Women's neurology and obstetrics/gynecology experts convened to consolidate the best available evidence on multiple sclerosis (MS) management in reproductive-aged women, especially regarding the use of MS disease-modifying therapies (DMTs) surrounding pregnancy and lactation. To update 2014 clinical recommendations, an expert clinical review informed by a systematic literature search of PubMed, LactMed, and ClinicalTrials.gov was conducted utilizing keywords "multiple sclerosis" and "pregnancy." A total of 774 papers were screened for inclusion. To provide updated guidelines, two reviewers prioritized studies according to strength of evidence and relevance to validating/updating our clinical management recommendations. To provide updated information about pregnancy and lactation safety of available MS DMTs, an additional reviewer synthesized all available studies. All authors then reviewed data to craft consensus guidelines. We encourage collaborative care models to optimize symptom control, social support, and maternal wellbeing before, during, and after pregnancy. In most cases, MS is not associated with increased risks of adverse pregnancy outcomes, although some studies have reported slightly elevated risks of lower birthweight, preterm birth, and operative delivery. With appropriate monitoring, MS disease activity can often be minimized throughout the childbearing period by continuation or strategic timing of many DMTs to optimize maternal disease control while minimizing fetal risk. The postpartum period represents a period of increased medical and psychological risk, and close follow-up is recommended. After childbearing is complete, gynecological care can shift to prevention and management of gynecological complications (DMT-associated infections and risk of cervical dysplasia) and of the menopausal transition.
BACKGROUND:Uterine leiomyomas are genetically heterogeneous, yet the clinical and prognostic implications of their primary molecular drivers remain poorly integrated into surgical practice. OBJECTIVE:This study aims to characterize the clinical phenotypes and pharmacogenomic responses of major molecular subtypes and evaluate the predictive value of T2-weighted magnetic resonance imaging (T2WI) for surgical prognosis. STUDY DESIGN:We enrolled premenopausal women who underwent myomectomy or hysterectomy at the Department of Gynaecology, the First Affiliated Hospital of Zhengzhou University from January 2019 to June 2025. All leiomyomas were molecularly genotyped as MED12-mutant, HMGA2-overexpressing, FH-deficient, or triple-negative (3X, not belonging to the MED12-mutant, HMGA2-overexpressing, or FH-deficient genotypes). First, clinical and morphological characteristics were compared across the full cohort (n = 720). Second, a pharmacogenomic subset of patients receiving pre-operative gonadotropin-releasing hormone agonist (GnRHa) (n = 84) was analyzed for genotype-specific volume reduction. Third, a subset of 502 patients receiving myomectomy and completing a follow-up of more than 12 months was analyzed for genotype-specific re-intervention risk. Finally, an imaging "gold standard" consisting of 461 patients with pre-operative magnetic resonance imaging (MRI) and long-term follow-up post-myomectomy was used to assess surgical re-intervention rates via Kaplan-Meier estimators. RESULTS:HMGA2 tumors were most likely to be solitary and submucosal (FIGO type 0-2), while FH-deficient cases showed the highest rates of multiple tumors (≥5). MED12-mutant tumors demonstrated significantly lower GnRHa-induced volume reduction compared to 3X variants (P = 0.009). The FH group exhibited the highest surgical re-intervention rate, a trend that was even more pronounced after excluding patients receiving post-operative GnRHa. MRI analyses revealed that low T2WI signal intensity was highly specific for MED12 mutations, whereas a "mixed high" signal was prognostically indicative for FH deficiency and correlated with a higher surgical re-intervention rate. CONCLUSIONS:Molecular subtypes of uterine leiomyomas dictate distinct clinical behaviors. MED12 mutations predict hormonal therapy resistance, while FH deficiency signals aggressive recurrence. A T2-weighted MRI-based classification system showed some phenotype-genotype relationships, although these findings require validation in independent cohorts.
Deoxysphingolipids (dSLs) are atypical sphingolipids that accumulate in several pathological settings, yet their impact on hematologic malignancies is poorly understood. Here, we investigate the pathways and mechanisms of deoxysphinganine (dSA) cytotoxicity in lymphoma cells and its potential as a therapeutic agent. dSA exhibited markedly greater cytotoxicity than canonical sphingoid bases in lymphoma cell lines, yet induced only cytostatic effects in normal human T cells, indicating a therapeutically exploitable window. Inhibition of ceramide synthase blocked the generation of deoxy(dihydro)ceramides, prevented mitochondrial depolarization, caspase activation, ER stress, and DNA damage, establishing CerS-dependent deoxysphingolipids as essential mediators of dSA-induced death. Mechanistically, dSA engaged a mitochondrial apoptotic pathway, with DNA damage occurring downstream of mitochondrial permeabilization and caspase activation, while PERK-driven ER stress occurred in parallel and was dispensable for cytotoxicity. Subtype-specific engagement of ER stress and DNA damage further suggests that dSL signaling is shaped by lineage context. The differential sensitivity between malignant lymphoid cells and normal T cells, together with the central role of CerS-derived deoxy(dihydro)ceramides, highlights deoxysphingolipid metabolism as a druggable vulnerability in lymphoma. These findings support further exploration of dSA-based strategies and targeted modulation of dSL synthesis as a novel therapeutic avenue for non-solid hematologic malignancies.
Determining whether treatment of gestational diabetes mellitus benefits the newborn is central to clinical guidelines and patient counseling. However, the conclusions drawn from major trials may depend not only on the biological effect of treatment, but also on the neonatal outcomes and fetal growth standards selected. Composite endpoints can obscure or exaggerate treatment effects when they combine events that differ in clinical importance, frequency, or responsiveness to treatment. Similarly, different definitions of fetal overgrowth can substantially alter the reported prevalence of large- and small-for-gestational-age infants and therefore the apparent balance between treatment benefit and possible overtreatment.This review examines landmark and illustrative studies, including ACHOIS, MFMU, HAPO, TOBOGM, DipGluMo, Big Baby, and GRACE, together with methodological literature on composite outcomes and birth weight classification. Across these studies, treatment effects were sometimes driven by a single frequent component, masked by biochemical or rare outcomes, or altered by the growth chart applied. Absolute birth weight thresholds are transparent but do not account for gestational age or infant sex, whereas percentile-based definitions provide adjustment but yield different results across GROW, INTERGROWTH-21st, WHO, and other standards.Clinicians and investigators should therefore assess neonatal benefit using clinically coherent outcomes reported individually, together with prespecified measures of fetal growth and potential treatment-related harm. Absolute birth weight thresholds and percentile-based measures, including both large- and small-for-gestational-age outcomes, should be reported together, with explicit specification of the growth chart and sensitivity analyses using alternative standards.
Whether the fecal metabolome differs according to intensive low-density lipoprotein cholesterol (LDL-C) target achievement among statin-treated patients is unclear. In this cross-sectional study, 124 statin-treated adults with chronic disease were stratified by fasting LDL-C into a target-achieved group (< 70 mg/dL, n = 52) and a target-not-achieved group (≥ 70 mg/dL, n = 72). Stool samples were profiled by untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry, and multivariable models adjusted for age, sex, chronic kidney disease, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were used to identify metabolites independently associated with target achievement. Statin dose, treatment duration and glucose-lowering therapy were also compared between the groups. Paired 16S rRNA gene sequencing data available for a subset (n = 86) were used for integrative correlation and network analyses. Partial least-squares discriminant analysis showed separation between the two groups. Eight annotated metabolites-glutamine, glutamate, phenylalanine, N-acetyl-L-phenylalanine, L-methionine, N-acetyl-L-methionine, lysine, and N-methyl-D-aspartic acid, predominantly amino acids and their derivatives-were present at lower fecal levels in participants who achieved the LDL-C target. Metabolite set enrichment analysis implicated amino acid and nitrogen metabolism, and multiomics network analysis identified an Anaerotruncus-centered amino acid module with high degree centrality. In conclusion, LDL-C target achievement under statin therapy was associated with a coherent "low fecal amino acid" signature and an Anaerotruncus-linked microbe-metabolite hub. These findings suggest that intestinal nutrient handling and gut microbial amino acid metabolism may contribute to variability in LDL-C response, and they warrant prospective mechanistic evaluation.
Metabolic dysfunction-associated liver disease (MASLD) arises from the accumulation of triglycerides within the liver. MASLD can advance to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. Monoacylglycerol acyltransferase 2 (MOGAT2) is essential for triglyceride synthesis and plays a significant role in regulating lipid metabolism. Here, we demonstrate the ability of a new human MOGAT 2 inhibitor, VB-85387, to inhibit the development of MASLD/MASH and further define its effects on the key metabolic pathways that progress MASH development. MASLD/MASH was induced using a methionine, choline-deficient diet (LMCD) or by streptozotocin treatment combined with high fat diet feeding (STAM-HFD). VB-85387 significantly mitigated the severity of MASLD and reduced signs of MASH in mice subjected to these two distinct diets. VB-85387-treated mice exhibited decreased fibrosis, evidenced by reduced hepatic triglyceride concentrations, hydroxyproline levels, and collagen deposition. NAS scores were consistently lower in VB-85387-treated mice across both models. VB-85387-treated mice showed induced PPARα signaling and reduced SREBP transcription, demonstrating a likely role for VB-85387 in regulating lipogenesis and fatty acid β-oxidation. STAM-HFD treated mice showed lower NF-κBp65 activation, which was associated with lower TNFα expression. IL-1β and IFNβ levels were also both reduced, suggesting VB-85387 can reduce pro-inflammatory pattern recognition receptor signaling. In addition, treatment suppressed IL-4/IL-6-dependent JAK activation. Overall, VB-85387 inhibited MASLD development by reducing liver triglyceride levels, fibrosis, and meta-inflammatory signaling. VB-85387 was as effective or superior to the MOGAT2 inhibitor phase I clinical trial drug BMS-963272 in reducing MASLD and fibrosis. VB-85387 has considerable potential for developing therapeutics targeting MASLD/MASH.
Glioma represents one of the most aggressive tumors in the central nervous system, with clinical management facing significant challenges including high recurrence rates and therapeutic resistance. Ferroptosis, an iron-dependent form of cell death, holds potential for glioma treatment, yet tumor cells frequently develop evasion mechanisms. This study elucidates the molecular mechanisms by which hypoxic microenvironment confers ferroptosis resistance in glioma cells, focusing on the pivotal role of the HIF-1α/SREBP1 signaling axis and its downstream effectors FASN and SCD1. Our experimental results demonstrate that hypoxic conditions significantly upregulate HIF-1α expression and confer resistance to RSL3-induced ferroptosis. Mechanistic studies reveal that HIF-1α promotes SREBP1 activation, which subsequently upregulates FASN and SCD1 expression to suppress lipid peroxidation.Furthermore, the HIF-1α-specific inhibitor PX-478 effectively reverses hypoxia-induced ferroptosis resistance and significantly enhances tumor cell sensitivity to ferroptosis inducers. In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies.
BACKGROUND:Lipoprotein(a) [Lp(a)] reflects inherited atherothrombotic risk, whereas the C-reactive protein-triglyceride-glucose index (CTI) integrates systemic inflammation, triglyceride-related lipid disturbance, and glucose-related metabolic stress. Their individual and joint association with angiographic coronary lesion burden in acute coronary syndrome (ACS) remain incompletely defined. We examined whether CTI complements Lp(a) in characterizing coronary lesion burden in ACS. MATERIALS AND METHODS:This retrospective, single-center study included 2,836 consecutive patients with ACS who underwent coronary angiography. Coronary lesion burden was assessed using continuous Gensini score, a high Gensini score, and multivessel disease (MVD). Multivariable regression, restricted cubic spline analyses, CTI-stratified analyses, incremental receiver operating characteristic analyses, and internally validated machine-learning analyses with SHAP interpretation were performed. RESULTS:Higher Lp(a) and CTI level were both associated with greater coronary lesion burden. Compared with Lp(a) <75 nmol/L, Lp(a) ≥175 nmol/L was associated with high Gensini score (OR, 1.51 [95% CI, 1.17-1.96]) and MVD (OR, 1.69 [95% CI, 1.27-2.26]). Each 1-SD increase in CTI was associated with high Gensini score (OR, 1.47 [95% CI, 1.35-1.60]) and MVD (OR, 1.18 [95% CI, 1.08-1.28]). Among inflammatory-lipid indices, CTI showed the most consistent associations and provided the largest numerical incremental discrimination beyond Lp(a). The associaton between ver high Lp(a) and coronary lesion burden was more pronounced at higher CTI levels, particular for MVD. Machine-learning analyses further supported the relevance of both CTI and Lp(a). CONCLUSIONS:In patients with ACS, higher Lp(a) and CTI level were associated with greater angiographic coronary lesion burden. CTI may complement Lp(a) by capturing inflammatory-metabolic status, supporting their joint assessment for more refined characterization of lesion-burden risk in ACS.
Lipoprotein metabolism is significantly different between mice and humans thus making it difficult to model disorders of human lipid metabolism in transgenic mice. Systemic lipoprotein metabolism is predominantly governed by hepatocytes, and mice with humanized livers display human-like lipid profiles. Here we report a highly efficient method to knock out genes in human hepatocytes while retaining their ability to repopulate immune deficient rodents. As proof-of-principle Fah deficient, immune compromised mice were repopulated with Apolipoprotein B (APOB) knockout human hepatocytes. Mice humanized with knockout cells recapitulated typical features of human hypobetalipoproteinemia. We conclude that at least some human lipid metabolism disorders can be modeled in liver chimeric mice using human knockout hepatocytes.
BACKGROUND:Preterm prelabor rupture of membranes (PROM) comprises four intra-amniotic categories defined by the presence or absence of intra-amniotic inflammation and microbial invasion of the amniotic cavity. Their gestational age distribution, amniotic fluid microbial profiles, and associated perinatal and neonatal outcomes have not been comprehensively characterized. OBJECTIVE:The primary aim was to determine the gestational age-dependent prevalence, amniotic fluid microbial profiles, and short-term perinatal and neonatal outcomes of the intra-amniotic categories. The secondary aim was to evaluate the feasibility of identifying these categories in pregnancies complicated by preterm PROM. STUDY DESIGN:This single-institution cohort study included women with singleton pregnancies complicated by preterm PROM between 230/7 and 366/7 weeks of gestation who underwent transabdominal amniocentesis at admission. Intra-amniotic inflammation was assessed by measuring amniotic fluid interleukin-6 concentrations using a point-of-care test or an automated electrochemiluminescence immunoassay and was defined as an elevated interleukin-6 concentration at or above the platform-specific threshold. Microbial invasion of the amniotic cavity was assessed by microbiologic analysis of amniotic fluid using culture and molecular methods and was defined as the detection of microorganisms and/or their nucleic acids in amniotic fluid. Based on the presence or absence of these conditions, women were classified into four intra-amniotic categories. RESULTS:Among 961 pregnancies, 158 (17%) had intra-amniotic infection, 70 (7%) had sterile intra-amniotic inflammation, 106 (11%) had microbial invasion of the amniotic cavity without inflammation, and 627 (65%) had amniotic fluid negative for inflammation and microorganisms; their distribution varied with gestational age. Overall, 64 microbial species were identified in amniotic fluid, with Ureaplasma spp. accounting for nearly two-thirds of all microbial detections. The unadjusted frequencies of early-onset neonatal sepsis were 12% (19/154), 4% (3/68), 5% (5/106), and 2% (14/624) in the intra-amniotic infection, sterile intra-amniotic inflammation, microbial invasion without inflammation, and negative amniotic fluid for inflammation and microorganisms categories, respectively (P < 0.0001). In a focused analysis comparing intra-amniotic infection with the remaining three categories combined, intra-amniotic infection was associated, after adjustment, with higher odds of early-onset neonatal sepsis (adjusted odds ratio, 3.4; 95% confidence interval, 1.7-7.0; P < 0.001) and serious composite adverse perinatal outcome (adjusted odds ratio, 2.0; 95% confidence interval, 1.1-3.4; P = 0.02). Among pregnancies with microbial invasion of the amniotic cavity, bacteria other than Ureaplasma spp. in amniotic fluid were associated with worse perinatal and neonatal outcomes than Ureaplasma spp. alone or in combination with other bacteria. Transabdominal amniocentesis yielded amniotic fluid in 93% (961/1,037) of eligible pregnancies and 98% (961/979) of attempted procedures. CONCLUSION:Preterm PROM is a heterogeneous syndrome comprising four intra-amniotic categories that differ in gestational age distribution, amniotic fluid microbial composition, and short-term perinatal and neonatal outcomes. Intra-amniotic infection and the presence of bacteria other than Ureaplasma spp. in amniotic fluid were associated with the highest risk of adverse perinatal and neonatal outcomes.
Polycystic ovary syndrome (PCOS) has been renamed polyendocrine metabolic ovarian syndrome (PMOS) following a multistep international consensus process endorsed by 56 professional and patient organizations. The new name corrects a longstanding misnomer. The characteristic ovarian morphology reflects numerous arrested antral follicles, not pathologic cysts, and the legacy term has reinforced an overly ovarian and fertility-centered view of a lifelong endocrine-metabolic condition. For obstetrician-gynecologists (OBGYNs), this reframing has immediate clinical relevance. PMOS affects approximately 10%-13% of reproductive-age women, yet it remains underdiagnosed and inconsistently documented in routine care. It is associated with insulin resistance, hyperandrogenism, ovulatory dysfunction, psychological morbidity, and cardiometabolic risk across the life course. During pregnancy, PMOS is linked to higher risks of miscarriage, gestational diabetes, hypertensive disorders of pregnancy, cesarean delivery, preterm birth, fetal growth restriction, low birthweight, and small-for-gestational-age infants, with many associations persisting after adjustment for age and body mass index. Despite this evidence, PMOS is not routinely captured as an obstetric risk modifier at the first obstetric visit, nor is it consistently embedded in antenatal decision-support pathways. Patients also remain inconsistently screened and counseled for psychological, metabolic, and long-term cardiometabolic risks. This Special Report discusses the rationale for the PCOS-to-PMOS rename, reviews evidence linking PMOS with adverse pregnancy and offspring outcomes and outlines practical implications for obstetric and gynecologic care. Diagnostic criteria remain unchanged; namely, two of the following three: irregular menstrual cycles and ovulatory dysfunction, clinical or biochemical hyperandrogenism, and elevated anti-Müllerian hormone (AMH) levels or multiple follicles on ovarian ultrasound in adults. What changes is the clinical frame. OBGYNs are uniquely positioned to improve earlier diagnosis, risk recognition, counseling, and coordinated care from adolescence through menopause and beyond.
