A 3D spheroid model of quadruple cell co-culture with improved liver functions for hepatotoxicity prediction.

Drug-induced liver injury (DILI) is one of the major concerns during drug development. Wide acceptance of the 3 R principles and the innovation of in-vitro techniques have introduced various novel model options, among which the three-dimensional (3D) cell spheroid cultures have shown a promising prospect in DILI prediction. The present study developed a 3D quadruple cell co-culture liver spheroid model for DILI prediction via self-assembly. Induction by phorbol 12-myristate 13-acetate at the concentration of 15.42 ng/mL for 48 hours with a following 24-hour rest period was used for THP-1 cell differentiation, resulting in credible macrophagic phenotypes. HepG2 cells, PUMC-HUVEC-T1 cells, THP-1-originated macrophages, and human hepatic stellate cells were selected as the components, which exhibited adaptability in the designated spheroid culture conditions. Following establishment, the characterization demonstrated the competence of the model in long-term stability reflected by the maintenance of morphology, viability, cellular integration, and cell-cell junctions for at least six days, as well as the reliable liver-specific functions including superior albumin and urea secretion, improved drug metabolic enzyme expression and CYP3A4 activity, and the expression of MRP2, BSEP, and P-GP accompanied by the bile acid efflux transport function. In the comparative testing using 22 DILI-positive and 5 DILI-negative compounds among the novel 3D co-culture model, 3D HepG2 spheroids, and 2D HepG2 monolayers, the 3D culture method significantly enhanced the model sensitivity to compound cytotoxicity compared to the 2D form. The novel co-culture liver spheroid model exhibited higher overall predictive power with margin of safety as the classifying tool. In addition, the non-parenchymal cell components could amplify the toxicity of isoniazid in the 3D model, suggesting their potential mediating role in immune-mediated toxicity. The proof-of-concept experiments demonstrated the capability of the model in replicating drug-induced lipid dysregulation, bile acid efflux inhibition, and α-SMA upregulation, which are the key features of liver steatosis and phospholipidosis, cholestasis, and fibrosis, respectively. Overall, the novel 3D quadruple cell co-culture spheroid model is a reliable and readily available option for DILI prediction.

Terrestrial locomotion characteristics of climbing perch (Anabas testudineus).

The evolution and utilization of limbs facilitated earlier terrestrial vertebrate movement on land, but little is known about how other lateral structures enhance terrestrial locomotion in amphibian fishes without terrestrialized limb structures. Climbing perch (Anabas testudineus) exhibit sustained terrestrial locomotion using uniaxial rotating gill covers instead of appendages. To investigate the role of such simple lateral structures in terrestrial locomotion and the motion generating mechanism of the corresponding locomotor structure configuration (gill covers and body undulation), we measured the terrestrial kinematics of climbing perch and quantitatively analysed its motion characteristics. Here, the digitalized locomotor kinematics show a unique body postural adjustment ability that enables the regulation of the posture of the caudal peduncle for converting lateral bending force into propulsion. An analysis of the coordination characteristics demonstrated that the motion of the gill cover is kinematically independent of axial undulation, suggesting that the gill cover functions as an anchored simple support pole while axial undulation actively mediates body posture and produces propulsive force. The two identified feature-shapes explained more than 87% of the complex lateral undulation in multistage locomotion. The kinematic characteristics enhance our understanding of the underlying coordinating mechanism corresponding to locomotor configurations. Our work provides quantitative insight into the terrestrial locomotor adaptation of climbing perch and sheds light on terrestrial motion potential of locomotor configurations containing a typical aquatic body and restricted lateral structure.

Inflammatory, Metabolic and Endothelial Biomarkers Before and After Pregnancy Complications.

Women with gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), and preterm birth (PTB) have excess cardiovascular disease compared to those with uncomplicated births, perhaps related to pre-pregnancy inflammation, dysmetabolism or endothelial dysfunction. We included 1238 women in the Coronary Artery Risk Development in Young Adults Study (1985-2011) with 2215 births classified according to outcomes (term, uncomplicated births were the referent). Repeated measures ANOVA estimated pre-pregnancy, post-pregnancy and biomarker change according to pregnancy outcomes, adjusted for confounders. GDM and HDP groups had higher pre-pregnancy hsCRP (+0.37 [0.08, 0.65]; +0.29 [0.04, 0.55] log mg/L), leptin (+0.29 [0.09, 0.50]; +0.37 [0.17, 0.56] log ng/ml), and lower adiponectin (-0.25 [-0.36, -0.13); -0.11 [-0.22, -0.01] log ng/ml) than those with uncomplicated births and these profiles persisted in magnitude post-pregnancy. Controlling for BMI attenuated most profiles, except lower pre-pregnancy adiponectin remained associated with GDM. PTB without HDP or GDM was related to lower pre-pregnancy hsCRP and sICAM-1 (-0.31 [-0.56, -0.06] log mg/L; -0.05 [-0.09, - 0.01] log ng/ml) and a larger leptin increase from pre- to post-pregnancy, (+0.20 [0.02, 0.37] log ng/ml). Pre-pregnancy inflammation and metabolic dysfunction contributed to GDM and HDP, perhaps due to higher BMI. PTB may be related to adverse metabolic changes post-pregnancy, though the unexpected endothelial biomarker profile warrants further study.

Erratum to 'Low gestational weight gain (+2.0 to 4.9 kg) for singleton-term gestations associated with favorable perinatal outcomes for all prepregnancy obesity classes' [AJOG Global Reports 3 (2023) 100246].

[This corrects the article DOI: 10.1016/j.xagr.2023.100246.].

Low gestational weight gain (+2.0 to 4.9 kg) for singleton-term gestations associated with favorable perinatal outcomes for all prepregnancy obesity classes.

BACKGROUND: Previous studies that evaluated low gestational weight gain or weight loss among prepregnancy obesity classes have not determined the amount of gestational weight gain associated with the lowest risk of adverse perinatal outcomes and neonatal morbidity among singleton term births. OBJECTIVE: This study aimed to evaluate the relationship of specific gestational weight gain categories of weight loss, stable weight, and low gain considered below the 2009 Institute of Medicine guidelines to perinatal outcomes and neonatal morbidity for singleton, term live births among prepregnancy obesity classes. STUDY DESIGN: This was a retrospective cohort study of 18,476 women among 3 classes of prepregnancy obesity, based on measured prepregnancy weight, and delivering a live singleton pregnancy at ≥37 weeks of gestation at a Kaiser Permanente Northern California hospital (2009-2012). Variables from electronic medical records included perinatal outcomes, sociodemographics, and measured prepregnancy and delivery weights to calculate total gestational weight gain, used to define 5 gestational weight gain categories: weight loss (<-2.0 kg), stable weight (-2.0 to +1.9 kg), low gain (+2.0 to 4.9 kg), gain within guidelines (+5.0 to 9.1 kg; referent), and gain above guidelines (>9.1 kg). Logistic regression models estimated adjusted odds ratios and 95% confidence intervals of maternal and newborn perinatal outcomes (hypertensive disorders, cesarean delivery, size for gestational age, length of stay, neonatal intensive care unit admission) associated with gestational weight gain categories stratified by prepregnancy obesity classes 1, 2, and 3. RESULTS: Low gain occurred in 8%, 12%, and 13% of women in obesity class 1 (body mass index, 30.0-34.9), class 2 (body mass index, 35.0-39.9), and class 3 (body mass index, ≥40), respectively. Compared with gestational weight gain within Institute of Medicine guidelines, low gain was associated with similar or improved maternal and newborn perinatal outcomes for all obesity classes without increased odds of neonatal intensive care unit admission, neonatal length of stay ≥3 days, or small for gestational age. The percentages of small for gestational age for the low gain category were 4.4%, 3.0%, and 4.3% among prepregnancy obesity classes 1, 2, and 3, respectively, and comparable with the gestational weight gain within the guideline category (P>.05). The adjusted odds ratios of small-for-gestational age were not statistically significant for all obesity classes; class 1 (1.16; 95% confidence interval, 0.79-1.71) , class 2 (1.05; 95% confidence interval 0.58-1.93), and class 3 (2.03; 95% confidence interval 0.97-4.27). CONCLUSION: Lower gestational weight gain of +2.0 to 4.9 kg showed the most favorable perinatal outcomes, without higher small for gestational age or neonatal morbidity for all obesity classes.

Early Pregnancy Systolic Blood Pressure Patterns Predict Early- and Later-Onset Preeclampsia and Gestational Hypertension Among Ostensibly Low-to-Moderate Risk Groups.

Background Clinical risk factors, a single blood pressure (BP) measurement, current biomarkers, and biophysical parameters can effectively identify risk of early-onset preeclampsia but have limited ability to predict later-onset preeclampsia and gestational hypertension. Clinical BP patterns hold promise to improve early risk stratification for hypertensive disorders of pregnancy. Methods and Results After excluding preexisting hypertension, heart, kidney, or liver disease, or prior preeclampsia, the retrospective cohort (n=249 892) all had systolic BP <140 mm Hg and diastolic BP <90 mm Hg or a single BP elevation ≤20 weeks' gestation, prenatal care at <14 weeks' gestation, and a still or live birth delivery at Kaiser Permanente Northern California hospitals (2009-2019). The sample was randomly split into development (N=174 925; 70%) and validation (n=74 967; 30%) data sets. Predictive performance of multinomial logistic regression models for early-onset (<34 weeks) preeclampsia, later-onset (≥34 weeks) preeclampsia, and gestational hypertension was evaluated in the validation data set. There were 1008 (0.4%), 10 766 (4.3%), and 11 514 (4.6%) patients with early-onset preeclampsia, later-onset preeclampsia, and gestation hypertension, respectively. Models with 6 systolic BP trajectory groups (0-20 weeks' gestation) plus standard clinical risk factors performed substantially better than risk factors alone to predict early- and later-onset preeclampsia and gestational hypertension, with C-statistics (95% CIs) of 0.747 (0.720-0.775), 0.730 (0.722-0.739), and 0.768 (0.761-0.776) versus 0.688 (0.659-0.717), 0.695 (0.686-0.704) and 0.692 (0.683-0.701), respectively, with excellent calibration (Hosmer-Lemeshow P=0.99, 0.99, and 0.74, respectively). Conclusions Early pregnancy BP patterns up to 20 weeks' gestation plus clinical, social, and behavioral factors more accurately discriminate hypertensive disorders of pregnancy risk among low-to-moderate risk pregnancies. Early pregnancy BP trajectories improve risk stratification to reveal higher-risk individuals hidden within ostensibly low-to-moderate risk groups and lower-risk individuals considered at higher risk by US Preventive Services Task Force criteria.

Decomposition and Reconstruction of Human Palm Movements.

OBJECTIVE: The human hand is known to have excellent manipulation ability compared to other primate hands. Without the palm movements, the human hand would lose more than 40% of its functions. However, uncovering the constitution of palm movements is still a challenging problem involving kinesiology, physiology, and engineering science. METHODS: By recording the palm joint angles during common grasping, gesturing, and manipulation tasks, we built a palm kinematic dataset. Then, a method for extracting the eigen-movements to characterize the common motion correlation relationships of palm joints was proposed to explore the palm movement constitution. RESULTS: This study revealed a palm kinematic characteristic that we named the joint motion grouping coupling characteristic. During natural palm movements, there are several joint groups with a high degree of motor independence, while the movements of joints within each joint group are interdependent. Based on these characteristics, the palm movements can be decomposed into seven eigen-movements. The linear combinations of these eigen-movements can reconstruct more than 90% of palm movement ability. Moreover, combined with the palm musculoskeletal structures, we found that the revealed eigen-movements are associated with joint groups that are defined by muscular functions, which provided a meaningful context for palm movement decomposition. CONCLUSION: This paper suggests that some invariable characteristics underlie the variable palm motor behaviors and can be used to simplify palm movement generation. SIGNIFICANCE: This paper provides important insights into palm kinematics, and helps facilitate motor function assessment and the development of better artificial hands.

Exploring the effects of skeletal architecture and muscle properties on bipedal standing in the common chimpanzee (Pan troglodytes) from the perspective of biomechanics.

Introduction: It is well known that the common chimpanzee, as both the closest living relative to humans and a facultative bipedal, has the capability of bipedal standing but cannot do so fully upright. Accordingly, they have been of exceeding significance in elucidating the evolution of human bipedalism. There are many reasons why the common chimpanzee can only stand with its hips-knees bent, such as the distally oriented long ischial tubercle and the almost absent lumbar lordosis. However, it is unknown how the relative positions of their shoulder-hip-knee-ankle joints are coordinated. Similarly, the distribution of the biomechanical characteristics of the lower-limb muscles and the factors that affect the erectness of standing as well as the muscle fatigue of the lower limbs remain a mystery. The answers are bound to light up the evolutional mechanism of hominin bipedality, but these conundrums have not been shed much light upon, because few studies have comprehensively explored the effects of skeletal architecture and muscle properties on bipedal standing in common chimpanzees. Methods: Thus, we first built a musculoskeletal model comprising the head-arms-trunk (HAT), thighs, shanks, and feet segments of the common chimpanzee, and then, the mechanical relationships of the Hill-type muscle-tendon units (MTUs) in bipedal standing were deduced. Thereafter, the equilibrium constraints were established, and a constrained optimization problem was formulated where the optimization objective was defined. Finally, thousands of simulations of bipedal standing experiments were performed to determine the optimal posture and its corresponding MTU parameters including muscle lengths, muscle activation, and muscle forces. Moreover, to quantify the relationship between each pair of the parameters from all the experimental simulation outcomes, the Pearson correlation analysis was employed. Results: Our results demonstrate that in the pursuit of the optimal bipedal standing posture, the common chimpanzee cannot simultaneously achieve maximum erectness and minimum muscle fatigue of the lower limbs. For uni-articular MTUs, the relationship between muscle activation, relative muscle lengths, together with relative muscle forces, and the corresponding joint angle is generally negatively correlated for extensors and positively correlated for flexors. For bi-articular MTUs, the relationship between muscle activation, coupled with relative muscle forces, and the corresponding joint angles does not show the same pattern as in the uni-articular MTUs. Discussion: The results of this study bridge the gap between skeletal architecture, along with muscle properties, and biomechanical performance of the common chimpanzee during bipedal standing, which enhances existing biomechanical theories and advances the comprehension of bipedal evolution in humans.

In pursuit of reconstructing missing human hands.

Exploring bio-intelligence of human limbs could provide a new perspective for reconstructing missing limbs.

Prepregnancy weight change associated with high gestational weight gain.

OBJECTIVE: Gestational weight gain (GWG) above recommendations is a risk factor for adverse maternal, perinatal, and long-term outcomes. This study hypothesized that prepregnancy weight gain may portend excess GWG. METHODS: Among 1,126 women (51% of whom were of Black race) in the Coronary Artery Risk Development in Young Adults (CARDIA) study with post-baseline births, the prepregnancy annual rate of BMI change per woman was estimated (slope; 5 years before pregnancy) and was related to the risk of GWG above Institute of Medicine recommendations using mixed-effects models (binary) and GWG z score (continuous), adjusting for confounders, and stratified by prepregnancy overweight/obesity status. RESULTS: A total of 626 women (56%) had excess GWG. Each standard deviation increase in prepregnancy BMI (0.16 kg/m2 per year) was associated with an 18% increased risk of excess GWG (95% CI: 1.13-1.23), adjusted for covariates. Stratified results showed an association for women without overweight or obesity (adjusted relative risk = 1.71 [95% CI: 1.38-2.13]) but not among those with overweight or obesity (adjusted relative risk = 0.98 [95% CI: 0.91-1.05]). When evaluated as a z score, prepregnancy weight gain was associated with higher GWG among women with and without overweight or obesity (mean = 0.24 [0.10] and 0.28 [0.12] z score, respectively). CONCLUSIONS: Weight gain before pregnancy is associated with higher GWG during pregnancy. Assessment of prepregnancy weight changes may identify those at risk for high GWG.

Anthropomorphic Reaching Movement Generating Method for Human-Like Upper Limb Robot.

How to generate anthropomorphic reaching movement remains a challenging problem in service robots and human motor function repair/reconstruction equipment. However, there is no universally accepted computational model in the literature for reproducing the motion of the human upper limb. In response to the problem, this article presents a computational framework for generating reaching movement endowed with human motion characteristics that imitated the mechanism in the control and realization of human upper limb motions. This article first establishes the experimental paradigm of human upper limb functional movements and proposes the characterization of human upper limb movement characteristics and feature movement clustering methods in the joint space. Then, according to the specific task requirements of the upper limb, combined with the human sensorimotor model, the estimation method of the human upper limb natural postures was established. Next, a continuous task parametric model matching the characteristic motion class is established by using the Gaussian mixture regression method. The anthropomorphic motion generation method with the characteristics of the smooth trajectory and the ability of natural obstacle avoidance is proposed. Finally, the anthropomorphic motion generation method proposed in this article is verified by a human-like robot. The measurement index of the human-likeness degree of the trajectory is given. The experimental results show that for all four tested tasks, the human-likeness degrees were greater than 90.8%, and the trajectories' jerk generated by this method is very similar to the trajectories' jerk of humans, which validates the proposed method.

Two-Dimensional TeB Structures with Anisotropic Carrier Mobility and Tunable Bandgap.

Two-dimensional (2D) semiconductors with desirable bandgaps and high carrier mobility have great potential in electronic and optoelectronic applications. In this work, we proposed α-TeB and ß-TeB monolayers using density functional theory (DFT) combined with the particle swarm-intelligent global structure search method. The high dynamical and thermal stabilities of two TeB structures indicate high feasibility for experimental synthesis. The electronic structure calculations show that the two structures are indirect bandgap semiconductors with bandgaps of 2.3 and 2.1 eV, respectively. The hole mobility of the ß-TeB sheet is up to 6.90 × 102 cm2 V-1 s-1. By reconstructing the two structures, we identified two new horizontal and lateral heterostructures, and the lateral heterostructure presents a direct band gap, indicating more probable applications could be further explored for TeB sheets.

Hemorrhagic pericardial effusion following treatment with infliximab: A case report and literature review.

BACKGROUND: Infliximab (IFX) is an anti-tumor necrosis factor alpha (TNF-α) agent that is widely used for the management of a variety of autoimmune and inflammatory diseases, including Crohn's disease (CD). As a result of its increasing administration, new complications have emerged. Hemorrhagic pericardial effusion, secondary to IFX therapy, is a rare but life-threatening complication. CASE SUMMARY: A 27-year-old man was diagnosed with CD (Montreal A2L3B1) 6 years prior. After failing to respond to mesalazine and methylprednisolone, he took the first dose of IFX 300 mg based on his weight (60 kg, dose 5 mg/kg) on December 3, 2018. He responded well to this therapy. However, on January 21, 2019, 1 wk after the third injection, he suddenly developed dyspnea, fever, and worsening weakness and was admitted to our hospital. On admission, computed tomography scan of the chest revealed a large pericardial effusion and a small right-side pleural effusion. An echocardiogram showed a large pericardial effusion and normal left ventricular function. Then successful ultrasound-guided pericardiocentesis was performed and 600 mL hemorrhagic fluid was drained. There was no evidence of infection and the concentrations of TNF-α, IFX, and anti-IFX antibody were 7.09 pg/mL (reference range < 8.1 pg/mL), < 0.4 µg/mL (> 1.0 µg/mL), and 373 ng/mL (< 30 ng/mL), respectively. As the IFX instruction manual for injection does mention pericardial effusion as a rare adverse reaction (≥ 1/10000, < 1/1000), so we discontinued the IFX. Monitoring of the patient's echocardiogram for 2 mo without IFX therapy showed no recurrence of hemorrhagic pericardial effusion. Follow-up visits and examinations every 3 to 6 mo until April 2021 showed no recurrence of CD or pericardial effusion. CONCLUSION: This is a case of hemorrhagic pericardial effusion following treatment with IFX. It is a rare but life-threatening complication of IFX. Early recognition helps prevent the occurrence of hemorrhagic pericardial effusion and minimize the impact on the natural evolution of the disease.

Common kinematic synergies of various human locomotor behaviours.

Humans show a variety of locomotor behaviours in daily living, varying in locomotor modes and interaction styles with the external environment. However, how this excellent motor ability is formed, whether there are some invariants underlying various locomotor behaviours and simplifying their generation, and what factors contribute to the invariants remain unclear. Here, we find three common kinematic synergies that form the six joint motions of one lower limb during walking, running, hopping and sitting-down-standing-up (movement variance accounted for greater than 90%), through identifying the coordination characteristics of 36 lower limb motor tasks in diverse environments. This finding supports the notion that humans simplify the generation of various motor behaviours through re-using several basic motor modules, rather than developing entirely new modules for each behaviour. Moreover, a potential link is also found between these synergies and the unique biomechanical characteristics of the human musculoskeletal system (muscular-articular connective architecture and bone shape), and the patterns of inter-joint coordination are consistent with the energy-saving mechanism in locomotion by using biarticular muscles as efficient mechanical energy transducers between joints. Altogether, our work helps understand the formation mechanisms of human locomotion from a holistic viewpoint and evokes inspirations for the development of artificial limbs imitating human motor ability.

Gestational Diabetes History and Glucose Tolerance After Pregnancy Associated With Coronary Artery Calcium in Women During Midlife: The CARDIA Study.

BACKGROUND: Gestational diabetes (GD) leads to earlier onset and heightened risk of type 2 diabetes, a strong risk factor for cardiovascular disease (CVD). However, it is unclear whether attaining normoglycemia can ameliorate the excess CVD risk associated with GD history. This study sought to evaluate GD history and glucose tolerance after pregnancy associated with coronary artery calcification (CAC) in women, a manifestation of atherosclerotic CVD and a predictor of CVD clinical events. METHODS: Data were obtained from the CARDIA study (Coronary Artery Risk Development in Young Adults), a US multicenter, community-based prospective cohort of young Black (50%) and White adults aged 18 to 30 years at baseline (1985-1986). The sample included 1133 women without diabetes at baseline, who had ≥1 singleton births (n=2066) during follow-up, glucose tolerance testing at baseline and up to 5 times during 25 years (1986-2011), GD status, and CAC measurements obtained from 1 or more follow up examinations at years 15, 20, and 25 (2001-2011). CAC was measured by noncontrast cardiac computed tomography; dichotomized as Any CAC (score>0) or No CAC (score=0). Complementary log-log models for interval-censored data estimated adjusted hazard ratios of CAC and 95% confidence intervals for GD history and subsequent glucose tolerance groups (normoglycemia, prediabetes, or incident diabetes) on average 14.7 years after the last birth adjusted for prepregnancy and follow-up covariates. RESULTS: Of 1133 women, 139 (12.3%) reported GD and were 47.6 years of age (4.8 SD) at follow-up. CAC was present in 25% (34/139) of women with GD and 15% (149/994) of women with no GD. In comparison with no GD/normoglycemia, adjusted hazard ratios (95% CIs) were 1.54 (1.06-2.24) for no GD/prediabetes and 2.17 (1.30-3.62) for no GD/incident diabetes, and 2.34 (1.34-4.09), 2.13 (1.09-4.17), and 2.02 (0.98-4.19) for GD/normoglycemia, GD/prediabetes, and GD/incident diabetes, respectively (overall P=0.003). CONCLUSIONS: Women without previous GD showed a graded increase in the risk of CAC associated with worsening glucose tolerance. Women with a history of GD had a 2-fold higher risk of CAC across all subsequent levels of glucose tolerance. Midlife atherosclerotic CVD risk among women with previous GD is not diminished by attaining normoglycemia.

A science-driven method for determining morphological parameters of prosthetic hands.

The unique morphological bases of human hands, which are distinct from other primates, endow them with excellent grasping and manipulative abilities. However, the lack of understanding of human hand morphology and its parametric features is a major obstacle in the scientific design of prosthetic hands. Existing designs of prosthetic hand morphologies mostly adopt engineering-based methods, which depend on human experience, direct measurements of human hands, or numerical simulation/optimization. This paper explores for the first time a science-driven design method for prosthetic hand morphology, aiming to facilitate the development of prosthetic hands with human-level dexterity. We first use human morphological, movement, and postural data to quantitatively cognize general morphological characteristics of human hands in static, dynamic, functional, and non-functional perspectives. Taking these cognitions as bases, we develop a method able to quickly transfer human morphological parameters to prosthetic hands and endow the prosthetic hands with great grasping/manipulative potential at the same time. We apply this method to the design of an advanced prosthetic hand (called X-hand II) embedded with compact actuating systems. The human-size prosthetic hand can reach wide grasping/manipulative ranges close to those of human hands, replicate various daily grasping types and even execute dexterous in-hand manipulation. This science-driven method may also inspire other artificial limb and bionic robot designs.

Changes in Cardiometabolic Risk Factors Before and After Gestational Diabetes: A Prospective Life-Course Analysis in CARDIA Women.

OBJECTIVE: This study hypothesized that both preconception and postchildbearing patterns of cardiometabolic risk factors may be different for women with gestational diabetes mellitus (GDM) compared with women without GDM. METHODS: Among 1,302 (51% black) women in the Coronary Artery Risk Development in Young Adults (CARDIA) study with births and followed for 30 years, this study evaluated changes in cardiometabolic factors (BMI, waist circumference [WC], lipids, blood pressure) during prechildbearing (prior to the first postbaseline birth) and postchildbearing periods (after the last birth) by GDM status using piecewise linear mixed models adjusted for sociodemographics, parity, and time-varying covariates. RESULTS: Compared with women who did not develop GDM, weight and WC increases in women who developed GDM (n = 152, 12%) were faster (BMI difference: +0.12 kg/m2 /y, P = 0.04; WC difference: +0.28 cm/y, P = 0.04) during the prechildbearing period, accounting for covariates. This translated to an average of 1.3 kg of excess weight gain across 4 years among women with subsequent GDM versus non-GDM births. In contrast, slopes after childbearing did not differ by GDM status, nor were there other cardiometabolic differences. CONCLUSIONS: Women with GDM exhibited an increasing prepregnancy pattern of weight gain and central adiposity. Absolute postchildbearing weight was also higher in GDM-affected women, but the slope of gain after GDM was not.

Life Course Changes in Cardiometabolic Risk Factors Associated With Preterm Delivery: The 30-Year CARDIA Study.

Background Women who deliver preterm infants (<37 weeks) have excess cardiovascular risk; however, it is unclear whether the unfavorable changes in the cardiometabolic profile associated with preterm delivery initiate before, during, or after childbearing. Methods and Results We identified 1306 women (51% Black) with births between baseline (1985-1986) and year 30 in the CARDIA (Coronary Artery Risk Development in Young Adults) study. We compared life course changes in blood pressure, body mass index, waist circumference, and lipids in women with preterm deliveries (n=318) with those with all term deliveries (n=988), using piecewise linear mixed-effects models. Specifically, we evaluated group differences in rates of change before and after the childbearing period and change in level across the childbearing period. After adjusting for the covariates, women with preterm deliveries had a higher change in diastolic blood pressure across the childbearing period than those with all term deliveries (1.59 versus -0.73 mm Hg, P<0.01); the rates of change did not differ by group, both prechildbearing and postchildbearing. Women with preterm deliveries had a larger body mass index increase across the childbearing period (1.66 versus 1.22 kg/m2, P=0.03) compared with those with all term deliveries, followed by a steeper increase after the childbearing period (0.22 versus 0.17 kg/m2 per year, P=0.02). Conclusions Preterm delivery was associated with unfavorable patterns of change in diastolic blood pressure and adiposity that originate during the childbearing years and persist or exacerbate later in life. These adverse changes may contribute to the elevated cardiovascular risk among women with preterm delivery.

Identification and validation of metformin protects against PM2.5-induced macrophages cytotoxicity by targeting toll like receptor pathway.

Fine particle matter (PM2.5) has been extensively reported to contribute to the pathogenesis of pulmonary diseases. Recently, metformin has been reported to attenuate PM2.5 associated respiratory and cardiovascular injury, but the underling mechanism has not been discovered. Here, we performed comprehensively bioinformatics analysis and fully validation experiment to investigate the protection role of metformin and underling mechanism with RNAseq profile in GEO database. A combination of various bioinformatics tools including edgeR, principal component analysis (PCA), K-Means clustering, Gene Set Enrichment Analysis (GSEA), GO and KEGG enrichment were performed to identify the TLRs/MyD88/NF-κB axis functional as the key signaling transduction during PM2.5 associated toxicity. PM2.5 activated TLRs/MyD88/NF-κB pathway and resulted in significantly generation of IL-6, TNF-α, mitochondrial damage, decreasing of cell viability and increased LDH activity in RAW264.7 cells. Metformin significantly attenuated the production of IL-6, mitochondrial damage, cell viability and LDH activity by limiting TLRs/MyD88/NF-κB pathway. The siRNA against AMPKα2 or negative control were transfected to RAW264.7 cells to identify whether metformin protects PM2.5-induced cytotoxicity in an AMPKα2-dependent manner. Pretreatment with metformin significantly attenuated PM2.5 induced decreasing of cell viability and increased LDH activity, as well as inhibited the TLRs/MyD88/NF-κB pathway in both siControl or siAMPKα2 cells. Taken together, our results indicate that metformin protects against PM2.5-induced mitochondrial damage and cell cytotoxicity by inhibiting TLRs/MyD88/NF-κB signaling pathway in an AMPKα2 independent manner.