Life Sciences

ABSTRACT Objective Delayed cerebral infarction (DCIn) is a severe complication following aneurysmal subarachnoid hemorrhage (aSAH). Previous studies suggest that glycemic variability is associated with DCIn. However, whether diabetes status modifies the relationship between glycemic traits and DCIn remains unknown. Methods Clinical data were collected from aSAH patients admitted to the First Affiliated Hospital of Shantou University Medical College between January 2015 and April 2025. The collected data included demographic characteristics, clinical variables, and glycemic traits. Glycemic traits included mean blood glucose (GLU-M), standard deviation of blood glucose (GLU-SD), coefficient of variation of blood glucose (GLU-CV), variance of blood glucose (GLU-Var), range of blood glucose (GLU-R), average real variability of blood glucose (GLU-ARV), and variability independent of the mean (GLU-VIM). After 1:2 case-control matching, conditional logistic regression models were used to evaluate the associations between glycemic traits and DCIn risk, with stratified analyses performed according to diabetes status. Multiplicative interaction terms were additionally included to assess the potential modifying effect of diabetes status. Results A total of 306 patients with aSAH were included. Among them, 102 developed DCIn cases. For each of these 102 cases, two controls were matched by age ({+/-}5 years), sex and year of admission ({+/-}5 years). In the overall population, higher GLU-M and GLU-ARV were associated with increased DCIn risk, with odds ratios (ORs) per 1-SD increase of 1.62 (95% CI, 1.25-2.11) and 1.63 (95% CI, 1.25-2.11), respectively. Among patients without diabetes (n=266), the associations with DCIn per 1-SD were observed for GLU-M (OR, 2.23; 95% CI, 1.56-3.19), GLU-SD (OR, 1.53; 95% CI, 1.13-2.06), GLU-Var (OR, 1.48; 95% CI, 1.04-2.10), and GLU-ARV (OR, 1.88; 95% CI, 1.38-2.55). No significant associations were observed among patients with diabetes. Significant interactions were observed between diabetes status and GLU-SD and GLU-Var, with P for interaction values of 0.033 and 0.032, respectively. Conclusion Higher mean blood glucose and greater glycemic variability are associated with an increased risk of DCIn in aSAH patients, especially in those without diabetes.

Background Functional neurological disorder (FND), one of the most common neurological conditions, affects women almost twice as frequently as men. The reasons for this are unknown, and there has been minimal research into how physiological and pathological features of women's health interact with symptoms of FND. Methods We conducted an online survey assessing the effect of several aspects of women's health with the severity of symptoms of FND. Results 484 people completed the survey. Among the 223 who had regular or fairly regular menstrual cycles, a strong difference across the menstrual cycle was seen, with symptoms at their best in the follicular phase, worsening in the luteal phase, and worst in the pre-menstrual period and the menses. This effect was not moderated by a proxy measure of pre-menstrual dysphoric disorder (PMDD). Participants who were taking the combined oral contraceptive (COC, n=43) and progesterone-based contraception (n=80) were more likely to report symptom improvement from starting the medication than worsening. When compared to menstruating participants who were not taking the COC, participants taking the COC reported less worsening in their symptoms of FND in the luteal, pre-menstrual, and menstrual phases. Of the 99 women who had passed menopause since developing FND, 76% reported worsening of their FND symptoms after menopause. Discussion This study demonstrates interactions between several aspects of women's health and symptoms of FND. The observed pattern of symptom fluctuation across hormonal states suggests a potential modulatory role of oestrogen, warranting further targeted investigation.

Bipolar androgen therapy (BAT) exploits the paradoxical vulnerability of castration-resistant prostate cancer (CRPC) cells to rapid cycling between castrate and supraphysiologic androgen concentrations, but clinical BAT uses testosterone, which can also activate wild-type androgen receptor (AR) in androgen-responsive tissues, causing systemic side effects. 5{beta}-dihydrotestosterone (5{beta}-DHT) is a naturally occurring testosterone metabolite generally considered androgenically inactive because it binds wild-type AR weakly, yet its activity against clinically relevant AR mutants has not been systematically evaluated. Here, we tested whether 5{beta}-DHT and related 5{beta}-reduced testosterone metabolites activate AR signaling and growth programs in prostate cancer models that carry AR mutations. In C4-2 cells, 5{beta}-DHT and 3{beta}-etiocholanediol (3{beta}-ecdiol) increased canonical AR target genes, including KLK3 and TMPRSS2, with weaker activity than testosterone, whereas other 5{beta} metabolites showed limited activity. In androgen-responsive LNCaP and C4-2 models, 5{beta}-DHT and 3{beta}-ecdiol promoted cell growth under androgen-depleted conditions, and this effect was suppressed by enzalutamide, supporting AR dependence. RNA-seq confirmed that 5{beta}-DHT and 3{beta}-ecdiol induced androgen-response gene sets substantially overlapping with testosterone, albeit at lower transcriptional magnitude. Further, we found that 5{beta}-DHT, but not 3{beta}-ecdiol, suppresses cell proliferation of LNCaP, C4-2, and PC-3 cells stably expressing the clinically relevant AR gain-of-function mutants W742C and H875Y through activating AR-induced senescence-like features after high-dose exposure, consistent with the therapeutic logic of BAT. These findings identify 5{beta}-DHT as an overlooked mutant-AR agonist capable of BAT-like tumor suppression and propose it as a testosterone surrogate in BAT with potentially reduced systemic androgenic side effects. HighlightsO_LI5{beta}-DHT and 3{beta}-ecdiol promote AR-dependent prostate cancer cell growth C_LIO_LIBoth are weaker AR agonists than testosterone by RNA-seq and qPCR C_LIO_LISupraphysiologic 5{beta}-DHT suppresses growth via AR-mediated senescence C_LIO_LIGrowth suppression extends to AR mutants W742C and H875Y C_LIO_LI5{beta}-DHT may be a lower-androgenicity testosterone surrogate for BAT C_LI

Study Objectives Co morbid insomnia and sleep apnea (COMISA) is challenging clinically and difficult to treat. Our goal was to assess how much COMISA is the mere addition of two phenotypes or display features indicative of genuine statistical interactions. Methods A total of 152,487 patients from 240 sleep centers across 30 US states were included. Insomnia was defined as difficulty initiating/maintaining sleep with daytime fatigue/sleepiness occurring "often"/"always". OSA was defined as having an Apnea Hypopnea Index (AHI) more than 15 events/h. Modified Poisson regression was conducted to evaluate multiplicative interactions between insomnia and OSA on common comorbidities and sleep symptoms. Additive interactions were also examined. Linear regression models were used to evaluate additive interactions for PSG parameters. The false discovery rate was controlled using the Benjamini Hochberg procedure. Results After adjustment for confounders, insomnia and OSA demonstrated positive interactions for depression, chronic muscular pain, headache, subjective excessive daytime sleepiness (EDS), naps, and pre-sleep anxious and muscular tension (adjusted p < 0.05). Furthermore, insomnia and OSA demonstrated positive interactions for parameters related to respiratory disturbance, including AHI, oxygen desaturation index (ODI), respiratory disturbance index (RDI), total arousal index (AI) and respiratory AI, and negative interactions for minimum oxygen saturation and percentage of rapid eye movement stage (REM%) (adjusted p < 0.05). Furthermore, the adverse effects of insomnia and OSA on AHI, ODI, RDI and REM% were substantially amplified in males. Conclusions Our findings demonstrate that insomnia and OSA do not merely coexist but genuinely interact synergistically to amplify selected adverse clinical outcomes.

Preeclampsia (PE), new onset hypertension after 20 weeks of gestation, affects 10% of all pregnancies in the U.S. and it is associated with progesterone deficiency, chronic inflammation, elevated angiotensin II type 1 receptor agonistic autoantibody (AT1-AA) and endothelial dysfunction. Progesterone, through its receptors, stimulates an anti- inflammatory protein called Progesterone Induced Blocking Factor (PIBF) which decreases during various pregnancy disorders. Therefore, this study was designed to test the hypothesis that a progestogen, in the form of 17-hydroxyprogesterone caproate, stimulates PIBF, lowers vasoactive mechanisms which reduces maternal blood pressure in women with early-onset preeclampsia (EOPE). PE women received 17-OHPC (250 mg, I.M.) and blood draws were collected before and after 17-OHPC supplementation. Placentas were collected at the delivery. 17-OHPC prolonged time of delivery beyond 72h on average and maternal blood pressure was significantly decreased in PE+17- OHPC. Progesterone and PIBF levels were reduced in PE group vs. NP group. Importantly, 17-OHPC increased PIBF and decreased vasoactive mechanisms and markers of inflammation. In conclusion, 17-OHPC or progesterone supplementation improves maternal outcomes in response to EOPE without causing further harm to the fetus.

Importance Sleep-disordered breathing (SDB) is common in childhood and is associated with attentional and behavioral impairments despite largely preserved sleep macrostructure and minimal abnormalities in conventional electroencephalographic measures. This discrepancy has contributed to the perception that sleep is relatively preserved in pediatric SDB and has limited understanding of the physiological mechanisms underlying morbidity. Objective To determine whether pediatric SDB is associated with disruption of the regional organization and homeostatic dynamics of slow-wave activity (SWA), a key physiological marker of sleep-dependent neural recovery and development. Design, Setting, and Participants Cross-sectional study of 62 children aged 4 to 12 years who underwent overnight polysomnography with high-density electroencephalography in a laboratory setting. Participants were recruited from clinical referrals and the community, spanning the full spectrum of SDB severity. Exposures SDB severity indexed by hypopnea index (HI), apnea-hypopnea index (AHI), and obstructive apnea index (OAI). Main Outcomes and Measures Regional electroencephalogram-derived SWA (0.5 to 4 Hz) topography and exponential decay parameters derived from frontal and posterior cortical regions. The frontal-to-posterior decay-rate ratio was evaluated as a summary measure of regional sleep homeostasis. Results In children with lower hypopnea index, SWA demonstrated the expected developmental pattern, with posterior predominance in younger children and a progressive shift toward a more balanced anterior-posterior distribution with age. Increasing HI was associated with attenuation or reversal of this spatial organization. Global SWA showed no meaningful association with SDB severity. In contrast, regional frontal and posterior decay parameters were strongly associated with HI (adjusted R2 = 0.53; p < 1e-6) but not OAI (adjusted R2 = 0.05; p = .95). The frontal-to-posterior decay-rate ratio showed the strongest association with HI {beta} = 4.15; 95% CI, 3.17-5.13; p < 1e-10; adjusted R2 = 0.55. Conclusions and Relevance Pediatric SDB was associated with regional disruption of slow-wave sleep homeostasis rather than global loss of deep sleep. These alterations affected both the spatial organization and temporal dynamics of SWA during a period of active cortical maturation and were not captured by conventional sleep metrics. Regional SWA dynamics may provide a developmentally sensitive marker of physiological disease burden in children with SDB.

Background Menstrual cycle disturbances have been increasingly reported after COVID-19 vaccination, raising questions about their prevalence and clinical significance among women of reproductive age. Objective This study aimed to investigate the incidence and types of menstrual cycle alterations following different doses of COVID-19 vaccines among Iranian women of reproductive age. Methods A cross-sectional survey was conducted among vaccinated women who reported their menstrual cycle status before and after each vaccine dose. Data on cycle regularity, flow characteristics, and specific menstrual disorders were collected and analyzed. Results Menstrual cycle alterations were reported by 28.8%, 25.4%, 30.3%, and 68.4% of participants after the first, second, third, and fourth vaccine doses, respectively. The most common changes were oligomenorrhea after the first and second doses (8.9% and 5.6%), menorrhagia after the third dose (5.3%), and hypomenorrhea after the fourth dose (8.3%). Comparisons with international studies revealed a wide variation in prevalence (ranging from 25% to 78%), which may be explained by differences in methodology, population characteristics, vaccine types, and pre-vaccination health status. Conclusion A considerable proportion of Iranian women experienced menstrual alterations following COVID-19 vaccination, most commonly oligomenorrhea, menorrhagia, and hypomenorrhea. While generally self-limiting, these findings highlight the need to integrate menstrual health into post-vaccination monitoring and patient counseling. Future research should explore the underlying immune-endocrine mechanisms and long-term clinical implications of these changes.

Background: Cerebral vasospasm is a frequent complication after aneurysmal subarachnoid hemorrhage (aSAH) and is associated with delayed cerebral ischemia (DCI) and unfavorable outcome. While CTA-based vasospasm grading is frequently used, its relationship with actual cerebral perfusion remains incompletely understood. This study investigates the association between vasospasm severity and distribution and territorial perfusion deficits. Methods: In this retrospective single-center study, 513 CT examinations (CTA and CT perfusion) from 194 patients with aSAH were analyzed. Vasospasm was graded per vessel segment using the CTA Vasospasm Score, and perfusion deficits were assigned to corresponding vascular territories (left/right anterior circulation, posterior circulation). Vasospasm distribution was further classified by severity and multifocality. Associations between vasospasm score and perfusion deficits were assessed using a generalized linear mixed model with binomial distribution, adjusting for Hunt & Hess grade, modified Fisher score, and days since hemorrhage. Results: Vasospasm was detected in 79.3% of examinations, and a perfusion deficit in at least one territory was present in 62.6%. The proportion of perfusion deficits increased progressively with both vasospasm severity and multifocality, ranging from 21.7-25.0% in the absence of vasospasm to 81.2-82.2% in severe multifocal vasospasm. The CTA Vasospasm Score was significantly associated with perfusion deficits in all territories (OR 1.36-1.50), with stronger associations in the anterior than posterior circulation. Conclusion: Vasospasm severity and distribution are strongly associated with perfusion deficits, supporting a continuum model of ischemic risk. However, the substantial proportion of perfusion deficits occurring independent of vasospasm suggests additional microcirculatory mechanisms not captured by CTA. CT perfusion should be considered complementary to CTA, particularly in clinically deteriorating or non-assessable patients.

Prenatal alcohol exposure (PAE) is a major cause of neurodevelopmental disorders, yet most children are diagnosed late or misdiagnosed. Neuroplacentology suggest that placental factors released into maternal and/or umbilical cord blood contribute to fetal brain development. Consistently, a preclinical inter-organ transcriptomic database revealed that PAE disrupts the expression ratio of angiogenic and inflammatory factors suggesting an angio-inflammatory response. This study aimed i) to assay, by multiplex immunoassay, angiogenic and inflammatory factors in maternal and umbilical cord blood from alcohol-consuming women and ii) to perform a maternofetal analysis according to neonatal sex. Afterwards, dysregulated factors from mothers who gave birth to females or males were submitted to STRING and ShinyGO analyses. Results showed that PAE differently altered the distribution profiles of dysregulated angiogenic and inflammatory factors in maternal and umbilical cord blood. Moreover, sex-specific differences were observed, with 36% of dysregulated proteins specific to males, 48% to females, and 16% common to both. STRING analysis revealed robust functional protein-protein interactions linking together inflammatory and angiogenic clusters while the ShinyGO analysis identified enriched pathways related to vascular shear stress. These findings provide the first maternofetal analysis of combined angiogenic and inflammatory factors from alcohol-consuming mothers.

Breast cancer is a heterogeneous disease whose clinical management relies heavily on accurate molecular subtyping. The murine E0771 mammary carcinoma cell line is widely used in preclinical studies, yet its molecular identity remains controversial, with reports variably classifying it as luminal B or triple-negative. In this study, we performed an integrated molecular and functional characterization of two independently sourced E0771 cell line stocks to resolve this discrepancy. Both stocks were genetically authenticated and exhibited concordant phenotypes. Immunohistochemical and molecular analyses demonstrated absence of oestrogen and progesterone receptors, classifying E0771 as triple-negative. Functionally, E0771 cells showed no transcriptional response to oestrogen and displayed resistance to endocrine therapy both in vitro and in vivo. Collectively, our results establish E0771 as an oestrogen-independent, basal-like triple-negative breast cancer model, supporting its appropriate use in studies of hormone-resistant breast cancer biology.

Analyses of human breast carcinomas (BCs) and premalignant breast lesions show that the loss of RASSF1A is an early event in the development of ER+ BCs, which correlates linearly with malignant progression. This observation suggests that RASSF1A inhibition is important for the development and progression of ER+ BCs. In addition to RASSF1A, concurrent caveolin-1 (Cav-1) inhibition may further promote ER+ breast carcinogenesis. In the present study, transgenic Rassf1a-/- and Cav-1(-/-) single as well as Rassf1a-/-, Cav-1(-/-) double knockout mice were used to investigate the impact of single or combined Rassf1a and Cav-1 inactivation on BC initiation. Loss of either one or both proteins led to different, pre-malignant histopathological alterations within the mammary glands of the mice, but not to fully developed BC, confirming that Rassf1a and Cav-1 are both important for maintaining the integrity of mammary gland epithelial structure, but suggesting that further intracellular changes or extracellular factors are required for the development of luminal BC when both genes are lost.

BackgroundTuberculosis remains a leading global infectious killer, with BCG offering inconsistent adult protection and rising drug-resistant strains demanding novel vaccine strategies. We report the first multi-epitope vaccine construct simultaneously targeting three previously unexplored Mycobacterium tuberculosis virulence proteins; EccB3, MycP, and polyketide synthase which collectively govern nutrient acquisition, ESX secretion integrity, and innate immune evasion. MethodsUsing a reverse vaccinology pipeline, B-cell, CTL, and HTL epitopes were predicted, filtered for allergenicity, toxicity, and IFN-{gamma} induction, then assembled into an 823-residue chimeric construct incorporating beta-defensin and PADRE adjuvants with AAY/GPGPG linkers, covering [~]90% global HLA diversity. The construct underwent AlphaFold structure prediction, 3DRefine refinement, disulfide engineering, PROCHECK/ProSA validation, ClusPro 2.0 docking against TLR1/TLR2, and C-IMMSIM immune simulation. ResultsThe construct (82.3 kDa, instability index 32.48) showed strong structural quality (94.7% favoured Ramachandran residues), stable TLR1/TLR2 binding (weighted energy: -1,371.0 kcal/mol), and robust in silico immune responses and durable memory cell formation following booster simulation. ConclusionThis computationally validated construct represents a promising multi-target TB vaccine candidate warranting experimental advancement.

Background: Diabetes mellitus is an increasing public health challenge in Sierra Leone, where access to diagnosis, treatment, and long-term care remains limited. Traditional medicine continues to play a significant role in disease management; however, ethnobotanical knowledge related to diabetes remains insufficiently documented. Methods: A cross-sectional ethnobotanical survey was conducted among 40 informants, including traditional healers, herbalists, and knowledgeable community members in Waterloo, Pendembu, and Bo. Data were collected using structured questionnaires administered via Kobo Toolbox and paper-based tools. Information on medicinal plants, plant parts used, preparation methods, routes of administration, and knowledge transmission pathways was obtained. Quantitative ethnobotanical indices, including Frequency of Citation (FC), Relative Frequency of Citation (RFC), and Informant Consensus Factor (ICF), were calculated. Results: A total of 21 medicinal plant species were documented. The most frequently cited species were Moringa oleifera (FC = 9; RFC = 0.225), Vernonia amygdalina (FC = 7; RFC = 0.175), and both Cassia siberiana and Telfairia occidentalis (FC = 6; RFC = 0.150). Leaves were the most commonly utilized plant part (40.9%), and decoction was the predominant preparation method (76.2%), with oral administration accounting for 95.2% of use. The Informant Consensus Factor (ICF = 0.69) indicated a relatively high level of agreement among informants. Knowledge was primarily transmitted through apprenticeship and inherited family practices. Conclusion: Traditional medicinal plants remain an important component of diabetes management in Sierra Leone. The high level of consensus among informants and the repeated citation of specific plant species suggest structured and culturally validated therapeutic practices. The findings provide a foundation for future phytochemical and pharmacological investigations and highlight the need for documentation, preservation, and sustainable utilization of ethnobotanical knowledge.

RNA-binding protein LARP4 plays an important role in T cell activation and differentiation, but its role in B cell biology and the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. This study found that LARP4 was specifically highly expressed in B cells of SLE patients and was positively correlated with disease activity. By constructing T cell-specific and B cell-specific conditional knockout mice, we found that deletion of LARP4 in B cells, but not in T cells, significantly alleviated pristane-induced and Bm12-induced lupus nephritis. Further analysis showed that LARP4 deletion selectively inhibited B cell differentiation into plasma cells, but did not affect germinal center B cell formation. Integrated transcriptomic and metabolomics analyses revealed that this effect is due to reduced phosphatidic acid synthesis and decreased mTORC1 activity caused by mitochondrial oxidative phosphorylation dysfunction. Furthermore, we used LIPEP, a LARP4 inhibitory peptide that effectively mimicked the therapeutic effects of LARP4 gene knockout in the MRL/lpr spontaneous lupus model and outperformed cyclophosphamide in reducing glomerular immune complex deposition and improving extrarenal dermatitis. These results indicates that LARP4 is a key metabolic checkpoint regulating B cell differentiation into Plasma cells and suggest that it may be a potential therapeutic target for SLE.

Glycation, a non-enzymatic reaction occurring between sugars and biological macromolecules, plays a critical role in ageing and disease pathogenesis. Methylglyoxal (MG) is a highly reactive -oxoaldehyde that leads to the formation of endogenous advanced glycation end products (AGEs). These AGEs are associated with diabetes and many other diseases, including neurodegeneration and cancer. This is often through interactions with the receptor for advanced glycation end products (RAGE). Inhibition of glycation/AGEs formation using natural products to target cancer is an area of recent interest. In vitro AGEs formation was observed by browning of samples, increased fluorescence, and carbonyl stress. MG induced changes in the structure of BSA were analysed using electrophoresis, spectroscopy, TEM, AFM, DLS, and CD spectroscopy. Our results show that AGEs form random structures, oligomeric aggregates, and {beta}-sheets. Thioflavin T and Congo red staining further validated these findings. Galangin and Caffeic acid demonstrated significant antiglycation activity, suppressing AGEs formation in vitro. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/737425v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@113b391org.highwire.dtl.DTLVardef@7208a1org.highwire.dtl.DTLVardef@94c2e1org.highwire.dtl.DTLVardef@867b85_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMethylglyoxal-induced Advanced Glycation End Products were prepared in vitro C_LIO_LIMethylglyoxal -induced structural modifications in BSA C_LIO_LIAGEs were characterised using various parameters C_LIO_LIBoth fluorescent and non-fluorescent AGEs were formed. C_LIO_LIPhytochemical treatment induced inhibition of AGEs formation C_LI

Background: aneurysmal subarachnoid hemorrhage (aSAH) is neurological emergency associated with substantial mortality and disability. Current grading systems such as the modified Fisher Scale (mFS) and World Federation of Neurological Societies (WFNS) score, rely on semiquantitative and examination based assessments. Hence, they demonstrate limited predictive precision. The enhanced subarachnoid hemorrhage (eSAH) score is a simplified quantitative model integrating age, Glasgow Coma Scale (GCS), and cisternal subarachnoid hemorrhage volume (SAHV) to predict clinical outcomes after aSAH. Methods: We performed a retrospective multicenter cohort study that included 1088 patients across three tertiary-care centers the United States. Predictive performance for unfavorable functional outcome, in-hospital mortality and delayed cerebral ischemia (DCI) was evaluated using receiver operating characteristic (ROC) analysis and area under the curve (AUC). Comparative analyses were performed and compared to the WFNS and mFS grading systems. Results: the eSAH score demonstrated excellent discrimination for unfavorable functional outcome at discharge ( AUC 0.89 ) and in-hospital mortality (AUC 0.87). The DCI subscore demonstrated good discriminatory performance for predicting DCI (AUC 0.77). Compared with conventional grading systems, this was superior to both the WFNS (AUC 0.75) and the mFS ( AUC 0.70). increasing eSAH scores were additionally associated with progressively higher rates of mortality and unfavorable functional outcomes. Conclusion: the eSAH score demonstrates strong external validity, reproducibility and superior predictive performance compared with conventional grading systems in a large multicenter cohort. These findings support the clinical utility of quantitative hemorrhage burden integration for early risk stratification in patients with aSAH.

Background: Mechanical thrombectomy (MT) is a time-sensitive reperfusion treatment for acute ischemic stroke caused by large-vessel occlusion. Workflow time metrics for MT remain poorly characterized in Indonesia, where stroke burden is substantial. This study describes pre-hospital and in-hospital time-interval metrics for MT across two major tertiary hospitals in Jakarta and evaluates institutional trends over a nine-year period. Methods: We conducted a retrospective descriptive study of consecutive patients undergoing MT at dr. Cipto Mangunkusumo National General Hospital (RSCM) and Prof. Dr. dr. Mahar Mardjono National Brain Center Hospital (RSPON) from 2017 to 2025. Pre-hospital and in-hospital time-interval metrics were reported as median (interquartile range [IQR]) and stratified by institution. Results: Among 330 registered patients, 71 were excluded due to incomplete data, leaving 259 in the final cohort (RSCM n=38; RSPON n=221). The pooled cohort had a mean age of 58.12 {+/-} 11.09 years; 63.71% were male. Hypertension was the most prevalent vascular risk factor (53.67%). Median door-to-CT time was 9 minutes (IQR 18), door-to-decision 101 minutes (IQR 100), and door-to-groin puncture 272 minutes (IQR 152). Total ischemic time (onset-to-groin puncture) was 468 minutes (IQR 294). MT volume increased substantially over the study period, particularly after 2022 at RSPON, which also demonstrated progressive improvement in in-hospital workflow times. RSCM showed increasing delays in later years, consistent with institutional congestion at a general multispecialty center. Conclusions: Early brain imaging was achievable at both centers; however, post-imaging delays particularly in CT-to-groin intervals, represent the dominant in-hospital bottleneck. Future quality-improvement efforts should prioritize decision-making, team mobilization, and pre-hospital coordination to reduce total ischemic time and improve access to reperfusion therapy.

Stem cells proliferate rapidly to maintain fast tissue turnover during regeneration. However, the feedback mechanisms in stem cells that prevent hyperproliferation remain unclear, and their dysregulation can lead to organ failure and cancer. Here, we identified nuclear factor-Y (NF-Y) as the transcriptional repressors to maintain the stem cell quiescence during intestinal homeostasis. We found that NF-Y negatively regulates intestinal stem cell (ISC) proliferation through preferentially occupying the promoters of EGFR signaling pathway components Egfr/Mkp3/Raf/Ras/pointed, via the action of histone acetyltransferase Nejire (Nej)/p300 dependent transcription regulation. While the loss of NF-Y enhances ISC proliferation, cell death and sensitivity to stress and tumor induced mortality. Moreover, NF-Y acts together with Nej to restrict Egfr expression and suppress ISC hyperproliferation. Together, these results demonstrate NF-Y acts with Nej serve as a key negative feedback module to orchestrate transcription initiation and termination of growth signaling in the control of stem cell activity in homeostatic and disease conditions.

Objective: To compare first-line emergency department (ED) treatment classes for acute headache on short-term all-cause ED return and index admission across two independent health systems. Background: ED trials of acute headache treatment are judged on in-ED pain relief, a documented endpoint that is recorded incompletely and shifts with the scoring rule, and is a weak surrogate for what happens after discharge. All-cause ED return after an index headache visit (any subsequent ED encounter within the window) has not been used to compare first-line treatments at scale, and society guidance favors dopamine-receptor antagonists while recommending against routine opioids. Methods: Retrospective two-center cohort of adults treated for headache in the ED, using MIMIC-IV-ED (Beth Israel Deaconess Medical Center, 2011-2019) and MC-MED (Stanford, 2020-2022). The first-line class was the earliest qualifying acute agent. The primary contrast was opioids versus dopamine-receptor antagonists (the guideline-preferred class). Outcomes were 72-hour and 7-day all-cause ED return (among discharged patients; any subsequent ED encounter within the window) and index hospital admission. Confounding by indication was addressed with propensity overlap weighting; associations are reported as adjusted risk ratios (RRs) with bootstrap 95% CIs and E-values. Estimates were pooled with a site term and examined per site. Results: Among 13,285 treated adults (10,799 MIMIC-IV-ED; 2,486 MC-MED), opioid recipients were older and higher-acuity than dopamine-antagonist recipients (index admission 38.1% vs 16.4%). In the MIMIC-IV-ED discharged primary-contrast population, overlap weighting reduced the maximum standardized mean difference from 0.35 to 0.002; pooled and site-specific balance diagnostics are provided in the Supplement. First-line opioids remained associated with a higher 72-hour all-cause ED return (6.8% vs 3.8%; adjusted RR 1.79; 95% CI 1.31 to 2.33), 7-day return (10.7% vs 6.6%; RR 1.62; 95% CI 1.28 to 1.98), and index admission (RR 2.32; 95% CI 2.11 to 2.58, consistent with strong residual severity differences in patients selected for opioids). The direction of association was concordant across both health systems, although MC-MED return estimates were imprecise given the smaller opioid-treated discharged sample. In MIMIC-IV-ED, the cumulative all-cause return incidence by treatment class separated by day 3 and persisted through 30 days. The direction was consistent, though attenuated and no longer statistically significant, when the outcome was restricted to a headache-specific return (72-hour RR 1.31; 95% CI 0.91 to 1.88); the direction persisted for the composite of admission or 72-hour return, which does not condition on discharge but is influenced by the more confounded admission component (RR 2.16; 95% CI 1.98 to 2.39). Conclusion: Across two health systems, first-line opioid treatment for ED headache was associated with higher all-cause short-term ED return among discharged patients and higher index admission than dopamine antagonists. These observational associations reflect downstream all-cause ED utilization after an index headache visit rather than confirmed headache recurrence or treatment failure; they are consistent with guideline-concordant, opioid-sparing first-line treatment and warrant prospective confirmation. Plain Language Summary: Emergency departments treat headaches with several different medicines, but the usual way of judging which works, the pain score recorded during the visit, is often missing or inconsistent. Using two large hospital systems and a clearer outcome, whether patients came back to the emergency department for any reason, we found that patients first treated with opioids returned within 72 hours about 1.8 times as often as those given the guideline-preferred dopamine-blocking medicines and were admitted more than twice as often. These patterns pointed the same direction in both hospital systems after adjustment for the measured differences available in both databases. Because this was an observational comparison and returns were counted for any reason, the findings are consistent with using guideline-preferred non-opioid medicines first, rather than proof that opioids worsen headache.

Premature ovarian insufficiency (POI) significantly impacts quality of life, yet the immediate cognitive landscape and lived experience of younger women remain under-researched. In 125 young women (aged 19-48; 66 with idiopathic POI, 59 age-matched controls), we examined self-reported cognitive distress and symptom burden within the POI cohort and compared objective global and domain-specific cognitive performance between groups. Objective accuracy scores were derived from six online tasks (Cognitron) and combined into a robust global measure. Within the POI cohort, there were significant differences in symptom burden domains ({chi}(3) = 61.90, p<0.001), with psychological and sexual symptoms reported at a significantly higher intensity than physical and vasomotor symptoms (all p<0.001). Furthermore, the standardised magnitude of perceived cognitive distress (56.20%) was significantly greater than that of overall symptom burden (42.00%, p<0.001). Case-control comparisons revealed no significant differences in global cognitive performance (p=0.615), yet the POI cohort performed significantly less accurate than controls in verbal analogical reasoning (-0.86 SD, 95% CI: -1.52, -0.20, p = 0.011). The findings highlight an urgent need for comprehensive emotional and psychosexual support in POI care. Additionally, the presence of high cognitive distress alongside localised objective deficits demonstrates that cognitive health monitoring must be proactive in early adulthood, especially given their established long-term risks for later-life cognitive decline and dementia.