Maternal cardiovascular health in early pregnancy and the risk of congenital heart defects in offspring.

BACKGROUND: Congenital heart disease (CHD) is the predominant birth defect. This study aimed to explore the association between maternal cardiovascular health (CVH) and the CHD risk in offspring. METHODS: We used the prospective data from the Fujian Birth Cohort Study, collected from March 2019 to December 2022 on pregnant women within 14 weeks of gestation. Overall maternal CVH was assessed by seven CVH metrics (including physical activity, smoking, sleep duration, body mass index, blood pressure, total cholesterol, and fasting plasma glucose), with each metric classified as ideal, intermediate or poor with specific points. Participants were further allocated into high, moderate and low CVH categories based on the cumulative CVH score. The association with offspring CHD was determined with log-binominal regression models. RESULTS: A total of 19810 participants aged 29.7 (SD: 3.9) years were included, with 7846 (39.6%) classified as having high CVH, 10949 (55.3%) as having moderate CVH, and 1015 (5.1%) as having low CVH. The average offspring CHD rate was 2.52%, with rates of 2.35%, 2.52% and 3.84% across the high, moderate and low CVH categories, respectively (P = 0.02). Adjusted relative risks (RRs) of having offspring CHD were 0.64 (95% CI: 0.45-0.90, P = 0.001) for high CVH and 0.67 (95% CI: 0.48-0.93, P = 0.02) for moderate CVH compared to low CVH. For individual metrics, only ideal total cholesterol was significantly associated with lower offspring CHD (RR: 0.73, 95% CI: 0.59-0.83, P = 0.002). CONCLUSIONS: Pregnant women of high or moderate CVH categories in early pregnancy had reduced risks of CHD in offspring, compared to those of low CVH. It is important to monitor and improve CVH during pre-pregnancy counseling and early prenatal care.

Association of sleep duration and sleep quality with gestational diabetes mellitus in pregnant women after treatment with assisted reproductive technology: A birth cohort study.

Maternal sleep is closely related to subsequent gestational diabetes mellitus (GDM) in natural pregnancies. However, whether this connection exists in pregnant women conceiving with the help of assisted reproductive technology (ART) has not been confirmed. Hence, in this study, we evaluated whether early pregnancy sleep duration or sleep quality is associated with gestational diabetes mellitus in ART-pregnant women, as well as the influence of maternal age on this association. This prospective birth cohort study included 856 pregnant women who successfully conceived with the help of ART treatment. The sleep parameters of ART-pregnant women were assessed using the Pittsburgh Sleep Quality Index (PSQI) in early pregnancy. We explored the association between sleep and the risk of gestational diabetes mellitus using an unconditional binary logistic regression model. Different models were constructed to examine the robustness of the estimation by incorporating different confounding factors. Multivariable logistic regression revealed that sleep duration of more than 10 h among ART-pregnant women was significantly associated with the risk of GDM, and the association between sleep duration and gestational diabetes mellitus varied by maternal age. We found an increased risk of subsequent gestational diabetes mellitus with increasing sleep duration only in pregnant women aged <35 years. Additionally, no statistically significant association between sleep quality and gestational diabetes mellitus was found in this study. In conclusion, excessive sleep duration (≥10 h) is associated with a high risk of gestational diabetes mellitus in pregnant women who conceived with the help of assisted reproductive technology, and maternal age may modify this effect.

Association between lipid profile in early pregnancy and the risk of congenital heart disease in offspring: a prospective cohort study.

This study aimed to investigate the association of lipid profile in early pregnancy and the risk of congenital heart disease (CHD) in offspring. This study was a prospective cohort design based on the Fujian Birth Cohort Study in China. We recruited pregnant women at ≤ 14 weeks of gestation between 2019 and 2022, and all participants in this study filled out the questionnaire about periconceptional exposure. Simultaneously, we collected participants' fasting blood samples to measure their lipid profile by automatic biochemical analyzer. The outcome was defined as offspring with CHD. A multivariable logistic regression model was used to calculate adjusted odds ratio (AOR) risk estimates, which indicate the associations between maternal lipid profiles and CHD in offspring. Restricted cubic splines were used to estimate their nonlinear relationship. A total of 21,425 pregnant women with an average gestational age of 11.3 (± 1.40) weeks were included in the analysis. The higher triglyceride (AOR 1.201, 95% CI [1.036, 1.394]), low-density lipoprotein (AOR 1.216, 95% CI [1.048, 1.410]), apolipoprotein B (Apo B) (AOR 2.107, 95% CI [1.179, 3.763]) levels were correlated with increased odds of CHD in offspring, while high-density lipoprotein (OR 0.672, 95% CI [0.490, 0.920]) related with decreased odds of CHD in offspring. The restricted cubic spline suggested a nonlinear relationship between total cholesterol (TC) levels and the risk of CHD in offspring (P = 0.0048), but no significant nonlinear relationships were found in other lipid profile. Apolipoprotein A was not related to the risk of CHD in offspring as either a continuous variable or a hierarchical variable. Elevated lipid profile in early pregnancy levels are associated with an increased risk of CHD in offspring. Additionally, there is a non-linear relationship between TC levels and the risk of CHD in offspring.

Inverse association between maternal serum concentrations of trace elements and risk of spontaneous preterm birth: a nested case-control study in China.

Few studies have evaluated the joint effect of trace elements on spontaneous preterm birth (SPTB). This study aimed to examine the relationships between the individual or mixed maternal serum concentrations of Fe, Cu, Zn, Se, Sr and Mo during pregnancy, and risk of SPTB. Inductively coupled plasma MS was employed to determine maternal serum concentrations of the six trace elements in 192 cases with SPTB and 282 controls with full-term delivery. Multivariate logistic regression, weighted quantile sum regression (WQSR) and Bayesian kernel machine regression (BKMR) were used to evaluate the individual and joint effects of trace elements on SPTB. The median concentrations of Sr and Mo were significantly higher in controls than in SPTB group (P < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted OR (aOR) of 0·432 (95 CI < 0·05). In multivariate logistic regression analysis, compared with the lowest quartile levels of individual trace elements, the third- and fourth-quartile Sr or Mo concentrations were significantly associated with reduced risk of SPTB with adjusted aOR of 0·432 (95 % CI 0·247, 0·756), 0·386 (95 % CI 0·213, 0·701), 0·512 (95 % CI 0·297, 0·883) and 0·559 (95 % CI 0·321, 0·972), respectively. WQSR revealed the inverse combined effect of the trace elements mixture on SPTB (aOR = 0·368, 95 % CI 0·228, 0·593). BKMR analysis confirmed the overall mixture of the trace elements was inversely associated with the risk of SPTB, and the independent effect of Sr and Mo was significant. Our findings suggest that the risk of SPTB decreased with concentrations of the six trace elements, with Sr and Mo being the major contributors.

Methionine restriction constrains lipoylation and activates mitochondria for nitrogenic synthesis of amino acids.

Methionine restriction (MR) provides metabolic benefits in many organisms. However, mechanisms underlying the MR-induced effect remain incompletely understood. Here, we show in the budding yeast S. cerevisiae that MR relays a signal of S-adenosylmethionine (SAM) deprivation to adapt bioenergetic mitochondria to nitrogenic anabolism. In particular, decreases in cellular SAM constrain lipoate metabolism and protein lipoylation required for the operation of the tricarboxylic acid (TCA) cycle in the mitochondria, leading to incomplete glucose oxidation with an exit of acetyl-CoA and α-ketoglutarate from the TCA cycle to the syntheses of amino acids, such as arginine and leucine. This mitochondrial response achieves a trade-off between energy metabolism and nitrogenic anabolism, which serves as an effector mechanism promoting cell survival under MR.

Trajectories of maternal D-dimer are associated with the risk of developing adverse maternal and perinatal outcomes: A prospective birth cohort study.

OBJECTIVE: To assess the relationships of maternal D-dimer trajectories with the risk of developing adverse maternal and perinatal outcomes (AMPOs). METHODS: A prospective birth cohort study was conducted in China, and 7,095 women who had singleton birth were included. The latent class growth model was used to determine the maternal D-dimer trajectory. RESULTS: Three maternal D-dimer trajectories were identified: (1) slight increase (43.6%), (2) rapid rise (51.3%), (3) sustained high (5.1%). Compared to pregnant women with a slight increase in D-dimer trajectory, the risk of gestational diabetes mellitus, placenta previa, macrosomia, large for gestational age (LGA), and increased postpartum bleeding was significantly increased in those with a rapid rise trajectory (adjusted OR = 1.22, 2.00, 1.80, and 1.56, adjusted ß = 15.92 âˆ¼ 25.1 ml, respectively, P < 0.05), and women with a sustained high trajectory also demonstrated a relatively elevated risk of macrosomia and LGA (adjusted OR = 2.11 and 1.82, respectively, P < 0.05). While the odds of pregnancy-induced hypertension, low birth weight, and small for gestational age in pregnant women with the rapid rise D-dimer trajectory and fetal distress in those with sustained high trajectory exhibited a reduction (adjusted OR = 0.62, 0.38, 0.54, and 0.64, respectively, P < 0.05). CONCLUSION: This study highlights the influence of inappropriate maternal D-dimer trajectories on the risk of AMPOs.

An analysis of risk factors associated with recurrent wheezing in the pediatric population.

BACKGROUND: Recurrent wheezing is a common clinical problem in early childhood, which is associated with significant morbidity. There is no international consensus on the management and prevention of recurrent wheezing; therefore, identifying the risk factors associated with recurrent wheezing is crucial to prevent episodes of wheezing in young children. METHODS: In this retrospective study, we collected the data of 24,737 patients who were admitted to our hospital between 27th April 2012 and 11th September 2019. After screening for patients with wheezing, we identified 8572 patients with a primary diagnosis of pneumonia with wheezing. Patients' clinical data were collected from the hospital medical records. Patients were stratified for age in the groups of < 6 months, 6-12 months, and > 12 months. RESULTS: Among the 8569 pediatric pneumonia patients with wheezing, there were 343 patients with recurrent wheezing. Most enrolled patients were under 6 months of age (45.17%) and had a normal birth weight (86.95%). Winter was the most common onset season for the first episode of wheezing, while spring was the most common season for the second episode of wheezing for those with recurrent wheezing. The univariate and multivariate logistic regression analysis for the risk factor associated with recurrent wheezing showed that male gender, past history of respiratory and cardiovascular diseases, low birth weight, development of severe pneumonia, and PICU admission were significantly associated with recurrent wheezing. CONCLUSION: Male gender, past history of respiratory and cardiovascular diseases, low birth weight, severe pneumonia, and PICU admission are independent risk factors of recurrent wheezing in the pediatric population.

Precursor-Led Grain Boundary Engineering for Superior Thermoelectric Performance in Niobium Strontium Titanate.

We present a novel method to significantly enhance the thermoelectric performance of ceramics in the model system SrTi0.85Nb0.15O3 through the use of the precursor ammonium tetrathiomolybdate (0.5-2% w/w additions). After sintering the precursor-infused green body at 1700 K for 24 h in 5% H2/Ar, single-crystal-like electron transport behavior developed with electrical conductivity reaching ∼3000 S/cm at ∼300 K, almost a magnitude higher than that in the control sample. During processing, the precursor transformed into MoS2, then into MoOx, and finally into Mo particles. This limited grain growth promoted secondary phase generation but importantly helped to reduce the grain boundary barriers. Samples prepared with additions of the precursor exhibited vastly increased electrical conductivity, without significant impact on Seebeck coefficients giving rise to high power factor values of 1760 µW/mK2 at ∼300 K and a maximum thermoelectric figure-of-merit zT of 0.24 at 823 K. This processing strategy provides a simple method to achieve high charge mobility in polycrystalline titanate and related materials and with the potential to create "phonon-glass-electron-crystal" oxide thermoelectric materials.

First-Trimester Triglyceride-Glucose Index and Risk of Pregnancy-Related Complications: A Prospective Birth Cohort Study in Southeast China.

Purpose: To evaluate the relationships of the triglyceride-glucose (TyG) index with pregnancy-related complications (PRCs) and to clarify the predictability of the TyG index for PRCs. Patients and Methods: Totally of 11,387 women with a singleton pregnancy were prospectively followed until after delivery. Maternal fasting lipids and glucose concentration were measured in the first trimester (11 weeks gestation on average). The TyG index was calculated as ln [triglyceride (mg/dL) × fasting plasma glucose (mg/dL)/2]. We used generalized linear models to calculate the relative risks and 95% confidence intervals. Receiver-operating characteristic curve analysis was employed to assess the ability of the TyG index to predict the risks of PRCs. Results: Smooth spline reveals that the probability of gestational diabetes mellitus (GDM) is intensified with the increasing TyG index. Multivariate logistic regression adjusted for risk factors demonstrates a 1-unit and a 1-SD increment in the TyG index raises the risk of GDM by 3.63 and 1.57 times, respectively. Identically, the risk of GDM maximizes in the TyG quintile 5 (OR: 3.14; 95% CI: 2.55~3.85) relative to the lowest TyG index group. However, no association between TyG index and the risk of other PRCs was observed after full adjustment. The area under receiver operating characteristic curves is 0.647 (95% CI: 0.632-0.66) for GDM, and the optimal predictive cut-off is 8.55, with a specificity of 0.679 and sensitivity of 0.535. Conclusion: The first-trimester TyG index is significantly associated with the risk of incident GDM, while the relationships between the TyG index and other PRCs need further exploration.

Association of Household Utility of Cleaner Fuel With Lower Hypertension Prevalence and Blood Pressure in Chinese Adults.

Objectives: To investigate whether lower hypertension prevalence or blood pressure was associated with cleaner household fuel usage for cooking and heating among Chinese adults. Methods: We enrolled 44,862 Chinese adults at the baseline of the prospective urban and rural epidemiology (PURE) study in China during 2005-2009, as a subset of the PURE-global China site. Multilevel logistic regression and generalized linear mixed models were conducted to estimate the adjusted odds ratio (AOR) and regression coefficient for hypertension and blood pressure respectively, while subgroup analysis by ambient PM2.5 concentration and location was also examined. Results: Compared with the least clean household solid fuel group, gas (AOR = 0.91, 95% CI: 0.83, 0.99) or electricity (AOR = 0.72, 95% CI: 0.60, 0.87) was associated with significantly lower levels of hypertension prevalence and blood pressure, and a similar pattern of the association was consistently observed among participants with high ambient PM2.5 exposure and those living in urban areas. Conclusion: Household utility of cleaner fuel type was associated with lower hypertension prevalence and blood pressure in Chinese adults. Our study urges the utilization of cleaner household energy to mitigate the burden of hypertension.

Energy sensor AMPK gamma regulates translation via phosphatase PPP6C independent of AMPK alpha.

Maintenance of energy level to drive movements and material exchange with the environment is a basic principle of life. AMP-activated protein kinase (AMPK) senses energy level and is a major regulator of cellular energy responses. The gamma subunit of AMPK senses elevated ratio of AMP to ATP and allosterically activates the alpha catalytic subunit to phosphorylate downstream effectors. Here, we report that knockout of AMPKγ, but not AMPKα, suppressed phosphorylation of eukaryotic translation elongation factor 2 (eEF2) induced by energy starvation. We identified PPP6C as an AMPKγ-regulated phosphatase of eEF2. AMP-bound AMPKγ sequesters PPP6C, thereby blocking dephosphorylation of eEF2 and thus inhibiting translation elongation to preserve energy and to promote cell survival. Further phosphoproteomic analysis identified additional targets of PPP6C regulated by energy stress in an AMPKγ-dependent manner. Thus, AMPKγ senses cellular energy availability to regulate not only AMPKα kinase, but also PPP6C phosphatase and possibly other effectors.

Nitrogen balance and outcomes in critically ill patients: A systematic review and meta-analysis.

Objective: Nitrogen balance (NB) is a commonly used nutrition indicator in clinical practice, while its relation to the interpretation of protein malnutrition and outcomes in critically ill patients remains unclear. This study aimed to evaluate the impact of NB on prognosis in such a patient population. Methods: We searched for relevant studies in PubMed, EMBASE, and the Cochrane Database up to May 10, 2022. Meta-analyses were performed to evaluate the relationship between NB (initial, final, or absolute change of NB levels) and prognosis and important clinical outcomes in critically ill patients. Pooled odds ratios (ORs) and mean differences (MDs) together with their 95% confidence intervals (CIs) were calculated. We also conducted subgroup analyses to explore the sources of heterogeneity. Results: Eight studies with 1,409 patients were eligible. These studies were moderate to high quality. When pooled, the initial NB was comparable between the survival and non-survival groups (five studies, MD 1.20, 95% CI, -0.70 to 3.11, I 2 = 77%; P = 0.22), while a significantly higher final NB in the survival group than that in the death group (two studies, MD 3.69, 95% CI, 1.92-5.46, I 2 = 55%; P < 0.0001). Two studies provided the absolute change of NB over time and suggested survival patients had more increased NB (MD 4.16 g/day, 95% CI, 3.70-4.61, I 2 = 0%; P < 0.00001). Similarly, for studies utilizing multivariate logistic regression, we found an improved NB (four studies, OR 0.85, 95% CI, 0.73-0.99, I 2 = 61%; P = 0.04) but not an initial NB (two studies, OR 0.92, 95% CI 0.78-1.08, I 2 = 55%; P = 0.31) was significantly associated the risk of all-cause mortality. These results were further confirmed in subgroup analyses. In addition, patients with improved NB had more protein and calorie intake and a similar length of stay in hospital than those without. Conclusions: Our results suggested that an improved NB but not the initial NB level was associated with all-cause mortality in critically ill patients. This highlights the requirement for dynamic monitoring of NB during nutrition treatment. Further randomized clinical trials examining the impact of NB-guided protein intake on clinical outcomes in critically ill patients are warranted. Systematic review registration: INPLASY202250134, https://doi.org/10.37766/inplasy2022.5.0134.

Awake prone positioning for patients with COVID-19 pneumonia in intensive care unit: A systematic review and meta-analysis.

Background: Awake prone positioning (APP) has been widely used in non-intubated COVID-19 patients during the pandemic. However, high-quality evidence to support its use in severe COVID-19 patients in an intensive care unit (ICU) is inadequate. Therefore, we aimed to assess the efficacy and safety of APP for intubation requirements and other important outcomes in this patient population. Methods: We searched for potentially relevant articles in PubMed, Embase, and the Cochrane database from inception to May 25, 2022. Studies focusing on COVID-19 adults in ICU who received APP compared to controls were included. The primary outcome was the intubation requirement. Secondary outcomes were mortality, ICU stay, and adverse events. Study quality was independently assessed, and we also conducted subgroup analysis, sensitivity analysis, and publication bias to explore the potential influence factors. Results: Ten randomized controlled trials with 1,686 patients were eligible. The quality of the included studies was low to moderate. Overall, the intubation rate was 35.2% in the included patients. The mean daily APP duration ranged from <6 to 9 h, with poor adherence to APP protocols. When pooling, APP significantly reduced intubation requirement (risk ratio [RR] 0.84; 95%CI, 0.74-0.95; I 2 = 0%, P = 0.007). Subgroup analyses confirmed the reduced intubation rates in patients who were older (≥60 years), obese, came from a high mortality risk population (>20%), received HFNC/NIV, had lower SpO2/FiO2 (<150 mmHg), or undergone longer duration of APP (≥8 h). However, APP showed no beneficial effect on mortality (RR 0.92 [95% CI 0.77-1.10; I 2 = 0%, P = 0.37] and length of ICU stay (mean difference = -0.58 days; 95% CI, -2.49 to 1.32; I 2 = 63%; P = 0.55). Conclusion: APP significantly reduced intubation requirements in ICU patients with COVID-19 pneumonia without affecting the outcomes of mortality and ICU stay. Further studies with better APP protocol adherence will be needed to define the subgroup of patients most likely to benefit from this strategy.

The lag-effects of meteorological factors and air pollutants on child respiratory diseases in Fuzhou, China.

Background: The effects of meteorological factors and air pollutants on respiratory diseases (RDs) were various in different populations according to the demographic characteristics, and children were considered a vulnerable population. Previous studies were mainly based in cities with serious air pollution. This study aimed to qualify the lag effects of meteorological factors and air pollution on respiratory diseases among children under 18 years old in Fuzhou. Methods: Meteorological data, air pollutants concentrations and hospital admission data of Fujian Maternity and Child Health Hospital between 2015 and 2019 were collected. A Distributed Lag Nonlinear Model (DLNM) was used to evaluate the nonlinear and lagged effect of meteorological factors and air pollutants on daily RDs number. A subgroup analysis was also conducted to evaluate the effect on different sex groups and age groups. Results: A total number of 796 125 RDs visits was included during the study period. For meteorological factors, lower mean temperature and relative humidity were significantly associated with daily RDs number (peak relative risk (RR) = 1.032 (95% confidence interval (CI) = 1.011-1.053) and 1.021 (95% CI = 1.013-1.029)), while lower wind speed showed a significant association at low range (peak RR = 0.995 (95% CI = 0.992-0.999)). Temperature warming was a significant protective factor for RDs (peak RR = 0.989 (95% CI = 0.986-0.993)). For air pollutants, SO2, NO2, PM10 and PM2.5 were all significantly associated with RDs (peak RR = 1.028 (95% CI = 1.022-1.035), 1.024 (95% CI = 1.013-1.034), 1.036 (95% CI = 1.025-1.047), 1.028 (95% CI = 1.019-1.037)), and the relationship had no threshold. The estimated RR and peak lag day did not change extremely between subgroups. Conclusions: The findings provide statistical evidence for the prevention of child RDs. In addition, our findings suggested that even at low concentrations, air pollutants still have negative effects on the respiratory system.

Targeted Temperature Management for Cardiac Arrest Due to Non-shockable Rhythm: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Background: Targeted temperature management (TTM) is recommended in adult patients following cardiac arrest (CA) with any rhythm. However, as to non-shockable (NSR) CA, high-quality evidence of TTM supporting its practices remains uncertain. Thus, we aimed to conduct a systematic review and meta-analysis with randomized controlled trials (RCTs) to explore the efficacy and safety of TTM in this population. Methods: We searched PubMed, Embase, and Cochrane library databases for potential trials from inception through Aug 25, 2021. RCTs evaluating TTM for CA adults due to NSR were included, regardless of the timing of cooling initiation. Outcome measurements were mortality and good neurological function. We used the Cochrane bias tools to evaluate the quality of the included studies. Heterogeneity, subgroup analyses, and sensitivity analysis were investigated to test the robustness of the primary outcomes. Results: A total of 14 RCTs with 4,009 adults were eligible for the final analysis. All trials had a low to moderate risk of bias. Of the included trials, six compared NSR patients with or without TTM, while eight compared pre-hospital to in-hospital TTM. Pooled data showed that TTM was not associated with improved mortality (Risk ratio [RR] 1.00; 95% CI, 0.944-1.05; P = 0.89, I 2 = 0%) and good neurological outcome (RR 1.18; 95% CI 0.90-1.55; P = 0.22, I 2 = 8%). Similarly, use of pre-hospital TTM resulted in neither an improved mortality (RR 0.99, 95% CI 0.97-1.03; I 2 = 0%, P = 0.32) nor favorable neurological outcome (RR 1.13, 95% CI 0.93-1.38; I 2 = 0%, P = 0.22). These results were further confirmed in the sensitivity analyses and subgroup analyses. Conclusions: Our results showed that using the TTM strategy did not significantly affect the mortality and neurologic outcomes in CA survival presenting initial NSR.

FUNDC2 promotes liver tumorigenesis by inhibiting MFN1-mediated mitochondrial fusion.

Mitochondria generate ATP and play regulatory roles in various cellular activities. Cancer cells often exhibit fragmented mitochondria. However, the underlying mechanism remains elusive. Here we report that a mitochondrial protein FUN14 domain containing 2 (FUNDC2) is transcriptionally upregulated in primary mouse liver tumors, and in approximately 40% of human hepatocellular carcinoma (HCC). Importantly, elevated FUNDC2 expression inversely correlates with patient survival, and its knockdown inhibits liver tumorigenesis in mice. Mechanistically, the amino-terminal region of FUNDC2 interacts with the GTPase domain of mitofusin 1 (MFN1), thus inhibits its activity in promoting fusion of outer mitochondrial membrane. As a result, loss of FUNDC2 leads to mitochondrial elongation, decreased mitochondrial respiration, and reprogrammed cellular metabolism. These results identified a mechanism of mitochondrial fragmentation in cancer through MFN1 inhibition by FUNDC2, and suggested FUNDC2 as a potential therapeutic target of HCC.

Reciprocal regulation of phosphatidylcholine synthesis and H3K36 methylation programs metabolic adaptation.

Phospholipid biosynthesis plays a role in mediating membrane-to-histone communication that influences metabolic decisions. Upon nutrient deprivation, phospholipid methylation generates a starvation signal in the form of S-adenosylmethionine (SAM) depletion, leading to dynamic changes in histone methylation. Here we show that the SAM-responsive methylation of H3K36 is critical for metabolic adaptation to nutrient starvation in the budding yeast Saccharomyces cerevisiae. We find that mutants deficient in H3K36 methylation exhibit defects in membrane integrity and pyrimidine metabolism and lose viability quickly under starvation. Adjusting the synthesis of phospholipids potently rewires metabolic pathways for nucleotide synthesis and boosts the production of antioxidants, ameliorating the defects resulting from the loss of H3K36 methylation. We further demonstrate that H3K36 methylation reciprocally regulates phospholipid synthesis by influencing redox balance. Our study illustrates an adaptive mechanism whereby phospholipid synthesis entails a histone modification to reprogram metabolism for adaptation in a eukaryotic model organism.

Association between Latent Trajectories of Fluid Balance and Clinical Outcomes in Critically Ill Patients with Acute Kidney Injury: A Prospective Multicenter Observational Study.

INTRODUCTION: We aimed to identify different trajectories of fluid balance (FB) and investigate the effect of FB trajectories on clinical outcomes in intensive care unit (ICU) patients with acute kidney injury (AKI) and the dose-response association between fluid overload (FO) and mortality. METHODS: We derived data from the Beijing Acute Kidney Injury Trial (BAKIT). A total of 1,529 critically ill patients with AKI were included. The primary outcome was 28-day mortality, and hospital mortality, ICU mortality and AKI stage were the secondary outcomes. A group-based trajectory model was used to identify the trajectory of FB during the first 7 days. Multivariable logistic regression was performed to examine the relationship between FB trajectories and clinical outcomes. A logistic regression model with restricted cubic splines was used to examine the dose relationship between FO and 28-day mortality. RESULTS: Three distinct trajectories of FB were identified: low FB (1,316, 86.1%), decreasing FB (120, 7.8%), and high FB (93, 6.1%). Compared with low FB, high FB was associated with increased 28-day mortality (odds ratio [OR] 1.94, 95% confidence interval [CI] 1.17-3.19) and AKI stage (OR 2.04, 95% CI 1.23-3.37), whereas decreasing FB was associated with a reduction in 28-day mortality by approximately half (OR 0.53, 95% CI 0.32-0.87). Similar results were found for the outcomes of ICU mortality and hospital mortality. We observed a J-shaped relationship between maximum FO and 28-day mortality, with the lowest risk at a maximum FO of 2.8% L/kg. CONCLUSION: Different trajectories of FB in critically ill patients with AKI were associated with clinical outcomes. An FB above or below a certain range was associated with an increased risk of mortality. Further studies should explore this relationship and search for the optimal fluid management strategies for critically ill patients with AKI.