TIMEDB: tumor immune micro-environment cell composition database with automatic analysis and interactive visualization.

Deciphering the cell-type composition in the tumor immune microenvironment (TIME) can significantly increase the efficacy of cancer treatment and improve the prognosis of cancer. Such a task has benefited from microarrays and RNA sequencing technologies, which have been widely adopted in cancer studies, resulting in extensive expression profiles with clinical phenotypes across multiple cancers. Current state-of-the-art tools can infer cell-type composition from bulk expression profiles, providing the possibility of investigating the inter-heterogeneity and intra-heterogeneity of TIME across cancer types. Much can be gained from these tools in conjunction with a well-curated database of TIME cell-type composition data, accompanied by the corresponding clinical information. However, currently available databases fall short in data volume, multi-platform dataset integration, and tool integration. In this work, we introduce TIMEDB (https://timedb.deepomics.org), an online database for human tumor immune microenvironment cell-type composition estimated from bulk expression profiles. TIMEDB stores manually curated expression profiles, cell-type composition profiles, and the corresponding clinical information of a total of 39,706 samples from 546 datasets across 43 cancer types. TIMEDB comes readily equipped with online tools for automatic analysis and interactive visualization, and aims to serve the community as a convenient tool for investigating the human tumor microenvironment.

Genomic profiling informs therapies and prognosis for patients with hepatocellular carcinoma in clinical practice.

Hepatocellular carcinoma (HCC) genomic research has discovered actionable genetic changes that might guide treatment decisions and clinical trials. Nonetheless, due to a lack of large-scale multicenter clinical validation, these putative targets have not been converted into patient survival advantages. So, it's crucial to ascertain whether genetic analysis is clinically feasible, useful, and whether it can be advantageous for patients. We sequenced tumour tissue and blood samples (as normal controls) from 111 Chinese HCC patients at Qingdao University Hospital using the 508-gene panel and the 688-gene panel, respectively. Approximately 95% of patients had gene variations related to targeted treatment, with 50% having clinically actionable mutations that offered significant information for targeted therapy. Immune cell infiltration was enhanced in individuals with TP53 mutations but decreased in patients with CTNNB1 and KMT2D mutations. More notably, we discovered that SPEN, EPPK1, and BRCA2 mutations were related to decreased median overall survival, although MUC16 mutations were not. Furthermore, we found mutant MUC16 as an independent protective factor for the prognosis of HCC patients after curative hepatectomy. In conclusion, this study connects genetic abnormalities to clinical practice and potentially identifies individuals with poor prognoses who may benefit from targeted treatment or immunotherapy.

Association of free fatty acid in first trimester with the risk of gestational diabetes mellitus: a nested case-control study.

BACKGROUND: Accumulating evidence shows that free fatty acids (FFA) are associated with gestational diabetes mellitus (GDM). However, most of the studies focus on a few specific types of FFA, such as α-linolenic acid (C18:3n3) and Arachidonic acid (C20:4n6) or a total level of FFA. OBJECTIVE: This study aimed to test the association between a variety of FFAs during the first trimester and the risk of GDM. METHODS: The participants came from the Zhoushan Pregnant Women Cohort (ZWPC). A 1:2 nested case-control study was conducted: fifty mothers with GDM were matched with 100 mothers without GDM by age, pre-pregnancy body mass index (BMI), month of oral glucose tolerance test (OGTT) and parity. Thirty-seven FFAs (including 17 saturated fatty acids (SFA), 8 monounsaturated fatty acids (MUFA), 10 polyunsaturated fatty acids (PUFA) and 2 trans fatty acids (TFA)) in maternal plasma during the first trimester were tested by Gas Chromatography-Mass Spectrometry (GC-MS). Conditional logistic regression models were performed to assess the associations of FFA with the risk of GDM. RESULTS: Nine FFAs were respectively associated with an increased risk of GDM (P < 0.05), and four FFAs were respectively associated with a decreased risk of GDM (P < 0.05). SFA risk score was associated with a greater risk of GDM (OR = 1.34, 95% CI: 1.12-1.60), as well as UFA risk score (OR = 1.26, 95% CI: 1.11-1.44), MUFA risk score (OR = 1.70, 95%CI: 1.27-2.26), PUFA risk score (OR = 1.32, 95%CI: 1.09-1.59) and TFA risk score (OR = 2.51, 95%CI: 1.23-5.13). Moreover, joint effects between different types of FFA risk scores on GDM were detected. For instance, compared with those with low risk scores of SFA and UFA, women with high risk scores of SFA and UFA had the highest risk of GDM (OR = 8.53, 95%CI: 2.41-30.24), while the Odds ratio in those with a low risk score of SFA and high risk score of UFA and those with a high risk score of SFA and low risk score of UFA was 6.37 (95%CI:1.33- 30.53) and 4.25 (95%CI: 0.97-18.70), respectively. CONCLUSION: Maternal FFAs during the first trimester were positively associated with the risk of GDM. Additionally, there were joint effects between FFAs on GDM risk. CONDENSATION: Elevated FFA levels in the first trimester increased the risk of GDM.

Global trends in total fertility rate and its relation to national wealth, life expectancy and female education.

OBJECTIVES: Along with the development of the times and progress of the society, the total fertility rate (TFR) markedly changed in each country. Therefore, it is critical to describe the trend of TFR and explore its influencing factors. However, previous studies did not consider the time lag and cumulative effect in the associations between the influencing factors and TFR. Thus, our study aimed to analyze the associations from a new dimension. METHODS: The study was employed using national-level data from the World Bank and United Nations Development Programme. Distributed lag non-linear models with 5-year lag were used to examine the independent associations between the relevant factors and TFR. RESULTS: The cumulative exposure-TFR curves were inverted U-shaped for log gross domestic product (GDP) per capita and life expectancy at birth, while the cumulative exposure-response curves were approximately linear for female expected years of schooling and human development index (HDI). However, it is worth noting that in the developed regions, TFR increased slightly with the high level of GDP per capita, female expected years of schooling and HDI. CONCLUSIONS: Nowadays, with the growth of GDP per capita, life expectancy at birth, female expected years of schooling and HDI, TFR are on a drastic downward trend in most regions. Besides, with the development of society, when levels of the factors continued to increase, TFR also showed a slight rebound. Therefore, governments, especially those in developing countries, should take measures to stimulate fertility and deal with a series of problems caused by declining TFR.

Associations of maternal liver biomarkers in the first trimester with the risk of hypertensive disorders of pregnancy.

This study aimed to evaluate the association between maternal liver biomarkers in early pregnancy and the risk of hypertensive disorders of pregnancy (HDP), as well as to evaluate interaction between liver enzymes and BMI on the development of HDP. Pregnant women in our study were recruited from the Zhoushan Pregnant Women Cohort. Participants who had their first prenatal follow-up and the blood pressure follow-up records, and measured liver biomarkers in the first trimester were eligible for inclusion in the study. A total of 10,610 pregnant women were included in the analysis, and 305 (2.87%) developed the HDP. There were positive associations between AST, GGT, ALP, HSI and SBP, as well as between ALT, GGT, ALP, HSI and DBP. In addition, AST/ALT level was negatively associated with DBP. The highest quartile of GGT, ALP, AST/ALT and HSI were significantly associated with 1.71-fold (95% Cl: 1.23-2.41), 1.53-fold (95% Cl: 1.10-2.14), 0.62-fold (95% Cl: 0.43-0.90) and 1.67-fold (95% Cl: 1.05-2.67) increased risk of HDP, respectively. There was no significant association between ALT, AST and HDP. These associations remained consistent in pregnant women with liver enzymes within the clinical reference range. Besides, we found an interaction between GGT and BMI (Pinteraction = 0.013) in the development of HDP. In summary, the level of GGT, ALP, AST/ALT and HSI were associated with the subsequent risk of HDP, even within the clinical reference range. And there was an interaction between liver biomarkers and BMI in the development of HDP. Our study showed the level of GGT, ALP, AST/ALT and HSI were associated with the subsequent risk of HDP. And there was an interaction between GGT and BMI in the risk of HDP.

Association of systemic chronic inflammation during pregnancy in different periods and its trajectories with preterm birth.

PROBLEM: Systemic chronic inflammation (SCI) is a prevalent characteristic observed in various diseases originating from different tissues, while the association of SCI with preterm birth (PTB) remains uncertain. This study aimed to analyze the association between a nonspecific biomarker of SCI and PTB, while also exploring the trajectories of SCI in pregnant women at risk of PTB. METHOD OF STUDY: The study used data from the Electronic Medical Record System (EMRS) of a hospital in Zhejiang, China and 9226 pregnant women were included. The duration of pregnancy was categorized into four distinct periods: the first, early-second, late-second, and third trimester. Latent class trajectory modeling (LCTM) was used to identify the trajectories of SCI during pregnancy. RESULTS: The elevated WBC counts in the late-second (OR = 1.14, 95% CI: 1.06-1.23) and third (OR = 1.16, 95% CI: 1.09-1.24) trimester were both positively associated with an evaluated risk of PTB. Moreover, significant dose-response relationships were observed. There were three distinct SCI trajectories found: progressing SCI (2.89%), high SCI (7.13%), and low SCI (89.98%). Pregnant women with progressive SCI had the highest risk of PTB (OR = 3.03, 95% CI: 1.47-6.25). CONCLUSIONS: In conclusion, elevated SCI after 23 weeks was a risk factor for PTB in healthy women, even if the SCI indicator was within normal range. Pregnant women with progressive SCI during pregnancy had the highest risk of PTB.

The associations of maternal liver biomarkers in early pregnancy with the risk of gestational diabetes mellitus: a prospective cohort study and Mendelian randomization analysis.

Background: Associations of liver function with the risk of gestational diabetes mellitus (GDM) remain unclear. This study aimed to examine the relationship and the potential causality between maternal liver biomarkers and the risk of subsequent GDM, as well as to evaluate the interaction between liver biomarkers and lipids on GDM risk. Methods: In an ongoing Zhoushan Pregnant Women Cohort, pregnant women who finished the first prenatal follow-up record, underwent liver function tests in early pregnancy, and completed the GDM screening were included in this study. Logistic regression models were used to investigate the association, and the inverse-variance weighted method supplemented with other methods of two-sample Mendelian randomization (MR) analysis was applied to deduce the causality. Results: Among 9,148 pregnant women, 1,668 (18.2%) developed GDM. In general, the highest quartile of liver function index (LFI), including ALT, AST, GGT, ALP, and hepatic steatosis index, was significantly associated with an increased risk of GDM (OR ranging from 1.29 to 3.15), especially an elevated risk of abnormal postprandial blood glucose level. Moreover, the causal link between ALT and GDM was confirmed by the MR analysis (OR=1.28, 95%CI:1.05-1.54). A significant interaction between AST/ALT and TG on GDM risk was observed (P interaction = 0.026). Conclusion: Elevated levels of LFI in early pregnancy were remarkably associated with an increased risk of GDM in our prospective cohort. Besides, a positive causal link between ALT and GDM was suggested.

Breastfeeding, Gestational Diabetes Mellitus, Size at Birth and Overweight/Obesity in Early Childhood.

Background: Breastfeeding appears to reduce the risk of childhood overweight/obesity. However, it remains unclear whether this protective effect persists among high-risk populations. This study aims to investigate the association of breastfeeding with the risk of overweight/obesity in early childhood and whether this association is altered by gestational diabetes mellitus (GDM) or size at birth. Methods: Feeding practices during the first 12 months of age and weight and length at 12-36 months of age were collected. Full breastfeeding includes exclusive and predominant breastfeeding. Children with body mass index (BMI) values greater than 1 standard deviation from the mean of sex- and age-specific BMI were classified as overweight/obese. Multiple generalized estimating equations models were applied to analyze the associations of full breastfeeding duration with overweight/obesity risk. Results: Among all participants (n = 9329), infants with a longer full-breastfeeding duration had a reduced risk of overweight/obesity in early childhood compared with those breastfed for less than one month. Infants exposed to GDM and those born large for gestational age (LGA) had a higher risk of overweight/obesity in early childhood. Among infants of mothers with GDM (n = 1748), infants with full breastfeeding for greater than 6 months (aOR: 0.58; 95% CI: 0.44, 0.78) showed a decreased risk of overweight/obesity in early childhood compared with those breastfed for less than one month. Among LGA infants (n = 1279), infants with full breastfeeding for 3-5 months (aOR: 0.66; 95% CI: 0.57, 0.76) and greater than 6 months (aOR: 0.70; 95% CI: 0.56, 0.88) showed a decreased risk of overweight/obesity in early childhood. Similar results were observed among LGA infants of mothers with GDM. Conclusions: Initiating and prolonging breastfeeding would reduce the risk of overweight/obesity in early childhood, and LGA infants and infants born to mothers with GDM would experience greater benefits.

Effects of thyroid hormones modify the association between pre-pregnancy obesity and GDM: evidence from a mediation analysis.

Objective: Conflicting associations have been noted between thyroid function and gestational diabetes mellitus (GDM), with indications that pre-pregnancy BMI might influence these relationships. This study aims to examine the effect of thyroid hormone indices and their mediation role on the risk of GDM. Methods: Pregnant women in our study were recruited from the Zhoushan Pregnant Women Cohort, Zhejiang Province, China. Participants who had their first prenatal follow-up and measured thyroid biomarkers in the first trimester, and oral glucose tolerance test (OGTT) records in the second trimester were eligible for inclusion in this study. The data were extracted from the Electronic Medical Record System database, at Zhoushan Maternal and Child Care Hospital. Maternal information about sociodemographic and health-related characteristics was extracted from the dataset. A unique personal identification number was provided to link both datasets. Multivariate logistic regression models were applied to investigate the correlations between thyroid hormone indices with GDM. The interaction effects of first-trimester thyroid hormone indices with pre-pregnancy BMI on GDM risk using a generalized linear regression model. Furthermore, the mediation analysis was used to explore the potential mediating effects of thyroid hormone indices on the relationship between pre-pregnancy BMI and GDM. Results: Overall, 5895 pregnant women were included in this study. The first-trimester FT4, thyroid feedback quantile-based index (TFQI), thyrotropin index (TSHI) and thyrotroph thyroxine resistance index (TT4RI) levels were negatively associated with fasting blood glucose (FBG) and postprandial blood glucose (PBG2H) in the second trimester (all P<0.05); FT3 and the FT3-to-FT4 ratio levels were positively associated with PBG1H and PBG2H in the second trimester (all P<0.05). Moreover, there were significant correlations between the highest quartile FT4, FT3, FT3-to-FT4 ratio, TSHI, and TFQI with GDM (all P < 0.05). The mediating effect of thyroid hormone parameters was 24.9% on the association between pre-pregnancy BMI and GDM. Conclusions: In conclusion, the low FT4, high FT3-to-FT4 ratio, and low TFQI in the first trimester significantly increase the risk of GDM and should be given more attention. Furthermore, increased pre-pregnancy BMI might partially increase the risk of GDM by influencing the body's thyroid function.

25-Hydroxyvitamin D, Vitamin D Binding Protein and Gestational Diabetes Mellitus: A Two-Sample Mendelian Randomization Study.

BACKGROUND: Numerous studies have examined whether vitamin D is associated with gestational diabetes mellitus (GDM). Nevertheless, it is still challenging to determine the causality, due to a number of shortcomings in observational research and randomized controlled trials. OBJECTIVE: Mendelian randomization (MR) with two samples was conducted to investigate the potential causative association between 25-hydroxyvitamin D (25(OH)D), vitamin D binding protein (VDBP) and GDM risk. METHODS: Publicly accessible summary data from independent cohorts were used for two-sample MR. For 25(OH)D, we obtained data from UK Biobank, IEU and EBI, then performed a meta-analysis to enhance the statistical power (via METAL); for VDBP, data were obtained from the INTERVAL study; for GDM, data were obtained from FinnGen. The inverse variance weighted (IVW) approach was performed as the main analysis, together with several sensitivity analyses, such as MR-Egger, maximum likelihood, weighted median, and weighted mode. RESULTS: The IVW results revealed a weak negative causal connection between 25(OH)D and GDM risk [OR (95% CI) = 0.71 (0.50, 0.99), p = 0.046]. However, the causal association was unstable according to sensitivity analyses, and Cochran's Q test revealed significant heterogeneity. After removing BMI-related IVs, the causal association between 25(OH)D and GDM disappeared [OR (95% CI) = 0.76 (0.55, 1.06), p = 0.101]. In addition, our study found no proof to support the assumption that VDBP level was related to GDM risk causally [OR (95% CI) = 0.98 (0.93, 1.03), p = 0.408]. CONCLUSIONS: According to this study, a weak negative causal association between 25(OH)D and GDM risk was found, while we had little proof to support the link between VDBP and GDM. To further explore whether total or free 25(OH)D levels and GDM are causally related, GWAS data with an emphasis on women of reproductive age and other ethnic groups are required.

The association of Chinese and American antenatal care utilization indices with birth outcomes.

Objective: Few comparisons have been implemented between different prenatal care utilization indices and their effects on adverse outcomes. This study investigated the appropriateness of Chinese antenatal care (ANC) regulations and compared Chinese and American adequacy of prenatal care utilization (APNCU) scores. Methods: From 2010 to 2022, the medical records of 60,114 pregnant women were collected from the electronic medical record system (EMRS) in Zhoushan, China. ANC utilization was measured using the APNCU score and five times antenatal care (ANC5). Birth weight outcomes, including small for gestational age (SGA) and large for gestational age (LGA), low birth weight (LBW), macrosomia, birth weight, and preterm birth (PTB), were utilized as outcomes. Multinomial, linear, and logistic regression were used to analyze the association of ANC5 and APNCU with outcomes, respectively. Crossover analysis was implemented to compare the interaction between ANC5 and APNCU on the outcomes. Results: Women who received inadequate prenatal care had increased odds for PTB (ANC5: odds ratio (OR) = 1.12, 95% confidence interval (95%CI) = 1.03-1.21; APNCU: OR = 1.18, 95%CI: 1.07-1.29), delivering SGA infants (ANC5: OR = 1.13, 95%CI = 1.07-1.21; APNCU: OR = 1.11, 95%CI = 1.03-1.20). Crossover analysis revealed that inadequate prenatal care in APNCU only was significantly associated with an increased risk of PTB (OR = 1.48, 95%CI: 1.26-1.73). Conclusion: Women with inadequate prenatal care in ANC5 or APNCU were more likely to suffer from adverse birth outcomes, including PTB, birth weight loss, SGA, and LBW. It indicated that adequate prenatal care is necessary for pregnant women. However, there were interactions between ANC5 and APNCU on PTB, with inadequate prenatal care use by APNCU showing the highest risk of PTB. This indicates that APNCU would be a better tool for evaluating prenatal care use.

The Association of Reproductive Hormones During the Menstrual Period with Primary Dysmenorrhea.

Objective: This study aimed to investigate the association of reproductive hormones with primary dysmenorrhea in Chinese women. Methods: A case-control study was conducted and patients with primary dysmenorrhea and non-dysmenorrhea participants were recruited. Oxytocin, PGF2α, vasopressin, estriol and estradiol were respectively measured in plasma collected three to five days after menstruation. Restricted cubic spline and multiple logistic regression models were adopted to analyze the association between hormones and primary dysmenorrhea. Results: There were 604 participants enrolled in our study including 300 patients with primary dysmenorrhea. After adjustment for the potential confounders, oxytocin levels (Q3: OR (95% CI) = 0.50 (0.27~0.95) (p=0.035); Q4: 0.34 (0.17~0.66) (p=0.001)) and PGF2α levels (Q3: 0.45 (0.24~0.87) (p=0.017); Q4: 0.43 (0.22~0.84) (p=0.013)) were respectively associated with an decreased risk of primary dysmenorrhea, but estradiol (Q2: 2.18 (1.13~4.19) (p=0.020); Q3: 2.17 (1.12~4.19) (p=0.022)) and vasopressin (Q3: 2.88 (1.48~5.63) (p=0.002); Q4: 3.20 (1.65~6.22) (p<0.001)) with an increased risk of primary dysmenorrhea, respectively. Among patients with primary dysmenorrhea, the higher estriol level was associated with higher frequent dysmenorrhea (Q2: 3.12 (1.32~7.34) (p=0.009); Q3: 4.97 (2.08~11.85) (p<0.001)) and always dysmenorrhea (Q2: 2.51 (1.03~6.11) (p=0.041); Q3: 3.10 (1.25~7.73) (p=0.015)). Similarly, high estriol levels were associated with the higher degree of pain significantly only when hormone levels were at a high level (Q3: 2.06 (1.03~4.18) (p=0.043)). Conclusion: Higher serum vasopressin and estradiol concentrations as well as lower oxytocin and PGF2α levels were associated with higher risk of primary dysmenorrhea. Estrogen showed a reverse U-shape association on the frequency and degree of pain among patients with primary dysmenorrhea.

Detection of various fusion genes by one-step RT-PCR and the association with clinicopathological features in 242 cases of soft tissue tumor.

Introduction: Over the past decades, an increasing number of chromosomal translocations have been found in different STSs, which not only has value for clinical diagnosis but also suggests the pathogenesis of STS. Fusion genes can be detected by FISH, RT-PCR, and next-generation sequencing. One-step RT-PCR is a convenient method to detect fusion genes with higher sensitivity and lower cost. Method: In this study, 242 cases of soft tissue tumors were included, which were detected by one-step RT-PCR in multicenter with seven types of tumors: rhabdomyosarcoma (RMS), peripheral primitive neuroectodermal tumor (pPNET), synovial sarcoma (SS), myxoid liposarcomas (MLPS), alveolar soft part sarcoma (ASPS), dermatofibrosarcoma protuberans (DFSP), and soft tissue angiofibroma (AFST). 18 cases detected by one-step RT-PCR were further tested by FISH. One case with novel fusion gene detected by RNA-sequencing was further validated by one-step RT-PCR. Results: The total positive rate of fusion genes was 60% (133/213) in the 242 samples detected by one-step RT-PCR, in which 29 samples could not be evaluated because of poor RNA quality. The positive rate of PAX3-FOXO1 was 88.6% (31/35) in alveolar rhabdomyosarcoma, EWSR1-FLI1 was 63% (17/27) in pPNET, SYT-SSX was 95.4% in SS (62/65), ASPSCR1-TFE3 was 100% in ASPS (10/10), FUS-DDIT3 was 80% in MLPS (4/5), and COL1A1-PDGFB was 66.7% in DFSP (8/12). For clinicopathological parameters, fusion gene status was correlated with age and location in 213 cases. The PAX3-FOXO1 fusion gene status was correlated with lymph node metastasis and distant metastasis in RMS. Furthermore, RMS patients with positive PAX3-FOXO1 fusion gene had a significantly shorter overall survival time than those patients with the negative fusion gene. Among them, the FISH result of 18 cases was concordant with one-step RT-PCR. As detected as the most common fusion types of AHRR-NCOA2 in one case of AFST were detected as negative by one-step RT-PCR. RNA-sequencing was used to determine the fusion genes, and a novel fusion gene PTCH1-PLAG1 was found. Moreover, the fusion gene was confirmed by one-step RT-PCR. Conclusion: Our study indicates that one-step RT-PCR displays a reliable tool to detect fusion genes with the advantage of high accuracy and low cost. Moreover, it is a great tool to identify novel fusion genes. Overall, it provides useful information for molecular pathological diagnosis and improves the diagnosis rate of STSs.

Efficacy of intermittent versus daily vitamin D supplementation on improving circulating 25(OH)D concentration: a Bayesian network meta-analysis of randomized controlled trials.

Background: Vitamin D deficiency is a widespread issue globally, resulting in increased use of vitamin D supplements. However, it is unclear whether intermittent (weekly or monthly) vitamin D supplementation is as effective as daily supplementation in improving circulating 25-hydroxyvitamin D [25(OH)D] levels. Methods: Three databases including Medline, EMBASE, and the Cochrane Library were systematically searched up to 10 November 2020. The risk of bias was evaluated according to Cochrane Collaboration's tool for rating methodological quality assessment. Direct and indirect comparisons between interventions and controls were performed by a Bayesian network meta-analysis (NMA), where the mean difference (MD) and its 95% confidence interval (CI) were used to indicate the efficacy. Results: This NMA analysis included 116 RCTs with a total of 11,376 participants. Generally, we observed that 25(OH)D concentrations were significantly elevated regardless of vitamin D supplementation frequency. Although the findings of SUCRA indicated that daily vitamin D supplementation had a higher rank value than intermittent supplementation when the supplement dosage was similar, no statistically significant pooled mean differences of 25(OH)D concentration were noted between the daily supplementation group and intermittent supplementation group. Additionally, weekly supplementation with a total of 600,000 IU vitamin D supplementation during 3 months had the best efficacy in elevating 25(OH)D concentration (pooled MD = 63 nmol/L, 95%CI: 49-77). To achieve optimal 25(OH)D concentration (>75 nmol/L), we recommend 60,000 IU vitamin D supplementation monthly (~2,000 IU/day). Conclusion: The efficacy of intermittent vitamin D supplementation was similar to daily supplementation. Coupled with its convenience, the frequency and dosage of intermittent vitamin D supplements were recommended to reach the optimal 25(OH)D level.Systematic review registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=257257, PROSPERO CRD42021257257.

The Association of Vitamin D during Pregnancy and mRNA Expression Levels of Inflammatory Factors with Preterm Birth and Prelabor Rupture of Membranes.

The aim of this study was to elucidate the association between vitamin D (VD) and the risk for preterm birth (PTB) and prelabor rupture of membranes (PROM). This study included two parts, with a cohort study and a case-control study. Plasma 25-hydroxyvitamin vitamin D [25(OH)D] levels in three trimesters in the cohort study and maternal 25(OH)D before delivery in the case-control study were measured. Quantitative real-time PCR was used to detect relative mRNA expression levels of the inflammatory factors associated with pyroptosis in peripheral blood mononuclear cell (PBMC), placenta and fetal membranes. Multinomial logistic regression and the Wilcoxon test were applied to analyze the associations. In the cohort study, 6381 pregnant women were included. We found that VD deficiency in T3 (PTB without PROM: OR = 1.90, 95% CI: 1.02-3.55, Term PROM (TPROM): OR = 0.76, 95% CI: 0.59-0.98) and less change of 25(OH)D between T1 and T3 (PTB without PROM: OR = 2.32, 95% CI: 1.07-5.06, TPROM: OR = 0.73, 95% CI: 0.56-0.96) were associated with the increased risk of PTB without PROM, while there was a decreased risk of TPROM. Neither VD, nor the increase of VD during pregnancy was associated with the premature rupture of membranes preterm delivery (PPROM). In the case-control study, there were no associations between VD during delivery and PTB or PROM (TPROM: OR = 1.33, 95% CI: 0.52-3.44); PTB without PROM: OR = 1.66, 95% CI: 0.33-8.19; PPROM: OR = 1.19, 95% CI: 0.42-3.40). The mRNA expression of NLRP1 (NOD-like receptor thermal protein domain associated protein 1) (p = 0.0165) in PBMC in the TPROM group was higher than that in the term group, and IL-18 (p = 0.0064) was lower than that in the term group. Plasma 25(OH)D in T3 and the increase of 25(OH)D between T1 and T3 were associated with a lower risk for PTB without PROM but a higher risk for TPROM. Further studies are warranted to clarify the association between VD and PTB and PROM and its mechanism.

Association of 25-Hydroxyvitamin D with Preterm Birth and Premature Rupture of Membranes: A Mendelian Randomization Study.

Low vitamin D (VitD) level is a risk factor for preterm birth (PTB), but the results of previous studies remained inconsistent, which may be influenced by the confounding factors and different types of PTB. We performed Mendelian randomization (MR) to uncover the association of 25-hydroxyvitamin D (25(OH)D) with PTB, premature rupture of membranes (PROM), and preterm premature rupture of membranes (PPROM). This study was conducted in Zhoushan Maternal and Child Health Hospital, Zhejiang, from August 2011 to March 2022. Plasma 25(OH)D levels in three trimesters of pregnancy were measured. We conducted an MR analysis utilizing a genetic risk score (GRS) approach, which was based on VitD-associated single-nucleotide polymorphisms. The prospective cohort study included 3923 pregnant women. The prevalence of PTB, PROM, and PPROM were 6.09%, 13.18%, and 1.33%, respectively. Compared to those without vitamin D deficiency (VDD), only vaginally delivering pregnant women with VDD had a 2.69 (1.08-6.68) times risk of PTB. However, MR analysis did not support the association. One-unit higher GRS was not associated with an increased risk of PTB, regardless of the trimesters (OR [95% CI]: 1.01 [0.93-1.10], 1.06 [0.96-1.18], and 0.95 [0.82-1.10], respectively). When further taking PROM and PPROM as the outcomes, the MR analysis also showed no consistent evidence of a causal effect of VitD levels on the risk of them. Our MR analyses did not support a causal effect of 25(OH)D concentrations in the three trimesters on PTB, PROM, and PPROM.

Association of Vitamin D in Different Trimester with Hemoglobin during Pregnancy.

The association between vitamin D and hemoglobin has been suggested. Vitamin D can affect erythropoiesis by the induction of erythroid progenitor cell proliferation and enhance iron absorption by regulating the iron-hepcidin-ferroportin axis in monocytes. However, this relationship in pregnant women is scarce. The purpose of this study was to investigate the association between plasma vitamin D levels with hemoglobin concentration in pregnant women considering each trimester and iron supplementation. The data were obtained from Zhoushan Pregnant Women Cohort, collected from 2011 to 2018. Plasma 25(OH)D was measured in each trimester using liquid chromatography−tandem mass spectrometry. Generalized estimating equations and multiple linear regressions were performed. Finally, 2962 pregnant women and 4419 observations in the first trimester were included in this study. Plasma 25(OH)D in first trimester (T1) (ß = 0.06, p = 0.0177), second trimester (T2) (ß = 0.15, p < 0.0001), and third trimester (T3) (ß = 0.12, p = 0.0006) were positively associated with Hb. Association between plasma 25(OH)D levels in T1 and Hb concentration was positively associated with gestational age (ß = 0.005, p = 0.0421). Pregnant women with VD deficiency in T1 (OR = 1.42, 95% CI: 1.07−1.88) or T2 (OR = 1.94, 95% CI: 1.30−2.89) presented an increased risk of anemia, compared with women without VD deficiency. Moreover, the significant relationship between VD and Hb was only observed among women with iron supplementation during pregnancy. Plasma 25(OH)D levels in each trimester were positively associated with Hb concentration. Iron supplementation might be an important factor affecting the relationship between VD and Hb.

The Associations of Maternal Hemoglobin Concentration in Different Time Points and Its Changes during Pregnancy with Birth Weight Outcomes.

Maternal hemoglobin (Hb) is related to nutritional status, which affects neonatal birth weight. However, it is very common for maternal Hb to fluctuate during pregnancy. To evaluate the associations of maternal Hb in different time points and its changes during pregnancy with neonatal birth weight, small for gestational age (SGA)/low birth weight (LBW) and large for gestational age (LGA)/macrosomia, we conducted this study by using data from the Electronic Medical Record System (EMRS) database of Zhoushan Maternal and Child Care Hospital in Zhejiang province, China. The pregnancy was divided into five periods: first, early-second, mediate-second, late-second, early-third and late-third trimesters; we further calculated the maternal Hb changes during pregnancy. Overall, the socio-demographic characteristics, health-related information and childbirth-related information of 24,183 mother−infant pairs were obtained. The average Hb concentration during the different periods were 123.95 ± 10.14, 117.95 ± 9.84, 114.31 ± 9.03, 113.26 ± 8.82, 113.29 ± 8.68 and 115.01 ± 8.85 g/L, respectively. Significant dose−response relationships between maternal Hb and birth weight were observed in the first, late-second and later trimesters (p non-linear < 0.05). Maternal Hb < 100 g/L was related to a high risk of LGA/macrosomia in the late-second (OR: 1.47, 95% CI: 1.18, 1.83) and later trimesters; additionally, high maternal Hb (>140 g/L) increased the risk of SGA/LBW in the first (OR: 1.26, 95% CI: 1.01, 1.57) and late-third trimesters (OR: 1.96, 95% CI: 1.20, 3.18). In addition, the increase in maternal Hb from the late-second to late-third trimesters had a positive correlation with SGA/LBW. In conclusion, maternal Hb markedly fluctuated during pregnancy; the negative dose−response association of maternal Hb in the late-second and third trimesters, and Hb change during pregnancy with neonatal birth weight outcomes were observed, respectively. Furthermore, the phenomenon of high Hb in the first trimester and after the late-second trimester and the increase of maternal Hb from the late-second to late-third trimesters more significantly increasing the risk of SGA/LBW should especially be given more attention. Its biological mechanism needs to be further explored.

Neutralization Activity against SARS-CoV-2 Variants after Booster Vaccination in Populations without COVID-19: A Meta-Analysis.

A number of SARS-CoV-2 variants that have evolved to have significant immune escape have emerged worldwide since the COVID-19 outbreak. The efficacy of prime vaccination is waning with the evolution of SARS-CoV-2, and the necessity of booster doses is more and more prominent. Therefore, this study aimed to compare the neutralization activity against the wild type and variants (Beta, Delta, and Omicron) in different prime-boost vaccination regimens. Electronic databases including PubMed, the Cochrane Library, Embase, medRxiv, Wanfang and CNKI were used to retrieve original studies. A total of 16 studies, 9 prime-boost vaccination regimes, and 3134 subjects were included in the meta-analysis and random effect models were used to estimate pooled neutralization titers. The neutralization activity against SARS-CoV-2 showed a significant decline with the evolution of the virus, especially in the populations primed with inactivated vaccines. For homologous immunization, only the populations boosted with mRNA vaccines consistently had a significant rise in neutralization titers (Beta: MD = 0.97; Delta: MD = 1.33; Omicron: MD = 0.74). While the heterologous immunization was more effective, the increment of neutralization titers against wild type, Beta, Delta and Omicron was 1.65 (95% CI: 1.32-1.96), 1.03 (95% CI: 0.53-1.54), 1.46 (95% CI: 1.07-1.85) and 1.15 (95% CI: 0.68-1.61), respectively. With the evolution of SARS-CoV-2, the effectiveness of prime immunization is waning. Although the administration of the booster dose could ameliorate the neutralization titers, homologous immunization regimens were gradually losing their effectiveness. Therefore, a heterologous booster dose is required, especially in populations primed with inactivated vaccines.

The Association of Vitamin D and Its Pathway Genes' Polymorphisms with Hypertensive Disorders of Pregnancy: A Prospective Cohort Study.

Objective: We aimed to explore the effect of single nucleotide polymorphism (SNP) in the genes of the vitamin D (VitD) metabolic pathway and its interaction with VitD level during pregnancy on the development of hypertensive disorders of pregnancy (HDP). Methods: The study was conducted in the Zhoushan Maternal and Child Health Care Hospital, China, from August 2011 to May 2018. The SNPs in VitD metabolic pathway-related genes were genotyped. Plasma 25-hydroxyvitamin vitamin D (25(OH)D) levels was measured at first (T1), second (T2), and third (T3) trimesters. The information of systolic blood pressure (SBP) and diastolic blood pressure (DBP), and the diagnosis of HDP were extracted from the electronic medical record system. Multivariable linear and logistic regression models and crossover analysis were applied. Results: The prospective cohort study included 3699 pregnant women, of which 105 (2.85%) were diagnosed with HDP. After adjusting for potential confounders, VitD deficiency at T2, as well as the change of 25(OH)D level between T1 and T2, were negatively associated with DBP at T2 and T3, but not HDP. Polymorphisms in CYP24A1, GC, and LRP2 genes were associated with blood pressure and HDP. In addition, VitD interacted with CYP24A1, GC, and VDR genes' polymorphisms on blood pressure. Furthermore, participants with polymorphisms in CYP24A1-rs2248137, LRP2-rs2389557, and LRP2-rs4667591 and who had VitD deficiency at T2 showed an increased risk of HDP. Conclusions: The individual and interactive association between VitD deficiency during pregnancy and SNPs in the genes of the VitD metabolic pathway on blood pressure and HDP were identified.