The EPICure study: association between hemodynamics and lung function at 11 years after extremely preterm birth.

To investigate the relationship between disturbed lung function and large-artery hemodynamics in school-age children born extremely preterm (EP) (at 25 completed weeks of gestation or less)

Cycle-centrality in complex networks

Networks are versatile representations of the interactions between entities in complex systems. Cycles on such networks represent feedback processes which play a central role in system dynamics. In this work, we introduce a measure of the importance of any individual cycle, as the fraction of the total information flow of the network passing through the cycle. This measure is computationally cheap, numerically well-conditioned, induces a centrality measure on arbitrary subgraphs and reduces to the eigenvector centrality on vertices. We demonstrate that this measure accurately reflects the impact of events on strategic ensembles of economic sectors, notably in the US economy. As a second example, we show that in the protein-interaction network of the plant Arabidopsis thaliana, a model based on cycle-centrality better accounts for pathogen activity than the state-of-art one. This translates into pathogen-targeted-proteins being concentrated in a small number of triads with high cycle-centrality. Algorithms for computing the centrality of cycles and subgraphs are available for download

A demonstration of using formal consensus methods within guideline development; a case study

Background: Recommendations within guidelines are developed by synthesising the best available evidence; when limited evidence is identified recommendations are generally based on informal consensus. However, there are potential biases in group decision making, and formal consensus methods may help reduce these. Methods: We conducted a case study using formal consensus, to develop one set of recommendations within the Neonatal Parenteral Nutrition guideline being produced for the National Institute for Health and Care Excellence. Statements were generated through identification of published guidelines on several topics relating to neonatal parenteral nutrition. Ten high quality guidelines were included, and 28 statements were generated; these statements were rated by the committee via two rounds of voting. The statements which resulted in agreement were then used to develop the recommendations. Results: The approach was systematic and provided transparency. Additionally, a number of lessons were learnt; including the value of selecting the appropriate topic, giving adequate time to the process, and ensuring methodologies are understood by the committee for their value and relevance. Conclusion: Formal consensus is a valuable option for use within guideline development when specific criteria are met. The approach provides transparent methodology, ensuring clarity on how recommendations are developed

Cervical Mucus Properties Stratify Risk for Preterm Birth

Background: Ascending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of preterm birth. The primary physical barrier to microbial ascension is the cervical canal, which is filled with a dense and protective mucus plug. Despite its central role in separating the vaginal from the intrauterine tract, the barrier properties of cervical mucus have not been studied in preterm birth. Methods and Findings: To study the protective function of the cervical mucus in preterm birth we performed a pilot case-control study to measure the viscoelasticity and permeability properties of mucus obtained from pregnant women at high-risk and low-risk for preterm birth. Using extensional and shear rheology we found that cervical mucus from women at high-risk for preterm birth was more extensible and forms significantly weaker gels compared to cervical mucus from women at low-risk of preterm birth. Moreover, permeability measurements using fluorescent microbeads show that high-risk mucus was more permeable compared with low-risk mucus. Conclusions: Our findings suggest that critical biophysical barrier properties of cervical mucus in women at high-risk for preterm birth are compromised compared to women with healthy pregnancy. We hypothesize that impaired barrier properties of cervical mucus could contribute to increased rates of intrauterine infection seen in women with preterm birth. We furthermore suggest that a robust association of spinnbarkeit and preterm birth could be an effectively exploited biomarker for preterm birth prediction.Massachusetts Institute of Technology. Charles E. Reed Faculty Initiative FundBurroughs Wellcome Fund (Preterm Birth Research Grant)National Science Foundation (U.S.). Graduate Research Fellowship Progra

Development of lung function in very low birth weight infants with or without bronchopulmonary dysplasia: Longitudinal assessment during the first 15 months of corrected age

<p>Abstract</p> <p>Background</p> <p>Very low birth weight (VLBW) infants (< 1,500 g) with bronchopulmonary dysplasia (BPD) develop lung damage caused by mechanical ventilation and maturational arrest. We compared functional lung development after discharge from hospital between VLBW infants with and without BPD.</p> <p>Methods</p> <p>Comprehensive lung function assessment was performed at about 50, 70, and 100 weeks of postmenstrual age in 55 sedated VLBW infants (29 with former BPD [O₂supplementation was given at 36 weeks of gestational age] and 26 VLBW infants without BPD [controls]). Mean gestational age (26 vs. 29 weeks), birth weight (815 g vs. 1,125 g), and the proportion of infants requiring mechanical ventilation for ≥7 d (55% vs. 8%), differed significantly between BPD infants and controls.</p> <p>Results</p> <p>Both body weight and length, determined over time, were persistently lower in former BPD infants compared to controls, but no significant between-group differences were noted in respiratory rate, respiratory or airway resistance, functional residual capacity as determined by body plethysmography (FRC_pleth), maximal expiratory flow at the FRC (V'max _FRC), or blood gas (pO₂, pCO₂) levels. Tidal volume, minute ventilation, respiratory compliance, and FRC determined by SF6 multiple breath washout (representing the lung volume in actual communication with the airways) were significantly lower in former BPD infants compared to controls. However, these differences became non-significant after normalization to body weight.</p> <p>Conclusions</p> <p>Although somatic growth and the development of some lung functional parameters lag in former BPD infants, the lung function of such infants appears to develop in line with that of non-BPD infants when a body weight correction is applied. Longitudinal lung function testing of preterm infants after discharge from hospital may help to identify former BPD infants at risk of incomplete recovery of respiratory function; such infants are at risk of later respiratory problems.</p

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2

Although two-dose mRNA vaccination provides excellent protection against SARS-CoV-2, there is little information about vaccine efficacy against variants of concern (VOC) in individuals above eighty years of age1. Here we analysed immune responses following vaccination with the BNT162b2 mRNA vaccine2 in elderly participants and younger healthcare workers. Serum neutralization and levels of binding IgG or IgA after the first vaccine dose were lower in older individuals, with a marked drop in participants over eighty&nbsp;years old. Sera from participants above eighty showed lower neutralization potency against the B.1.1.7 (Alpha), B.1.351 (Beta) and P.1. (Gamma) VOC than against the wild-type virus and were more likely to lack any neutralization against VOC following the first dose. However, following the second dose, neutralization against VOC was detectable regardless of age. The frequency of SARS-CoV-2 spike-specific memory B cells was higher in elderly responders (whose serum showed neutralization activity) than in non-responders after the first dose. Elderly participants showed a clear reduction in somatic hypermutation of class-switched cells. The production of interferon-γ and interleukin-2 by SARS-CoV-2 spike-specific T cells was lower in older participants, and both cytokines were secreted primarily by CD4 T cells. We conclude that the elderly are a high-risk population and that specific measures to boost vaccine responses in this population are warranted, particularly where variants of concern are circulating

SARS-CoV-2 B.1.617.2 Delta variant replication and immune evasion

The B.1.617.2 (Delta) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in the state of Maharashtra in late 2020 and spread throughout India, outcompeting pre-existing lineages including B.1.617.1 (Kappa) and B.1.1.7 (Alpha)1. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era

SARS-CoV-2 spike N-terminal domain modulates TMPRSS2-dependent viral entry and fusogenicity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike N-terminal domain (NTD) remains poorly characterized despite enrichment of mutations in this region across variants of concern (VOCs). Here, we examine the contribution of the NTD to infection and cell-cell fusion by constructing chimeric spikes bearing B.1.617 lineage (Delta and Kappa variants) NTDs and generating spike pseudotyped lentivirus. We find that the Delta NTD on a Kappa or wild-type (WT) background increases S1/S2 cleavage efficiency and virus entry, specifically in lung cells and airway organoids, through use of TMPRSS2. Delta exhibits increased cell-cell fusogenicity that could be conferred to WT and Kappa spikes by Delta NTD transfer. However, chimeras of Omicron BA.1 and BA.2 spikes with a Delta NTD do not show more efficient TMPRSS2 use or fusogenicity. We conclude that the NTD allosterically modulates S1/S2 cleavage and spike-mediated functions in a spike context-dependent manner, and allosteric interactions may be lost when combining regions from more distantly related VOCs

Longitudinal analysis reveals that delayed bystander CD8+ T cell activation and early immune pathology distinguish severe COVID-19 from mild disease

The kinetics of the immune changes in COVID-19 across severity groups have not been rigorously assessed. Using immunophenotyping, RNA sequencing, and serum cytokine analysis, we analyzed serial samples from 207 SARS-CoV2-infected individuals with a range of disease severities over 12 weeks from symptom onset. An early robust bystander CD8+ T cell immune response, without systemic inflammation, characterized asymptomatic or mild disease. Hospitalized individuals had delayed bystander responses and systemic inflammation that was already evident near symptom onset, indicating that immunopathology may be inevitable in some individuals. Viral load did not correlate with this early pathological response but did correlate with subsequent disease severity. Immune recovery is complex, with profound persistent cellular abnormalities in severe disease correlating with altered inflammatory responses, with signatures associated with increased oxidative phosphorylation replacing those driven by cytokines tumor necrosis factor (TNF) and interleukin (IL)-6. These late immunometabolic and immune defects may have clinical implications