The Impact of PCSK9 Gene Polymorphisms on Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene are known to be associated with susceptibility to several cerebrovascular diseases, including ischemic stroke (IS). The aims of this study was to evaluate associations between PCSK9 gene polymorphisms and the risk of IS. Based on previous reports linking PCSK9 SNPs to plasma lipid levels and to atherosclerosis, and to inconsistencies in the reported associations between the SNPs, plasma lipid levels and IS risk, we choose the PCSK9 rs505151, rs529787, and rs17111503 to performe the association analysis. METHODS: Using multiple databases, all relevant case-control and cohort studies that matched our search criteria were collected. Quality assessment of included studies was performed using the Newcastle-Ottawa Scale. Demographic and genotype data were extracted from each study, and meta-analysis was performed using Stata/MP 17.0. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed and random effects models. RESULTS: A critical evaluation was conducted on ten case-control studies, involving a total of 2426 cases and 2424 controls. Pooled results from the allelic models indicated the PCSK9 rs505151 G allele (OR: 1.41, 95% CI: 1.06-1.87, p = 0.019, I2 = 53.9%) and the PCSK9 rs17111503 A allele (OR: 1.38, 95% CI: 1.22-1.55, p < 0.001, I2 = 43.5%) were significantly associated with IS. Study qualities ranged from moderate (n = 4) to good (n = 6). Begg's and Egger's tests results indicated there was no evidence of publication bias in the findings (p > 0.05). CONCLUSIONS: This meta-analysis demonstrated that G allele variant of PCSK9 rs505151 and A allele variant of PCSK9 rs17111503 were associated with an increased risk of IS. Based on our findings, these SNPs could serve as potential targets for the diagnosis and treatment of IS. The integration of information on genetic polymorphism into IS risk prediction model may be beneficial in routine clinical practice.

Association of serum uric acid with women's ovarian reserve: observational study and Mendelian randomization analyses.

OBJECTIVE: To investigate the association between serum uric acid and women's ovarian reserve. DESIGN: Retrospective observational study and Mendelian randomization study. SETTING: University-affiliated in vitro fertilization center. PATIENTS: Observational analyses were undertaken using data from 8,257 women with infertility who finished their first in vitro fertilization treatments between May 2017 and December 2021. Mendelian randomization analyses were based on genome-wide association summary statistics from several biobanks of predominantly European ancestries. INTERVENTIONS: Observational study involved testing log2 transformed serum uric acid levels (for linear, negative regression, and logistic regression analyses); original uric acid levels (for nonlinear association analyses). Mendelian randomization study involved testing genetically predicted uric acid levels. MAIN OUTCOME MEASURES: Biomarkers including antimüllerian hormone, basal antral follicle count, follicle-stimulating hormone, luteinizing hormone, ratio of follicle-stimulating hormone to luteinizing hormone, estradiol; indices of ovarian response to stimulation including poor ovarian response according to different criteria and oocyte yield. RESULTS: In retrospective observational study, all ovarian reserve-related outcomes demonstrated significant differences across serum uric acid quartiles. A two-fold uric acid increase was associated with increased antimüllerian hormone (adjusted ß = 0.69; 95% confidence interval [CI], 0.43-0.95), antral follicle count (adjusted incidence rate ratio = 1.10, 95% CI, 1.05-1.14), luteinizing hormone (adjusted ß = 0.53, 95% CI, 0.28-0.78), decreased risks of Bologna poor ovarian response (adjusted odds ratio = 0.97; 95% CI, 0.95-0.99) and groups 2-4 Poseidon poor ovarian response (group 2: 0.63, 0.56-0.71; group 3: 0.71, 0.65-0.78; group 4: 0.50, 0.46-0.55), whereas an increased risk of group 1 (1.26, 1.13-1.41). Nonlinear analyses showed a common inflection point at 320-340 µmol/L of uric acid. Interactions between uric acid and antimüllerian hormone and antral follicle count were presented in association with oocyte yield. Mendelian randomization results suggested a significant association between genetically predicted uric acid levels and antimüllerian hormone levels (ß = 0.08; 95% CI, 0.04-0.12) but none for uric acid in relation to polycystic ovarian syndrome or other related hormones. CONCLUSION: Higher uric acid levels were associated with better ovarian reserve and increased levels of antimüllerian hormone albeit an increased risk of unexpected poor ovarian response.

Genetic and Epigenetic Landscape for Drug Development in Polycystic Ovary Syndrome.

The treatment of polycystic ovary syndrome (PCOS) faces challenges as all known treatments are merely symptomatic. The U.S. Food and Drug Administration (FDA) has not approved any drug specifically for treating PCOS. As the significance of genetics and epigenetics rises in drug development, their pivotal insights have greatly enhanced the efficacy and success of drug target discovery and validation, offering promise for guiding the advancement of PCOS treatments. In this context, we outline the genetic and epigenetic advancement in PCOS, which provide novel insights into the pathogenesis of this complex disease. We also delve into the prospective method for harnessing genetic and epigenetic strategies to identify potential drug targets and ensure target safety. Additionally, we shed light on the preliminary evidence and distinctive challenges associated with gene and epigenetic therapies in the context of PCOS.

Risk prediction of CISS classification in endovascular treatment of basilar artery stenosis.

Objective: To investigate the incidence of ischemic stroke complications after endovascular treatment for basilar artery stenosis used preoperative high-resolution magnetic resonance vascular wall imaging (HRMR/VWI) and diffusion-weighted imaging (DWI). Methods: The clinical data of 47 patients with severe symptomatic basilar artery stenosis (stenosis rate ≥70 %) treated with endovascular therapy at the Neuro-interventional Center from December 2017 to December 2021 were retrospectively analyzed. High-resolution magnetic resonance angiography (HRMR VWI) and DWI were used to evaluate the location of atherosclerotic plaque at basilar artery stenosis and the distribution of cerebral infarction lesions in all patients before surgery.According to the CISS classification system for ischemic stroke, patients were divided into a perforation group and a hypoperfusion group, and the general situation, plaque distribution, and incidence of ischemic stroke complications 7 days after endovascular treatment in the two groups were analyzed. Results: There was no significant difference in baseline data between the two groups. After 7 days of intravascular treatment, the incidence of ischemic stroke was higher in the perforation group (20.0 %) than in the hypoperfusion group (0.0 %), and the difference was statistically significant (P = 0.027). A significant association was found between the perforation group and the hypoperfusion group for the incidence of ischemic stroke at 7 days (P = 0.003, OR = 2.347; 95 % CI = 2.056-4.268). There were a higher proportion of ventral plaques (74.1 %) and a lower proportion of dorsal plaques (33.3 %) in the hypoperfusion group, which were 15.0 % and 90.0 % in the perforation group, respectively (χ2 = 16.045, P < 0.001; χ2 = 15.092, P < 0.001). There was no significant difference in the proportion of left and right plaques between the two groups. Conclusions: The risk of ischemic stroke is greater in patients with perforator artery obstruction undergoing endovascular therapy, and lower in patients with hypoperfusion/embolus removal.

Circulating Inflammatory Cytokines and Female Reproductive Diseases: A Mendelian Randomization Analysis.

CONTEXT: Extensive studies have provided considerable evidence suggesting the role of inflammation in the development of female reproductive diseases. However, causality has not been established. OBJECTIVE: To explore whether genetically determined circulating levels of cytokines are causally associated with female reproductive diseases and discover potential novel drug targets for these diseases. METHODS: Instrumental variables (IVs) for 47 circulating cytokines were obtained from a genome-wide association study (GWAS) meta-analysis of 31 112 European individuals. Protein quantitative trait loci and expression quantitative trait loci close to genes served as our IVs. Summary data of 9 female reproductive diseases were mainly derived from GWAS meta-analysis of the UK biobank and FinnGen. We elevated the association using the Wald ratio or inverse variance-weighted Mendelian randomization (MR) with subsequent assessments for MR assumptions in several sensitivity and colocalization analyses. We consider a false discovery rate <0.05 as statistical significance in MR analyses. Replication studies were conducted for further validation, and phenome-wide association studies were designed to explore potential side effects. RESULTS: Our results indicated that high levels of macrophage colony-stimulating factor (MCSF), growth-regulated oncogene-alpha (GROα), and soluble intercellular adhesion molecule-1 were associated with increased risks of endometriosis, female infertility, and pre-eclampsia, respectively. High platelet-derived growth factor-BB (PDGF-BB) levels that reduced the risk of ovarian aging were also supported. Replication analysis supported the relationship between GROα and female infertility, and between MCSF and endometriosis. CONCLUSION: We identified 4 correlated pairs that implied potential protein drug targets. Notably, we preferred highlighting the value of PDGF-BB as a drug target for ovarian aging, and MCSF as a drug target for endometriosis.

Serum steroid metabolome on the day of oocyte retrieval in women with polycystic ovarian syndrome and its association with pregnancy outcome of in vitro fertilization.

Steroid hormone level is a crucial factor affecting the outcomes of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). The purpose of this study was to evaluate serum steroid metabolome on the day of oocyte retrieval in women with polycystic ovarian syndrome (PCOS) and explore whether specific steroids can be potential indicators to improve the prediction of pregnancy outcomes in PCOS patients undergoing IVF/ICSI. In this study, the serum levels of 21 steroids in 89 women with PCOS and 73 control women without PCOS on the day of oocyte retrieval of the first IVF/ICSI treatment cycle were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). All patients subsequently received good-quality embryo transfer, and the correlation between their steroid profiles and pregnancy outcomes of the first embryo transfer (ET) was retrospectively analyzed. We found PCOS patients had aberrant levels of 11 out of 21 steroid hormones compared to control individuals, with androgen steroid hormones being considerably enhanced. Enzyme activity evaluation indicated that PCOS women might have abnormal activity of CYP17A1, CYP21A2, CYP11B2, CYP19A1, HSD3B, HSD11B, and HSD17B. Additionally, the level of 18-hydroxycorticosterone (p = 0.014), corticosterone (p = 0.035), and 17-hydroxypregnenolone (p = 0.005) were markedly higher in live birth group than in non- live birth group for PCOS women following frozen embryo transfer (FET). Multiple logistic regressions indicated that 18-hydrocorticosterone and 17-hydroxypregnenolone were independently associated with live birth outcomes of PCOS women following FET. Receiver operating characteristic (ROC) curve analysis revealed that 0.595 ng/mL for 18-hydrocorticosterone level (AUC: 0.6936, p = 0.014).and 2.829 ng/mL for 17-hydroxypregnenolone level (AUC: 0.7215, p = 0.005) were the best cutoff values to predict live birth outcomes of PCOS. In conclusion, the blood steroid metabolome was closely related to the IVF/ICSI outcomes of PCOS patients. 18-hydroxycorticosterone and 17-hydroxypregnenolone might be potential indicators to predict pregnancy outcomes of PCOS undergoing IVF/ICSI treatment.

Elevated serum uric acid level is associated with adverse reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles: a retrospective cohort study.

BACKGROUND: Serum uric acid levels are elevated in polycystic ovary syndrome, however, the relationship between serum uric acid level and reproductive outcomes in women with polycystic ovary syndrome remains unclear. OBJECTIVE: This study aimed to investigate the association between serum uric acid level and the reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles. STUDY DESIGN: This was a retrospective cohort study performed at a university-affiliated reproductive medicine center. A total of 1903 women with polycystic ovary syndrome undergoing their first in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles between January 2010 and January 2021 were initially included. The trends for reproductive outcomes in polycystic ovary syndrome across quartiles of serum uric acid levels were assessed. A logistic regression analysis was performed to obtain the odds ratios for in vitro fertilization outcomes based on the quartiles of serum uric acid with or without adjusting for potential confounding variables. Using generalized additive models, serum uric acid was further treated as its original continuous property to visualize its nonlinear relationship with in vitro fertilization outcomes. The live birth rate was the main outcome. RESULTS: After exclusions, a total of 883 women with polycystic ovary syndrome with their first fresh-embryo transfer cycles were included. In quartiles of serum uric acid levels, there was a significant decreasing trend in the live birth rate from the lowest quartile (Q1: 61.8%) to the highest (Q4: 45.9%) (Ptrend=.002). The percentage of low birthweight increased from Q1 (22.3%) to Q4 (31.7%) (Ptrend=.049). Compared with those in Q1, women in Q4 showed a significant lower probability of live birth and clinical pregnancy and a higher risk for low birthweight (all P<.05). Both the unadjusted and adjusted generalized additive models indicated that as the serum uric acid level increased, the probability of clinical pregnancy and the live birth rate exhibited an overall decreasing profile, and the risk for low birthweight showed an increasing profile. CONCLUSION: An elevated serum uric acid level is associated with decreased probabilities of live birth and clinical pregnancy and an increased risk for low birthweight in women with polycystic ovary syndrome. However, these associations may be confounded by other factors and more well-designed studies are needed to confirm these findings in the future.

Performances of whole-brain dynamic and static functional connectivity fingerprinting in machine learning-based classification of major depressive disorder.

Background: Alterations in static and dynamic functional connectivity during resting state have been widely reported in major depressive disorder (MDD). The objective of this study was to compare the performances of whole-brain dynamic and static functional connectivity combined with machine learning approach in differentiating MDD patients from healthy controls at the individual subject level. Given the dynamic nature of brain activity, we hypothesized that dynamic connectivity would outperform static connectivity in the classification. Methods: Seventy-one MDD patients and seventy-one well-matched healthy controls underwent resting-state functional magnetic resonance imaging scans. Whole-brain dynamic and static functional connectivity patterns were calculated and utilized as classification features. Linear kernel support vector machine was employed to design the classifier and a leave-one-out cross-validation strategy was used to assess classifier performance. Results: Experimental results of dynamic functional connectivity-based classification showed that MDD patients could be discriminated from healthy controls with an excellent accuracy of 100% irrespective of whether or not global signal regression (GSR) was performed (permutation test with P < 0.0002). Brain regions with the most discriminating dynamic connectivity were mainly and reliably located within the default mode network, cerebellum, and subcortical network. In contrast, the static functional connectivity-based classifiers exhibited unstable classification performances, i.e., a low accuracy of 38.0% without GSR (P = 0.9926) while a high accuracy of 96.5% with GSR (P < 0.0002); moreover, there was a considerable variability in the distribution of brain regions with static connectivity most informative for classification. Conclusion: These findings suggest the superiority of dynamic functional connectivity in machine learning-based classification of depression, which may be helpful for a better understanding of the neural basis of MDD as well as for the development of effective computer-aided diagnosis tools in clinical settings.

Diffusion-Free Scaling in Rotating Spherical Rayleigh-Bénard Convection.

Direct numerical simulations are employed to reveal three distinctly different flow regions in rotating spherical Rayleigh-Bénard convection. In the high-latitude region I vertical (parallel to the axis of rotation) convective columns are generated between the hot inner and the cold outer sphere. The mid-latitude region I I is dominated by vertically aligned convective columns formed between the Northern and Southern hemispheres of the outer sphere. The diffusion-free scaling, which indicates bulk-dominated convection, originates from this mid-latitude region. In the equator region I I I , the vortices are affected by the outer spherical boundary and are much shorter than in region I I .

Predicting Vertical Concentration Profiles in the Marine Atmospheric Boundary Layer With a Markov Chain Random Walk Model.

In an effort to better represent aerosol transport in mesoscale and global-scale models, large eddy simulations (LES) from the National Center for Atmospheric Research (NCAR) Turbulence with Particles (NTLP) code are used to develop a Markov chain random walk model that predicts aerosol particle profiles in a cloud-free marine atmospheric boundary layer (MABL). The evolution of vertical concentration profiles are simulated for a range of aerosol particle sizes and in a neutral and an unstable boundary layer. For the neutral boundary layer we find, based on the LES statistics and a specific model time step, that there exist significant correlation for particle positions, meaning that particles near the bottom of the boundary are more likely to remain near the bottom of the boundary layer than being abruptly transported to the top, and vice versa. For the unstable boundary layer, a similar time interval exhibits a weaker tendency for an aerosol particle to remain close to its current location compared to the neutral case due to the strong nonlocal convective motions. In the limit of a large time interval, particles have been mixed throughout the MABL and virtually no temporal correlation exists. We leverage this information to parameterize a Markov chain random walk model that accurately predicts the evolution of vertical concentration profiles. The new methodology has significant potential to be applied at the subgrid level for coarser-scale weather and climate models, the utility of which is shown by comparison to airborne field data and global aerosol models.

Effect of pretreatment oral contraceptives on fresh and cumulative live birth in vitro fertilization outcomes in ovulatory women.

OBJECTIVE: To evaluate the impact of oral contraceptives (OC) on live birth rate (LBR) following a fresh embryo transfer and cumulative live birth rate (cLBR) in normal ovulatory women undergoing in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Reproductive center. PATIENTS: A total of 3,110 normo-ovulatory women aged 20-40 years undergoing IVF either using or not using OC pretreatment in their first autologous cycle. INTERVENTION(S): Patients initiated gonadotropins for their IVF cycle either after a spontaneous menses or following OC pretreatment, which was at the discretion of the provider or according to patients preference. MAIN OUTCOME MEASURE(S): The primary outcomes were LBR after fresh transfer (fLBR) and cLBR. RESULTS: fLBR was significantly lower in women using OC compared to those not (42.6% vs. 52.8%). Although LBR after frozen embryo transfer cycles were similar (42.7% vs. 41.1%), cLBR was significantly lower in women using OC (62.8% vs. 67.6%). Multivariate logistic and COX regression analysis adjusting for baseline characteristics demonstrated that IVF cycle synchronization with OC was significantly associated with a lower fLBR (adjusted odds ratio 0.73, 95% confidence interval 0.62-0.86) and cLBR (adjusted hazard ratio 0.89, 95% confidence interval 0.80-0.98). CONCLUSIONS: Pretreatment OC use is associated with a reduction in fLBR and cLBR.

Effects of Inoculation on the Pearlitic Gray Cast Iron with High Thermal Conductivity and Tensile Strength.

With the aim of improving the thermal conductivity and tensile strength of pearlitic gray cast iron, the influence of inoculation on structure and properties was experimentally investigated. Three group of irons with similar compositions were inoculated by Zr-FeSi, Sr-FeSi, and SiC inoculants, respectively. The metallographic analysis was used to measure the maximum graphite length, primary dendrites amount and eutectic colonies counts. For a certain carbon equivalent, it was confirmed that the thermal conductivity of pearlitic gray cast iron has a direct correlation with the maximum graphite length while the tensile strength was influenced mainly by the primary dendrites amount. The optimal structure and highest thermal conductivity and tensile strength were obtained by Sr-FeSi inoculant. MnS particles act a pivotal part in modifying the structure of gray cast iron. It was found that providing nucleation sites both for graphite and primary austenite is important to promote the thermal conductivity and strength. However, excessive nuclei (MnS particles) results in shorter graphite flakes and thus the depressive growth of primary dendrites.