Assessment of mortality and hospital admissions associated with confirmed infection with SARS-CoV-2 Alpha variant: a matched cohort and time-to-event analysis, England, October to December 2020.

BackgroundThe emergence of the SARS-CoV-2 Alpha variant in England coincided with a rapid increase in the number of PCR-confirmed COVID-19 cases in areas where the variant was concentrated.AimOur aim was to assess whether infection with Alpha was associated with more severe clinical outcomes than the wild type.MethodsLaboratory-confirmed infections with genomically sequenced SARS-CoV-2 Alpha and wild type between October and December 2020 were linked to routine healthcare and surveillance datasets. We conducted two statistical analyses to compare the risk of hospital admission and death within 28 days of testing between Alpha and wild-type infections: a matched cohort study and an adjusted Cox proportional hazards model. We assessed differences in disease severity by comparing hospital admission and mortality, including length of hospitalisation and time to death.ResultsOf 63,609 COVID-19 cases sequenced in England between October and December 2020, 6,038 had the Alpha variant. In the matched cohort analysis, we matched 2,821 cases with Alpha to 2,821 to cases with wild type. In the time-to-event analysis, we observed a 34% increased risk in hospitalisation associated with Alpha compared with wild type, but no significant difference in the risk of mortality.ConclusionWe found evidence of increased risk of hospitalisation after adjusting for key confounders, suggesting increased infection severity associated with the Alpha variant. Rapid assessments of the relative morbidity in terms of clinical outcomes and mortality associated with emerging SARS-CoV-2 variants compared with dominant variants are required to assess overall impact of SARS-CoV-2 mutations.

Impaired NLRP3 inflammasome activity during fetal development regulates IL-1ß production in human monocytes.

Interleukin-1ß (IL-1ß) production is impaired in cord blood monocytes. However, the mechanism underlying this developmental attenuation remains unclear. Here, we analyzed the extent of variability within the Toll-like receptor (TLR)/NLRP3 inflammasome pathways in human neonates. We show that immature low CD14 expressing/CD16(pos) monocytes predominate before 33 weeks of gestation, and that these cells lack production of the pro-IL-1ß precursor protein upon LPS stimulation. In contrast, high levels of pro-IL-1ß are produced within high CD14 expressing monocytes, although these cells are unable to secrete mature IL-1ß. The lack of secreted IL-1ß in these monocytes parallels a reduction of NLRP3 induction following TLR stimulation resulting in a lack of caspase-1 activity before 29 weeks of gestation, whereas expression of the apoptosis-associated speck-like protein containing a CARD and function of the P2×7 receptor are preserved. Our analyses also reveal a strong inhibitory effect of placental infection on LPS/ATP-induced caspase-1 activity in cord blood monocytes. Lastly, secretion of IL-1ß in preterm neonates is restored to adult levels during the neonatal period, indicating rapid maturation of these responses after birth. Collectively, our data highlight important developmental mechanisms regulating IL-1ß responses early in gestation, in part due to a downregulation of TLR-mediated NLRP3 expression. Such mechanisms may serve to limit potentially damaging inflammatory responses in a developing fetus.

Attenuated innate immune defenses in very premature neonates during the neonatal period.

BACKGROUND: Antimicrobial responses have been shown to be profoundly attenuated in very preterm neonates when examined on cord blood. However, we lack data on these responses at the time these neonates are most vulnerable to infections. METHODS: Multiple cytokine responses to two prototypic Toll-like receptor (TLR) agonists: lipopolysaccharide (LPS) (TLR4) and R848 (TLR7/8) were prospectively measured in preterm neonates born ≤30 wk of gestation (n = 50) during the first 28 d of age using whole blood and single-cell multiparameter flow cytometry assays. Results were compared to term neonates (n = 30) and adult controls (n = 25). RESULTS: In preterm neonates, LPS and R848 responses remained attenuated in both cord blood and in the first 28 d of age. These responses showed significant maturation over time after adjusting for gestational age and were confirmed in monocytes and dendritic cells on a per-cell basis. We detected no major contribution of chorioamnionitis, maternal antenatal corticosteroids or magnesium sulfate treatment, labor, or mode of delivery to the maturation of cytokine responses. CONCLUSION: Innate immune antimicrobial defenses are profoundly attenuated developmentally in very preterm neonates during the neonatal period, suggesting that exogenous factors drive the sustained systemic inflammation that has been linked to increased morbidities in these infants.

Comparison of differential protein expression of the marginal transitional zone in neonatal and weanling-aged foals.

The marginal transitional zone (MTZ) is peripherally located within the diarthrodial joint, and represents the junction of synovium, fibrous joint capsule, articular cartilage, periosteum, and bone. The purpose of this study is to characterize age-related differences in protein expression of matrix and molecular regulators in the marginal transitional zone of neonatal and weanling foals. Several families of proteins with known roles in cartilage and bone development are investigated, including matrix molecules, members of the Wnt signaling family, apoptotic factors and paracrine cell signaling molecules. Our results demonstrate differential protein expression in the marginal transitional zone from the lateral femoral trochlear ridge of neonatal and weanling foals. Protein expression of several paracrine signaling molecules (Ihh, PTHrP, PDGF, VEGF, ß-catenin, cytochrome C) within MTZ cartilage is higher in weanling-aged foals. Collagen type II and lubricin expression is similarly greater in weanling-aged foals, while matrix metalloproteinases are lower, likely reflecting the remodeling that occurs during cartilage development as increasing forces are placed on cartilage.

Neonatal sepsis due to coagulase-negative staphylococci.

Neonates, especially those born prematurely, are at high risk of morbidity and mortality from sepsis. Multiple factors, including prematurity, invasive life-saving medical interventions, and immaturity of the innate immune system, put these infants at greater risk of developing infection. Although advanced neonatal care enables us to save even the most preterm neonates, the very interventions sustaining those who are hospitalized concurrently expose them to serious infections due to common nosocomial pathogens, particularly coagulase-negative staphylococci bacteria (CoNS). Moreover, the health burden from infection in these infants remains unacceptably high despite continuing efforts. In this paper, we review the epidemiology, immunological risk factors, diagnosis, prevention, treatment, and outcomes of neonatal infection due to the predominant neonatal pathogen CoNS.

Identifying Sources of Lead Exposure for Children in the Republic of Georgia, with Lead Isotope Ratios.

In the Republic of Georgia, a 2018 national survey estimated that more than 40% of children aged 2-7 years had a blood lead concentration (BLC) of more than 5 µg/dL. The objective of this study was to document the feasibility of employing lead isotope ratios (LIRs) to identify and rank the Pb (lead) exposure sources most relevant to children across Georgia. A cross-sectional survey between November 2019 and February 2020 of 36 children previously identified as having BLCs > 5 µg/dL from seven regions of Georgia involved the collection of blood and 528 environmental samples, a questionnaire on behaviours and potential exposures. The LIRs in blood and environmental samples were analysed in individual children and across the whole group to ascertain clustering. A fitted statistical mixed-effect model to LIR data first found that the blood samples clustered with spices, tea, and paint, then, further isotopically distinct from blood were sand, dust, and soil, and lastly, milk, toys, pens, flour, and water. Analysis of the LIRs provided an indication and ranking of the importance of Pb environmental sources as explanatory factors of BLCs across the group of children. The findings support the deployment of interventions aimed at managing the priority sources of exposure in this population.

Differential Protein Expression of the Marginal Transitional Zone in Foals with Osteochondrosis.

The marginal transitional zone is peripherally located within the diarthrodial joint, and represents the interface of articular cartilage, periosteum, and the fibrous joint capsule. The purpose of this study is to characterize the protein expression of matrix and molecular regulators in the marginal transitional zone of foals having osteochondrosis (OC) compared to normal foals. Several families of proteins with known roles in cartilage and bone development are investigated, including matrix molecules, Wnt signaling, apoptotic factors and paracrine cell signaling molecules. Our results demonstrate differential protein expression in the marginal transitional zone from the lateral femoral trochlear ridge of foals affected by osteochondrosis. Alterations in protein expression of OC-affected foals mainly involve components of extracellular matrix homeostasis and canonical Wnt signaling. Matrix expression of collagen type IIB and lubricin are decreased and matrix metalloproteinase-3 expression is increased in OC-affected marginal transitional zone samples. Canonical Wnt signaling is inhibited in OC-affected marginal transitional zone samples, based on increased Dickkopf-1 and decreased ß-catenin protein expression. Most apoptotic and paracrine signaling proteins are not altered in OC-affected marginal transitional zone samples.

The Use of Pb Isotope Ratios to Determine Environmental Sources of High Blood Pb Concentrations in Children: A Feasibility Study in Georgia.

The incidence of lead (Pb) poisoning in children in Georgia has been identified as a major health concern, with a recent national survey identifying that 41% of children aged 2-7 years had blood lead concentrations (BLCs) greater than the blood lead reference value (BLRV) of ≥5 µg dL-1. This study collected samples of blood, spices, paint, soil, dust, flour, tea, toys, milk, and water from 36 households in Georgia where a child had previously been identified as having a BLC > BLRV. The Pb concentrations of these samples were determined and compared to Georgian reference values. Samples from 3 households were analysed for their Pb isotope composition. The Pb isotope composition of the environmental and blood samples were compared to identify the most likely source(s) of Pb exposure. This approach identified that some spice and dust samples were the likely sources of Pb in the blood in these cases. Importantly, some soil, paint, and dust sources with high Pb concentrations could be discounted as contributing to blood Pb based on their distinct isotope composition. The data presented demonstrate the significant contribution that Pb surveillance and Pb isotope ratio analyses can make to managing Pb exposure in regions where high BLCs are identified.

Penetration and impact of COVID-19 in long term care facilities in England: population surveillance study.

BACKGROUND: Long-term care facilities (LTCF) worldwide have suffered high rates of COVID-19, reflecting the vulnerability of the persons who live there and the institutional nature of care delivered. This study describes the impact of the pandemic on incidences and deaths in LTCF across England. METHODS: Laboratory-confirmed SARS-CoV-2 cases in England, notified to Public Health England from 01 Jan to 25 Dec 2020, were address-matched to an Ordnance Survey reference database to identify residential property classifications. Data were analysed to characterize cases and identify clusters. Associated deaths were defined as death within 60 days of diagnosis or certified as cause of death. RESULTS: Of 1 936 315 COVID-19 cases, 81 275 (4.2%) and 10 050 (0.52%) were identified as resident or staff in an LTCF, respectively, with 20 544 associated deaths in residents, accounting for 31.3% of all COVID-19 deaths. Cases were identified in 69.5% of all LTCFs in England, with 33.1% experiencing multiple outbreaks. Multivariable analysis showed a 67% increased odds of death in residents [adjusted odds ratio (aOR): 1.67, 95% confidence interval (CI): 1.63-1.72], compared with those not residing in LTCFs. A total of 10 321 outbreaks were identified at these facilities, of which 8.2% identified the first case as a staff member. CONCLUSIONS: Over two-thirds of LTCFs have experienced large and widespread outbreaks of COVID-19, and just under one-third of all COVID-19 deaths occurring in this setting in spite of early policies. A key implication of our findings is upsurges in community incidences seemingly leading to increased outbreaks in LTCFs; thus, identifying and shielding residents from key sources of infection are vital to reduce the number of future outbreaks.

Outbreak of Shiga toxin-producing Escherichia coli O157 linked with consumption of a fast-food product containing imported cucumbers, United Kingdom, August 2020.

BACKGROUND: In August 2020, an outbreak of Shiga toxin-producing Escherichia coli (STEC) O157:H7 occurred in the United Kingdom. Whole genome sequencing revealed that these cases formed a genetically distinct cluster. METHODS: Hypotheses generated from case interviews were tested in analytical studies, and results informed environmental sampling and food chain analysis. A case-case study used non-outbreak 'comparison' STEC cases; a case-control study used a market research panel to recruit controls. RESULTS: A total of 36 cases were identified; all cases reported symptom onset between August 3 and August 16, 2020. The majority of cases (83%) resided in the Midlands region of England and in Wales. A high proportion of cases reported eating out, with one fast-food restaurant chain mentioned by 64% (n = 23) of cases. Both the case-case study (adjusted odds ratio (aOR) 31.8, 95% confidence interval (CI) 1.6-624.9) and the case-control study (aOR 9.19, 95% CI 1.0-82.8) revealed statistically significant results, showing that the consumption of a specific fast-food product was independently associated with infection. CONCLUSIONS: Consumption of a specific fast-food product was a likely cause of this outbreak. The only ingredient specific to the product was cucumbers. The supply of cucumbers was immediately halted, and no further cases have been identified.

Cellular metabolism constrains innate immune responses in early human ontogeny.

Pathogen immune responses are profoundly attenuated in fetuses and premature infants, yet the mechanisms underlying this developmental immaturity remain unclear. Here we show transcriptomic, metabolic and polysome profiling and find that monocytes isolated from infants born early in gestation display perturbations in PPAR-γ-regulated metabolic pathways, limited glycolytic capacity and reduced ribosomal activity. These metabolic changes are linked to a lack of translation of most cytokines and of MALT1 signalosome genes essential to respond to the neonatal pathogen Candida. In contrast, they have little impact on house-keeping phagocytosis functions. Transcriptome analyses further indicate a role for mTOR and its putative negative regulator DNA Damage Inducible Transcript 4-Like in regulating these metabolic constraints. Our results provide a molecular basis for the broad susceptibility to multiple pathogens in these infants, and suggest that the fetal immune system is metabolically programmed to avoid energetically costly, dispensable and potentially harmful immune responses during ontogeny.

Inactivation of Cytomegalovirus in Breast Milk Using Ultraviolet-C Irradiation: Opportunities for a New Treatment Option in Breast Milk Banking.

Pasteurized donor human milk is provided by milk banks to very preterm babies where their maternal supply is insufficient or unavailable. Donor milk is currently processed by Holder pasteurization, producing a microbiologically safe product but significantly reducing immunoprotective components. Ultraviolet-C (UV-C) irradiation at 254 nm is being investigated as an alternative treatment method and has been shown to preserve components such as lactoferrin, lysozyme and secretory IgA considerably better than Holder pasteurization. We describe the inactivation of cytomegalovirus, a virus commonly excreted into breast milk, using UV-C irradiation. Full replication was ablated by various treatment doses. However, evidence of viral immediate early proteins within the cells was never completely eliminated indicating that some viral gene transcription was still occurring. In conclusion, UV-C may be a safe alternative to pasteurisation for the treatment of human donor milk that preserves the bioactivity. However, our data suggests that CMV inactivation will have to be carefully evaluated for each device designed to treat breast milk using UV-C irradiation.

Cardiac Autonomic Function at Baseline and under Stress and Its Relationship to Circulatory Markers of Inflammation in Obese Compared to Nonobese Children: A Pilot Study.

BACKGROUND/AIMS: The autonomic nervous system (ANS) provides neurogenic control of inflammatory reactions. ANS changes in obesity may result in inflammation. This study sought to gain insight into cardiac autonomic dysfunction and inflammation in childhood obesity, and to gather pilot data on the potential relationship between altered ANS and inflammation. METHODS: Fifteen obese children and adolescents without metabolic complications and 15 nonobese controls underwent heart rate variability and impedance cardiography testing during rest, mental stress, and physical stress. Inflammatory cytokines and immune reactivity were measured. RESULTS: There was no statistically significant difference between groups in cardiac ANS testing at rest or in response to stress. Median high-sensitivity C-reactive protein (hsCRP) was higher in the obese group [obese 2.6 mg/l (IQR 1.6-11.9); nonobese 0.3 mg/l (IQR 0.2-0.7); p < 0.001]. Interleukin-6 and tumour necrosis factor-α were similar between groups. Immune reactivity testing (in vitro Toll-like receptor stimulation) revealed a strong, but comparable, inflammatory response in both groups. CONCLUSIONS: Obese children and adolescents without metabolic complications did not have cardiac ANS dysfunction. While hsCRP was elevated, systemic cytokines were not raised. Compared to prior studies, which often focused on children with obesity and its complications, it is encouraging that obese children without metabolic complications may not yet have autonomic dysfunction.