Intrauterine adhesions (IUA) and endometriosis are debilitating gynecological disorders that impair endometrial function and fertility. IUA, typically caused by iatrogenic trauma to the basal endometrium, leads to fibrosis and infertility, whereas endometriosis, characterized by ectopic endometrial growth, induces chronic inflammation, pain, and subfertility. Current treatments, such as surgical adhesiolysis for IUA and hormonal suppression for endometriosis, frequently fail to address underlying pathological mechanisms, including aberrant fibrosis, inflammatory cascades, and impaired tissue regeneration. Recently, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach. Their therapeutic benefits are mediated primarily through paracrine actions, which modulate immune responses, promote tissue repair, and attenuate inflammation and fibrosis. Recent studies have further highlighted the potential of MSC-derived exosomes (MSC-Exos) as a cell-free alternative. In this review, we comprehensively summarize current evidence from animal models and clinical studies on the application of MSCs and MSC-Exos in treating IUA and endometriosis, focusing on their therapeutic potential, mechanisms of action, and future directions. We also discuss remaining challenges and promising strategies to overcome them, thereby positioning MSC-based therapies as transformative options for endometrial restoration and disease management.
There are few objective tools to quantify lymphatic disease changes in anatomy and physiology of affected tissues. Tissue sodium could be a relevant physiological indicator of lymphatic disease. However, the importance of sodium to lymphatic physiology in humans has not been well-characterized nor exploited for clinical applications due to a lack of imaging methods to observe sodium and lymphatics together in vivo. The purpose of this study was to apply 23Na-MRI to measure tissue sodium content (TSC) in human subjects with or without lower extremity lymphedema (LEL) and investigate the relationship between lymphatic dysfunction and tissue sodium. A prospective, cross-sectional observational clinical trial enrolled participants with LEL and controls without lymphedema. 23Na-MRI measured standardized TSC in the mid-calf. For each leg with lymphedema, clinical stage was determined by a licensed clinician, and lymphedema severity was determined by radiology assessment of noncontrast hydrogen (1H)-magnetic resonance lymphangiography (MRL). Linear mixed-effects models determined differences in TSC between cases and controls and measured the association of TSC with clinical stage and lymphedema severity. Image subregions were analyzed to observe spatial patterns of TSC involvement. Results found that TSC was nearly 50% higher in lymphedema (n = 52 legs) in the skin (1.51-fold) and adipose tissue (1.47-fold) compared with controls (n = 31 legs; p < 0.001) and was directly related to both clinical stage and lymphedema severity by 1H-MRL in the skin (p < 0.001) and adipose tissue (p < 0.001). TSC accumulated in patterns in the anterior subcutaneous adipose tissue, increasing with disease severity. 23Na-MRI demonstrates that standardized TSC is distinctly elevated in lymphedema, sensitive to lymphedema disease severity, and a potential objective imaging tool for evaluating lymphedema in future clinical trials.
To characterize longitudinal metabolic alterations associated with gestational diabetes mellitus (GDM) and to identify candidate metabolite signals for earlier risk assessment using a widely targeted metabolomics platform. In this prospective cohort, 35 women who developed GDM and 35 matched healthy controls underwent fasting blood sampling in early pregnancy (6-13 weeks) and mid-pregnancy (24-28 weeks). Widely targeted metabolomics and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed. Multivariate analyses, logistic regression, receiver operating characteristic (ROC) analysis, internal cross-validation, and restricted cubic spline modeling were applied within an exploratory framework. In early pregnancy, 11 differential metabolites were identified, including 6 amino acid-related metabolites, but no robust signal remained after false discovery rate (FDR) correction. By mid-pregnancy, 35 differential metabolites were identified, including 13 amino acid-related metabolites. Among 19 amino acid-related metabolites examined in focused analyses, L-arginine was the only amino acid-related metabolite that remained significant after FDR correction (FDR = 0.043). Higher mid-pregnancy L-arginine was associated with increased odds of GDM (aOR = 2.840, 95% CI 1.481-5.446), was positively correlated with 1-h (r = 0.28) and 2-h (r = 0.26) glucose levels during OGTT, and showed modest discrimination (AUC = 0.754; mean cross-validated AUC = 0.754). Quartile analyses showed a more pronounced risk increase in the highest exposure group, and restricted cubic spline analysis suggested an overall positive association with a possible nonlinear trend at higher levels. KEGG analyses highlighted arginine- and amino acid-related pathways, including arginine and proline metabolism and arginine biosynthesis, while network analysis suggested a potential link to mTOR signaling. In this exploratory longitudinal analysis, pregnancies complicated by GDM showed progressively increasing amino acid-related metabolic disturbances from early to mid-pregnancy. Mid-pregnancy L-arginine emerged as a candidate metabolic signal associated with GDM risk, post-load glycemia, and greater risk elevation at higher levels. These findings support further investigation of amino acid-focused metabolic profiling as a research-stage approach for earlier GDM risk identification.
This study examines adolescent experiences with intrauterine device (IUD) insertion under conscious sedation. We conducted a prospective pilot study of 11-21-year-olds who chose conscious sedation for their IUD insertion. Participants completed pre-procedure surveys (e.g., demographics, anticipated pain, reproductive history) and post-procedure surveys (e.g., pain during insertion and overall experience). Providers completed a survey on the day of IUD insertion with sedation type, complications, and reason for sedation. In 16 youth (16.1 ± 1.8 years), 14 received moderate sedation (intravenous midazolam and fentanyl) and 2 received light sedation (nitrous oxide). The most reported "worst part" was procedural cramps (n=5, 31%). The "best part" was sedation effects (n=7, 44%). All patients who received light sedation remembered the insertion compared to 2 of 14 (14%) patients who received moderate sedation. Patients reported an average satisfaction score of 83 on a 100-point visual analogue scale, with no difference between sedation types. Adolescents were highly satisfied with procedural sedation for IUD insertion. Fewer participants remembered the procedure when they received moderate compared to light sedation. IUDs are effective as reversible contraception and menstrual management. The pelvic exam and pain may discourage use of the IUD, but sedation offers an alternate experience. Examining patient experiences will help clinicians counsel future patients on their anticipated experience and provides evidence-based rationale for modification and expansion of this service.
To characterize how non-interventional radiology (IR) medical providers discuss IR procedures on X.com (formerly Twitter, Inc; San Francisco, CA), including awareness, referral intent, engagement, and misinformation. This retrospective infodemiology study evaluated public English-language X posts from January 1, 2024, through December 31, 2025. Long-form queries were used to identify posts related to uterine fibroid embolization (UFE), prostatic artery embolization (PAE), Y90 radioembolization (Y90), transarterial chemoembolization (TACE), gastric artery embolization (GAE), tumor ablation, and related procedures. After de-duplication and exclusion of reposts without commentary, IR-authored posts, and likely marketing or spam accounts, the final primary corpus comprised approximately 5,220 posts. Posts were coded for sentiment, awareness level, and thematic content. Statistical analyses included chi-square tests for categorical comparisons, Kruskal-Wallis tests for nonparametric continuous comparisons, Mann-Kendall trend tests for directional volume analysis, and Wilson's method for confidence interval estimation of referral-intent prevalence. Discussion volume increased over the study period, although quarterly trend testing did not reach conventional statistical significance (tau = 0.43; P = .07). PAE and Y90/TACE produced the highest adjusted post volumes (approximately 4,387 and 4,458 posts, respectively), whereas UFE yielded a smaller but more procedure-specific corpus (approximately 466 posts). GAE demonstrated a high raw post volume (n = 13,853) but an estimated on-topic rate of only 12%, reflecting heavy contamination from non-medical acronyms; the adjusted on-topic estimate was approximately 1,662 posts. Urology and radiation oncology providers showed the clearest engagement with PAE-related content, including explicit referral-intent posts. Medical and surgical oncology accounts were active in Y90/TACE discussions, including research and access-barrier themes. No verified obstetrics and gynecology physician accounts were identified in the long-form UFE corpus. Referral-intent posts represented 8.1% of the primary corpus (95% confidence interval, 6.5%-9.8%; approximately 418 posts) and generated greater engagement than routine educational posts. Misinformation represented approximately 7% of posts by volume but achieved disproportionate reach. Awareness of IR procedures on social media was uneven and specialty-dependent, with misinformation achieving disproportionate reach. These findings support targeted outreach to referring specialties and proactive monitoring of promoted information on social media.
Maternal Early Warning System (MEWS) protocols are promising clinical tools to enhance maternal care for acute conditions. Effective implementation of new evidence-based practices relies on implementation fidelity (i.e., the degree to which the implementation strategy is delivered as intended). Thus, we evaluated the fidelity of the implementation strategy for the MEWS protocol, with a focus on educational activities. This cross-sectional evaluation was part of a Quality Improvement initiative. We used a fidelity framework assessing adherence (alignment with design), dose (amount/intensity), and participant responsiveness (engagement and adoption) to the implementation strategy. Results were summarized with descriptive statistics and content analysis. The implementation comprised 20 out of 21 planned training and orientation activities, including multidisciplinary simulations, skills drills, and departmental Grand Rounds. These activities were attended by 246 participants (137 nurses, 40 residents, 36 physicians, and allied-health professionals), of whom 77 (31.3%) completed the post-session survey. In a post-session survey, 52.6% (n = 40/76) and 43.4% (n = 33/76) of participants reported feeling "extremely comfortable" escalating care and activating a code blue, respectively. Qualitative feedback from 23 respondents identified benefits in autonomy/confidence (n = 9), safety (n = 6), communication (n = 3), and teamwork (n = 3), while emphasizing bias reduction in patient assessments (n = 5) and patient-centered care (n = 6) in emergency situations. Most sessions were completed as intended and led to high participant engagement. Responsiveness results suggest that the implementation strategy prepared healthcare providers for uptake of the MEWS protocol and supported them in carrying out patient-centered assessments, while maximizing professional autonomy/collaboration, and optimizing equitable care delivery.
Very early-onset autosomal dominant polycystic kidney disease (VEO-ADPKD) caused by biallelic PKD1 mutations is extremely rare and often phenocopies autosomal recessive PKD (ARPKD), complicating prenatal diagnosis and genetic counseling. We report an extremely preterm Korean male infant (27 + 3 weeks, 1300 g) with fetal polycystic kidney disease and severe oligohydramnios from 24 + 6 weeks. The infant died on day 2 with refractory hypoxemia despite maximal support. Clinical exome sequencing revealed compound heterozygous PKD1 variants: a paternally inherited truncating variant (c.11343 C > A, p.Tyr3781Ter) and a maternally inherited non-truncating hypomorphic variant (c.3876 C > A, p.Phe1292Leu). Segregation analysis confirmed trans configuration and identified paternal somatic mosaicism (imbalanced heterozygous peaks on Sanger sequencing), accounting for the phenotypic discordance between the infant's lethal presentation and the father's mild disease at age 31. No pathogenic variants were identified in PKHD1, PKD2, or other cystic kidney disease genes. This first Korean case demonstrates that biallelic PKD1 mutations cause neonatal-lethal disease that mimics ARPKD via gene-dosage effects, with parental mosaicism creating unpredictable recurrence risks. Genomic autopsy enabled an accurate diagnosis and strongly supports preimplantation genetic testing for this couple.
Inflammation in the female genital tract (FGT) is a key risk factor for HIV acquisition, but it remains unclear whether clinical or immunological measures best predict risk. We aimed to prospectively compare HIV acquisition among women with clinically and/or immunologically defined inflammation. HIV-uninfected women enrolled in the CAPRISA 004 tenofovir gel randomized controlled trial in South Africa were followed for up to 34 months. We analyzed data from 889 women, with cytokine measurements available for 774 participants. Clinical genital abnormalities were assessed at scheduled visits, and 48 cytokines were measured in cervicovaginal lavage samples. HIV incidence was compared across categories of clinical and immunological inflammation using time varying Cox proportional hazards models, adjusting for relevant covariates. Immunological inflammation, defined as ≥9 elevated cytokines, was present in 18% (140/774) of women. Among specific clinical signs, abnormal genital discharge (aHR: 2.67, 95% CI: 1.14-6.23, p=0.024) and cervicitis (aHR: 10.34, 95% CI: 2.46-43.65, p=0.001) were significantly associated with increased HIV acquisition. Women with both clinical and immunological inflammation had the highest risk of HIV acquisition, with adjusted hazard ratios of 2.08 (95% CI: 1.10-3.91, p=0.022) and 2.46 (95% CI: 1.21-5.03, p=0.013), respectively. Clinical and immunological definitions of inflammation were each independently associated with increased HIV acquisition risk and combined they reflected greater susceptibility. These findings highlight the important role of genital inflammation in women's HIV susceptibility, suggesting that clinical signs may provide practical early indicators of risk even as cytokine profiles provide a more sensitive measure of underlying inflammation.
Although menstrual disorders are frequent in adolescent girls, limited data exist regarding their occurrence and characteristics in patients with juvenile idiopathic arthritis (JIA). This study aimed to determine the frequency of menstrual problems, premenstrual syndrome (PMS), and dysmenorrhea-related coping skills in adolescents with JIA, and to examine their potential associations with disease-related parameters, treatment, and quality of life (QoL). This cross-sectional study included 51 adolescents with JIA and 56 age- and BMI-matched healthy controls (HC) recruited from pediatric rheumatology and adolescent health clinics. Menstrual characteristics, PMS, and dysmenorrhea were assessed using structured questionnaires, the Premenstrual Syndrome Scale, and the Adolescent Dysmenorrhea Self-Care Scale (ADSCS). QoL was measured by the Pediatric Quality of Life Inventory (PedsQL). Disease-related data, treatment history, and laboratory findings were obtained from medical records. The age at menarche was significantly later in the JIA group than in HC (13 vs. 12 years, p = 0.001). Dysmenorrhea was common in both groups (74.5% vs. 89.2%, p = 0.046) but coping scores were lower in the JIA group (79 vs. 99, p = 0.004). PMS frequency was lower in JIA (39.2% vs. 57.1%, p = 0.064), and total PMS scores were significantly reduced (102 vs. 118.5, p = 0.005). No associations were found between menstrual problems and disease activity, steroid dose, or methotrexat/biologic use. Adolescents with JIA experience frequent menstrual problems and delayed menarche. During routine pediatric rheumatology visits, adolescent girls' menstrual history should be systematically assessed, and those with significant or troubling gynecological problems should be referred appropriately.
Fibroadipogenic progenitors (FAPs) play a key role in skeletal muscle homeostasis and regeneration. They produce extracellular matrix components and secrete cytokines that regulate muscle stem cell function. The number of FAPs and their activity need to be dynamically regulated to avoid their chronic accumulation and overproduction of fibrosis. However, the intrinsic factors by which FAPs control their cell fate decisions remain elusive. Here, we show that FAPs-secreted prostaglandin-E2 (PGE2) functions as a key autoregulatory factor. Using lipidomics and single cell transcriptomics, we show that FAPs are a main cellular source of PGE2 in resting muscle and during regeneration. FAP-secreted PGE2 exerts paracrine effects that maintain the muscle stem cell pool at steady state and stimulate their proliferation post-injury. Moreover, it functions as an autocrine regulator of FAP fate decisions (apoptosis) and subpopulation dynamics. Acute or chronic administration of non-steroidal anti-inflammatory drugs that inhibit the prostaglandin-synthesizing enzyme COX2 increases FAPs content post-injury. Using Pdgfrα-CreERT2_Cox2flox mice, we showed that conditional ablation of COX2 specifically in FAPs increases FAPs content, fibrosis, and impairs muscle regeneration, which can be rescued by PGE2 administration. Furthermore, we show that PGE2 production in FAPs is impaired in mouse models of Duchenne muscular dystrophy, and we provide a proof-of-concept that PGE2 administration can reduce FAPs numbers, fibrosis accumulation, and increase muscle strength. Overall, we uncover a novel role for PGE2 beyond its function in inflammation and identify a mechanism by which FAPs intrinsically regulate their own cell fate, revealing therapeutic potential for muscle injury and dystrophic conditions.
Apicobasal polarity plays key roles in airway epithelial maturation and regeneration. Once polarized, the airway epithelium functions as a barrier against opportunistic pathogens. Yet, the mechanisms that temporally regulate polarization, a process which is disrupted in cystic fibrosis (CF), remain unclear. Here, we demonstrate the functional importance of connexin 43 (Cx43), a gap junction protein, which is normally repressed during regeneration of the airway epithelium. We show that prolonged post-transcriptional stabilization of Cx43 leads to altered collective cell orientation and compromised CF airway epithelial barrier. We report a bidirectional cooperation between Cx43 hemichannel function and adenosine signaling in disrupting ER-Golgi secretory axis, cytoskeleton dynamic and ectopic apical fibronectin production. Genetic and pharmacological inhibition of Cx43 channels re-established polarity and spatial organization of CF airway epithelial cells. Finally, targeting Cx43 hemichannels with mimetic peptides normalizes the CF-dependent fibronectin ectopic expression and prevents the enhanced Pseudomonas aeruginosa trapping to the CF epithelium. Our findings reveal a mechanism in which temporally controlled Cx43-mediated intercellular communication is crucial for coordinating intrinsic polarity programs and maintaining airway epithelium integrity.
HPV testing has been implemented in many organised cervix screening programs; however, understanding how this screening methodology impacts rates of colposcopy and further follow-up procedures remains underexplored, especially amongst women with HIV. In the absence of HPV screening program data in BC, Canada, we sought to determine HPV prevalence and estimates for colposcopies among a cohort of women with HIV using the BC Cervix Screening algorithm. HPV data was collected and analysed from a prospective HPV vaccine immunogenicity cohort study of women with HIV from 14 sites of HIV care across Canada from 2008-2015. HPV data was obtained during the screening (month -3), baseline (month 0), month 12, and month 24 time points (Linear Array assay). Participant demographic and clinical characteristics (CD4+ count, HIV viral load, etc.) were assessed to determine associations between HPV prevalence and estimates for colposcopy using rate ratios and 95% confidence intervals. Overall, 47.2% of participants had oncogenic HPV detected at screening which would result in a colposcopy referral. 15.9% of participants had oncogenic HPV detected at screening, month 12, and month 24 time points, which would result in three consecutive referrals to colposcopy. Participants with repeat oncogenic HPV detected were less likely to have a suppressed HIV viral load compared to participants without oncogenic HPV detected. Our results suggest that HPV testing will result in a high proportion of referrals to colposcopy and follow-up procedures among women with HIV which will require preparation and planning. Further work is needed to provide the appropriate support and education for women with HIV when incorporating HPV testing into cervix screening programs.
Male infertility is increasingly recognized as a systemic condition associated with impaired long-term health, yet clinically applicable frameworks linking reproductive dysfunction to comorbidity burden remain limited. Here, we investigated whether a composite immuno-metabolic signature could capture comorbidity burden and reduced reproductive capacity in men with primary male factor infertility (MFI). In a cross-sectional cohort of 2953 men, metabolic and inflammatory variables were systematically screened for directional and independent associations with comorbidity burden, defined by the Charlson Comorbidity Index (CCI) ≥1, and impaired reproductive capacity, assessed by total motile sperm count (TMSC) <5 million. Three variables-LDL cholesterol, waist circumference, and C-reactive protein (CRP)-met selection criteria and were integrated into an unweighted standardized score. Three variables met selection criteria: LDL cholesterol, waist circumference, and C-reactive protein. Higher immuno-metabolic scores were observed in men with comorbidity burden (0.20 ± 0.73 vs. -0.02 ± 0.62, p < 0.001) and in those with TMSC <5M (0.13 ± 0.64 vs. -0.07 ± 0.62, p < 0.001). Each unit increase in the score was independently associated with comorbidity burden (OR 1.50, 95% CI 1.23-1.82, p < 0.001) and TMSC <5M (OR 1.67, 95% CI 1.48-1.89, p < 0.001). Predicted probabilities rose across the score range from 2% to 40% for comorbidity and from 12% to 75% for reduced reproductive capacity. These findings identify a biologically coherent immuno-metabolic signature linking spermatogenic impairment with systemic comorbidity in men with primary MFI and support a model in which male infertility reflects broader immuno-metabolic vulnerability. Prospective external validation is warranted before clinical implementation.
Puerarin (Pue), an isoflavone with diverse pharmacological activities, exhibits poor oral bioavailability due to its low solubility and permeability. To improve its oral delivery, phytosterol ester (PE) was employed as a membrane stabilizer to replace cholesterol (CH) in liposomal formulations. Two Pue-loaded nanoliposomes, CH-Pue-NLs and PE-Pue-NLs, were successfully prepared via ethanol injection. PE-Pue-NLs exhibited a particle size of 219.80 ± 1.81 nm, a zeta potential of 48.76 ± 1.65 mV, and an encapsulation efficiency (EE) of 74.59 ± 1.25%, outperforming CH-Pue-NLs. FTIR and DSC analyses confirmed successful encapsulation of Pue. During 15 days of storage at 4 °C, PE-Pue-NLs showed superior physical stability, maintaining PDI < 0.3, zeta potential > +35 mV, and higher EE (59.42 ± 1.17%) than CH-Pue-NLs, which exhibited marked aggregation and drug leakage. In simulated gastrointestinal fluids, PE-Pue-NLs demonstrated enhanced structural stability and a slower biphasic release profile, with a lower cumulative release in simulated intestinal fluid at 6 h (36.87 ± 1.47%) compared with CH-Pue-NLs (50.29 ± 2.57%). Furthermore, PE-Pue-NLs exhibited reduced binding with mucin and a 1.32-fold higher apparent permeability coefficient (Papp) in Transwell studies, indicating enhanced mucus penetration. In vivo intestinal fluorescence imaging further confirmed improved mucosal permeability of PE-Pue-NLs. These findings suggest that phytosterol ester is a promising alternative to cholesterol for constructing liposomes with improved gastrointestinal stability and intestinal permeability for poorly soluble bioactive compounds.
Postpartum haemorrhage (PPH) is common, affecting an estimated 13% of women having vaginal birth and 31% of women having caesarean birth. Successful management of PPH requires early and accurate diagnosis and effective treatment. A systematic review found that subjective visual estimation of blood loss misses 52% of PPH diagnoses at vaginal birth (pooled sensitivity 48%, 95% CI 44-53), and probably more at caesarean birth. The WHO-International Federation of Gynecology and Obstetrics-International Confederation of Midwives consolidated guidelines on PPH therefore recommend objective quantification of blood loss with products such as a calibrated blood collection drape. When supported by a robust implementation strategy and a first-response treatment bundle, objective measurement of blood loss and monitoring of vital signs has been shown to diagnose PPH accurately and early, and improve clinical outcomes. Refractory PPH can progress to life-threatening PPH, which should be managed by a multidisciplinary team providing aggressive resuscitation and targeted treatment. Saving the life of a woman with excessive postpartum bleeding is a race against time. The six delays to avoid are: (1) in the diagnosis (by use of objective cumulative blood loss measurement and early trigger criteria), (2) in the first-response treatment (by authorising midwives to administer all components of a standardised bundle of interventions), (3) in the escalation (by use of explicit escalation criteria and red flags), (4) in the use of temporising measures (eg, non-pneumatic anti-shock garment), (5) in the identification and targeted management of any specific causes of bleeding, and (6) in the provision of blood and blood products. Quick actions to avoid these delays can mean the difference between life and death for a woman with PPH.
Breast cancer (BC) is a highly heterogeneous malignancy, and transcriptional programs associated with histone deacetylases (HDACs) may provide clinically relevant prognostic information. However, the downstream prognostic significance of HDAC-associated molecular heterogeneity remains incompletely understood. Non-negative matrix factorization (NMF) was performed in the TCGA cohort to identify HDAC-related molecular subtypes, followed by weighted gene co-expression network analysis and differential-expression analysis to derive candidate genes. A prognostic signature was then constructed using multiple machine-learning algorithms and validated across external BC cohorts. Additional analyses included multivariable and continuous-risk Cox regression, correlation analysis between the HDAC-related risk score (HRS) and HDAC family member expression, and single-cell gene-set scoring using Seurat's AddModuleScore function. Key hub genes were further examined by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). NMF consensus clustering identified five HDAC-related molecular clusters with distinct survival outcomes and immune-infiltration patterns in TCGA-BRCA. WGCNA further identified subtype-associated co-expression modules, and candidate features were obtained by intersecting HDAC-cluster-associated DEGs with WGCNA-derived hub genes. A 24-gene HRS model based on CoxBoost + SuperPC showed stable prognostic performance across the TCGA training cohort and seven external breast cancer validation cohorts. Multivariable Cox analyses supported the independent prognostic value of HRS in several major cohorts. Single-cell analysis showed cell-type-specific heterogeneity of the model-related signature score, and UTRN, LIMCH1, ARNT2, and PYDC1 showed concordant expression patterns in public datasets and preliminary qRT-PCR/WB validation. These findings suggest that the HDAC-associated HRS model may serve as an exploratory prognostic framework for breast cancer, while further mechanistic and prospective validation is required before clinical translation.
Human vaccine responses vary widely, but the determinants remain incompletely defined. Here we analyzed 66 cytokines across four inactivated influenza vaccine (IIV) cohorts over five seasons (n = 581) and identified baseline serum interleukin (IL)-18 and interferon (IFN)-β as correlates of day 28 antibody responses. To test causality, we evaluated 19 cytokines in human tonsil and spleen organoids and found that type I IFNs, IL-21 and IL-12, but not IL-18 or IFNγ, enhanced antibody production. The addition of IFNβ to IIV recapitulated key features of the live-vaccine cytokine program. IL-12 and IL-21 defined a parallel pathway independent of type I IFNs, with IL-12 inducing IL-21 in humans, unlike in mice. Delivery of IL-21 or IFNβ via mRNA lipid nanoparticles in vivo promoted long-lived plasma cell formation. Together, these findings define parallel pathways that regulate vaccine immunity. Our approach unites high-throughput organoid testing and human cohort studies, establishing a human-centric platform to identify adjuvant candidates.
To evaluate whether pre-conception surgery for deep endometriosis (DE) is associated with obstetric outcomes compared with conservative management. Retrospective cohort study. Single-center tertiary hospital. Nulliparous women with singleton pregnancies and diagnosed DE who delivered between 2017 and 2024. Pre-conception surgery for DE. Obstetric outcomes were compared between women undergoing pre-conception DE surgery and those managed non-surgically. The primary outcome was a composite adverse obstetric outcome, including major maternal, fetal, and neonatal complications, analyzed using multivariable logistic regression, adjusted for maternal age, body mass index, adenomyosis, anatomical disease extent (#Enzian classification), and mode of conception, with additional sensitivity analyses to assess robustness. A total of 298 nulliparous women were included, of whom 65.8% (196/298) were managed without surgery, and 34.2% (102/298) underwent pre-conception DE surgery. The composite adverse obstetric outcome occurred in 37.3% (38/102) of the surgery group and 18.9% (37/196) of the no-surgery group (p<0.001). After multivariable adjustment, pre-conception surgery remained associated with higher odds of the composite outcome (adjusted OR 2.3, 95% CI 1.2-4.3). The surgery group had higher rates of placenta previa, gestational hypertensive disorders, postpartum hemorrhage, blood transfusion, and cesarean delivery, whereas fetal and neonatal outcomes were comparable between groups. Pre-conception surgical treatment of DE was associated with increased maternal obstetric morbidity; however, given the observational design and baseline differences in disease severity, this finding should be interpreted as an association rather than evidence of causation.
Physician burnout, often driven by documentation burden in electronic health records (EHRs), remains a major challenge in clinical care. Ambient artificial intelligence (AI) scribes generate draft notes from clinical encounters, offering a scalable approach to reduce administrative workload, yet population-level evaluations remain limited. To assess changes over time in clinician perceptions of workload, well-being, and care delivery following implementation of ambient AI scribes. We conducted a prospective repeated cross-sectional survey study of physicians and advanced practice providers at four time points: baseline and approximately 1, 3, and 6 months post-implementation. Outcomes included cognitive workload (NASA Task Load Index), professional fulfillment and burnout (Professional Fulfillment Index and Mini-Z), and perceptions of documentation burden, communication, and clinical capacity. Responses were grouped into clinically meaningful categories, and chi-square tests compared distributions across time. Secondary analyses compared baseline characteristics of respondents with linkable data across timepoints to the full cohort and evaluated subgroup differences for specific items. 1,600 clinicians responded at baseline, with 172, 117, and 101 respondents at 1-, 3-, and 6-month follow-up, respectively. Over 95% of follow-up respondents reported generating ≥5 ambient AI-supported notes, with use increasing significantly over time (p < 0.05). Clinicians reported statistically significant reductions in mental demand, time pressure, and documentation effort at post-implementation intervals (p < 0.05). Time spent on documentation outside clinic declined, with more clinicians reporting <2 hours/day (p < 0.05). Burnout increased across follow-up timepoints (p < 0.05). Confidence in patient comprehension and willingness to increase patient volume improved. Subgroup analyses mirrored overall trends. Ambient AI scribes were associated with sustained reductions in cognitive workload and perceived documentation burden. Despite these improvements, burnout increased over time, likely reflecting multifactorial influences and limitations of unpaired survey data. These findings support continued implementation and further longitudinal evaluation of clinician well-being.