The international perinatal outcomes in the pandemic (iPOP) study: Protocol

Preterm birth is the leading cause of infant death worldwide, but the causes of preterm birth are largely unknown. During the early COVID-19 lockdowns, dramatic reductions in preterm birth were reported; however, these trends may be offset by increases in stillbirth rates. It is important to study these trends globally as the pandemic continues, and to understand the underlying cause(s). Lockdowns have dramatically impacted maternal workload, access to healthcare, hygiene practices, and air pollution - all of which could impact perinatal outcomes and might affect pregnant women differently in different regions of the world. In the international Perinatal Outcomes in the Pandemic (iPOP) Study, we will seize the unique opportunity offered by the COVID-19 pandemic to answer urgent questions about perinatal health. In the first two study phases, we will use population-based aggregate data and standardized outcome definitions to: 1) Determine rates of preterm birth, low birth weight, and stillbirth and describe changes during lockdowns; and assess if these changes are consistent globally, or differ by region and income setting, 2) Determine if the magnitude of changes in adverse perinatal outcomes during lockdown are modified by regional differences in COVID-19 infection rates, lockdown stringency, adherence to lockdown measures, air quality, or other social and economic markers, obtained from publicly available datasets. We will undertake an interrupted time series analysis covering births from January 2015 through July 2020. The iPOP Study will involve at least 121 researchers in 37 countries, including obstetricians, neonatologists, epidemiologists, public health researchers, environmental scientists, and policymakers. We will leverage the most disruptive and widespread natural experiment of our lifetime to make rapid discoveries about preterm birth. Whether the COVID-19 pandemic is worsening or unexpectedly improving perinatal outcomes, our research will provide critical new information to shape prenatal care strategies throughout (and well beyond) the pandemic

Reduced IL-17A Secretion Is Associated with High Levels of Pneumococcal Nasopharyngeal Carriage in Fijian Children.

Streptococcus pneumonia (the pneumococcus) is the leading vaccine preventable cause of serious infections in infants under 5 years of age. The major correlate of protection for pneumococcal infections is serotype-specific IgG antibody. More recently, antibody-independent mechanisms of protection have also been identified. Preclinical studies have found that IL-17 secreting CD4+ Th17 cells in reducing pneumococcal colonisation. This study assessed IL-17A levels in children from Fiji with high and low pneumococcal carriage density, as measured by quantitative real-time PCR (qPCR). We studied Th17 responses in 54 children who were designated as high density carriers (N=27, >8.21x10(5) CFU/ml) or low density carriers (N=27, <1.67x10(5) CFU/ml). Blood samples were collected, and isolated peripheral blood mononuclear cells (PBMCs) were stimulated for 6 days. Supernatants were harvested for cytokine analysis by multiplex bead array and/or ELISA. Th17 cytokines assayed included IL-17A, IL-21, IL-22 as well as TNF-α, IL-10, TGF-β, IL-6, IL-23 and IFNγ. Cytokine levels were significantly lower in children with high density pneumococcal carriage compared with children with low density carriage for IL-17A (p=0.002) and IL-23 (p=0.04). There was a trend towards significance for IL-22 (p=0.057) while no difference was observed for the other cytokines. These data provide further support for the role of Th17-mediated protection in humans and suggest that these cytokines may be important in the defence against pneumococcal carriage

Factors associated with pneumococcal carriage and density in children and adults in Fiji, using four cross-sectional surveys.

This study describes predictors of pneumococcal nasopharyngeal carriage and density in Fiji. We used data from four annual (2012-2015) cross-sectional surveys, pre- and post-introduction of ten-valent pneumococcal conjugate vaccine (PCV10) in October 2012. Infants (5-8 weeks), toddlers (12-23 months), children (2-6 years), and their caregivers participated. Pneumococci were detected and quantified using lytA qPCR, with molecular serotyping by microarray. Logistic and quantile regression were used to determine predictors of pneumococcal carriage and density, respectively. There were 8,109 participants. Pneumococcal carriage was negatively associated with years post-PCV10 introduction (global P<0.001), and positively associated with indigenous iTaukei ethnicity (aOR 2.74 [95% CI 2.17-3.45] P<0.001); young age (infant, toddler, and child compared with caregiver participant groups) (global P<0.001); urban residence (aOR 1.45 [95% CI 1.30-2.57] P<0.001); living with ≥2 children <5 years of age (aOR 1.42 [95% CI 1.27-1.59] P<0.001); low family income (aOR 1.44 [95% CI 1.28-1.62] P<0.001); and upper respiratory tract infection (URTI) symptoms (aOR 1.77 [95% CI 1.57-2.01] P<0.001). Predictors were similar for PCV10 and non-PCV10 carriage, except PCV10 carriage was negatively associated with PCV10 vaccination (0.58 [95% CI 0.41-0.82] P = 0.002) and positively associated with exposure to household cigarette smoke (aOR 1.21 [95% CI 1.02-1.43] P = 0.031), while there was no association between years post-PCV10 introduction and non-PCV10 carriage. Pneumococcal density was positively associated with URTI symptoms (adjusted median difference 0.28 [95% CI 0.16, 0.40] P<0.001) and toddler and child, compared with caregiver, participant groups (global P = 0.008). Predictors were similar for PCV10 and non-PCV10 density, except infant, toddler, and child participant groups were not associated with PCV10 density. PCV10 introduction was associated with reduced the odds of overall and PCV10 pneumococcal carriage in Fiji. However, after adjustment iTaukei ethnicity was positively associated with pneumococcal carriage compared with Fijians of Indian Descent, despite similar PCV10 coverage rates

Cohort Profile: the COVID-19 in Pregnancy in Scotland (COPS) dynamic cohort of pregnant women to assess effects of viral and vaccine exposures on pregnancy

Funding: EAVE II is funded by the Medical Research Council (MR/R008345/1) with the support of BREATHE—the Health Data Research Hub for Respiratory Health [MC_PC_19004] which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Additional EAVE II support has been provided through the Scottish Government DG Health and Social Care. COPS receive additional funding from Tommy’s Charity (Charity number 1060508; SC039280) and is supported by Sands (Charity number 299679). S.J.S. is supported by the Wellcome Trust (209560/Z/17/Z). S.V.K. acknowledges funding from an NRS Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2) and the Scottish Government Chief Scientist Office (SPHSU17). B.A. was supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No.813546, the Baily Thomas Charitable Fund, the Data Driven Innovation and the UK Economic and Social Research Council (ES/N018877/1) during the course of this work.Publisher PDFPeer reviewe

Effect of a pneumococcal whole cell vaccine on influenza A-induced pneumococcal otitis media in infant mice.

The pneumococcus remains a common cause of otitis media (OM) despite the widespread introduction of pneumococcal conjugate vaccines. In mice, a pneumococcal whole cell vaccine (WCV) induces serotype-independent protection against pneumococcal colonisation and invasive disease via TH17- and antibody-mediated immunity, respectively. We investigated the effect of WCV on influenza A-induced pneumococcal OM in an infant mouse model. C57BL/6 mice were immunised subcutaneously with a single dose of WCV or adjuvant at 6 days of age, infected with pneumococci (EF3030 [serotype 19F] or PMP1106 [16F]) at 12 days of age, and given influenza A virus (A/Udorn/72/307 [H3N2], IAV) at 18 days of age to induce pneumococcal OM. Pneumococcal density in middle ear and nasopharyngeal tissues was determined 6 and 12 days post-virus. Experiments were repeated in antibody (B6.μMT-/-)- and CD4+ T-cell-deficient mice to investigate the immune responses involved. A single dose of WCV did not prevent the development of pneumococcal OM, nor accelerate pneumococcal clearance compared with mice receiving adjuvant alone. However, WCV reduced the density of EF3030 in the middle ear at 6 days post-viral infection (p = 0.022), and the density of both isolates in the nasopharynx at 12 days post-viral infection (EF3030, p = 0.035; PMP1106, p = 0.011), compared with adjuvant alone. The reduction in density in the middle ear required antibodies and CD4+ T cells: WCV did not reduce EF3030 middle ear density in B6.μMT-/- mice (p = 0.35) nor in wild-type mice given anti-CD4 monoclonal antibody before and after IAV inoculation (p = 0.91); and WCV-immunised CD4+ T cell-deficient GK1.5 mice had higher levels of EF3030 in the middle ear than their adjuvant-immunised counterparts (p = 0.044). A single subcutaneous dose of WCV reduced pneumococcal density in the middle ears of co-infected mice in one of two strains tested, but did not prevent OM from occurring in this animal model

Effect of ten-valent pneumococcal conjugate vaccine introduction on pneumonia hospital admissions in Fiji: a time-series analysis.

BACKGROUND: In October, 2012, Fiji introduced routine infant immunisation with a ten-valent pneumococcal conjugate vaccine (PCV10) using three primary doses and no booster dose (3 + 0 schedule). Data are scarce for the effect of PCV in the Asia and Pacific region. We aimed to evaluate the effect of PCV10 on pneumonia hospital admissions in children younger than 5 years and adults aged 55 years and older in Fiji, 5 years after vaccine introduction. METHODS: We did a time-series analysis assessing changes in pneumonia hospital admissions at three public tertiary hospitals in Fiji. Four pneumonia outcomes were evaluated: all-cause pneumonia, severe or very severe pneumonia, hypoxic pneumonia, and radiological pneumonia. Participants aged younger than 2 months, 2-23 months, 24-59 months, and 55 years and older were included. Data were extracted from the national hospital admission database according to International Classification of Diseases-tenth revision codes J10·0-18·9, J21, and J22 for all-cause pneumonia. Medical records and chest radiographs were reviewed for the main tertiary hospital to reclassify hospital admissions in children aged younger than 2 years as severe or very severe, hypoxic, or radiological pneumonia as per WHO definitions. Time-series analyses were done using the synthetic control method and multiple imputation to adjust for changes in hospital usage and missing data. FINDINGS: Between Jan 1, 2007, and Dec 31, 2017, the ratio of observed cases to expected cases for all-cause pneumonia was 0·92 (95% CI 0·70-1·36) for children aged younger than 2 months, 0·86 (0·74-1·00) for children aged 2-23 months, 0·74 (0·62-0·87) for children aged 24-59 months, and 1·90 (1·53-2·31) in adults aged 55 years and older, 5 years after PCV10 introduction. These findings indicate a reduction in all-cause pneumonia among children aged 24-59 months and an increase in adults aged 55 years and older, but no change among children aged younger than 2 months. Among children aged 2-23 months, we observed declines of 21% (95% CI 5-35) for severe or very severe pneumonia, 46% (33-56) for hypoxic pneumonia, and 25% (9-38) for radiological pneumonia. Mortality reduced by 39% (95% CI 5-62) for all-cause pneumonia, bronchiolitis, and asthma admissions in children aged 2-23 months. INTERPRETATION: The introduction of PCV10 was associated with a decrease in pneumonia hospital admissions in children aged 2-59 months. This is the first study in a middle-income country in the Asia and Pacific region to show the effect of PCV on pneumonia, filling gaps in the literature on the effects of PCV10 and 3 + 0 schedules. These data support decision making on PCV introduction for other low-income and middle-income countries in the region. FUNDING: Department of Foreign Affairs and Trade of the Australian Government

Effect of temperature on rates of ammonium uptake and nitrification in the western coastal Arctic during winter, spring, and summer

Biogeochemical rate processes in the Arctic are not currently well constrained, and there is very limited information on how rates may change as the region warms. Here we present data on the sensitivity of ammonium (NH4+) uptake and nitrification rates to short-term warming. Samples were collected from the Chukchi Sea off the coast of Barrow, Alaska, during winter, spring, and summer and incubated for 24h in the dark with additions of (NH4+)-N-15 at -1.5, 6, 13, and 20 degrees C. Rates of NH4+ uptake and nitrification were measured in conjunction with bacterial production. In all seasons, NH4+ uptake rates were highest at temperatures similar to current summertime conditions but dropped off with increased warming, indicative of psychrophilic (i.e., cold-loving) microbial communities. In contrast, nitrification rates were less sensitive to temperature and were higher in winter and spring compared to summer. These findings suggest that as the Arctic coastal ecosystem continues to warm, NH4+ assimilation may become increasingly important, relative to nitrification, although the magnitude of NH4+ assimilation would be still be lower than nitrification

Nitrogen fixation and transfer in open ocean diatom–cyanobacterial symbioses

Many diatoms that inhabit low-nutrient waters of the open ocean live in close association with cyanobacteria. Some of these associations are believed to be mutualistic, where N2-fixing cyanobacterial symbionts provide N for the diatoms. Rates of N2 fixation by symbiotic cyanobacteria and the N transfer to their diatom partners were measured using a high-resolution nanometer scale secondary ion mass spectrometry approach in natural populations. Cell-specific rates of N2 fixation (1.15–71.5 fmol N per cell h−1) were similar amongst the symbioses and rapid transfer (within 30 min) of fixed N was also measured. Similar growth rates for the diatoms and their symbionts were determined and the symbiotic growth rates were higher than those estimated for free-living cells. The N2 fixation rates estimated for Richelia and Calothrix symbionts were 171–420 times higher when the cells were symbiotic compared with the rates estimated for the cells living freely. When combined, the latter two results suggest that the diatom partners influence the growth and metabolism of their cyanobacterial symbionts. We estimated that Richelia fix 81–744% more N than needed for their own growth and up to 97.3% of the fixed N is transferred to the diatom partners. This study provides new information on the mechanisms controlling N input into the open ocean by symbiotic microorganisms, which are widespread and important for oceanic primary production. Further, this is the first demonstration of N transfer from an N2 fixer to a unicellular partner. These symbioses are important models for molecular regulation and nutrient exchange in symbiotic systems

Associations between ethnicity, social contact, and pneumococcal carriage three years post-PCV10 in Fiji.

BACKGROUND: Pneumococcal carriage is a prerequisite for pneumococcal disease. Little is known about whether social contact frequency and intensity are associated with pneumococcal carriage. In Fiji, indigenous iTaukei have higher prevalence of pneumococcal carriage compared with Fijians of Indian Descent (FID). We hypothesised that contact differences may contribute to ethnic differences in pneumococcal carriage prevalence and density. METHODS: In 2015, young infants (5-8 weeks), toddlers (12-23 months), children (2-6 years), and caregivers from Suva and surrounding areas, participated in a cross-sectional survey (n = 2014), three years post pneumococcal conjugate vaccine introduction. Demographic and contact data, and nasopharyngeal swabs were collected. Pneumococci were detected, and quantified using quantitative real-time PCR, with molecular serotyping by microarray. Associations between ethnicity, contact, and pneumococcal carriage and density were estimated using multivariable generalised estimating equation regression models. RESULTS: iTaukei participants had larger household sizes, higher pneumococcal carriage rates, more contacts, and more frequent contacts of longer duration, compared with FID. The odds of vaccine-type carriage increased by 28% (95% CI 8-53%) P < 0.01 in association with physical contact with 7-14 year old children. iTaukei ethnicity was associated with vaccine-type carriage (aOR) 1.73; 95% CI 1.06-2.82, P = 0.03) and non-vaccine type carriage (aOR 5.98; 95% CI 4.47-8.00, P < 0.01). Ethnicity and contact were not associated with pneumococcal density. CONCLUSIONS: iTaukei had greater frequency and intensity of contact compared with FID. Physical contact was associated with pneumococcal carriage. Observed differences in pneumococcal nasopharyngeal carriage prevalence between iTaukei and FID were not explained by differences in social contact patterns by ethnicity