Standalone Stretchable Biophysical Sensing System Based on Laser Direct Write of Patterned Porous Graphene/Co3O4 Nanocomposites.

Skin-interfaced wearable sensors can continuously monitor various biophysical and biochemical signals for health monitoring and disease diagnostics. However, such devices are typically limited by unsatisfactory and unstable output performance of the power supplies under mechanical deformations and human movements. Furthermore, there is also a lack of a simple and cost-effective fabrication technique to fabricate and integrate varying materials in the device system. Herein, we report a fully integrated standalone stretchable biophysical sensing system by combining wearable biophysical sensors, triboelectric nanogenerator (TENG), microsupercapacitor arrays (MSCAs), power management circuits, and wireless transmission modules. All of the device components and interconnections based on the three-dimensional (3D) networked graphene/Co3O4 nanocomposites are fabricated via low-cost and scalable direct laser writing. The self-charging power units can efficiently harvest energy from body motion into a stable and adjustable voltage/current output to drive various biophysical sensors and wireless transmission modules for continuously capturing, processing, and wirelessly transmitting various signals in real-time. The novel material modification, device configuration, and system integration strategies provide a rapid and scalable route to the design and application of next-generation standalone stretchable sensing systems for health monitoring and human-machine interfaces.

[Structural design and evaluation of bone remodeling effect of fracture internal fixation implants with time-varying stiffness].

The stiffness of an ideal fracture internal fixation implant should have a time-varying performance, so that the fracture can generate reasonable mechanical stimulation at different healing stages, and biodegradable materials meet this performance. A topology optimization design method for composite structures of fracture internal fixation implants with time-varying stiffness is proposed, considering the time-dependent degradation process of materials. Using relative density and degradation residual rate to describe the distribution and degradation state of two materials with different degradation rates and elastic modulus, a coupled mathematical model of degradation simulation mechanical analysis was established. Biomaterial composite structures were designed based on variable density method to exhibit time-varying stiffness characteristics. Taking the bone plate used for the treatment of tibial fractures as an example, a composite structure bone plate with time-varying stiffness characteristics was designed using the proposed method. The optimization results showed that material 1 with high stiffness formed a columnar support structure, while material 2 with low stiffness was distributed at the degradation boundary and inside. Using a bone remodeling simulation model, the optimized bone plates were evaluated. After 11 months of remodeling, the average elastic modulus of callus using degradable time-varying stiffness plates, titanium alloy plates, and stainless steel plates were 8 634 MPa, 8 521 MPa, and 8 412 MPa, respectively, indicating that the use of degradable time-varying stiffness plates would result in better remodeling effects on the callus.

The HLA-I landscape confers prognosis and antitumor immunity in breast cancer.

Breast cancer is a highly heterogeneous disease with varied subtypes, prognoses and therapeutic responsiveness. Human leukocyte antigen class I (HLA-I) shapes the immunity and thereby influences the outcome of breast cancer. However, the implications of HLA-I variations in breast cancer remain poorly understood. In this study, we established a multiomics cohort of 1156 Chinese breast cancer patients for HLA-I investigation. We calculated four important HLA-I indicators in each individual, including HLA-I expression level, somatic HLA-I loss of heterozygosity (LOH), HLA-I evolutionary divergence (HED) and peptide-binding promiscuity (Pr). Then, we evaluated their distribution and prognostic significance in breast cancer subtypes. We found that the four breast cancer subtypes had distinct features of HLA-I indicators. Increased expression of HLA-I and LOH were enriched in triple-negative breast cancer (TNBC), while Pr was relatively higher in hot tumors within TNBCs. In particular, a higher Pr indicated a better prognosis in TNBCs by regulating the infiltration of immune cells and the expression of immune molecules. Using the matched genomic and transcriptomic data, we found that mismatch repair deficiency-related mutational signature and pathways were enriched in low-Pr TNBCs, suggesting that targeting mismatch repair deficiency for synthetic lethality might be promising therapy for these patients. In conclusion, we presented an overview of HLA-I indicators in breast cancer and provided hints for precision treatment for low-Pr TNBCs.

Topology optimization of embracing fixator considering bone remodeling to mitigate stress shielding effect.

The embracing fixator is one of the widely used internal fixation implants for bone fracture treatment. However, the stress shielding effect, a stress imbalance between the implant and bone caused by the mismatch in mechanical properties between them, is a significant and critical issue that may lead to treatment failure. Thus, it is of great importance to design the implant with an appropriate stiffness which can mitigate the stress shielding effect and provide the most favorable mechanical environment for bone healing and remodeling. To this end, a time-dependent topology optimization algorithm considering bone remodeling is proposed to optimize an embracing fixator used in the tibia fracture treatment. The change of callus density over time is simulated based on a bone remodeling model, and the callus density after a period of bone remodeling is selected to be the design objective to maximize. The design constraints include volume and the compliance of the whole fixation system. Meanwhile, the influence of the constraints on the regularity of material distribution of the optimized result is also studied. Besides, to test the effectiveness of the consideration of the bone remodeling in the embracing fixator design, a topology optimization concerning the minimization of the compliance of the entire system is also performed to make a comparison. Finally, the safety performance of optimized results considering bone remodeling is also verified by static analysis.

Guanosine diphosphate-mannose suppresses homologous recombination repair and potentiates antitumor immunity in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor prognosis. TNBCs with high homologous recombination deficiency (HRD) scores benefit from DNA-damaging agents, including platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, whereas those with low HRD scores still lack therapeutic options. Therefore, we sought to exploit metabolic alterations to induce HRD and sensitize DNA-damaging agents in TNBCs with low HRD scores. We systematically analyzed TNBC metabolomics and identified a metabolite, guanosine diphosphate (GDP)-mannose (GDP-M), that impeded homologous recombination repair (HRR). Mechanistically, the low expression of the upstream enzyme GDP-mannose-pyrophosphorylase-A (GMPPA) led to the endogenous up-regulation of GDP-M in TNBC. The accumulation of GDP-M in tumor cells further reduced the interaction between breast cancer susceptibility gene 2 (BRCA2) and ubiquitin-specific peptidase 21 (USP21), which promoted the ubiquitin-mediated degradation of BRCA2 to inhibit HRR. Therapeutically, we illustrated that the supplementation of GDP-M sensitized DNA-damaging agents to impair tumor growth in both in vitro (cancer cell line and patient-derived organoid) and in vivo (xenograft in immunodeficient mouse) models. Moreover, the combination of GDP-M with DNA-damaging agents activated STING-dependent antitumor immunity in immunocompetent syngeneic mouse models. Therefore, GDP-M supplementation combined with PARP inhibition augmented the efficacy of anti-PD-1 antibodies. Together, these findings suggest that GDP-M is a crucial HRD-related metabolite and propose a promising therapeutic strategy for TNBCs with low HRD scores using the combination of GDP-M, PARP inhibitors, and anti-PD-1 immunotherapy.

Genomic alterations affecting tumor-infiltrating lymphocytes and PD-L1 expression patterns in triple-negative breast cancer.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) and programmed cell death 1 ligand 1 (PD-L1) remain imperfect in predicting clinical outcomes of triple-negative breast cancer because outcomes do not always correlate with the expression of these biomarkers. Genomic and transcriptomic alterations that may contribute to the expression of these biomarkers remain incompletely uncovered. METHODS: We evaluated PD-L1 immunohistochemistry scores (SP142 and 28-8 assays) and TILs in our triple-negative breast cancer multiomics dataset and 2 immunotherapy clinical trial cohorts. Then, we analyzed genomic and transcriptomic alterations correlated with TILs, PD-L1 expression, and patient outcomes. RESULTS: Despite TILs serving as a decent predictor for triple-negative breast cancer clinical outcomes, exceptions remained. Our study revealed that several genomic alterations were correlated with unexpected events. In particular, PD-L1 expression may cause a paradoxical relationship between TILs and prognosis in certain patients. Consequently, we classified triple-negative breast cancers into 4 groups based on PD-L1 and TIL levels. The TIL-negative PD-L1-positive and TIL-positive PD-L1-negative groups were not typical "hot" tumors; both were associated with worse prognoses and lower immunotherapy efficacy than TIL-positive PD-L1-positive tumors. Copy number variation of PD-L1 and oncogenic signaling activation were correlated with PD-L1 expression in the TIL-negative PD-L1-positive group, whereas GSK3B-induced degradation may cause undetectable PD-L1 expression in the TIL-positive PD-L1-negative group. These factors have the potential to affect the predictive function of both PD-L1 and TILs. CONCLUSIONS: Several genomic and transcriptomic alterations may cause paradoxical effects among TILs, PD-L1 expression, and prognosis in triple-negative breast cancer. Investigating and targeting these factors will advance precision immunotherapy for patients with this disease.

Laser Processing of Crumpled Porous Graphene/MXene Nanocomposites for a Standalone Gas Sensing System.

Integrating wearable gas sensors with energy harvesting and storage devices can create self-powered systems for continuous monitoring of gaseous molecules. However, the development is still limited by complex fabrication processes, poor stretchability, and sensitivity. Herein, we report the low-cost and scalable laser scribing of crumpled graphene/MXenes nanocomposite foams to combine stretchable self-charging power units with gas sensors for a fully integrated standalone gas sensing system. The crumpled nanocomposite designed in island-bridge device architecture allows the integrated self-charging unit to efficiently harvest kinetic energy from body movements into stable power with adjustable voltage/current outputs. Meanwhile, given the stretchable gas sensor with a large response of ∼1% ppm-1 and an ultralow detection limit of ∼5 ppb to NO2/NH3, the integrated system provides real-time monitoring of the exhaled human breath and the local air quality. The innovations in materials and structural designs pave the way for the future development of wearable electronics.

Biomechanical evaluation of a healed acetabulum with internal fixators: finite element analysis.

BACKGROUND: Treatment of complicated acetabular fracture with internal fixation usually has high risk of failure because of unbefitting fixation. However, evaluation of the biomechanical effect of internal fixation under physiological loading for fracture healing is still generally rarely performed. The purpose of this study is to analyze the biomechanical characteristics of a healed acetabulum with designed internal fixators under gait and to explore the biomechanical relationship between the healed bone and the internal fixator. METHODS: A patient-specific finite element model of whole pelvis with designed internal fixators was constructed based on the tomographic digital images, in which the spring element was used to simulate the main ligaments of the pelvis. And the finite element analysis under both the combination loading of different phases and the individual loading of each phase during the gait cycle was carried out. The displacement, von Mises stress, and strain energy of both the healed bone and the fixation were calculated to evaluate the biomechanical characteristics of the healed pelvis. RESULTS: Under the combination loading of gait, the maximum difference of displacement between the left hip bone with serious injury and the right hip bone with minor injury is 0.122 mm, and the maximum stress of the left and right hemi-pelvis is 115.5 MPa and 124.28 MPa, respectively. Moreover, the differences of average stress between the bone and internal fixators are in the range of 2.3-13.7 MPa. During the eight phases of gait, the stress distribution of the left and right hip bone is similar. Meanwhile, based on the acetabular three-column theory, the strain energy ratio of the central column is relatively large in stance phases, while the anterior column and posterior column of the acetabular three-column increase in swing phases. CONCLUSIONS: The acetabular internal fixators designed by according to the anatomical feature of the acetabulum are integrated into the normal physiological stress conduction of the pelvis. The design and placement of the acetabular internal fixation conforming to the biomechanical characteristics of the bone is beneficial to the anatomical reduction and effective fixation of the fracture, especially for complex acetabular fracture.

The optimal design of 3D-printed lattice bone plate by considering fracture healing mechanism.

The biomechanical stimulus is the most important factor for fracture healing and mainly determined by the structural stiffness of bone plate. Currently, the materials commonly used in bone plates are stainless steel and titanium, which often lead to stress shielding effects because of their higher elastic modulus compared with the bone. This article suggests an optimal design method of lattice bone plate based on fracture healing theory. First, the mechanical regulation model with deviatoric strain is established to simulate the tissue differentiation process during fracture healing process. The ratio of the average elastic modulus of callus at the 120th day to the elastic modulus of mature bone is used to characterize the fracture healing rate. Second, the optimal elastic modulus of the design domain is obtained by the optimization mathematical model with the maximum fracture healing rate. Then, the design domain is filled with microstructures, the porosity of which is adjusted to make it possible that the equivalent elastic modulus is equal to the optimized value. And the finite element analysis of the bone plate with microstructure is executed. Finally, the designed lattice bone plates are manufactured through 3D printing, and the mechanical test is carried out. The simulation results indicate that the fracture healing rate is maximum when the elastic modulus of material in design domain is 38 GPa under the constraints of fixation stability. And both the finite element analysis and experiment results show that the designed lattice bone plate meet the strength requirements of fracture internal fixation implants.

In situ laser-assisted synthesis and patterning of graphene foam composites as a flexible gas sensing platform.

Gas-sensitive semiconducting nanomaterials (e.g., metal oxides, graphene oxides, and transition metal dichalcogenides) and their heterojunctions hold great promise in chemiresistive gas sensors. However, they often require a separate synthesis method (e.g., hydrothermal, so-gel, and co-precipitation) and their integration on interdigitated electrodes (IDE) via casting is also associated with weak interfacial properties. This work demonstrates in situ laser-assisted synthesis and patterning of various sensing nanomaterials and their heterojunctions on laser-induced graphene (LIG) foam to form LIG composites as a flexible and stretchable gas sensing platform. The porous LIG line or pattern with nanomaterial precursors dispensed on top is scribed by laser to allow for in situ growth of corresponding nanomaterials. The versatility of the proposed method is highlighted through the creation of different types of gas-sensitive materials, including transition metal dichalcogenide (e.g., MoS2), metal oxide (e.g., CuO), noble metal-doped metal oxide (e.g., Ag/ZnO) and composite metal oxides (e.g., In2O3/Cr2O3). By eliminating the IDE and separate heaters, the LIG gas sensing platform with self-heating also decreases the device complexity. The limit of detection (LOD) of the LIG gas sensor with in situ synthesized MoS2, CuO, and Ag/ZnO to NO2, H2S, and trimethylamine (TMA) is 2.7, 9.8, and 5.6 ppb, respectively. Taken together with the high sensitivity, good selectivity, rapid response/recovery, and tunable operating temperature, the integrated LIG gas sensor array can identify multiple gas species in the environment or exhaled breath.

Bidirectional crosstalk between therapeutic cancer vaccines and the tumor microenvironment: Beyond tumor antigens.

Immunotherapy has rejuvenated cancer therapy, especially after anti-PD-(L)1 came onto the scene. Among the many therapeutic options, therapeutic cancer vaccines are one of the most essential players. Although great progress has been made in research on tumor antigen vaccines, few phase III trials have shown clinical benefits. One of the reasons lies in obstruction from the tumor microenvironment (TME). Meanwhile, the therapeutic cancer vaccine reshapes the TME in an ambivalent way, leading to immune stimulation or immune escape. In this review, we summarize recent progress on the interaction between therapeutic cancer vaccines and the TME. With respect to vaccine resistance, innate immunosuppressive TME components and acquired resistance caused by vaccination are both involved. Understanding the underlying mechanism of this crosstalk provides insight into the treatment of cancer by directly targeting the TME or synergizing with other therapeutics.

Comprehensive analysis of the cuproptosis-related model to predict prognosis and indicate tumor immune infiltration in lung adenocarcinoma.

Background: Cuproptosis is a novel form of programmed cell death termed as Cu-dependent cytotoxicity. However, the roles of cuproptosis-associated genes (CAGs) in lung adenocarcinoma (LUAD) have not been explored comprehensively. Methods: We obtained CAGs and utilized consensus molecular clustering by "non-negative matrix factorization (NMF)" to stratify LUAD patients in TCGA (N = 511), GSE13213 (N = 117), and GSE31210 (N = 226) cohorts. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of immune cell types in tumor microenvironment (TME). The risk score based on CAGs was calculated to predict patients' survival outcomes. Results: We identified three cuproptosis-associated clusters with different clinicopathological characteristics. We found that the cuproptosis-associated cluster with the worst survival rates exhibited a high enrichment of activated CD4/8+ T cells. In addition, we found that the cuproptosis-associated risk score could be used for patients' prognosis prediction and provide new insights in immunotherapy of LUAD patients. Eventually, we constructed a nomogram-integrated cuproptosis-associated risk score with clinicopathological factors to predict overall survival in LUAD patients, with 1-, 3-, and 5-year area under curves (AUCs) being 0.771, 0.754, and 0.722, respectively, all of which were higher than those of the TNM stage. Conclusions: In this study, we uncovered the biological function of CAGs in the TME and its correlations with clinicopathological parameters and patients' prognosis in LUAD. These findings could provide new angles for immunotherapy of LUAD patients.

Template assisted preparation of silicone (polydimethylsiloxane) elastomers and their self-cleaning application.

The formation of self-cleaning functions on silicone elastomers is crucial for practical applications but still challenging. In this study, superhydrophobic silicone elastomers (SHSEs) with a 3D-hierarchical microstructure were achieved during the curing process with the assistance of a homemade template. The micro-nano structure formed by the assistance of the template makes the silicone elastomer surface achieve robust superhydrophobicity with a WCA at ∼163°, which can easily self-clean, removing surface contamination. Also, TiO2 particles transferred from the template endow the surface with photocatalytic functions, which can degrade organic pollutants under UV irradiation. After sandpaper abrasion, the formed SHSE can maintain its excellent hydrophobicity and show liquid repellency to wine and coffee droplets. The SHSEs with self-cleaning functions have promising applications in water treatment, medical facilities, and wearable devices.

Circular RNA expression profile and competing endogenous RNA regulatory network in preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a pregnancy specific disorder which is significantly associated with maternal and neonatal morbidity and mortality. This study aimed to explore the potential role of circRNAs in PE. METHODS: The mRNA, miRNA, and circRNA expression profiles of PE were downloaded from GEO database. Bioinformatics analysis was conducted to characterize differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and circRNAs (DEcircRNAs) in the placental tissues of women with PE versus normal pregnancies. Then, expression validation of the mRNAs, miRNAs and circRNAs were performed with RT-qPCR and GEO datasets. RESULTS: A total of 1645 DEmRNAs, 41 DEmiRNAs and 2432 DEcircRNAs were acquired. The ceRNA network contained 4 circRNA-miRNA pairs and 64 miRNA-mRNA pairs, including 3 circRNAs, 3 miRNAs, and 63 mRNAs. Validation in RT-qPCR and GEO were generally in line with our integrated analysis results. DISCUSSION: In conclusion, we speculated that hsa_circRNA_0001687/hsa-miR-532-3p/MMP14/AXL, hsa_circ_0001513/hsa-miR-188-5p/HMGCS1 and hsa_circ_0001513/hsa_circ_0001329/hsa-miR-760/MAP1LC3B axes may participate in the pathological process of PE.

In situ formation of Co3O4 nanocrystals embedded in laser-induced graphene foam for high-energy flexible micro-supercapacitors.

The cost-effective synthesis of flexible energy storage devices with high energy and power densities is a challenge in wearable electronics. Here, we report a facile, efficient, and scalable approach for preparing three-dimensional (3D) laser-induced graphene foam (Co3O4@LIG) embedded with porous Co3O4 nanocrystals using a CO2 infrared laser. The in situ formed Co3O4@LIG nanocomposites directly serve as active materials, current collectors, and the conductive substrate for micro-supercapacitors (MSCs). Benefiting from rational structural features, the MSC based on Co3O4@LIG nanocomposites (Co3O4@LIG-MSC) with an interdigitated electrode configuration exhibits excellent electrochemical performance, including a high specific capacitance (143.5 F g-1), excellent rate capability, high energy density (19.9 W h kg-1 at a power density of 0.5 W kg-1), and remarkable power density (15.0 W kg-1 at an energy density of 15.8 W h kg-1). Furthermore, the device possesses good stability under different bending diameters and cycling stability. Such a highly integrated flexible MSC with high energy and power densities made by a directly laser scribing strategy has some potential for the fabrication of wearable energy storage devices.

Concurrent Topology Optimization of Composite Plates for Minimum Dynamic Compliance.

This paper proposes a novel density-based concurrent topology optimization method to support the two-scale design of composite plates for vibration mitigation. To have exceptional damping performance, dynamic compliance of the composite plate is taken as the objective function. The complex stiffness model is used to describe the material damping and accurately consider the variation of structural response due to the change of damping composite material configurations. The mode superposition method is used to calculate the complex frequency response of the composite plates to reduce the heavy computational burden caused by a large number of sample points in the frequency range during each iteration. Both microstructural configurations and macroscopic distribution are optimized in an integrated manner. At the microscale, the damping layer consists of periodic composites with distinct damping and stiffness. The effective properties of the periodic composites are homogenized and then are fed into the complex frequency response analysis at the macroscale. To implement the concurrent topology optimization at two different scales, the design variables are assigned for both macro- and micro-scales. The adjoint sensitivity analysis is presented to compute the derivatives of dynamic compliance of composite plates with respect to the micro and macro design variables. Several numerical examples with different excitation inputs and boundary conditions are presented to confirm the validity of the proposed methodologies. This paper represents a first step towards designing two-scale composite plates with optional dynamic performance under harmonic loading using an inverse design method.

VEGFR2 in vascular smooth muscle cells mediates H2S-induced dilation of the rat cerebral basilar artery.

INTRODUCTION: The aim of present study was to study whether the vascular endothelial growth factor receptor 2 (VEGFR2) mediates hydrogen sulfide (H2S)-induced relaxation of the rat cerebral vasculature. METHODS: Relaxation of cerebral basilar artery (CBA) and vascular smooth muscle cells (VSMCs) was measured by using a pressure myograph system and image analysis system, respectively. The intracellular calcium concentration ([Ca2+]i) in VSMCs was detected using fluorescence imaging analysis. RESULTS: We found that H2S donor NaHS induced significant relaxation of VSMCs from the CBA of wild type rat, but in VEGFR2 knockdown VSMCs, NaHS-induced relaxation reduced markedly. In addition, NaHS-induced vasodilation of rat CBA also attenuated obviously when the expression of VEGFR2 was knocked down in vivo. In addition, pretreatment with the VEGFR2 blocker SU5416 likewise lowered the NaHS-induced relaxation of rat CBA. Nevertheless, the VEGFR2 agonist, vascular endothelial growth factor 164 (VEGF164), induced a concentration-dependent relaxation of CBA, which is similar to the effect of NaHS. Furthermore, we found that both NaHS and VEGF164 significantly inhibited the U46619-induced increase of [Ca2+]i fluorescence intensity in the VSMCs. However, the inhibitory effect of NaHS on the [Ca2+]i fluorescence intensity in VSMCs was markedly inhibited by pretreatment with SU5416 or VEGFR2 knockdown. CONCLUSION: These findings indicated that H2S-induced CBA dilation and reduction of [Ca2+]i in VSMCs occur by acting on VEGFR2.

Total Syntheses of Aspidospermidine, N-Methylaspidospermidine, N-Acetylaspidospermidine, and Aspidospermine via a Tandem Cyclization of Tryptamine-Ynamide.

The total syntheses of aspidospermidine, N-methylaspidospermidine, N-acetylaspidospermidine, and aspidospermine were achieved from a common pentacyclic indoline intermediate. The common pentacyclic indoline intermediate was synthesized on a gram scale through a Stork-enamine alkylation of 1H-pyrrolo[2,3-d]carbazole derivatives, which were prepared through a Brønsted acid-catalyzed tandem cyclization of tryptamine-ynamide. The scalable synthesis of 1H-pyrrolo[2,3-d]carbazole afforded facile access and a practical approach to the Aspidosperma indole alkaloid family.

An Appraisal of the Role of Previously Reported Risk Factors in the Age at Menopause Using Mendelian Randomization.

OBJECTIVE: Menopause at a young age is associated with many health problems in women, including osteoporosis, depressive symptoms, coronary disease, and stroke. Many traditional observational studies have reported some potential risk factors for early menopause but have drawn different conclusions. This inconsistency can be attributed mainly to unmodified confounding factors. Identifying the factors causally associated with age at menopause is important for early intervention in women with abnormal menopause timing, and for improving the quality of life for postmenopausal women. This study aims to appraise whether the previously reported risk factors are causally associated with early age at natural menopause (ANM) susceptibility. METHODS: We used Mendelian randomization, a statistical method wherein genetic variants are used to determine whether an observational association between a risk factor and an outcome is consistent with a causal effect. RESULTS: Women with earlier age at menarche (ß = 0.34, se = 0.16, p = 0.035), lower education level (ß = 1.19, se = 0.41, p = 0.004) and higher body mass index (ß = -0.05, se = 0.02, p = 0.027) had greater risk for early ANM. The causal link between early age at menarche and early ANM was replicated using ReproGen consortium data (ß = 0.23, se = 0.07, p = 0.001). However, a current smoking habit, one of previously reported risk factors, was less likely to be correlated causally with early ANM, suggesting that previous observational studies may not have sufficiently adjusted for confounders. CONCLUSION: Our results help to identify the risk factors of ANM via a genetics approach and future research into the biological mechanism could further help with targeted prevention for early menopause.

Pregravid Oral Contraceptive Use and the Risk of Preterm Birth, Low Birth Weight, and Spontaneous Abortion: A Systematic Review and Meta-Analysis.

Background: Although oral contraceptives (OCs) have been widely used by women of childbearing age, their influence on pregnancy and birth outcomes, such as preterm birth (PB), low birth weight (LBW), and spontaneous abortion (SAB), is unclear. The aim of this systemic review was to assess these complications in women who had used OCs before pregnancy compared with those in a control group. Materials and Methods: The databases of PubMed, EMBASE, and Web of Science were searched up to December 2018. We included studies where the primary outcome was the risk of PB, LBW, and SAB in women with pregravid OCs use compared with the control group. Odds ratio (OR) value was calculated to assess the risk. Results: Eighteen studies were included in the systematic review, and a total of 148,406 subjects from 7 studies were pooled for the meta-analysis. Results showed that the risk of PB was slightly higher in the exposed group (OR = 1.17, 95% confidence interval [CI] = 1.07-1.27, p = 0.0005); however, there was a lower risk for SAB compared with the control group (OR = 0.63, 95% CI = 0.41-0.96, p = 0.03). No significant difference was found in the incidence of LBW (OR = 1.36, 95% CI = 0.92-2.02, p = 0.12). Conclusions: This systematic review and meta-analysis demonstrated a higher risk for PB and a lower risk for SAB in women with previous ORs use, whereas no association was found between ORs use and LBW risk.