Assessing the Impact of COVID-19 Vaccination on Preterm Birth: A Systematic Review with Meta-Analysis.

During the coronavirus diseases 2019 (COVID-19) pandemic, the safety and efficacy of vaccination during pregnancy, particularly regarding the risk of preterm birth, have been a subject of concern. This systematic review aims to evaluate the impact of COVID-19 vaccination on preterm birth risk and to inform clinical practice and public health policies. Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a database search included PubMed, Embase, and Scopus, conducted up until October 2023. Inclusion criteria focused on studies that examined COVID-19 vaccination during pregnancy and its correlation with preterm birth, defined as a birth before 37 weeks of gestation. Six studies met these criteria, encompassing 35,612 patients. A quality assessment was performed using the Newcastle-Ottawa Scale and the Cochrane Collaboration's tool, with the risk of bias evaluated via a funnel plot analysis and an Egger's regression test. The studies demonstrated geographical diversity, mainly from Israel, Romania, and the United States, with a blend of prospective and retrospective designs. The patient cohort's mean age was 31.2 years, with common comorbidities such as gestational diabetes and obesity affecting 9.85% of the total population. The vaccination types varied across the studies, with BNT162b2 being the most used. The results indicated a low heterogeneity among the included studies, evidenced by a Cochran's Q statistic of 2.10 and an I2 statistic of 13%. The meta-analysis yielded a pooled odds ratio (OR) for a preterm birth risk post-vaccination of approximately 1.03 (95% CI: 0.82-1.30), suggesting no significant increase in preterm birth risk was associated with COVID-19 vaccination. Notable findings included a low preterm birth rate (as low as 0.6% and up to 6.1%) with minimal differences in neonatal outcomes, such as birth weight and APGAR (appearance, pulse, grimace, activity, and respiration) scores between vaccinated and unvaccinated groups. This study concludes that a COVID-19 vaccination during pregnancy does not significantly increase the risk of preterm birth. These findings are crucial for reassuring healthcare providers and pregnant women about the safety of COVID-19 vaccines and supporting their use in public health strategies during the pandemic.

Host and immunosuppression-related factors influencing fibrosis occurrence post liver transplantation.

Post liver transplantation (LT) fibrosis has a negative impact on graft function. Cytokine production in the host immune response after LT may contribute to the variable CYP3A-dependent immunosuppressive drug disposition, with subsequent impact on liver fibrogenesis, together with host-related factors. We aimed to investigate whether the cytochrome P4503A5*3 (CYP3A5*3) or TBX21 genotypes impact post-LT liver fibrogenesis. Furthermore, the impact of immunosuppressants on cellular apoptosis has been evaluated using human hepatocytes harvested from cirrhotic explanted livers. We have enrolled 98 LT recipients that were followed for occurrence of liver fibrosis for at least 12 months. There was a statistically significant higher trough level of TAC in patients with homozygous CC-TBX21 genotype (7.83 ± 2.84 ng/ml) vs. 5.66 ± 2.16 ng/ml in patients without this genotype (p = 0.009). The following variables were identified as risk factors for fibrosis ≥2: donor age (p = 0.02), neutrophil to lymphocyte ratio (p = 0.04) and TBX21 genotype CC (p = 0.009). In the cell culture model cytometry analysis has indicated the lowest apoptotic cells percentage in human cirrhotic hepatocytes cultures treated with mycophenolate mofetil (MMF) (5%) and TAC + MMF (2%) whereas the highest apoptosis percentage was registered for the TAC alone (11%). The gene expression results are concordant to cytometry study results, indicating the lowest apoptotic effect for MMF and MMF + TAC immunosuppressive regimens. The allele 1993C of the SNP rs4794067 may predispose to the development of late significant fibrosis of the liver graft. MMF-based regimens have a favourable anti-apoptotic profile in vitro, supporting its use in case of LT recipients at high risk for liver graft fibrosis.

The Influence of Nutritional Supplementation for Iron Deficiency Anemia on Pregnancies Associated with SARS-CoV-2 Infection.

Anemia is a very common occurrence during pregnancy, with important variations during each trimester. Anemia was also considered as a risk factor for severity and negative outcomes in patients with SARS-CoV-2 infection. As the COVID-19 pandemic poses a significant threat for pregnant women in terms of infection risk and access to care, we developed a study to determine the impact of nutritional supplementation for iron deficiency anemia in correlation with the status of SARS-CoV-2 infection. In a case-control design, we identified 446 pregnancies that matched our inclusion criteria from the hospital database. The cases and controls were stratified by SARS-CoV-2 infection history to observe the association between exposure and outcomes in both the mother and the newborn. A total of 95 pregnant women were diagnosed with COVID-19, having a significantly higher proportion of iron deficiency anemia. Low birth weight, prematurity, and lower APGAR scores were statistically more often occurring in the COVID-19 group. Birth weight showed a wide variation by nutritional supplementation during pregnancy. A daily combination of iron and folate was the optimal choice to normalize the weight at birth. The complete blood count and laboratory studies for iron deficiency showed significantly decreased levels in association with SARS-CoV-2 exposure. Puerperal infection, emergency c-section, and small for gestational age were strongly associated with anemia in patients with COVID-19. It is imperative to screen for iron and folate deficiency in pregnancies at risk for complications, and it is recommended to supplement the nutritional intake of these two to promote the normal development and growth of the newborn and avoid multiple complications during pregnancy in the COVID-19 pandemic setting.

Phenotypic assessment of liver-derived cell cultures during in vitro expansion.

Background: Liver cells represent an attractive source of cells for autologous regenerative medicine. The present study assesses the liver cells' stability during in vitro expansion, as a prerequisite for therapeutic use. Results: The human liver cell cultures in this study were propagated efficiently in vitro for at least 12 passages. No significant changes in morphology, intracellular ultrastructures and characteristic markers expression were found during in vitro expansion of cells from all analyzed donors. However, expanded cells derived from male donors of >60 years old, lost the Y chromosome. Conclusion: Liver-derived cell cultures adopt a proliferative, stable mesenchymal phenotype, through an epithelial to mesenchymal transition process. The molecular and phenotypic changes of the cells during propagation are uniform, despite the heterogeneity of the different donors. Loss of Y chromosome occurs after cells' propagation in elder male donors.

Development of a DsRed-expressing HepaRG cell line for real-time monitoring of hepatocyte-like cell differentiation by fluorescence imaging, with application in screening of novel geometric microstructured cell growth substrates.

The bipotent nature of the HepaRG cell line is a unique property among human hepatoma-derived cells. Cell treatment with specific differentiation inducers results in a mixture of hepatocyte- and biliary-like cells, accompanied by upregulation of liver-specific proteins, drug metabolizing enzymes, transcription regulators, membrane receptors or innate immune response effectors. These features make the HepaRG cells a suitable and handy replacement for primary hepatocytes, to study hepatic functions in vitro. However, cell differentiation is a long, variable process, requiring special culture conditions, while the resulting mixed cell populations is usually a major drawback. This process can potentially be controlled by interface characteristics, such as substrate topography. To screen for such novel substrates, we have first developed a new HepaRG cell line, designated as HepaRGDsRed, expressing the reporter gene DsRed. The fluorescent protein was expressed in hepatocyte- and not biliary-like cells, in a differentiation dependent-manner. We have further used replicated microstructured gradients of polydimethylsiloxane (PDMS) that allow three-dimensional manipulation in vitro, to monitor HepaRGDsRed differentiation in real time. We demonstrate that this approach enables the controlled assembly of viable hepatocyte-like cells for functional studies, which can be maintained in culture without loss of differentiation. The regulated expression of the DsRed reporter proved a valuable tool not only for rapid screening of novel cell growth substrates favoring cell differentiation, but also, to enrich the hepatocyte-like cell population by fluorescence-activated cell sorting to investigate liver-specific processes in vitro.

Novel function of the endoplasmic reticulum degradation-enhancing α-mannosidase-like proteins in the human hepatitis B virus life cycle, mediated by the middle envelope protein.

Cells replicating the human hepatitis B virus (HBV) express high levels of degradation-enhancing α-mannosidase-like proteins (EDEMs), a family of proteins involved in the endoplasmic reticulum associated degradation, one of the pathways activated during the unfolded protein response. Owing to their α-1,2 mannosidase activity, the EDEM1-3 proteins are able to process the N-linked glycans of misfolded or incompletely folded proteins, providing the recognition signal for their subsequent degradation. The HBV small (S), medium (M), and large (L) surface proteins bear an N-linked glycosylation site in the common S domain that is partially occupied in all proteins. The M protein contains an additional site in its preS2 domain, which is always functional. Here, we report that these oligosaccharides are processed by EDEMs, more efficiently by EDEM3, which induces degradation of L and S proteins, accompanied by a reduction of subviral particles production. In striking contrast, M not only is spared from degradation but its trafficking is also accelerated leading to an improved secretion. This unusual behavior of the M protein requires strictly the mannose trimming of the preS2 N-linked glycan. Furthermore, we show that HBV secretion is significantly inhibited under strong endoplasmic reticulum stress conditions when M expression is prevented by mutagenesis of the viral genome. These observations unfold unique properties of the M protein in the HBV life cycle during unfolded protein response and point to alternative mechanisms employed by EDEMs to alleviate this stress in case of necessity by promoting glycoprotein trafficking rather than degradation.

Modulation of the unfolded protein response by the human hepatitis B virus.

During productive viral infection the host cell is confronted with synthesis of a vast amount of viral proteins which must be folded, quality controlled, assembled and secreted, perturbing the normal function of the endoplasmic reticulum (ER). To counteract the ER stress, cells activate specific signaling pathways, designated as the unfolded proteins response (UPR), which essentially increase their folding capacity, arrest protein translation, and degrade the excess of misfolded proteins. This cellular defense mechanism may, in turn, affect significantly the virus life-cycle. This review highlights the current understanding of the mechanisms of the ER stress activation by Human Hepatitis B virus (HBV), a deadly pathogen affecting more than 350 million people worldwide. Further discussion addresses the latest discoveries regarding the adaptive strategies developed by HBV to manipulate the UPR for its own benefits, the controversies in the field and future perspectives.