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Objective We aimed to summarize the association between gestational diabetes mellitus (GDM) and its intergenerational cardiovascular diseases (CVDs) impacts in both mothers and offspring post-delivery in existing literature. Methods PubMed, Embase, Web of Science, and Scopus were utilized for searching publications between January 1980 and June 2024, with data extraction and meta-analysis continuing until 31 July 2024. Based on a predefined PROSPERO protocol, studies published as full-length, English-language journal articles that reported the presence of GDM during pregnancy and its association with any CVD development post-delivery were selected. All studies were evaluated using the Newcastle-Ottawa Scale. Maximally adjusted risk estimates were pooled using random-effects meta-analysis to assess the risk ratio (RR) of GDM, and overall and subtypes of CVDs in both mothers and offspring post-delivery. Results The meta-analysis was based on 38 studies with a total of 77,678,684 participants. The results showed a 46% increased risk (RR 1.46, 95% CI 1.34–1.59) for mothers and a 23% increased risk (1.23, 1.05–1.45) for offspring of developing overall CVDs after delivery, following a GDM-complicated pregnancy. Our subgroup analysis revealed that mothers with a history of GDM faced various risks (20% to 2-fold) of developing different subtypes of CVDs, including cerebrovascular disease, coronary artery disease, heart failure, and venous thromboembolism. Conclusions These findings underscore the heightened risk of developing various CVDs for mothers and offspring affected by GDM, emphasizing the importance of preventive measures even right after birth to mitigate the burden of CVDs in these populations.

BackgroundSynergistic anti-tumor effects were observed in vivo and in vitro when immune checkpoint inhibitors (ICIs) were combined with denosumab. However, the clinical benefit and safety of this synergy have not been adequately evaluated in non-small cell lung cancer (NSCLC).MethodsConsecutive charts of NSCLC patients with bone metastases between December 2020 and December 2021 in the Chinese National Cancer Center were reviewed. The entire cohort was divided into one experimental group (denosumab + ICIs [DI]) and three control groups (denosumab + non-ICIs [DnI], phosphates + ICIs [PI], phosphates + non-ICIs [PnI]). Real-world objective response rates (ORRs), median progression-free survival (mPFS), skeletal-related events (SREs), and adverse events (AEs) were compared between groups.ResultsA total of 171/410 (41.7%) patients with advanced or recurrent NSCLC carrying bone metastases who received bone-targeted therapy were eligible for analysis. Although the DI group showed a better benefit trend, differences were not statistically significant concerning the therapeutic efficacy among the DI group (n = 40), PI group (n = 74), DnI group (n = 15), and PnI group (n = 42) (ORRs: 47.5%, 43.2%, 33.3%, and 40.5%, respectively, p = 0.799; and mPFS: 378, 190, 170, and 172 days, respectively, p = 0.115; SREs: 5%, 10.8%, 13.3%, and 11.9%, respectively, p = 0.733). Nevertheless, further analysis in the NON-DRIVER cohort revealed a greater benefit for the DI group ( p = 0.045). Additionally, the AEs of the DI group were not significantly different from those of the PI, DnI, and PnI groups (AEs: 27.5%, 39.2%, 26.7%, and 28.6%, respectively, p = 0.742). Furthermore, the multivariate analysis revealed the independent prognostic role of DI treatment for PFS in the overall cohort. Within the DI group, we did not observe differences in benefit among different mutational subgroups ( p = 0.814), but patients with single-site bone metastasis ( p = 0.319) and high PD-L1 expression ( p = 0.100) appeared to benefit more, though no significant differences were observed.ConclusionsDenosumab exhibited synergistic antitumor efficacy without increasing toxicity when used concomitantly with ICIs in patients with advanced non-small cell lung cancer carrying bone metastases.

The effect of saturated fatty acids (SFAs) on incident type 2 diabetes (T2D) is controversial and few have systematically appraised the evidence. We conducted a comprehensive search of prospective studies examining these relationships that were published in PubMed, Web of Science, or EMBASE from 21 February 1989 to 21 February 2019. A total of 19 studies were included for systematic review and 10 for meta-analysis. We estimated the summarized relative risk (RR) and 95% confidence interval (95% CI) using a random (if I2 > 50%) or a fixed effects model (if I2 ≤ 50%). Although the included studies reported inconclusive results, the majority supported a protective effect of odd-chain and an adverse impact of even-chain SFAs. Meta-analysis showed that the per standard deviation (SD) increase in odd-chain SFAs was associated with a reduced risk of incident T2D (C15:0: 0.86, 0.76–0.98; C17:0: 0.76, 0.59–0.97), while a per SD increase in one even-chain SFA was associated with an increased risk of incident T2D (C14:0: 1.13, 1.09–1.18). No associations were found between other SFAs and incident T2D. In conclusion, our findings suggest an overall protective effect of odd-chain SFAs and the inconclusive impact of even- and very-long-chain SFAs on incident T2D.

Background Early menarche is associated with lifelong health implications, including heightened risks for obesity, type 2 diabetes (T2D), cardiovascular disease, and overall mortality. This study explored the associations that link early menarche, major adiposity indices, and T2D in a group of multi-ethnic Asian women. Methods A prospective, hospital-based study was conducted in Singapore. Two thousand seven hundred fifteen women were recruited from 2014 to 2016 (45–69 years old) and 1201 women were followed up from 2021 to 2023. At baseline, age at menarche (AAM) was divided into sub-categories: < 12 (early AAM), 12–13, 14–15 (reference), > 15 years. Major adiposity indices and glycemic profiles were assessed, including fat mass index (FMI), visceral adipose tissue (VAT), and HOMA-IR (homeostatic model assessment for insulin resistance). At the 6.6-year follow-up, T2D was assessed. One-way ANOVA and chi-square were performed for continuous and categorical variables, respectively. Multivariable regression analysis was performed to determine the association between AAM and primary outcomes, including adiposity measurements (FMI, VAT) and metabolic assessments (HOMA-IR) at baseline. Modified Poisson regression was performed to assess relative risk (RR) between AAM and T2D at follow-up. Serial mediation analysis was performed to determine potential mediators underlying the link between AAM and T2D. All analyses accounted for major confounders including age, ethnicity, and education. Results Women with early AAM had significantly greater values in adiposity assessments, including increments in FMI (10.9 vs 10.3, p  < 0.001), VAT (134 vs 113 cm 2 , p  = 0.05) and HOMA-IR (1.20 vs 1.03, p  = 0.08) at baseline. Early AAM (< 12 vs. 14–15 years) was associated with a 60% increased risk of developing T2D (RR 1.60 (95%CI: 1.04, 2.45)). Serial mediation analysis suggested a significant pathway underlying early AAM and T2D, which was firstly mediated by FMI, followed by VAT and lastly by HOMA-IR ( p  < 0.05). Conclusions Our study provided valuable insight into the pathophysiology of T2D development amongst mid-life women with early AAM. The findings could potentially indicate strategies to target FMI and VAT among Asian women in the menopausal phase with early AAM, to prevent the development of T2D.

The development of small-molecule tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) has revolutionized the management of non-small-cell lung cancer (NSCLC). Because these drugs are commonly used in combination with other types of medication, the risk of clinically significant drug-drug interactions (DDIs) is an important consideration, especially for patients using multiple drugs for coexisting medical conditions. Clinicians need to be aware of the potential for clinically important DDIs when considering therapeutic options for individual patients. In this article, we describe the main mechanisms underlying DDIs with the EGFR-TKIs that are currently approved for the treatment of NSCLC, and, specifically, the potential for interactions mediated via effects on gastrointestinal pH, cytochrome P450-dependent metabolism, uridine diphosphate-glucuronosyltransferase, and transporter proteins. We review evidence of such DDIs with the currently approved EGFR-TKIs (gefitinib, erlotinib, afatinib, osimertinib, and icotinib) and discuss several information sources that are available online to aid clinical decision-making. We conclude by summarizing the most clinically relevant DDIs with these EFGR-TKIs and provide recommendations for managing, minimizing, or avoiding DDIs with the different agents.

Background Metabolomic changes during pregnancy have been suggested to underlie the etiology of gestational diabetes mellitus (GDM). However, research on metabolites during preconception is lacking. Therefore, this study aimed to investigate distinctive metabolites during the preconception phase between GDM and non-GDM controls in a nested case–control study in Singapore. Methods Within a Singapore preconception cohort, we included 33 Chinese pregnant women diagnosed with GDM according to the IADPSG criteria between 24 and 28 weeks of gestation. We then matched them with 33 non-GDM Chinese women by age and pre-pregnancy body mass index (ppBMI) within the same cohort. We performed a non-targeted metabolomics approach using fasting serum samples collected within 12 months prior to conception. We used generalized linear mixed model to identify metabolites associated with GDM at preconception after adjusting for maternal age and ppBMI. After annotation and multiple testing, we explored the additional predictive value of novel signatures of preconception metabolites in terms of GDM diagnosis. Results A total of 57 metabolites were significantly associated with GDM, and eight phosphatidylethanolamines were annotated using HMDB. After multiple testing corrections and sensitivity analysis, phosphatidylethanolamines 36:4 (mean difference β : 0.07; 95% CI: 0.02, 0.11) and 38:6 ( β : 0.06; 0.004, 0.11) remained significantly higher in GDM subjects, compared with non-GDM controls. With all preconception signals of phosphatidylethanolamines in addition to traditional risk factors (e.g., maternal age and ppBMI), the predictive value measured by area under the curve (AUC) increased from 0.620 to 0.843. Conclusions Our data identified distinctive signatures of GDM-associated preconception phosphatidylethanolamines, which is of potential value to understand the etiology of GDM as early as in the preconception phase. Future studies with larger sample sizes among alternative populations are warranted to validate the associations of these signatures of metabolites and their predictive value in GDM.

The evidence linking dietary intake with diabetic retinopathy (DR) is growing but unclear. We conducted a systematic review of the association between dietary intake and DR. We systematically searched PubMed, Embase, Medline, and the Cochrane Central register of controlled trials, for publications between January 1967 and January 2017 using standardized criteria for diet and DR. Interventional and observational studies investigating micro- and macro-nutrient intakes; food and beverage consumptions; and dietary patterns were included. Study quality was evaluated using a modified Newcastle-Ottawa scale for observational studies, and the Cochrane collaboration tool for interventional studies. Of 4265 titles initially identified, 31 studies (3 interventional, 28 Observational) were retained. Higher intakes of dietary fibre, oily fish, and greater adherence to a Mediterranean diet were protective of DR. Conversely, high total caloric intake was associated with higher risk of DR. No significant associations of carbohydrate, vitamin D, and sodium intake with DR were found. Associations of antioxidants, fatty acids, proteins and alcohol with DR remain equivocal. Dietary fibre, oily fish, a Mediterranean diet and a reduced caloric intake are associated with lower risk of DR. Longitudinal data and interventional models are warranted to confirm our findings and better inform clinical guidelines.

Background Amino acids (AAs) during pregnancy are crucial for fetal growth. Prior studies measured AA concentrations at single time points in pregnancy, despite their fluctuations throughout pregnancy. We measured plasma AA profiles in blood samples longitudinally collected from early through late pregnancy and evaluated their associations with neonatal anthropometry. Methods Concentrations of plasma aromatic AAs, branched-chain AAs, and AAs involved in one-carbon metabolism were assessed at 10–14, 15–26, 23–31, and 33–39 gestational weeks (GW) among 321 women from a case–control study from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singleton Cohort. Associations between AA concentrations in tertiles at each visit and neonatal anthropometric measures were assessed using weighted generalized estimating equations models, after adjusting for major confounders. Results Women with higher concentrations of glutamine (3rd vs. 1st tertile) at 10–14 GW had offspring with greater birthweight z -score (β [95% CI] = 0.31 [0.06, 0.56], p -trend = 0.04) and birth length (1.35 cm [0.32, 2.37], p- trend = 0.04). Women with higher concentrations of aspartic acid (3rd vs. 1st tertile) at 23–31 GW, however, had offspring with smaller sum of skinfolds (− 3.9 mm [− 6.0, − 1.7], p- trend = 0.007). Similarly, women with higher concentrations of glycine (3rd vs. 1st tertile) at 10–14 GW had offspring with lower birthweight z -score (− 0.37 [− 0.65, − 0.08], p -trend = 0.04). Conclusions Plasma AA concentrations during pregnancy appear to play a crucial role in neonatal anthropometry. Associations were observed as early as 10 GW and varied by type of AAs and gestational age. Trial registration Clinical Trial Registry number: NCT 00912132.

AbstractObjectiveTo test the hypothesis that non-invasive high frequency oscillatory ventilation (NHFOV) is more efficacious than nasal continuous positive airway pressure (NCPAP) in reducing invasive mechanical ventilation as primary respiratory support for extremely preterm infants with respiratory distress syndrome.DesignA multicentre, randomised controlled trial.SettingTwenty tertiary neonatal intensive care units in China.Participants342 extremely preterm infants (gestational age between 24 weeks +0 day and 28 weeks +6 days) with respiratory distress syndrome were enrolled in the study between August 2022 and August 2024.InterventionsParticipants were randomly allocated to receive NCPAP or NHFOV as primary respiratory support for respiratory distress syndrome.Main outcome measuresThe primary outcome was treatment failure, defined as the need for invasive mechanical ventilation within 72 hours after birth.ResultsTreatment failure within 72 hours occurred in 27 of` 170 infants (15.9%) in the NHFOV group and 48 of 172 infants (27.9%) in the NCPAP group (risk difference −12.0 percentage points, 95% confidence interval −20.7 to −3.4; P=0.007). Treatment failure within seven days was also lower in the NHFOV group (−12.5 percentage points, 95% confidence interval −21.9 to −3.2; P=0.008) compared with the NCPAP group. All observed associations remained significant after sensitivity analysis including study sites and antenatal steroid use. No significant differences were found in any other secondary outcomes between the two groups.ConclusionsNHFOV appeared superior to NCPAP in reducing the need for intubation when used as a primary respiratory support strategy in extremely preterm infants. Both techniques did not show significant differences in neonatal adverse events.Trial registrationClinicalTrials.gov NCT05141435

Background Parturition is an inflammation process. Exaggerated inflammatory reactions in infection lead to preterm birth. Although nuclear factor kappa B (NF-κB) has been recognized as a classical transcription factor mediating inflammatory reactions, those mediated by NF-κB per se are relatively short-lived. Therefore, there may be other transcription factors involved to sustain NF-κB-initiated inflammatory reactions in gestational tissues in infection-induced preterm birth. Methods Cebpd -deficient mice were generated to investigate the role of CCAAT enhancer-binding protein δ (C/EBPδ) in lipopolysaccharide (LPS)-induced preterm birth, and the contribution of fetal and maternal C/EBPδ was further dissected by transferring Cebpd −/− or WT embryos to Cebpd −/− or WT dams. The effects of C/EBPδ pertinent to parturition were investigated in mouse and human myometrial and amnion cells. The interplay between C/EBPδ and NF-κB was examined in cultured human amnion fibroblasts. Results The mouse study showed that LPS-induced preterm birth was delayed by Cebpd deficiency in either the fetus or the dam, with further delay being observed in conceptions where both the dam and the fetus were deficient in Cebpd . Mouse and human studies showed that the abundance of C/EBPδ was significantly increased in the myometrium and fetal membranes in infection-induced preterm birth. Furthermore, C/EBPδ participated in LPS-induced upregulation of pro-inflammatory cytokines as well as genes pertinent to myometrial contractility and fetal membrane activation in the myometrium and amnion respectively. A mechanistic study in human amnion fibroblasts showed that C/EBPδ, upon induction by NF-κB, could serve as a supplementary transcription factor to NF-κB to sustain the expression of genes pertinent to parturition. Conclusions C/EBPδ is a transcription factor to sustain the expression of gene initiated by NF-κB in the myometrium and fetal membranes in infection-induced preterm birth. Targeting C/EBPδ may be of therapeutic value in the treatment of infection-induced preterm birth.