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Frontiers in Allergy 2024Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children,...
INTRODUCTION
Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, exposures, and respiratory exposures in the first year of life.
METHODS
The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to 5 years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to 6 weeks, 1, 3, and 5 years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal sampling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses.
DISCUSSION
The AERIAL study will provide a comprehensive longitudinal assessment of factors influencing the association between epithelial dysfunction and respiratory morbidity in early life, and hopefully identify novel targets for diagnosis and early intervention.
PubMed: 38666051
DOI: 10.3389/falgy.2024.1349741 -
EBioMedicine Dec 2023Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised...
Local fistula injection of allogeneic human amnion epithelial cells is safe and well tolerated in patients with refractory complex perianal Crohn's disease: a phase I open label study with long-term follow up.
BACKGROUND
Local fistula injection of mesenchymal stromal/stem cells (MSC) is effective for complex perianal Crohn's fistulas but is also expensive and requires specialised facilities for cell revival before administration. Human amnion epithelial cells (hAEC) are non-MSC cells with therapeutic properties. The primary aim of this study was safety of hAEC therapy. Secondary aims included hAEC efficacy, feasibility of the protocol and impact on quality of life.
METHODS
A phase I open label study of ten adults with active complex Crohn's perianal fistulas refractory to conventional treatment, including anti-tumour necrosis factor alpha therapy, was undertaken. A single dose of hAEC was injected into the fistula tract(s) after surgical closure of the internal opening(s). Study outcomes were assessed at week 24 with follow up for at least 52 weeks.
FINDINGS
Local injection of hAEC was safe, well tolerated and the injection procedure was feasible. Complete response occurred in 4 patients, and a partial response in an additional 4 patients. There was a mean reduction in the Perianal Disease Activity Index of 6.5 points (95% CI -9.0 to -4.0, p = 0.0002, paired t-test), modified Van Assche MRI Index of 2.3 points (95% CI -3.9 to -0.6, p = 0.012, paired t-test) and a mean improvement of 15.8 points (95% CI 4.9 to 26.8, p = 0.010, paired t-test) in quality of life using the Short IBD-Questionnaire in complete responders.
INTERPRETATION
Local injection of hAEC therapy for refractory complex perianal fistulising Crohn's disease appears safe, well-tolerated, feasible and demonstrated improvement. Quality of life is improved in those who achieve complete fistula healing.
FUNDING
This study was funded by competitive research grant funding from the Gastroenterological Society of Australia Seed Grant 2018.
Topics: Adult; Humans; Amnion; Crohn Disease; Epithelial Cells; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Mesenchymal Stem Cell Transplantation; Quality of Life; Rectal Fistula; Treatment Outcome
PubMed: 38042747
DOI: 10.1016/j.ebiom.2023.104879 -
Frontiers in Cellular and Infection... 2023Preterm birth is a leading cause of neonatal mortality, which is often complicated by intrauterine infection and inflammation. We have established a nonhuman primate...
BACKGROUND
Preterm birth is a leading cause of neonatal mortality, which is often complicated by intrauterine infection and inflammation. We have established a nonhuman primate model of Group B (GBS, ) infection-associated preterm birth. Immune checkpoints are modulators of the immune response by activating or suppressing leukocyte function and are understudied in preterm birth. The objective of this study was to spatially profile changes in immune protein expression at the maternal-fetal interface during a GBS infection with a focus on immune checkpoints.
METHODS
Twelve nonhuman primates (pigtail macaques, ) received a choriodecidual inoculation of either: 1) 1-5 X 10 colony forming units (CFU) of hyperhemolytic/hypervirulent GBS (GBSΔ, N=4); 2) an isogenic/nonpigmented strain (GBS ΔΔ, N=4); or, 3) saline (N=4). A Cesarean section was performed at preterm labor or 3 days after GBS infection or 7 days after saline inoculation. Nanostring GeoMx® Digital Spatial Profiling technology was used to segment protein expression within the amnion, chorion, and maternal decidua at the inoculation site using an immuno-oncology panel targeting 56 immunoproteins enriched in stimulatory and inhibitory immune checkpoint proteins or their protein ligands. Statistical analysis included R studio, Kruskal-Wallis, Pearson and Spearman tests.
RESULTS
Both inhibitory and stimulatory immune checkpoint proteins were significantly upregulated within the chorioamniotic membranes and decidua (VISTA, LAG3, PD-1, CD40, GITR), as well as their ligands (PD-L1, PD-L2, CD40L; all p<0.05). Immunostaining for VISTA revealed positive (VISTA+) cells, predominantly in the chorion and decidua. There were strong correlations between VISTA and amniotic fluid concentrations of IL-1β, IL-6, IL-8, and TNF-α (all p<0.05), as well as maternal placental histopathology scores (p<0.05).
CONCLUSION
Differential regulation of multiple immune checkpoint proteins in the decidua at the site of a GBS infection indicates a major perturbation in immunologic homeostasis that could benefit the host by restricting immune-driven pathologies or the pathogen by limiting immune surveillance. Protein expression of VISTA, an inhibitory immune checkpoint, was upregulated in the chorion and decidua after GBS infection. Investigating the impact of innate immune cell expression of inhibitory immune checkpoints may reveal new insights into placental host-pathogen interactions at the maternal-fetal interface.
Topics: Infant, Newborn; Animals; Humans; Pregnancy; Female; Streptococcus agalactiae; Placenta; Immune Checkpoint Proteins; Up-Regulation; Premature Birth; Cesarean Section; Streptococcal Infections; Primates
PubMed: 38239507
DOI: 10.3389/fcimb.2023.1299644 -
BMJ Medicine 2023To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had...
OBJECTIVE
To assess risk of adverse pregnancy, fetal, and neonatal outcomes after a third dose (first booster dose) of covid-19 vaccine during pregnancy among individuals who had completed both doses of primary covid-19 vaccine series before pregnancy.
DESIGN
Population based, retrospective cohort study.
SETTING
Ontario, Canada, from 20 December 2021 to 31 August 2022.
PARTICIPANTS
Individuals were included if they were pregnant with an expected date of delivery from 20 December 2021 (start date of third dose eligibility for everyone ≥18 years) to 31 August 2022, who had completed the two doses of primary covid-19 messenger RNA vaccine series before pregnancy, and became eligible for a third dose (≥six months since dose two) before the end of pregnancy.
MAIN OUTCOME MEASURES
Pregnancy outcomes included hypertensive disorders of pregnancy, placental abruption, caesarean delivery, chorioamnionitis, and postpartum hemorrhage. Fetal and neonatal outcomes included stillbirth, preterm birth, admission to neonatal intensive care unit for >24 h, newborn 5 min Apgar score <7, and small-for-gestational age infant (<10th percentile). We estimated hazard ratios and 95% confidence intervals for study outcomes, treating dose three as a time varying exposure and adjusting for confounding using inverse probability weighting.
RESULTS
Among 32 689 births, 18 491 (56.6%) were born to individuals who received a third covid-19 dose during pregnancy. Compared with eligible individuals who did not receive a third dose during pregnancy, no increased risks were associated with receiving a third covid-19 vaccine dose during pregnancy for placental abruption (adjusted hazard ratio 0.84 (95% confidence interval 0.70 to 1.02)), chorioamnionitis (0.67 (0.49 to 0.90)), postpartum haemorrhage (1.01 (0.89 to 1.16)), caesarean delivery (0.90 (0.87 to 0.94)), stillbirth (0.56 (0.39 to 0.81)), preterm birth (0.91 (0.84 to 0.99)), neonatal intensive care unit admission (0.96 (0.90 to 1.03)), 5 min Apgar score<7 (0.96 (0.82 to 1.14)), or small-for-gestational age infant (0.86 (0.79 to 0.93)).
CONCLUSION
Receipt of a third covid-19 vaccine dose during pregnancy was not associated with an increased risk of adverse pregnancy, fetal, or neonatal outcomes. These findings can help to inform evidence based decision making about the risks and benefits of covid-19 booster doses during pregnancy.
PubMed: 37456362
DOI: 10.1136/bmjmed-2023-000632 -
BMC Pregnancy and Childbirth Mar 2024This systematic review and meta-analysis investigated whether the use of azithromycin during labour or caesarean section reduces the incidence of sepsis and infection... (Meta-Analysis)
Meta-Analysis
Can the use of azithromycin during labour reduce the incidence of infection among puerperae and newborns? A systematic review and meta-analysis of randomized controlled trials.
OBJECTIVE
This systematic review and meta-analysis investigated whether the use of azithromycin during labour or caesarean section reduces the incidence of sepsis and infection among mothers and newborns.
DATA SOURCES
We independently searched the PubMed, Web of Science, Cochrane Library and EMBASE databases for relevant studies published before February, 2024.
METHODS
We included RCTs that evaluated the effect of prenatal oral or intravenous azithromycin or placebo on intrapartum or postpartum infection incidence. We included studies evaluating women who had vaginal births as well as caesarean sections. Studies reporting maternal and neonatal infections were included in the current analysis. Review Manager 5.4 was used to analyse 6 randomized clinical trials involving 44,448 mothers and 44,820 newborns. The risk of bias of each included study was assessed using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.Primary outcomes included the incidence of maternal sepsis and all-cause mortality and neonatal sepsis and all-cause mortality; secondary outcomes included maternal (endometritis, wound and surgical site infections, chorioamnionitis, and urinary tract infections) and neonatal outcomes (infections of the eyes, ears and skin). A random-effects model was used to test for overall effects and heterogeneity.
RESULTS
The pooled odds ratios (ORs) were as follows: 0.65 for maternal sepsis (95% CI, 0.55-0.77; I, 0%; P < .00001); 0.62 for endometritis (95% CI, 0.52-0.74; I, 2%; P < .00001); and 0.43 for maternal wound or surgical site infection (95% CI, 0.24-0.78; P < .005); however, there was great heterogeneity among the studies (I, 75%). The pooled OR for pyelonephritis and urinary tract infections was 0.3 (95% CI, 0.17-0.52; I, 0%; P < .0001), and that for neonatal skin infections was 0.48 (95% CI, 0.35-0.65; I, 0%, P < .00001). There was no significant difference in maternal all-cause mortality or incidence of chorioamnionitis between the two groups. No significant differences were observed in the incidence of neonatal sepsis or suspected sepsis, all-cause mortality, or infections of the eyes or ears.
CONCLUSION
In this meta-analysis, azithromycin use during labour reduced the incidence of maternal sepsis, endometritis, incisional infections and urinary tract infections but did not reduce the incidence of neonatal-associated infections, except for neonatal skin infections. These findings indicate that azithromycin may be potentially beneficial for maternal postpartum infections, but its effect on neonatal prognosis remains unclear. Azithromycin should be used antenatally only if the clinical indication is clear and the potential benefits outweigh the harms.
Topics: Infant, Newborn; Pregnancy; Female; Humans; Azithromycin; Neonatal Sepsis; Cesarean Section; Chorioamnionitis; Endometritis; Incidence; Randomized Controlled Trials as Topic; Sepsis; Puerperal Infection; Surgical Wound Infection; Urinary Tract Infections
PubMed: 38486177
DOI: 10.1186/s12884-024-06390-6 -
Orthopaedic Journal of Sports Medicine Nov 2023It is theorized that the lack of a synovial lining after anterior cruciate ligament (ACL) injury and ACL reconstruction (ACLR) contributes to slow ligamentization and...
Augmentation of ACL Autograft Reconstruction With an Amnion Collagen Matrix Wrap and Bone Marrow Aspirate Concentrate: A Pilot Randomized Controlled Trial With 2-Year Follow-up.
BACKGROUND
It is theorized that the lack of a synovial lining after anterior cruciate ligament (ACL) injury and ACL reconstruction (ACLR) contributes to slow ligamentization and possible graft failure. Whether graft maturation and incorporation can be improved with the use of a scaffold requires investigation.
PURPOSE
To evaluate the safety and efficacy of wrapping an ACL autograft with an amnion collagen matrix and injecting bone marrow aspirate concentrate (BMAC), quantify the cellular content of the BMAC samples, and assess 2-year postoperative patient-reported outcomes.
STUDY DESIGN
Randomized controlled trial; Level of evidence, 2.
METHODS
A total of 40 patients aged 18 to 35 years who were scheduled to undergo ACLR were enrolled in a prospective single-blinded randomized controlled trial with 2 arms based on graft type: bone-patellar tendon-bone (BTB; n = 20) or hamstring (HS; n = 20). Participants in each arm were randomized into a control group who underwent standard ACLR or an intervention group who had their grafts wrapped with an amnion collagen matrix during graft preparation, after which BMAC was injected under the wrap layers after implantation. Postoperative magnetic resonance imaging (MRI) mapping/processing yielded mean T2* relaxation time and graft volume values at 3, 6, 9, and 12 months. Participants completed the Single Assessment Numeric Evaluation Score, Knee injury and Osteoarthritis Outcome Score, and pain visual analog scale. Statistical linear mixed-effects models were used to quantify the effects over time and the differences between the control and intervention groups. Adverse events were also recorded.
RESULTS
No significant differences were found at any time point between the intervention and control groups for BTB T2* (95% CI, -1.89 to 0.63; = .31), BTB graft volume (95% CI, -606 to 876.1; = .71), HS T2* (95% CI, -2.17 to 0.39; = .162), or HS graft volume (95% CI, -11,141.1 to 351.5; = .28). No significant differences were observed between the intervention and control groups of either graft type on any patient-reported outcome measure. No adverse events were reported after a 2-year follow-up.
CONCLUSION
In this pilot study, wrapping a graft with an amnion collagen matrix and injecting BMAC appeared safe. MRI T2* values and graft volume of the augmented ACL graft were not significantly different from that of controls, suggesting that the intervention did not result in improved graft maturation.
REGISTRATION
NCT03294759 (ClinicalTrials.gov identifier).
PubMed: 38021297
DOI: 10.1177/23259671231210035 -
Nutrients Feb 2024The aim of this scoping review was to investigate and synthesize existing evidence on the airway microbiome of preterm infants to outline the prognostic and therapeutic... (Review)
Review
The aim of this scoping review was to investigate and synthesize existing evidence on the airway microbiome of preterm infants to outline the prognostic and therapeutic significance of these microbiomes within the preterm population and identify gaps in current knowledge, proposing avenues for future research. We performed a scoping review of the literature following the Arskey and O'Malley framework. In accordance with our inclusion criteria and the intended purpose of this scoping review, we identified a total of 21 articles. The investigation of the airway microbiome in preterm infants has revealed new insights into its unique characteristics, highlighting distinct dynamics when compared to term infants. Perinatal factors, such as the mode of delivery, chorioamnionitis, the respiratory support, and antibiotic treatment, could impact the composition of the airway microbiome. The 'gut-lung axis', examining the link between the lung and gut microbiome as well as modifications in respiratory microbiome across different sites and over time, has also been explored. Furthermore, correlations between the airway microbiome and adverse outcomes, such as bronchopulmonary dysplasia (BPD), have been established. Additional research in neonatal care is essential to understand the early colonization of infants' airways and explore methods for its optimization. The critical opportunity to shape long-term health through microbiome-mediated effects likely lies within the neonatal period.
Topics: Infant; Pregnancy; Female; Infant, Newborn; Humans; Infant, Premature; Lung; Bronchopulmonary Dysplasia; Microbiota; Gastrointestinal Microbiome
PubMed: 38398790
DOI: 10.3390/nu16040465 -
Reproductive Sciences (Thousand Oaks,... Dec 2023This study compares the effectiveness and safety of oxytocin infusion against oral misoprostol for inducing labour in pregnant women with term prelabor membrane rupture.... (Randomized Controlled Trial)
Randomized Controlled Trial
This study compares the effectiveness and safety of oxytocin infusion against oral misoprostol for inducing labour in pregnant women with term prelabor membrane rupture. We randomized 173 pregnant women presenting with term prelabor rupture of membranes (PROM) at Ain Shams University Maternity Hospital into Group A (underwent induction of labor (IOL) by 25μg misoprostol oral tablet every 4 h, for maximum 5 doses) and an identical Group B: (underwent IOL by oxytocin infusion according to the hospital protocol). Our primary outcome was rate of vaginal delivery within 24 h, while the secondary outcomes included the time till active phase, induction to delivery interval, maternal pyrexia, nausea and vomiting, fetal distress, Apgar score, birth weight, and neonatal intensive care unit admission. Both groups showed high rates of vaginal delivery (82.4% & 87.1% for misoprostol group and oxytocin group respectively) with no significant difference between the two groups (p=0.394). However, patients induced by misoprostol took significantly less time to reach active phase with a shorter induction to delivery interval as compared to patients induced with oxytocin. This difference was clear in multiparous women, but not observed in primiparous women when subgroup analysis was done. No significant difference was found as regards other outcomes. Our study showed that both oral misoprostol and oxytocin are effective and safe for IOL in patients with PROM, with shorter induction-delivery interval in patients induced by oral misoprostol, an effect that is clear in multiparous but not primiparous women. TRIAL REGISTRATION: NCT05215873, on 31/01/2022, "retrospectively registered".
Topics: Infant, Newborn; Female; Pregnancy; Humans; Misoprostol; Oxytocin; Oxytocics; Pregnant Women; Fetal Membranes, Premature Rupture; Labor, Induced
PubMed: 37442883
DOI: 10.1007/s43032-023-01290-0 -
Cells Nov 2023Tissue regeneration is an essential requirement for wound healing and recovery of organs' function. It has been demonstrated that wound healing can be facilitated by...
Tissue regeneration is an essential requirement for wound healing and recovery of organs' function. It has been demonstrated that wound healing can be facilitated by activating paracrine signaling mediated by exosomes secreted from stem cells, since exosomes deliver many functional molecules including growth factors (GFs) and neurotrophic factors (NFs) effective for tissue regeneration. In this study, an exosome-rich conditioned medium (ERCM) was collected from human amniotic membrane stem cells (AMSCs) by cultivating the cells under a low oxygen tension (2% O and 5% CO). The contents of GFs and NFs including keratinocyte growth factor, epidermal growth factor, fibroblast growth factor 1, transforming growth factor-β, and vascular endothelial growth factor responsible for skin regeneration were much higher (10-30 folds) in the ERCM than in normal conditioned medium (NCM). In was found that CM-DiI-labeled exosomes readily entered keratinocytes and fibroblasts, and that ERCM not only facilitated the proliferation of keratinocytes in normal condition, but also protected against HO cytotoxicity. In cell-migration assay, the scratch wound in keratinocyte culture dish was rapidly closed by treatment with ERCM. Such wound-healing effects of ERCM were confirmed in a rat whole skin-excision model: i.e., the wound closure was significantly accelerated, remaining minimal crusts, by topical application of ERCM solution (4 × 10 exosome particles/100 μL) at 4-day intervals. In the wounded skin, the deposition of collagens was enhanced by treatment with ERCM, which was supported by the increased production of collagen-1 and collagen-3. In addition, enhanced angiogenesis in ERCM-treated wounds was confirmed by increased von Willebrand factor (vWF)-positive endothelial cells. The results indicate that ERCM from AMSCs with high concentrations of GFs and NFs improves wound healing through tissue regeneration not only by facilitating keratinocyte proliferation for skin repair, but also activating fibroblasts for extracellular matrix production, in addition to the regulation of angiogenesis and scar tissue formation.
Topics: Humans; Rats; Animals; Culture Media, Conditioned; Endothelial Cells; Exosomes; Vascular Endothelial Growth Factor A; Amnion; Angiogenesis; Hydrogen Peroxide; Wound Healing; Stem Cells; Collagen; Epidermal Growth Factor
PubMed: 38067126
DOI: 10.3390/cells12232698 -
Poultry Science Nov 2023In the commercial egg industry, avian pathogenic Escherichia coli (APEC) can lead to significant economic loss. The Poulvac E. coli vaccine (PECV) is a commercially...
In the commercial egg industry, avian pathogenic Escherichia coli (APEC) can lead to significant economic loss. The Poulvac E. coli vaccine (PECV) is a commercially available attenuated live vaccine commonly applied via spray or drinking water to protect against losses associated with colibacillosis. The PECV has not been tested in layer hatching eggs using in ovo injection. Therefore, the purpose of this experiment was to determine the effects of injecting 50 μL of different doses of the PECV into Hy-Line W-36-layer hatching eggs on the hatchability and quality characteristics of hatchlings. At 18 d of incubation (DOI), treatments included 1 noninjected and 1 diluent-injected control. Furthermore, PECV treatments included a full dose (4.4 × 10E. coli CFU) or serial dilutions of the full dose to produce 4.4 × 10, 4.4 × 10, or 4.4 × 10 CFU doses of E. coli. In ovo injections targeted the amnion. Percent hatchability of live embryonated eggs (HI), percent residue eggs, hatchling mortality, and female chick whole and yolk-free BW, relative yolk sac weight, and body length were among the variables examined. Treatment significantly (P < 0.0001) affected HI, with HI being highest in the control groups (97.3% in the noninjected and 94.2% in the diluent-injected), and with HI values being 89.0, 88.9, 84.4, and 71.2% in the 4.4 × 10, 4.4 × 10, 4.4 × 10, and 4.4 × 10 CFU E. coli dose treatments, respectively. The percentage of live embryos that did not complete hatch but that pipped internally (P = 0.024) or externally (P < 0.0001) were significantly affected by treatment, with percentages being highest in the 4.4 × 10 CFU treatment. Female chick body length was significantly (P < 0.0001) affected by treatment and was longer in both control groups and in the 1 × 10 CFU E. coli treatment in comparison to all other treatments. Yolk-free female chick BW was significantly (P = 0.034) affected by treatment and was lower in the 4.4 × 10 CFU and 4.4 × 10 CFU treatments when compared to the diluent-injected control group. An increase in the E. coli concentration administered in the amnion of embryonated layer hatching eggs at 18 DOI decreased hatch success and female chick yolk-free BW and body length.
PubMed: 37690369
DOI: 10.1016/j.psj.2023.103057