Inadvertent antibiotic exposure during pregnancy may increase the risk for neural tube defects in offspring.

BACKGROUND: As emerging environmental contaminants, antibiotics pose potential threats to human health, in particular to pregnant women and infants. However, the potential harm of inadvertent antibiotic exposure (IAE) is often disregarded in light of the focus on intentional antibiotic use during pregnancy. Currently, little is known about the effects of IAE during pregnancy on fetal neural tube development. METHODS: In this case-control study, we used questionnaire data from 855 subjects to investigate the effects of intentional antibiotic use in early pregnancy on neural tube defects (NTDs). Then we tested for placental antibiotics in mothers who had not intentionally used antibiotics, and the compounds were detected in 379 subjects; these were considered IAE cases. We assessed the association between IAE during pregnancy and fetal NTDs using both multivariable logistic and multi-pollutant exposure models. We also analyzed the correlation between maternal dietary habits and placental antibiotics to explore possible sources of IAE. RESULTS: Only 50 of 855 participants (5.8%) intentionally used antibiotics and such use showed no significant association with NTD risk (odds ratio [OR] = 1.92, confidence interval [95%CI] = [0.66, 5.59]). However, 14 of 15 placental antibiotics were detected in 378 of 379 subjects (99.7%) and multivariable logistic analysis indicated that high levels of placental macrolides were significantly associated with increased NTD risk (4.42 [2.01-10.45]). Multi-pollutant exposure analysis suggested an increase in NTD risk with an increase in exposure to a mixture of placental antibiotics, among which macrolides were the most important contributor. In addition, the level of placental macrolides was positively correlated with the intake frequency of milk. Finally, mothers who drank river, well, or pond water had higher levels of placental macrolides than those who drank only tap water. CONCLUSIONS: Intentional antibiotic use during early pregnancy may not be associated with NTDs, while IAE during pregnancy is associated with higher NTD risk in offspring. Macrolides are crucial risk factors. Milk, and river, well, or pond water may be important sources of IAE.

Predicting the risk of pulmonary infection in patients with chronic kidney failure: A-C2GH2S risk score-a retrospective study.

PURPOSE: The objective of this study is to investigate the associated risk factors of pulmonary infection in individuals diagnosed with chronic kidney disease (CKD). The primary goal is to develop a predictive model that can anticipate the likelihood of pulmonary infection during hospitalization among CKD patients. METHODS: This retrospective cohort study was conducted at two prominent tertiary teaching hospitals. Three distinct models were formulated employing three different approaches: (1) the statistics-driven model, (2) the clinical knowledge-driven model, and (3) the decision tree model. The simplest and most efficient model was obtained by comparing their predictive power, stability, and practicability. RESULTS: This study involved a total of 971 patients, with 388 individuals comprising the modeling group and 583 individuals comprising the validation group. Three different models, namely Models A, B, and C, were utilized, resulting in the identification of seven, four, and eleven predictors, respectively. Ultimately, a statistical knowledge-driven model was selected, which exhibited a C-statistic of 0.891 (0.855-0.927) and a Brier score of 0.012. Furthermore, the Hosmer-Lemeshow test indicated that the model demonstrated good calibration. Additionally, Model A displayed a satisfactory C-statistic of 0.883 (0.856-0.911) during external validation. The statistical-driven model, known as the A-C2GH2S risk score (which incorporates factors such as albumin, C2 [previous COPD history, blood calcium], random venous blood glucose, H2 [hemoglobin, high-density lipoprotein], and smoking), was utilized to determine the risk score for the incidence rate of lung infection in patients with CKD. The findings revealed a gradual increase in the occurrence of pulmonary infections, ranging from 1.84% for individuals with an A-C2GH2S Risk Score ≤ 6, to 93.96% for those with an A-C2GH2S Risk Score ≥ 18.5. CONCLUSION: A predictive model comprising seven predictors was developed to forecast pulmonary infection in patients with CKD. This model is characterized by its simplicity, practicality, and it also has good specificity and sensitivity after verification.

Associations among bisphenol A, its analogs, and chlorinated derivatives in placenta and risk for neural tube defects: A case-control study.

Bisphenol A (BPA) and its analogs such as bisphenol Z (BPZ) are widely used in the production of consumer products, but few studies have investigated the associations among BPA, its analogs, and chlorinated derivatives (collectively, BPs) and risk for NTDs. This study investigated the associations between concentrations of BPs in the placenta and risk for NTDs. This was a case-control study including 122 NTDs and 164 controls. BPs in the placenta were determined using liquid chromatography-tandem mass spectrometry. The associations between BPs and NTD risk were evaluated using conventional logistic regression and weighted quantile sum regression (WQS) models. In the logistic regression, exposure to higher levels of BPA and BPZ was associated with increased NTD risk (odds ratio [OR] = 3.17, 95 % confidence interval [CI], 1.22-8.22; OR = 3.11, 95 % CI, 1.20-8.09, respectively). Meanwhile, a significant dose-response relationship was found between BPA and BPZ concentrations and NTD risk. In the WQS model, a quartile increase in WQS index resulted in 4.34 (95 % CI: 1.69, 11.20) higher odds for NTDs, and BPA and BPZ accounted for most of the weight index in the joint effects of BPs. In conclusion, high levels of BPs in the placenta are associated with increased risk for NTDs, of which BPA and BPZ are important risk factors.

Discovery of Macrocycle-Based HPK1 Inhibitors for T-Cell-Based Immunotherapy.

Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell activation, and targeting HPK1 is considered a promising strategy for improving responses to antitumor immune therapies. The biggest challenge of HPK1 inhibitor design is to achieve a higher selectivity to GLK, an HPK1 homology protein as a positive regulator of T-cell activation. Herein, we report the design of a series of macrocycle-based HPK1 inhibitors via a conformational constraint strategy. The identified candidate compound 5i exhibited HPK1 inhibition with an IC50 value of 0.8 nM and 101.3-fold selectivity against GLK. Compound 5i also displayed good oral bioavailability (F = 27-49%) in mice and beagles and favorable metabolic stability (T1/2 > 186.4 min) in human liver microsomes. More importantly, compound 5i demonstrated a clear synergistic effect with anti-PD-1 in both MC38 (MSI) and CT26 (MSS) syngeneic tumor mouse models. These results showed that compound 5i has a great potential in immunotherapy.

Maternal serum zinc concentration and neural tube defects in offspring: a meta-analysis.

OBJECTIVE: This study was to assess the relationship between maternal serum zinc concentration and NTDs in offspring by conducting a meta-analysis. METHODS: We searched Pubmed, Medline and Web of Science for all English studies about the relationship between maternal serum zinc level and NTDs in offspring (published between 1 January 1975 and 1 January 2020). Pooled effect sizes with corresponding 95% CIs were calculated using a random-effect model by Revman 5.3 and Stata 15.1 software. RESULTS: Eight articles met our selection criteria and a total of 187 cases and 894 controls were included in this meta-analysis. Our results showed that mothers with NTDs infants had lower serum zinc concentration than those with healthy infants (SMD= -0.77, 95%CI [-1.16, -0.37], p = .0001, I2 = 73%). CONCLUSIONS: Compared with mothers with healthy infants, mothers with NTDs infants have lower serum zinc levels, suggesting that low maternal serum zinc level during pregnancy is probably associated with the risk of NTDs in offspring. But the mechanism of the association remains to be ascertained by large-scale cohort studies.

An artificially designed elastin-like recombinant polypeptide improves aging skin.

BACKGROUND: As a substrate for cell growth, elastin can promote the regeneration and remodeling of the epidermis, which plays an important role in delaying skin aging. However, elastin proteins are more than 700 amino acids long and cannot be absorbed through the skin, which prevents the direct utilization of elastin in the prevention and treatment of aging skin. METHODS: We designed an elastin-like recombinant polypeptide (ELR) which could be absorbed through the skin based on the property of hexapeptide VGVAPG. Thirty healthy Chinese Han female participants which met the criteria were enrolled in this study and all of them completed the tests including elasticity, tightness, and wrinkle detection. The participants used this polypeptide for 4 weeks and were tested in three visits: one day before trial started (D0), and 14 and 28 days after the trial (D14 and D28, respectively). Paired t-tests or Wilcoxon signed-rank tests for non-parametric measures were used to determine the difference between D0 and D14, or D0 and D28. RESULTS: The skin elasticity level in the thirty participants was significantly increased after using ELR for 28 days (P=0.024), and the average value of skin firmness (Uf) declined from 3.313 (D0) to 3.292 (D14) and 3.265 (D28), although there was no statistically significant difference between treatment and pre-treatment. Furthermore, the wrinkle count (D14: P<0.001; D28: P<0.001), wrinkles volume (D14: P<0.001; D28: P=0.008), and wrinkles area (D14: P<0.001; D28: P<0.001) of Crow's feet were significantly improved by using ELR for 14 days or 28 days. CONCLUSION: Continuous use of ELR could significantly improve skin elasticity and reduce wrinkles.