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Introduction: Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) are promising candidates for stem cell therapy. Various methods such as enzymatic treatment, cell scraping, and temperature reduction using temperature-responsive cell culture dishes have been employed to culture and harvest UC-MSCs. However, the effects of different harvesting methods on cell properties and functions in vitro remain unclear. In this study, we investigated the properties and functions of UC-MSC using various cell-harvesting methods. Methods: UC-MSC suspensions were prepared using treatments with various enzymes, cell scraping, and temperature reduction in temperature-responsive cell culture dishes. UC-MSC sheets were prepared in a temperature-responsive cell culture dish. The properties and functions of the UC-MSC suspensions and sheets were assessed according to Annexin V staining, lactate dehydrogenase (LDH) assay, re-adhesion behavior, and cytokine secretion analysis via enzyme-linked immunosorbent assay. Results: Annexin V staining revealed that accutase induced elevated UC-MSC apoptosis. Physical scraping using a cell scraper induced a relatively high LDH release due to damaged cell membranes. Dispase exhibited relatively low adhesion from initial incubation until 3 h. UC-MSC sheets exhibited rapid re-adhesion at 15 min and cell migration at 6 h. UC-MSC sheets expressed higher levels of cytokines such as HGF, TGF-β1, IL-10, and IL-6 than did UC-MSCs in suspension. Conclusions: The choice of enzyme and physical scraping methods for harvesting UC-MSCs significantly influenced their activity and function. Thus, selecting appropriate cell-harvesting methods is important for successful stem cell therapy.

Objectives: At the beginning of the COVID-19 pandemic, delayed umbilical cord clamping (CC) at birth may have been commonly discouraged despite a lack of convincing evidence of mother-to-neonate SARS-CoV-2 transmission. We aimed to systematically review guidelines, and reports of practice and to analyze associations between timing of CC and mother-to-neonate SARS-CoV-2 transmission during the early phases of the pandemic. Methods: Major databases were searched from December 1, 2019, to July 20, 2021. Inclusion: studies and guidelines describing CC practice in women with SARS-CoV-2 infection during pregnancy until 2 postnatal days, giving birth to live-born neonates. Exclusion: no extractable data. Two reviewers independently screened studies for eligibility and assessed study quality. Pooled prevalence rates were calculated. Results: Forty-eight studies (1476 neonates) and 40 guidelines were included. Delayed CC was recommended in 70.0% of the guidelines. Nevertheless, delayed CC was reported less often than early CC: 262/1476 (17.8%) vs 511/1476 (34.6%). Neonatal SARS-CoV-2 positivity rates were similar following delayed (1.2%) and early CC (1.3%). Most SARS-CoV-2 transmissions (93.3%) occurred in utero. Conclusion: Delayed CC did not seem to increase mother-to-neonate SARS-CoV-2 transmission. Due to its benefits, it should be encouraged even in births where the mother has a SARS-CoV-2 infection. Systematic review registration: Prospero CRD42020199500.

Background: Human umbilical cord mesenchymal stem cells (UC-MSCs) are one of the most extensively researched stem cell types due to their potential for multi-lineage differentiation, secretion of regenerative factors, modulations of immunological activities, and the release of regenerative substances and influence immunological processes. Since UC-MSCs must be cultivated on a large scale for clinical use, selecting the appropriate storing passage, such as the usage-based passage of UC-MSCs, is critical for long-term autologous or allogeneic usage. Long-term cultivation of stem cells, on the other hand, causes them to lose their pluripotent differentiation capacity. As a result, distinguishing between high and low passages of UC-MSCs and identifying the particular variations associated with stem cells and their modes of action is essential for regenerative medicine. Therefore, we investigated the biological features and transcriptional changes of UC-MSCs over passages. Methods: UC-MSCs were isolated from the tissues of the human umbilical cord, and UC-MSCs from five passages (P1, P3, P5, P10 and P15) with three repetitions were compared and identified based on morphology, cell markers, differentiation capacity, and aging-related characteristics. It was previously assumed that the phenotype of cells before the P10 passage was stable, defined as early passage, and that culture could be continued until the 15th passage, defined as late passage. Next, the five passages of UC-MSCs were sequenced using high-throughput complete transcriptome sequencing. Fuzzy C-Means Clustering (FCM) and Weighted Gene Co-expression Network Analysis (WGCNA) were used to find hub genes, and gene silencing was performed to investigate the impact of missing genes on the stemness of UC-MSC cells. Results: UC-MSCs of different passages displayed similar surface markers, including CD73, CD105, CD90, CD34, CD45 and HLA-DR. However, the proliferation time of late-phase UC-MSCs was longer than that of early-phase UC-MSCs, and the expression of the senescence-associated (SA)-β-gal staining marker was higher. At the same time, pluripotency markers (NANOG, OCT4, SOX2 and KIF4A) were down-regulated, and the multi-differentiation potential was reduced. Meanwhile, KIFC1 and UBE2C were down-regulated in late-phase UC-MSCs, which were involved in the maintenance of stemness. Conclusions: KIFC1 and UBE2C were highly expressed in early-UC-MSCs and showed a downward gradient trend with cell expansion in vitro. They regulated UC-MSC proliferation, colony sphere formation, multiple differentiation, stemness maintenance, and other biological manifestations. Therefore, they are anticipated to be new biomarkers for UC-MSCs quality identification in regenerative medicine applications.

Human-derived three-dimensional (3D) in vitro models are advanced human cell-based model for their complexity, relevance and application in toxicity testing. Intracellular accumulation of methylglyoxal (MGO), the most potent glycating agent in humans, mainly generated as a by-product of glycolysis, is associated with age-related diseases including neurodegenerative disorders.In our study, 3D human stem-cell-derived neuronal spheroids were set up and applied to evaluate cytotoxic effects after short-term (5 to 48 h) treatments with different MGO concentrations, including low levels, taking into consideration several biochemical endpoints.In MGO-treated neurospheroids, reduced cell growth proliferation and decreased cell viability occurred early from 5-10 μM, and their compactness diminished starting from 100 μM, apparently without affecting spheroid size. MGO markedly caused loss of the neuronal markers MAP-2 and NSE from 10-50 μM, decreased the detoxifying Glo1 enzyme from 50 μM, and activated NF-kB by nuclear translocation.The cytochemical evaluation of the 3D sections showed the presence of necrotic cells with loss of nuclei. Apoptotic cells were observed from 50 μM MGO after 48 h, and from 100 μM after 24 h. MGO (50–10 µM) also induced modifications of the cell–cell and cell-ECM interactions. These effects worsened at the higher concentrations (300–500 µM).In 3D neuronal spheroids, MGO tested concentrations comparable to human samples levels measured in MGO-associated diseases, altered neuronal key signalling endpoints relevant for the pathogenesis of neurodegenerative diseases and aging. The findings also demonstrated that the use of 3D neuronal spheroids of human origin can be useful in a strategy in vitro for testing MGO and other dicarbonyls evaluation.

Although mesenchymal stem cells (MSCs) can be obtained from various tissues such as bone marrow (BM), umbilical cord blood (UCB) and umbilical cord tissue (UC), the comparative efficacy of each MSC in tendon regeneration is unknown. Therefore, we investigated the efficacy of MSCs isolated from three different sources on tendon regeneration after injury.We evaluated the potential of BM-, UCB- and UC-MSC to differentiate into tendon-like cells in tensioned three-dimensional construct (T-3D) using gene and histological analysis. In animal experiments, full-thickness tendon defect (FTD) was created in supraspinatus of rats, and injected with Saline and BM-, UCB- and UC-MSC. After two and four weeks, histological evaluations were performed.After inducing tenogenic differentiation, the gene expression of scleraxis, mohawk, type I collagen and tenascin-C was upregulated by 3.12-, 5.92-, 6.01- and 1.61-fold respectively and formation of tendon-like matrix was increased 4.22-fold in UC-MSC compared to BM-MSC in T-3D. In animal experiments, the total degeneration score was lower in the UC-MSC group than in BM-MSC group at both weeks. In heterotopic matrix formation, glycosaminoglycan-rich area was reduced in the UC-MSC group, whereas area was larger in the BM-MSC group than in Saline group at four weeks.In conclusion, UC-MSC is superior to other MSCs in differentiating into tendon-like lineage cells and forming a well-organized tendon-like matrix under T-3D conditions. UC-MSC enhances regeneration of FTD in terms of histological properties compared to BM- and UCB-MSC.

Background/Purpose: To evaluate whether a shorter length (20 cm) of C-UCM has potential benefits, compared to immediate cord clamping (ICC), in very preterm babies. Methods: Inborn preterm infants less than 30 weeks of gestational age (GA) were randomly assigned to the 20-cm C-UMC and ICC groups. The primary outcome was the need for packed red blood cell (pRBC) transfusion before the 21st day of life. The secondary outcomes were short- and long-term outcomes related to premature birth. Results: Seventy-six neonates were randomized to the two groups. GA were 27.2 ± 1.8 and 27.5 ± 1.7 weeks (p = 0.389) and birth weights were 987 ± 269 and 1023 ± 313 g (p = 0.601) in the 20-cm C-UCM and ICC groups, respectively. There was no significant difference between the groups in terms of the need for pRBC transfusion before the 21st day of life (59.4% versus 71.8%, adjusted odds ratio [aOR] 0.311, 95% confidence interval [CI] 0.090–1.079). An increased prevalence of late-onset sepsis was observed in the 20-cm C-UCM group compared to the ICC group (21.6% versus 5.1%, aOR 5.434, 95% CI 1.033–23.580). The mortality rates were 13.5% and 2.6% in the 20-cm C-UCM and ICC groups, respectively (aOR 5.339, 95% CI 0.563–50.626). The neurodevelopmental outcomes at 2 years of corrected age between the groups were also not statistically significant. Conclusion: A 20-cm C-UCM showed no effect on reducing the incidence of pRBC transfusion in preterm babies with GA less than 30 weeks compared with ICC in this small-scale randomized controlled trial.

Introduction: The in-utero environment has dramatic effects on childhood development. We hypothesized prenatal levels of inorganic agents, thyroid levels, and Vitamin D effect childhood development. Methods: Umbilical cord blood was collected from April 3, 2013 to January 30, 2014 and analyzed for 20 different elements, thyroid and Vitamin D. A retrospective review (n = 60) was performed of well-child examinations from birth to 5 years old (y.o.). Results: There were associations with calcium and 4 month BMI (p =

Intravenous (IV) infusion of mesenchymal stem cells (MSCs) from nascent tissues like Wharton's Jelly of the umbilical cord is reported to offer therapeutic effects against chronic diseases. However, toxicological data essential for the clinical application of these cells are limited. Thus, this study aimed to determine the safety of IV infusion of Wharton's Jelly derived MSCs (WJ-MSCs) in rats. Fifteen male Sprague–Dawley rats were randomised into the control or treatment group. Each group received an equal volume of saline or WJ-MSC (10 × 106 cell/kg) respectively. The animals were evaluated for physical, biochemical and haematological changes at Week 0, 2, 4, 8 and 12 during the 12-week study. Acute toxicity was performed during Week 2 and sub-chronic toxicity during Week 12. At the end of the study, the relative weight of organs was calculated and histology was performed for lung, liver, spleen and kidney. The findings from physical, serum biochemistry and complete blood count demonstrated no statistically significant differences between groups. However, pathological evaluation reported minor inflammation in the lungs for all groups, but visible healing and resolution of inflammation were observed in the treatment group only. Additionally, the histological images of the treatment group had significantly improved pulmonary structures compared to the control group. In summary, the IV administration of WJ-MSC was safe in the rats. Further studies are needed to determine the long-term safety of the WJ-MSC in both healthy and diseased animal models.

Today, stem cell therapy has been shown to be a remarkable progress and an important application in the regeneration of defective tissues and organs. To deliver stem cells to the injured area, several methods have been proposed such as an intravenous infusion, direct damaged tissue injection, or stem cell sheet transplantation. In this study, we aimed to fabricate a stem cell sheet by culturing human umbilical cord mesenchymal stem cells (hUC-MSCs) on a Col-T scaffold to recover the structure and function of damaged tissues. The results showed that cells reach confluent on the scaffold surface 18 h after seeding. These stem cells were able to survive and proliferate on Col-T scaffold. The average tensile strength of the stem cell sheet was 2.65 MPa. The sheet reached the sterile standards when tested for total bacteria, Candida albicans, Pseudomonas aeruginosa, and Staphylococcus aureus according to Circular number 06/2011/TT-BYT of Vietnam Ministry of Health. In addition, the stem cell sheet was non-toxic when evaluated for exposure toxicity and fluid toxicity according to iSO-10993. Importantly, 5 days after culturing on the Col-T scaffold, the seeded hUC-MSCs were still possessed all properties of MSC such as spindle-shaped, adhesive, could differentiate into mesoderm-derived cells, showed to be CD90, CD105, CD73 positive and CD45, CD34, CD11b, CD19, HLA-DR negative. In summary, our study was successful in creating a stem cell sheet from hUC-MSCs and Col-T scaffold for subsequent in vivo transplantation in the future.

Background: This study aimed to evaluate the effect of ICC (cord clamping within the first 15 s), DCC (delayed cord clamping at 60 s), and cut-UCM (cut-umbilical cord milking, cord clamping within the first 15 s) groups on oxygen saturation (SpO2), heart rate (HR), and perfusion index (PI) up to 10 min after birth in newborn infants., Methods: We conducted this randomized clinical trial in the delivery unit of a University Hospital with 189 infants born between 35 and 42 weeks of gestation. Participants were randomly assigned to one of three groups: ICC, DCC, and cut-UCM. The primary outcomes measured were SpO2, HR, and PI at the 1st, 3rd, 5th, and 10th minutes after birth. We utilized ANOVA and Bayesian calculations in this study., Results: There was no difference between the ICC, DCC, and cut-UCM groups in SpO2, HR, and PI values at the 1st, 3rd, 5th, and 10th minutes of life, which did not significantly alter between the three groups in one-way ANOVA. Bayesian repeated-measure ANOVA calculations showed that SpO2 and heart rate results at the 1st, 3rd, 5th, and 10th minutes did not differ between ICC, DCC, and cut-UCM techniques with strong evidence. At the 3rd minute, PI was slightly higher in the DCC and cut-UCM groups compared to the ICC group, with anecdotal evidence. We found no difference between DCC and cut-UCM regarding the 3rd-minute PI, with moderate evidence., Conclusion: Umbilical clamping procedures (ICC, DCC, and cut-UCM) did not affect SpO2 and HR in the first ten minutes of life, but 3rd-minute PI values were slightly higher in DCC and cut-UCM compared with ICC among late preterm and term neonates., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Urethrocutaneous fistula (UCF) formation is a known complication following hypospadias repair, affecting between 5 and 70% of cases. Moreover, approximately 30% of patients experience refistulization after UCF repair. The use of extracellular matrices, such as AmnioCord, a dehydrated human umbilical cord allograft manufactured by MiMedx®, may mitigate high rates of refistulization., Objective: To determine whether the use of AmnioCord during UCF repair is associated with reduced incidence of subsequent UCFs among pediatric patients., Design, Setting, and Participants: Electronic medical records were retrospectively reviewed among 60 patients who underwent at least one UCF repair at a pediatric hospital in a large urban setting in the U.S. between January 2012-June 2018. Patients were followed through January 2024., Outcome Measurements and Statistical Analysis: Adjusted generalized estimating equation regression models were used to assess the association between AmnioCord use and rates of refistulization, while controlling for confounding variables., Results: The number of fistula presentations per patient ranged from one to four; 53.3% had one fistula, 30.0% had two, and 16.6% had three or more. Overall fistula repair success rate was 56.8% but significantly differed by AmnioCord use in adjusted modelling; 69.4% of cases that received AmnioCord were successfully repaired, compared to 47.2% of cases that did not receive AmnioCord. In adjusted models, patients who received AmnioCord had 2.66 times greater odds of surgical success than patients who did not receive AmnioCord (95% CI:1.13-6.24; p = 0.02)., Conclusions: This study demonstrates a positive association between AmnioCord use and successful UCF closure among pediatric patients., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2024 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background/aims: Mesenchymal stem cells (MSCs) are potential alternatives for liver fibrosis treatment; however, their optimal sources remain uncertain. This study compares the ex-vivo expansion characteristics of MSCs obtained from adipose tissue (AT) and umbilical cord (UC) and assesses their therapeutic potential for liver fibrosis treatment., Methods: Since MSCs from early to mid-passage numbers (P2-P6) are preferable for cellular therapy, we investigated the growth kinetics of AT-MSCs and UC-MSCs up to P6 and evaluated their therapeutic effects in a rat model of liver fibrosis induced by diethylnitrosamine., Results: Results from the expansion studies demonstrated that both cell types exhibited bona fide characteristics of MSCs, including surface antigens, pluripotent gene expression, and differentiation potential. However, AT-MSCs demonstrated a shorter doubling time (58.2 ± 7.3 vs. 82.3 ± 4.3 h; P  < 0.01) and a higher population doubling level (10.1 ± 0.7 vs. 8.2 ± 0.3; P  < 0.01) compared to UC-MSCs, resulting in more cellular yield (230 ± 9.0 vs. 175 ± 13.2 million) in less time. Animal studies demonstrated that both MSC types significantly reduced liver fibrosis ( P  < 0.05 vs. the control group) while also improving liver function and downregulating fibrosis-associated gene expression., Conclusion: AT-MSCs and UC-MSCs effectively reduce liver fibrosis. However, adipose cultures display an advantage by yielding a higher number of MSCs in a shorter duration, rendering them a viable choice for scenarios requiring immediate single-dose administration, often encountered in clinical settings., (© 2024 Indian National Association for Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Competing Interests: The authors declare that they have no conflicts of interest.

Background: Screening-based intrapartum antibiotic prophylaxis (IAP) has reduced the prevalence of early-onset group B Streptococcus (GBS) infection in newborns. Nevertheless, early-onset disease still occurs despite IAP, and IAP is not effective in preventing late-onset disease. This study aimed to determine the prevalence and risk factors of GBS neonatal umbilical colonization managed by dry cord care in Japan. Methods: Of 735 healthy newborns in the well-baby nursery at Saitama City Hospital, 353 from whom umbilical bacterial swabs were obtained before discharge were included in the analysis. Maternal and neonatal clinical characteristics were retrospectively reviewed. Results: GBS was detected in 4.2% (15/353) of umbilical swabs; 13/15 (86.8%) were born to GBS-negative mothers. The median (IQR) age at umbilical swab collection was 4.0 (4.0–5.0) days. Comparison of clinical characteristics between GBS-positive and negative neonates revealed a significant difference in the proportion of vaginal deliveries (15/15 [100%] in GBS-positive neonates vs. 115/338 [34.0%] in GBS-negative neonates, p

Many cultures have developed traditional practices around the management of the umbilical cord stump in the newborn. Treatment with hot water compress or fomentation is well-documented in sub-Saharan Africa but can result in thermal injuries in vulnerable neonatal skin. We report three cases of superficial partial thickness umbilical burns in infants following such treatment that presented to a paediatric burns unit in London, UK in 2020, all from a Nigerian background. In each case, the burn wound healed with conservative management only. This is a previously unreported cause of neonatal burn injury and we aim to raise awareness of the risks that traditional cord practices may pose to the newborn.

Purpose: To report the use of cryopreserved amniotic membrane from the umbilical cord (UC) in the reconstruction of a dehisced wound with the additional ability to increase orbital volume, expand superior and inferior fornices, and improve cosmesis following evisceration of a blind, painful, atrophic, sunken eye with ptosis. Observations: Patient developed conjunctival wound dehiscence without implant exposure following evisceration. One month later, reconstruction was performed with UC to cover the defect, increase the orbital volume, and expand orbital fornices to allow placement of a large ocular prosthesis with superior lip for ptosis elevation. Post-operatively, at the 6th week, the socket was healthy and the globe had good movement. At the 7th week, the ocular prosthesis was sized and fitted. At the 8th month, the structural integrity of the socket was maintained with deep fornices, and the patient had excellent cosmetic result with natural appearance and movement of the prosthetic eye. Conclusions and importance: This case highlights the successful utilization of UC graft to augment soft tissue volume, restore socket structural integrity and increase socket volume, and achieve good cosmesis and ocular motility following evisceration.

Hematopoietic stem and progenitor cells (HSPC) from umbilical cord blood (UCB) are used for transplantation to treat blood disorders. Methods to estimate the HSPC count in umbilical cord blood, and thereby identify high-value blood units, are time-consuming and costly. Recent studies indicate that the UCB plasma protein composition relates to the HSPC count. We compared the plasma proteome of UCB with high vs low HSPC cell count (>115 × 106 vs

Introduction: The p75 neurotrophin receptor (p75NTR) is known as an efficient marker for the prospective isolation of mesenchymal stem cells (MSCs) and neural crest-derived stem cells (NCSCs). To date, there is quite limited information concerning p75NTR-expressing cells in umbilical cord (UC), although UC is known as a rich source of MSCs. We show for the first time the localization, phenotype, and functional properties of p75NTR+ cells in UC. Methods: Human UC tissue sections were subjected to immunohistochemistry for MSC markers including p75NTR. Enzymatically isolated umbilical artery (UA) cells containing p75NTR+ cells were assessed for immunophenotype, clonogenic capacity, and differentiation potential. To identify the presence of neural crest-derived cells in the UA, P0-Cre/Floxed-EGFP reporter mouse embryos were used, and immunohistochemical analysis of UC tissue was performed. Results: Immunohistochemical analysis revealed that p75NTR+ cells were specifically localized to the subendothelial area of the UA and umbilical vein. The p75NTR+ cells co-expressed PDGFRβ, CD90, CD146, and NG2, phenotypic markers of MSCs and pericytes. Isolated UA cells possessed the potential to form neurospheres that further differentiated into neuronal and glial cell lineages. Genetic lineage tracing analysis showed that EGFP+ neural crest-derived cells were detected in the subendothelial area of UA with p75NTR immunoreactivity. Conclusions: These results show that UA tissue harbors p75NTR+ pericyte-like cells in the subendothelial area that have the capacity to form neurospheres and the potential for neurogenic differentiation. The lineage tracing data suggests the p75NTR+ cells are putatively derived from the neural crest.

Background: Nonsteroidal anti-inflammatory drugs are contraindicated in the third trimester of pregnancy due to negative effects including alteration of uteroplacental blood flow, premature ductus arteriosus closure, and adverse effects on the fetal kidney. However, many women are unaware of these risks, and commonly report their use in pregnancy. We aimed to determine if umbilical cord was a reliable matrix for detecting NSAID use, determine incidence of use close to labour, and uncover associations with obstetric/neonatal outcomes. Methods: We developed a UHPLC-MS/MS method to simultaneously detect diclofenac, ibuprofen, indomethacin, naproxen, and salicylic acid in plasma and umbilical cord lysate. Using this method, we screened 380 lysates to determine the prevalence of NSAID use. Results were compared to the clinical outcomes in pregnancy using ICD9/10 chart codes (n = 21). Results: The UHPLC-MS/MS method has excellent linearity, accuracy, and precision in solvent and plasma, but lower sensitivity in umbilical cord lysate. We report a 3 % rate of NSAID ingestion within days of labour – the pharmacokinetically-determined window for active ingestion. There were no significant differences observed for maternal, obstetric, or neonatal outcomes between the NSAID positive group (n = 11) and NSAID negative group (n = 369). Conclusions: Because NSAID use in third trimester is contraindicated, even a 3% usage rate is alarmingly high. Based on UHPLC-MS/MS performance of umbilical cord lysate, 3% is likely a conservative estimate. Recent adoption of NSAIDs under clinical supervision to support in vitro fertilisation and prevent pre-eclampsia indicates future work should focus on determining safe dosages of NSAIDs and the correct therapeutic window in pregnancy.

The biological properties of human mesenchymal stromal cells (hMSCs) have been explored in over a thousand clinical trials in the last decade. Although hMSCs can be isolated from multiple sources, the degree of biological similarity between cell populations from these sources remains to be determined. A comparative study was performed investigating the growth kinetics and functionality of hMSCs isolated from adipose tissue (AT), bone marrow (BM) and umbilical cord tissue (UCT) expanded in monolayer over five passages. Adult hMSCs (AT, BM) had a slower proliferation ability than the UCT-hMSCs, with no apparent differences in their glucose consumption profile. BM-hMSCs produced higher concentrations of endogenous vascular endothelial growth factor (VEGF) compared to AT- and UCT-hMSCs. This study also revealed that UCT-hMSCs were more efficiently transduced by a lentiviral vector carrying a VEGF gene than their adult counterparts. Following cellular immunophenotypic characterization, no differences across the sources were found in the expression levels of the typical markers used to identify hMSCs. This work established a systematic approach for cell source selection depending on the hMSC's intended clinical application., Competing Interests: Declaration of competing interest Pedro Silva Couto, Dale J. Stibbs, Marco C. Rotondi, Rana Khalife, Dennis Wolf, Yasuhiro Takeuchi and Qasim A. Rafiq have no conflicts of interest. With the exception of Dennis Wolf, all the authors listed here were UCL students or staff members when the experimental work was conducted., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Objective: To describe midwives' experiences of intact cord resuscitation close to the mother for nonvigorous neonates after vaginal birth., Design: Descriptive qualitative., Setting: Four labor wards in Sweden., Participants: Midwives (N = 13) currently or previously employed in labor wards where the Sustained Cord Circulation and Ventilation (SAVE) study was conducted., Methods: We analyzed semistructured interviews using reflexive thematic analysis., Results: Participants' experiences are presented in an overarching theme: Midwives balance knowledge with doing the right thing in a challenging work environment during intact cord resuscitation. Three primary themes emerged: A New Workflow, Zero Separation: The Big Advantage, and The Midwife: Guardian of Childbirth., Conclusion: The participants were keen to keep the umbilical cord intact even for nonvigorous neonates. They wanted to work with the neonate close to the mother to facilitate zero separation and family participation. Ventilation with an intact umbilical cord was considered a routine to be implemented in the future, but the participants identified certain difficulties with the design of the SAVE study., Competing Interests: Conflict of interest The authors report no conflicts of interest or relevant financial relationships., (Copyright © 2023 AWHONN, the Association of Women’s Health, Obstetric and Neonatal Nurses. Published by Elsevier Inc. All rights reserved.)

Introduction: Erectile dysfunction (ED) affects a significant portion of the United States population and causes negative psychological burdens that affects men and their partner's quality of life and satisfaction. Extracorporeal shock therapy (ESWT) utilizing focused ESWT and radial ESWT in Low-intensity shock wave therapy has been used to treat ED with some success. Wharton's Jelly (WJ) is a biologic substance with large amounts of stem cells, growth factors, cytokines and extracellular components. The use of combined focused and radial ESWT (DualStim therapy) with injected WJ have potential uses in ED that may have advantages over current treatments. Materials: A randomized, single-blinded, controlled clinical trial will be conducted to evaluate the efficacy and safety of DualStim therapy and intracavernosal injection of WJ in moderate to severe ED. A total of 60 patients with moderate to severe ED will be enrolled and treated with DualStim therapy with intracavernosal injection of WJ or saline for a period of 7 weeks. The International Index of Erectile Function – Erectile Function score will be used to gauge the treatment related changes in relation to the subject's baseline. The scores will be recorded at baseline and compared to follow-ups 1,3 and 6 months post-treatment. Any adverse events or severe adverse events will be recorded in the corresponding case report forms. Sexual Encounter Profile, as well as the Global Assessment Questionnaire and the Erection Hardness Score will be used to determine the sexual activity improvement from baseline leading to optimal penetration at follow-ups 1,3 and 6 months post-treatment. Discussion: This clinical trial is one of the first studies to determine the immediate and short-term efficacy of DualStim therapy, with and without intracavernosal injection of formulated umbilical cord-derived WJ to improve and/or restore erectile function in patients with moderate to severe ED. This study will also provide insight into the safety and efficacy of WJ. We anticipate clinically significant improvement in patients suffering from moderate and severe ED treated with DualStim therapy with WJ compared to their baseline and DualStim with saline.

Questions remain about the effects of rare earth elements (REEs) on reproductive health, and no study has explored in utero exposure to REEs and risk of orofacial clefts (OFCs). We recruited subjects from a case-control study conducted in Shanxi Province, China. Concentrations of fifteen REEs were quantified in umbilical cord samples by means of Inductively Coupled Plasma Mass Spectrometry measurements. We employed logistic regression and weighted quantile sum (WQS) regression models to estimate the association between REEs exposures and OFCs. Of 226 subjects included in our study, 34 were cleft lip only, 44 were cleft lip with cleft palate and 6 were cleft palate only. In the logistic regression model, concentrations above the median of all subjects were associated with an increased OFCs risk of 2.35-fold (95% CI: 1.22, 4.53) for Lanthanum and 2.12-fold for Neodymium (95% CI: 1.10, 4.10) adjusting for maternal age, BMI, gestational weeks, sex of infants and passive smoking. In WQS model, a quartile increase in the index resulting in an increase of 3.10 (95% CI: 1.38, 6.96) in the odds of OFC. Lanthanum and Neodymium were suggested to be important factors. The results were largely consistent for OFC subtypes. In conclusion, in utero exposure to mixtures of REEs increased the risk of OFCs. Lanthanum and Neodymium were likely to be important factors in the development of OFCs.

Background: Our previous single-center, randomized, double-blinded, placebo-controlled phase 2 study evaluated the safety and effectiveness of human umbilical cord mesenchymal stromal cell (UC-MSC) transfusion for treating patients with type 2 diabetes mellitus (T2DM). Indeed, this potential treatment strategy was able to reduce insulin use by half in a considerable number of patients. However, many other patients' responses to UC-MSC transfusion were insignificant. The selection of patients who might benefit from UC-MSC treatment is crucial from a clinical standpoint., Methods: In this post hoc analysis, 37 patients who received UC-MSC transfusions were divided into two groups based on whether their glycated hemoglobin (hemoglobin A1c, or HbA1c) level was less than 7% after receiving UC-MSC treatment. The baseline differences between the two groups were summarized, and potential factors influencing efficacy of UC-MSCs for T2DM were analyzed by univariate and multivariate logistic regression. The correlations between the relevant hormone levels and the treatment effect were further analyzed., Results: At the 9-week follow-up, 59.5% of patients achieved their targeted HbA1c level. Male patients with lower baseline HbA1c and greater C-peptide area under the curve (AUCC-pep) values responded favorably to UC-MSC transfusion, according to multivariate analysis. The effectiveness of UC-MSCs transfusion was predicted by AUCC-pep (cutoff value: 14.22 ng/h/mL). Further investigation revealed that AUCC-pep was increased in male patients with greater baseline testosterone levels., Conclusions: Male patients with T2DM with greater AUCC-pep may be more likely to respond clinically to UC-MSC therapy, and further large-scale multi-ethnic clinical studies should be performed to confirm the conclusion., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Environmental pollution has emerged as a global concern due to its detrimental effects on human health. One of the critical aspects of this concern is the impact of environmental pollution on sperm quality in males. Male factor infertility accounts for approximately 40%- 50% of all infertility cases. Nonobstructive azoospermia (NOA) is the most severe type of male infertility. Human umbilical cord mesenchymal stem cell (hUCMSC) exosomes enhance proliferation and migration, playing crucial roles in tissue and organ injury repair. However, whether hUCMSC exosomes impacting on NOA caused by chemotherapeutic agents remains unknown. This study aimed to explore the functional restoration and mechanism of hUCMSC exosomes on busulfan-induced injury in GC-1 spg cells and ICR mouse testes. Our results revealed that hUCMSC exosomes effectively promoted the proliferation and migration of busulfan-treated GC-1 spg cells. Additionally, oxidative stress and apoptosis were significantly reduced when hUCMSC exosomes were treated. Furthermore, the injection of hUCMSC exosomes into the testes of ICR mice treated with busulfan upregulated the expression of mouse germ cell-specific genes, such as vasa, miwi, Stra8 and Dazl. Moreover, the expression of cellular junction- and cytoskeleton-related genes, including connexin 43, ICAM-1, β-catenin and androgen receptor (AR), was increased in the testicular tissues treated with exosomes. Western blot analysis demonstrated significant downregulation of apoptosis-associated proteins, such as bax and caspase-3, and upregulation of bcl-2 in the mouse testicular tissues injected with hUCMSC exosomes. Further, the spermatogenesis in the experimental group of mice injected with exosomes showed partial restoration of spermatogenesis compared to the busulfan-treated group. Collectively, these findings provide evidence for the potential clinical applications of hUCMSC exosomes in cell repair and open up new avenues for the clinical treatment of NOA., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Embryo transfer (ET) and intracytoplasmic sperm injection (ICSI) are widely used in equine species, but their effects on fetal adnexa and neonates have not been investigated yet. The aim of this study was to retrospectively evaluate whether pregnancies obtained by ET or ICSI could be associated with the presence of macroscopic alterations of fetal membranes (FM) and umbilical cord (UC) and if the use of these techniques could influence neonatal outcome. Sixty-six light breed mares hospitalized at the Veterinary Teaching Hospital, University of Bologna, for attending delivery were included in the study. Mares were divided into Artificial Insemination (AI; 32/66 mares, 48 %), Embryo Transfer (ET; 12/66 mares, 18.2 %) and Intracytoplasmic Sperm Injection (ICSI; 22/66 mares, 33 %) groups. All the medical reports of mares and their foals were reviewed and data about mare, pregnancy, foaling, fetal membranes, umbilical cord and foal were recorded. The occurrence of dystocia resulted statistically different between AI group and ICSI group (p = 0.0066), and between AI group and ET group (p = 0.044). Macroscopic examination of FM revealed alterations in 30/66 mares (46 %): 8/32 in AI (25 %), 7/12 in ET (58 %) and 15/22 in ICSI (68 %) with significant lower incidence in AI compared to ET (p = 0.04) and ICSI (p = 0.002) groups. Alterations reported were chorionic villi hypoplasia, chorioallantois edema, allantois cysts, necrotic areas and greenish-grey concretions. Total length of UC resulted significantly shorter in ICSI group (49 ± 9 cm; p < 0.03) compared to AI (60 ± 17 cm) and ET (59 ± 15 cm). However, there were no differences in the incidence of foals' diseases at birth and in foals' survival among groups (p > 0.05). The results demonstrate that transfer of in vivo or in vitro produced embryos may lead to alterations of placental development, as observed in other species, without being associated with a higher incidence of neonatal morbidity and mortality. Further studies about trophoblast development, FM histological evaluation, and placental gene expression should be carried out to clarify the mechanisms underlying the placental alterations., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: Neonatal trials have traditionally used binary composite short-term (such as death or bronchopulmonary dysplasia) or longer-term (such as death or severe neurodevelopmental impairment) outcomes. We applied the Desirability Of Outcome Ranking (DOOR) method to rank the overall patient outcome by best (no morbidities) to worst (death)., Study Design: Using a completed large multicenter trial (Milking In Non-Vigorous Infants [MINVI]) of umbilical cord milking (UCM) vs. early cord clamping (ECC), we applied the DOOR methodology to neonatal outcomes. Six outcomes were chosen and ranked: no interventions or NICU admission (most desirable); received initial cardiorespiratory support at birth; neonatal intensive care unit (NICU) admission for predefined criteria; mild hypoxic-ischemic encephalopathy (HIE); moderate to severe HIE; and death (least desirable)., Results: 1524 non-vigorous newborns born between 35 and 42 weeks' gestation had data for analysis. The DOOR distribution was different between the UCM and ECC arms, with a significantly greater probability (55.8 % [95 % CI 53.1-58.5 %; p < 0.0001]) of a randomly selected neonate having a more desirable outcome if they were in the UCM arm. DOOR probabilities of averting individual adverse outcomes such as NICU admission for predefined criteria (52.8 %; 95%CI 50.5-55.1 %) and cardiorespiratory support (54.0 %; 95%CI 51.6-56.4 %) were significantly higher among those in the UCM group., Conclusion: DOOR provides an overall assessment of the benefits and harms with greater insight than typical binary composite measures to clinicians and parents when evaluating an intervention. Future neonatal trials should consider the a priori use of the DOOR methodology to evaluate trial outcomes., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Equine pregnancy failure can occur throughout gestation with etiologies varying by region. In Europe, umbilical cord torsion (UCT) has been reported to account for up to 52% of abortions and stillbirths. Little is known about what causes excessive twisting of the umbilical cord (UC), and up till now, only the length of the UC has been identified as a risk factor for UCT. The aim of the present study was to determine the association of potential maternal and fetal risk factors with UCT and umbilical cord length (UCL). A retrospective cohort study was performed on aborted or prematurely delivered stillborn fetuses submitted for necropsy, and a follow-up questionnaire survey was sent to mare owners to obtain additional anamnestic data. In total 72 cases were included in the study. Multivariable regression analyses were performed to evaluate the risk factors (mare size, period of gestation, gestational length, parity, previous abortion, UCL, maternal age at abortion and fetal sex) association with UCT and UCL, and Wilcoxon rank sum test tested pairwise differences in UCL for the risk factors mare size, period of gestation and cause of abortion. Abortion caused by UCT (UCTA) was diagnosed in 37 cases, and these had shorter gestational length (8.1 ± 0.3 months) compared to fetuses lost to other causes (8.9 ± 0.2 months) (p = 0.002). UCTAs accounted for the highest prevalence of abortions in the mid gestational period (113-227 days) (14/21, 67%) compared to the late period (228-314 days) (22/50, 44%) (p = 0.05). The cause of abortion was associated with period of gestation (p = 0.009) and UCL (p = 0.002), and fetuses aborted as a consequence of UCT had longer UCs (98.84 ± 5.14 cm) compared to abortions due to other causes (67.2 ± 4.9 cm). Mares in the mid period of gestation had 7.9 times the odds of UCTA compared to the late period (CI: 1.93, 32.2), and UCL was associated with increased odds of UCTA (OR: 1.05, CI: 1.02, 1.07). UCL was associated with mare size (p = 0.012), period of gestation (p = 0.002) and cause of abortion (p = 0.001). In conclusion, UCTA was significantly associated with UCL and gestational length. The prevalence of UCTA was not influenced by mare size, but pony fetuses from UCTAs had significantly shorter UCs compared to horse fetuses. UCs longer than 54 cm may predispose ponies for UCTA. No other maternal or fetal risk factors were found to be associated with the cause of abortion., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Spinal cord injury (SCI) can cause severe and permanent neurological damage, and neuronal apoptosis could inhibit functional recovery of damaged spinal cord greatly. Human umbilical cord mesenchymal stem cells (hUC-MSCs) have great potential to repair SCI because of a series of advantages, including inhibition of neuronal apoptosis and multiple differentiation. The former may play an important role. However, the detailed regulatory mechanism associated with the inhibition of neuronal apoptosis after hUC-MSCs administration has not been elucidated. In this study, proteomics analysis of precious human cerebrospinal fluid (CSF) samples collected from SCI subjects receiving hUC-MSCs delivery indicated that hepatocyte growth factor (HGF) is largely involved in SCI repair. Furthermore, overexpression of HGF derived from hUC-MSCs could decrease reactive oxygen species to prevent neuron apoptosis to the maximum, and thus lead to significant recovery of spinal cord dysfunction. Moreover, HGF could promote phosphorylation of Akt/FoxO3a pathway to decrease reactive oxygen species to reduce neuron apoptosis. For the first time, our research revealed that HGF secreted by hUC-MSCs inhibits neuron apoptosis by phosphorylation of Akt/FoxO3a to repair SCI. This study provides important clues associated with drug selection for the effective treatment of SCI in humans., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The regeneration of thin endometrium still remains as a great challenge in the field of reproductive medicine. Stem cells-based therapy has been considered as a promising strategy for the restoration of thin endometrium. However, the low transplantation and retention rate of stem cells and loss of stemness due to in vitro expansion limits the therapeutic efficacy. In our study, we combined collagen hydrogel and human umbilical cord mesenchymal stem cells (uMSCs) for improving the regeneration of thin endometrium, by using the potent pluripotency and low immunogenicity of uMSCs and collagen hydrogel that promotes the anchorage and proliferation of stem cells. Results showed that collagen hydrogel has favorable biocompatibility and the capacity to enhance the cell viability and expression of stemness-associated genes (including organic cation/carnitine transporter4 (Oct-4), Nanog homeobox (Nanog) and SRY-box transcription factor 2 (SOX2)) of uMSCs. The combination of collagen hydrogel and uMSCs prolonged the retention time of the constructs in the uterine cavity and improved endometrial thickness compared with uMSCs alone, leading to increase the fertility of the rats with thin endometrium. These highlighted therapeutic prospects of collagen hydrogel combined with uMSCs for the minimally invasive therapy of thin endometrium in the clinic., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Differentiation of human umbilical cord mesenchymal stem cells (Uc-MSCs) into islet-like clusters which are capable of synthesizing and secreting insulin can potentially serve as donors for islet transplantation in the patient deficiency in islet β cell function both in type 1 or type 2 diabetic patients. Therefore, we developed an easy and higher efficacy approach by trypsinazing the Uc-MSCs and followed culture in differentiation medium to induce of Uc-MSCs differentiation into islet-like clusters, and the potential mechanism that in the early stage of differentiation was also investigated by using RNA-sequencing and bioinformatics. Results show that induction efficacy was reached to 98% and TGF-β signaling pathway may play critical role in the early stage differentiation, it was further confirmed that the retardant effect of differentiation progress either in cell morphology or in islet specific genes expression can be observed upon blocking the activation of TGF-β signaling pathway using specific inhibitor of LY2109761 (TβRI/II kinase inhibitor). Our current study, for the first time, development a protocol for differentiation of Uc-MSCs into islet-like clusters, and revealed the importance of TGF-β signaling pathway in the early stage of differentiation of Uc-MSCs into islet-like clusters. Our study will provide alternative approach for clinical treatment of either type I or type II diabtes mellitus with dysfunctional pancreatic islets., (Copyright © 2023 International Society of Differentiation. Published by Elsevier B.V. All rights reserved.)

Wharton's Jelly (WJ) has attracted significant interest in the field of tissue healing thanks to its biological properties, including antibacterial activity and immunomodulation. However, due to the fast degradation and poor mechanical behavior in biological environment, its application in bone regeneration is compromised. Here, we proposed to use genipin as an efficient cross-linking agent to significantly improve the elasticity and the enzymatical stability of the WJ matrix. The degree of cross-linking, linear elastic moduli, and collagenase resistance varied over a wide range depending on genipin concentration. Furthermore, our results highlighted that an increase in genipin concentration led to a decreased surface wettability, therefore impairing cell attachment and proliferation. The genipin cross-linking prevented rapid in vitro and in vivo degradation, but led to an adverse host reaction and calcification. When implanted in the parietal bone defect, a limited parietal bone regeneration to the dura was observed. We conclude that genipin-cross-linked WJ is a versatile medical device however, a careful selection is required with regards to the genipin concentration., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Stem cell therapy is considered a promising approach in the treatment of amyotrophic lateral sclerosis (ALS) and mesenchymal stem cells (MSCs) seem to be the most effective in ALS animal models. The umbilical cord (UC) is a source of highly proliferating fetal MSCs, more easily collectable than other MSCs. Recently we demonstrated that human (h) UC-MSCs, double labeled with fluorescent nanoparticles and Hoechst-33258 and transplanted intracerebroventricularly (ICV) into SOD1G93A transgenic mice, partially migrated into the spinal cord after a single injection. This prompted us to assess the effect of repeated ICV injections of hUC-MSCs on disease progression in SOD1G93A mice. Although no transplanted cells migrated to the spinal cord, a partial but significant protection of motor neurons (MNs) was found in the lumbar spinal cord of hUC-MSCs-treated SOD1G93A mice, accompanied by a shift from a pro-inflammatory (IL-6, IL-1β) to anti-inflammatory (IL-4, IL-10) and neuroprotective (IGF-1) environment in the lumbar spinal cord, probably linked to the activation of p-Akt survival pathway in both motor neurons and reactive astrocytes. However, this treatment neither prevented the muscle denervation nor delayed the disease progression of mice, emphasizing the growing evidence that protecting the motor neuron perikarya is not sufficient to delay the ALS progression.

Objective: Clarify the prognosis of the prenatal ultrasound diagnosis of umbilical cord cysts at any gestation trimester and to assess the ultrasound findings and chromosomal alterations associated to this entity. Materials and methods: Between 2003 and 2015 a multicenter study was carried out, collecting, in five centers in Spain, the associated findings and perinatal outcomes of 27 cases of umbilical cord cysts, regardless of gestational age of diagnosis. A bibliographic review was conducted to identify previous studies in order to compare them with our data. Results: In our sample, the prognosis of this finding and the neonatal outcome, when isolated, is favorable, regardless of gestational age at diagnosis, multiple or unique presentation or vanishing or persistent cysts. Conclusions: It is important to properly assess the umbilical cord cyst and when is diagnosed, it is recommended to conduct a meticulous ultrasound examination searching for other associated malformations. In our study the prognosis of this finding seems to be favorable when isolated. Also, there is no relation between prognosis and gestation weeks at diagnosis. On the other hand, when we find this entity with associated anomalies, it is recommended to assess the need to carry out a karyotype.

Objective: Persistent right umbilical vein (PRUV) is a vascular anomaly where the right umbilical vein remains as the only conduit that returns oxygenated blood to the fetus. It has classically been described as associated with numerous defects. We distinguish the intrahepatic variant (better prognosis) and the extrahepatic variant (associated with worse prognosis). The objective of this study was to compare rates of congenital malformations in fetuses with intrahepatic PRUV (I-PRUV) versus singleton pregnancies without risk factors. Materials and Methods: A multicenter, crossover design, comparative study was performed between 2003 and 2013 on fetuses diagnosed with I-PRUV (n=56), and singleton pregnancies without congenital malformation risk factors (n=4050). Results: Fifty-six cases of I-PRUV were diagnosed (incidence 1:770). A statistically significant association between I-PRUV and the presence of congenital malformations (odds ratio 4.321; 95% confidence interval 2.15–8.69) was found. This positive association was only observed with genitourinary malformations (odds ratio 3.038; 95% confidence interval 1.08–8.56). Conclusion: Our rate of malformations associated with I-PRUV (17.9%) is similar to previously published rates. I-PRUV has shown a significant increase in the rate of associated malformations, although this association has only been found to be statistically significant in the genitourinary system. Noteworthy is the fact that this comparative study has not pointed to a significant increase in the congenital heart malformation rate. Diagnosis of isolated I-PRUV does not carry a worse prognosis.

Resumen: El cuidado del cordón umbilical hasta su desprendimiento continúa siendo motivo de controversia en la actualidad. La Organización Mundial de la Salud recomienda en su última revisión realizar la cura en seco en países con cuidados obstétricos adecuados y una tasa baja de mortalidad neonatal. Por otro lado, en los últimos años han surgido nuevos estudios y revisiones que atribuyen un beneficio a aplicar clorhexidina tópica en el muñón. El presente documento analiza la evidencia disponible y concluye en la conveniencia de continuar recomendando la cura en seco en los nacimientos de nuestro entorno. Abstract: The care of the umbilical cord until its detachment still remains controversial. The latest updated recommendations by the World Health Organisation advocate dry cord care in those countries with adequate obstetric care and low neonatal mortality rate. In recent years, new studies and reviews attribute some benefit to applying chlorhexidine on the umbilical stump. An analysis is presented here of the available evidence and results in the advisability of still recommending the dry cord care in the newborns in our setting.

Competing Interests: I declare no competing interests.

Background: Deferred (also known as delayed) cord clamping can improve survival of infants born preterm (before 37 weeks of gestation), but the optimal duration of deferral remains unclear. We conducted a systematic review and individual participant data network meta-analysis with the aim of comparing the effectiveness of umbilical cord clamping strategies with different timings of clamping or with cord milking for preterm infants., Methods: We searched medical databases and trial registries from inception until Feb 24, 2022 (updated June 6, 2023) for randomised controlled trials comparing cord clamping strategies for preterm infants. Individual participant data were harmonised and assessed for risk of bias and quality. Interventions were grouped into immediate clamping, short deferral (≥15 s to <45 s), medium deferral (≥45 s to <120 s), long deferral (≥120 s), and intact cord milking. The primary outcome was death before hospital discharge. We calculated one-stage, intention-to-treat Bayesian random-effects individual participant data network meta-analysis. This study was registered with PROSPERO, CRD42019136640., Findings: We included individual participant data from 47 trials with 6094 participants. Of all interventions, long deferral reduced death before discharge the most (compared with immediate clamping; odds ratio 0·31 [95% credibility interval] 0·11-0·80; moderate certainty). The risk of bias was low for 10 (33%) of 30 trials, 14 (47%) had some concerns, and 6 (20%) were rated as having a high risk of bias. Heterogeneity was low, with no indication of inconsistency., Interpretation: This study found that long deferral of clamping leads to reduced odds of death before discharge in preterm infants. In infants assessed as requiring immediate resuscitation, this finding might only be generalisable if there are provisions for such care with the cord intact. These results are based on thoroughly cleaned and checked individual participant data and can inform future guidelines and practice., Funding: Australian National Health and Medical Research Council., Competing Interests: Declaration of interests iCOMP trial representatives comprised principal investigators of studies included in this meta-analysis. Trial representatives did not input on study eligibility, data integrity assessments, data extraction, or risk of bias assessments for their own studies. Trial representatives did not make final decisions on certainty of evidence ratings. ALS reports Australian National Health and Medical Research Council (NHMRC) project and Investigator grants (funds paid directly to the University of Sydney). JXS reports travel grants and scholarships from the Association of Interdisciplinary Meta-science and Open-Science, Pediatric Academic Societies, and the Perinatal Society of Australia and New Zealand. KEH reports NHMRC funding paid directly to the University of Sydney. All other authors declare no competing interests. The full list of iCOMP Collaborators and their declaration of interests are noted in the appendix (pp 318–21)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Exosomes and hyaluronic acid influence tissue regeneration and may be used as an alternative to more conventional wound treatment methods. This study compared how well hyaluronic acid from the human umbilical cord and exosomes from fibroblast cells heal burn wounds in a preclinical model., Methods: Ninety-six male Westar rats were used and allocated into four groups: The treatment group received 10% hyaluronic acid (HA); the treatment group received 300 l of exosome solution (EX); the treatment group received phenytoin (PC); the negative control group received no treatment (NC). The wound healing process was evaluated after 3, 6, 9, and 12 days. Histopathological analysis was done on the skin biopsy taken from the wounds. Re-epithelialization, inflammatory cells (PMNs), lymphocytes (LYMs), granulation tissue, collagen maturation (fibrosis), and eschar formation parameters were assessed for histopathological evaluation. On a scale from 0 to 4, each parameter received a score., Results: Compared to the PC and NC groups, the median score for re-epithelialization was greater in the HA and EX groups (P < 0.05). At three days, PMN abundance distinguished the PC and NC groups from the HA and EX groups (P < 0.01). Compared to the PC and NC groups, the HA and EX groups had a lower median LYM score (P < 0.01). We found no statistical difference between the four groups for granulation tissue and fibrosis (P > 0.05). The EX group had a lower average score for eschar formation than the PC, NC, and HA groups (P < 0.01). The HA and EX groups demonstrated faster healing in the clinical and microscopic examinations than the NC and PC groups., Conclusion: The results showed that hyaluronic acid and exosomes improved wound healing. Also, the study demonstrated that hyaluronic acid has better effects in the re-epithelization. The exosome was more effective than HA in eschar formation. Both compounds were more influential in the PMNs and LYMs parameters than other groups. The combination of both compounds should be assessed further to achieve better therapeutic effects on wound healing., Competing Interests: Conflict of interest We declare that there is no conflict of interest., (Copyright © 2023 Elsevier Ltd and International Society of Burns Injuries. All rights reserved.)

Objectives: At the beginning of the COVID-19 pandemic, delayed umbilical cord clamping (CC) at birth may have been commonly discouraged despite a lack of convincing evidence of mother-to-neonate SARS-CoV-2 transmission. We aimed to systematically review guidelines, and reports of practice and to analyze associations between timing of CC and mother-to-neonate SARS-CoV-2 transmission during the early phases of the pandemic., Methods: Major databases were searched from December 1, 2019, to July 20, 2021., Inclusion: studies and guidelines describing CC practice in women with SARS-CoV-2 infection during pregnancy until 2 postnatal days, giving birth to live-born neonates., Exclusion: no extractable data. Two reviewers independently screened studies for eligibility and assessed study quality. Pooled prevalence rates were calculated., Results: Forty-eight studies (1476 neonates) and 40 guidelines were included. Delayed CC was recommended in 70.0% of the guidelines. Nevertheless, delayed CC was reported less often than early CC: 262/1476 (17.8%) vs 511/1476 (34.6%). Neonatal SARS-CoV-2 positivity rates were similar following delayed (1.2%) and early CC (1.3%). Most SARS-CoV-2 transmissions (93.3%) occurred in utero., Conclusion: Delayed CC did not seem to increase mother-to-neonate SARS-CoV-2 transmission. Due to its benefits, it should be encouraged even in births where the mother has a SARS-CoV-2 infection., Systematic Review Registration: Prospero CRD42020199500., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Early identification of infants at high risk of allergies can improve the efficacy of preventive interventions. However, an established quantifiable risk assessment method in the early postnatal period does not exist. TARC (or CCL17) is a Th2 chemokine used as an activity marker for atopic dermatitis (AD). Therefore, we evaluated the association between cord blood TARC (cTARC) and the development of allergic diseases in childhood., Methods: This is a high-risk birth cohort for allergy, consisting of children with a family history of allergy. We collected 263 pairs of maternal and child cord blood samples perinatally and child blood samples at ages 1, 2, and 5 years. TARC and allergen-specific immunoglobulin E levels were measured, and the relationship between allergic diseases was analyzed., Results: The median cTARC was 989 pg/mL (interquartile range [IQR]: 667-1430 pg/mL). The cTARC levels in children who developed AD were higher than those in children who did not develop AD, and the association strengthened with younger age (median [IQR] at 1 year: 1285 [816-1965] vs. 933 [662-1330] pg/mL, p < 0.01; at 2 years: 1114 [787-1753] vs. 950 [660-1373] pg/mL, p = 0.02). In the multivariate analysis, cTARC was associated with AD, egg white sensitization, food allergy, allergic rhinitis, and Japanese cedar pollen sensitization., Conclusions: cTARC was associated with the development of allergic diseases and allergen sensitization in early childhood. These results suggest that, infantile AD-mediated atopic march starts during fetal life, and this immune status is reflected in the cTARC at birth., (Copyright © 2023 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Background Aims: Human umbilical cord-derived mesenchymal stromal cells (hUC-MSCs) are increasingly used in research and therapy. To obtain hUC-MSCs, a diversity of isolation and expansion methods are applied. Here, we report on a robust and standardized method for hUC-MSC isolation and expansion., Methods: Using 90 hUC donors, we compared and optimized critical variables during each phase of the multi-step procedure involving UC collection, processing, MSC isolation, expansion and characterization. Furthermore, we assessed the effect of donor-to-donor variability regarding UC morphology and donor attributes on hUC-MSC characteristics., Results: We demonstrated robustness of our method across 90 UC donors at each step of the procedure. With our method, UCs can be collected up to 6 h after birth, and UC-processing can be initiated up to 48 h after collection without impacting on hUC-MSC characteristics. The removal of blood vessels before explant cultures improved hUC-MSC purity. Expansion in Minimum essential medium α supplemented with human platelet lysate increased reproducibility of the expansion rate and MSC characteristics as compared with Dulbecco's Modified Eagle's Medium supplemented with fetal bovine serum. The isolated hUC-MSCs showed a purity of ∼98.9%, a viability of >97% and a high proliferative capacity. Trilineage differentiation capacity of hUC-MSCs was reduced as compared with bone marrow-derived MSCs. Functional assays indicated that the hUC-MSCs were able to inhibit T-cell proliferation demonstrating their immune-modulatory capacity., Conclusions: We present a robust and standardized method to isolate and expand hUC-MSCs, minimizing technical variability and thereby lay a foundation to advance reliability and comparability of results obtained from different donors and different studies., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Wharton's jelly (WJ) is fundamental for the well-being of the fetus, binding to the umbilical vessels and protecting them from twisting and compression. Gross and microscopic studies have been undertaken on the umbilical cord (UC) of human placentae in both normal and high-risk pregnancies, however there is limited research on equine UC. The aim of this study was to describe microscopically and immunohistochemically the equine UC in normal pregnancies, with particular attention to WJ. Forty-seven healthy mares, with no complications during pregnancy, admitted to the hospital for attending delivery were enrolled. Clinical data was collected at foaling on foal health and placental characteristics. UC samples were collected from three sites (amniotic, allantoic and in the region of vein anastomosis) for histology. The thickness of different layers of arteries and veins and WJ in different UC portions were measured (μm). Wharton's Jelly was weighted (g) and its sections were stained with Masson's trichrome, orcein technique and silver impregnation. Immunohistochemistry was undertaken using antibodies raised-against collagen type I, V, VI and fibrillin. Forty-seven UCs, from 19 colt and 28 filly foals, were analyzed for WJ weight and 8/47 UCs were examined histologically. Warton's jelly was only found in the amniotic portion of the UC closest to the foal's abdomen. The weight of WJ (4.0 ± 3.3 g) did not vary between colts and fillies and it was not correlated with any of the clinical or UC parameters measured. The tunica media of arteries and veins was thicker in the amniotic portion of the UC, as described in human UCs in late pregnancy. This finding could be an adaptation to aid in resisting compression because of fetal movements and UC twisting. The umbilical vein was thicker than the umbilical arteries in the tunica media and tunica adventitia in the sections examined throughout the length of the cord. This preliminary study describes gross and histological WJ's structure in the equine species. However, further studies are required to better characterize UC's changes throughout pregnancy and in the presence of mare's or fetal disease., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Human umbilical cord (hUC) blood and tissue are non-invasive sources of potential stem/progenitor cells with similar cell surface properties as bone marrow stromal cells (BMSCs). While they are limited in cord blood, they may be more abundant in hUC. However, the hUC is an anatomically complex organ and the potential of cells in various sites of the hUC has not been fully explored. We dissected the hUC into its discrete sites and isolated hUC cells from the cord placenta junction (CPJ), cord tissue (CT), and Wharton's jelly (WJ). Isolated cells displayed fibroblastoid morphology, and expressed CD29, CD44, CD73, CD90, and CD105, and showed evidence of differentiation into multiple lineages in vitro. They also expressed low levels of pluripotency genes, OCT4, NANOG, SOX2 and KLF4. Passaging markedly affected cell proliferation with concomitant decreases in the expression of pluripotency and other markers, and an increase in chondrogenic markers. Microarray analysis further revealed the differences in the gene expression of CPJ-, CT- and WJ-hUC cells. Five coding and five lncRNA genes were differentially expressed in low vs. high passage hUC cells. Only MAEL was expressed at high levels in both low and high passage CPJ-hUC cells. They displayed a greater proliferation limit and a higher degree of multi-lineage differentiation in vitro and warrant further investigation to determine their full differentiation capacity, and therapeutic and regenerative medicine potential.

The translational potential of cell therapy to humans requires a deep knowledge of the interaction between transplanted cells and host tissues. In this study, we evaluate the behavior of umbilical cord mesenchymal stromal cells (UC-MSCs), labeled with fluorescent nanoparticles, transplanted in healthy or early symptomatic transgenic SOD1G93A mice (a murine model of Amyotrophic Lateral Sclerosis). The double labeling of cells with nanoparticles and Hoechst-33258 enabled their tracking for a long time in both cells and tissues. Whole-body distribution of UC-MSCs was performed by in-vivo and ex-vivo analyses 1, 7, 21 days after single intravenous or intracerebroventricular administration. By intravenous administration cells were sequestered by the lungs and rapidly cleared by the liver. No difference in biodistribution was found among the two groups. On the other hand, UC-MSCs transplanted in lateral ventricles remained on the choroid plexus for the whole duration of the study even if decreasing in number. Few cells were found in the spinal cord of SOD1G93A mice exclusively. No migration in brain parenchyma was observed. These results suggest that the direct implantation in brain ventricles allows a prolonged permanence of cells close to the damaged areas and makes this method of tracking reliable for future studies of efficacy.

Animals born from in-vitro-produced (IVP) embryos show changes in the placenta and umbilical cord vascularization. This study compares the placental and umbilical vascular morphometry in pigs (n = 19) born through artificial insemination (AI group) or after transfer of IVP embryos cultured with (RF-IVP group) or without (C-IVP group) reproductive fluids. The relationship between vascular parameters and animal growth during the first year of life was also analyzed. Samples were collected at birth, fixed, paraffin-embedded, cut in sections, stained, and photographed for vascular and morphometric analysis with ImageJ® and Slide Viewer®. The average daily weight gain was individually scored from birth to the first year of life. No differences were found in placental vascular morphometry among groups, except for the vascular area of small vessels (arterioles, venules, and small vessels) that was higher in the C-IVP group. Regarding the umbilical cord, the values for perimeter (AI: 26.40 ± 3.93 mm; IVP: 30.51 ± 4.74 mm), diameter (AI: 8.35 ± 1.01 mm; IVP: 10.26 ± 1.85 mm), area (AI: 43.18 ± 12.87; IVP: 56.61 ± 14.89 mm 2 ), and Wharton's jelly area (AI: 36.86 ± 12.04 mm 2 ; IVP 48.88 ± 12.80 mm 2 ) were higher in IVP-derived than AI-derived animals, whereas arterial and venous morphometric data were similar between groups. A correlation study showed that placental and umbilical cord vascular phenotypes affect the further growth of pigs. In conclusion, assisted reproductive technologies impact small caliber vessels in the placenta and morphometric parameters in the umbilical cord. The addition of reproductive fluids in IVP-embryo contributes to reduce the differences with in vivo-derived animals., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)