought to understand the molecular basis for the developmental lack of Th17 cell responses in circulating blood neonatal T cells. Naive cord blood CD4 T cells stimulated in Th17-differentiating conditions inherently produced high levels of the interleukin-22 immunoregulatory cytokine, particularly in the presence of neonatal antigen-presenting cells. A genome-wide transcriptome analysis comparing neonatal and adult naïve CD4 T cells ex vivo revealed major developmental differences in gene networks regulating Small Drosophila Mothers Against Decapentaplegic (SMAD) and Signal Transducer and Activator of Transcription 3 (STAT3) signaling. These changes were functionally validated by experiments showing that the requirement for TGF-β in human Th17 cell differentiation is age-dependent. Moreover, STAT3 activity was profoundly diminished while overexpression of the STAT3 gene restored Th17 cell differentiation capacity in neonatal T cells. These data reveal that Th17 cell responses are developmentally regulated at the gene expression level in human neonates. These developmental changes may protect newborns against pathological Th17 cell responses, at the same time increasing their susceptibility to mucocutaneous candidiasis.

Preexisting cross-reactivity to SARS-CoV-2 occurs in the absence of prior viral exposure. However, this has been difficult to quantify at the population level due to a lack of reliably defined seroreactivity thresholds. Using an orthogonal antibody testing approach, we estimated that about 0.6% of nontriaged adults from the greater Vancouver, Canada, area between May 17 and June 19, 2020, showed clear evidence of a prior SARS-CoV-2 infection, after adjusting for false-positive and false-negative test results. Using a highly sensitive multiplex assay and positive/negative thresholds established in infants in whom maternal antibodies have waned, we determined that more than 90% of uninfected adults showed antibody reactivity against the spike protein, receptor-binding domain (RBD), N-terminal domain (NTD), or the nucleocapsid (N) protein from SARS-CoV-2. This seroreactivity was evenly distributed across age and sex, correlated with circulating coronaviruses’ reactivity, and was partially outcompeted by soluble circulating coronaviruses’ spike. Using a custom SARS-CoV-2 peptide mapping array, we found that this antibody reactivity broadly mapped to spike and to conserved nonstructural viral proteins. We conclude that most adults display preexisting antibody cross-reactivity against SARS-CoV-2, which further supports investigation of how this may impact the clinical severity of COVID-19 or SARS-CoV-2 vaccine responses.

Conducting collaborative and comprehensive epidemiological research on neonatal sepsis in low- and middle-income countries (LMICs) is challenging due to a lack of diagnostic tests. This prospective study protocol aims to obtain epidemiological data on bacterial sepsis in newborns and young infants at Kamuzu Central Hospital in Lilongwe, Malawi. The main goal is to determine if the use of whole blood transcriptome host immune response signatures can help in the identification of infants who have sepsis of bacterial causes. The protocol includes a detailed clinical assessment with vital sign measurements, strict aseptic blood culture protocol with state-of-the-art microbial analyses and RNA-sequencing and metagenomics evaluations of host responses and pathogens, respectively. We also discuss the directions of a brief analysis plan for RNA sequencing data. This study will provide robust epidemiological data for sepsis in neonates and young infants in a setting where sepsis confers an inordinate burden of disease.

The risk and severity of specific infections are increased during pregnancy due to a combination of physiological and immunological changes. Characterizing the maternal immune system during pregnancy is important to understand how the maternal immune system maintains tolerance towards the allogeneic fetus. This may also inform strategies to prevent maternal fatalities due to infections and optimize maternal vaccination to best protect the mother-fetus dyad and the infant after birth. In this review, we describe what is known about the immunological changes that occur during a normal pregnancy.

Animal experiments suggest that total liquid ventilation (TLV) induces less ventilator-induced lung injury (VILI) than conventional mechanical gas ventilation. However, TLV parameters that optimally minimize VILI in newborns remain unknown. Our objective was to compare lung inflammation between low (L-VT) and high (H-VT) liquid tidal volume and evaluate impacts on the weaning process. Sixteen anesthetized and paralyzed newborn lambs were randomized in an L-VT group (initial tidal volume of 10 mL/kg at 10/min) and an H-VT group (initial tidal volume of 20 mL/kg at 5/min). Five unventilated newborn lambs served as controls. After 4 h of TLV in the supine position, the lambs were weaned in the prone position for another 4 h. The levels of respiratory support needed during the 4 h post-TLV were compared. The anterior and posterior lung regions were assessed by a histological score and real-time quantitative PCR for IL1B, IL6, and TNF plus 12 other exploratory VILI-associated genes. All but one lamb were successfully extubated within 2 h post-TLV (72 ± 26 min vs. 63 ± 25 min, p = 0.5) with similar FiO2 at 4 h post-TLV (27 ± 6% vs. 33 ± 7%, p = 0.3) between the L-VT and H-VT lambs. No significant differences were measured in histological inflammation scores between L-VT and H-VT lambs, although lambs in both groups exhibited slightly higher scores than the control lambs. The L-VT group displayed higher IL1B mRNA expression than the H-VT group in both anterior (2.8 ± 1.5-fold increase vs. 1.3 ± 0.4-fold increase, p = 0.02) and posterior lung regions (3.0 ± 1.0-fold change increase vs. 1.1 ± 0.3-fold increase, p = 0.002), respectively. No significant differences were found in IL6 and TNF expression levels. Gene expression changes overall indicated that L-VT was associated with a qualitatively distinct inflammatory gene expression profiles compared to H-VT, which may indicate different clinical effects. In light of these findings, further mechanistic studies are warranted. In conclusion, we found no advantage of lower tidal volume use, which was in fact associated with a slightly unfavorable pattern of inflammatory gene expression.

Little is known about developmental set points of immune responses, especially in humans. Here the authors show that the metabolic state of monocytes isolated from prematurely born infants underlies attenuated responsiveness to fungal infection via selective control of protein translation.

Abstract Background Premature infants are highly vulnerable to infection. This is partly attributable to the preterm immune system, which differs from that of the term neonate in cell composition and function. Multiple studies have found differential DNA methylation (DNAm) between preterm and term infants’ cord blood; however, interpretation of these studies is limited by the confounding factor of blood cell composition. This study evaluates the epigenetic impact of preterm birth in isolated hematopoietic cell populations, reducing the concern of cell composition differences. Methods Genome-wide DNAm was measured using the Illumina 450K array in T cells, monocytes, granulocytes, and nucleated red blood cells (nRBCs) isolated from cord blood of 5 term and 5 preterm ( 0.10) discovered between preterm and term infants compared to the

Mitochondrial complex I is encoded by 38 nuclear-encoded and 7 mitochondrial-encoded genes. FOXRED1 is one of the 13 additional nuclear genes known as assembly factors. So far, four patients have been described with complex I deficiency caused by autosomal recessive mutations in FOXRED1.Here, we report the fifth patient with FOXRED1 related complex 1 deficiency presenting with prenatal onset of bilateral periventricular cysts, congenital lactic acidosis, and persistent life-limiting pulmonary hypertension. Whole exome sequencing identified a compound heterozygosity for a known pathogenic variant (c.612_615dupAGTG; p.A206SfsX15) (paternal) and a likely pathogenic variant (c.874G>A; p.Gly292Arg) (maternal). Deficiency of complex I was demonstrated by the absence of complex I on Blue Native Gel Electrophoresis and by a significantly reduced complex I enzyme activity in the patient's fibroblasts.Compared with the previous known FOXRED1 cases, unique clinical features observed in our patient include bilateral periventricular cysts and severe pulmonary hypertension. Whole exome sequencing was instrumental in recognizing the underlying gene defect in this patient.

Background: Neonates and infants comprise the majority of the 6 million annual deaths under 5 years of age around the world. Most of these deaths occur in low/middle income countries (LMICs) and are preventable. However, the clinical identification of neonates and infants at imminent risk of death is challenging in developing countries.Objective: To systematically review the literature on clinical risk factors for mortality in infants under 12 months of age hospitalized for sepsis or serious infections in LMICs.Methods: MEDLINE and EMBASE were systematically searched using MeSH terms through April 2017. Abstracts were independently screened by two reviewers. Subsequently, full-text articles were selected by two independent reviewers based on PICOS criteria for inclusion in the final analysis. Study data were qualitatively synthesized without quantitative pooling of data due to heterogeneity in study populations and methodology.Results: A total of 1,139 abstracts were screened, and 169 full-text articles were selected for text review. Of these, 45 articles were included in the analysis, with 21 articles featuring neonatal populations (under 28 days of age) exclusively. Most studies were from Sub-Saharan Africa and South Asia. Risk factors for mortality varied significantly according to study populations. For neonatal deaths, prematurity, low birth-weight and young age at presentation were most frequently associated with mortality. For infant deaths, malnutrition, lack of breastfeeding and low oxygen saturation were associated with mortality in the highest number of studies.Conclusions: Risk factors for mortality differ between the neonatal and young infant age groups and were also dependant on the study population. These data can serve as a starting point for the development of individualized predictive models for in-hospital and post-discharge mortality and for the development of interventions to improve outcomes among these high-risk groups.

Monthly injections of palivizumab during the respiratory syncytial virus (RSV) season in at-risk infants reduces RSV-associated hospitalizations. However, the additive effect of naturally acquired immunity remains unclear. The objective of this study was to assess total neutralizing serum antibodies (NAb) against RSV in at-risk infants who had received an abbreviated course of palivizumab prophylaxis.Serum samples were collected from infants enrolled in the RSV Immunoprophylaxis Program in British Columbia, Canada over 2 consecutive RSV seasons (2013 to 2015). Infants in this program had received an abbreviated course of palivizumab in accordance with the provincial guidelines. Data were compared to adults and infants less than 12 months of age who did not receive palivizumab. Anti-RSV NAb titers were measured using an RSV microneutralization assay.Infants who received palivizumab had anti-RSV NAb titers at the end of the RSV season that persisted beyond what is expected from the pharmacokinetics of palivizumab alone. Moreover, 54% of the control infants who did not receive palivizumab and all tested adults had protective anti-RSV NAb titers.Based on our observations, we hypothesize that naturally acquired NAb provide additive protection, which may significantly reduce the need for additional doses of palivizumab in infants at risk of severe RSV infections.