The pond snail Lymnaea stagnalis displays clear photoperiodism; it lays more eggs in long-day conditions than in short to medium-day conditions. The lateral lobes (LLs) are paired small budding structures of the cerebral ganglia and regulate egg laying as a coordinating center between reproduction and body growth, and LL ablation causes gigantism and attenuates egg laying. Our previous study demonstrated that the canopy cell (CC) in LL photoperiodically changes the excitability; it excites more in long-day conditions than in medium-day conditions. Here, we examined the function of CC in egg laying by the microsurgery. As a result, in long-day conditions, snails without CCs exhibited smaller albumen gland somatic index (ASI, proportion of the albumen gland/soft body) and smaller total number of egg masses laid than intact snails. In contrast, in medium-day conditions, there were no significant differences in ASI among intact, sham and CC ablation groups. Since the albumen gland produces galactogen-rich perivitelline fluid and supplies eggs with it, the CCs seem to promote egg mass production via acceleration of the perivitelline fluid production in long-day conditions. It is noteworthy that CC ablation had no effects on gonadal somatic index (GSI, proportion of the ovotestis/soft body). Besides, CC ablation caused slight increase in shell size and body weight. These imply that CCs are at least partially responsible for gigantism and decrement of egg laying caused by LL ablation, and we revealed another regulator in photoperiod-dependent egg laying in L. stagnalis. Our findings contribute to understanding neuroendocrine mechanisms underlying molluscan photoperiodism.
To study the association between the leading follicle size on the day of human chorionic gonadotropin (hCG) trigger and clinical pregnancy in gonadotropin-stimulated intrauterine insemination (IUI) cycles. Retrospective cohort study. University-affiliated assisted reproduction unit. Women with ovulatory dysfunction or unexplained infertility undergoing gonadotropin-stimulated, hCG-triggered IUI cycles. Ovarian stimulation with gonadotropins, hCG trigger, and IUI. Clinical pregnancy rate (CPR) was the primary outcome. The primary analysis modeled leading follicle size continuously using a natural cubic spline within a modified Poisson regression model with robust standard errors clustered by woman. Secondary analyses used categorical modified Poisson models, and sensitivity analyses included a spline model of first-cycle-only and an adjusted generalized additive model (GAM). A total of 516 women with 801 gonadotropin-stimulated IUI cycles between 01/2019 and 12/2025 were included. CPRs were 16.5% (55/334), 12.5% (48/385), and 6.1% (5/82) for leading follicle sizes of 15-16 mm, 17-18 mm, and 19-21 mm, respectively. In the primary spline-based model, adjusted predicted CPR peaked at approximately 16 mm and declined beyond 17 mm. Compared with 16 mm, the adjusted risk ratio (aRR) was significantly lower at 18 mm (aRR 0.66, 95% CI 0.47-0.92), 19 mm (aRR 0.42, 95% CI 0.22-0.81), and 20 mm (aRR 0.27, 95% CI 0.10-0.75). Modified Poisson regression supported this pattern, showing lower adjusted CPR in the 19-21 mm group versus 15-16 mm (aRR 0.35, 95% CI 0.14-0.84) and for follicle size >17 mm versus ≤17 mm (aRR 0.62, 95% CI 0.40-0.97). First-cycle-only spline model and GAM sensitivity analyses supported a similar downward trend beyond approximately 17 mm. A leading follicle size of 15-16 mm appears to be the optimal range for clinical pregnancy in gonadotropin-stimulated, hCG-triggered IUI cycles, whereas leading follicles >17 mm were associated with a lower adjusted clinical pregnancy probability. These findings provide evidence-based guidance for optimizing gonadotropin-IUI treatments.
The Asian citrus psyllid, Diaphorina citri Kuwayama (Hemiptera: Psyllidae), is the main vector of Huanglongbing (HLB), the most destructive disease affecting citrus production worldwide. Sustainable management of this pest requires the integration of biological and chemical control strategies. This study evaluated the predatory capacity, functional response, and insecticide selectivity of Orius insidiosus (Say) (Hemiptera: Anthocoridae) toward D. citri. Predation assays showed that O. insidiosus consumed all developmental stages of D. citri, with higher predation on eggs and nymphs. Functional response analysis revealed a Type II response, with high efficiency at low prey densities (attack rate = 3.62; handling time = 0.04), corresponding to a maximum consumption of approximately 25 prey per predator. Predation bioassay indicated significant differences in toxicity, with acetamiprid + bifenthrin, abamectin + cyantraniliprole, and alpha-cypermethrin + teflubenzuron causing >90% mortality, whereas glyphosate, azoxystrobin + difenoconazole, and chlorantraniliprole + abamectin showed lower toxicity (<50%). Concentration-response analyses indicated lower susceptibility of O. insidiosus compared to D. citri, with LC50 values ranging from 1.23 to 99.50 mg ml-1 for the predator and from 0.0016 to 1.187 mg ml-1 for the pest. All insecticides were classified as selective (SR > 1), although ecological risk varied. Probit substitution analysis indicated low predicted mortality (<90%). Overall, O. insidiosus is an efficient predator of D. citri, and further studies on its development and reproduction when preying on this pest are required. The tested pesticide mixtures showed selectivity, and further studies are needed to evaluate their efficacy at reduced application rates.
Ant colonies are superorganisms containing a wingless, nonreproductive, worker caste. The suppression (loss or reduction) of worker organs involved in mating and reproduction is a feature of many ant superorganisms. It is largely assumed that these worker organs, where present, are functionless and in the process of being eliminated through neutral degeneration or selection. Here, we argue that an underappreciated dimension of social evolution involves the co-option of worker organs to serve superorganism-level functions. We draw on two examples: the wings and ovaries. In some ant species, transiently appearing wing rudiments have been co-opted to regulate worker differentiation into soldiers. Likewise, in many ant species, the ovaries in adult workers have been co-opted to produce trophic eggs. We propose that the degree of organ co-option may itself be an indicator of superorganismal complexity. We discuss the broader implications of this idea and suggest novel avenues for future work.
Women with diminished ovarian reserve represent a low-prognosis population in assisted reproduction, in whom improving the efficiency of converting the available antral follicle pool into retrievable oocytes may be clinically relevant. We conducted a retrospective single-center cohort study including 232 IVF/ICSI cycles (232 women) performed between January 2022 and April 2025 in POSEIDON groups 3-4 (anti-Müllerian hormone <1.2 ng/mL), comparing a high-dose antagonist regimen preceded by combined oral contraceptive pretreatment plus recombinant luteinizing hormone priming (150 IU/day for 7 days; LHP, n = 93) with a comparable high-dose antagonist regimen without priming (no-LHP, n = 139). Both groups received fixed high-dose stimulation with recombinant follicle-stimulating hormone (300 IU/day) plus recombinant luteinizing hormone (150 IU/day). The primary outcome was ongoing pregnancy at ≥12 weeks. Cycle suspension before oocyte retrieval was less frequent with LHP than with no-LHP (1.1% vs. 10.1%). Follicular efficiency also favored LHP, with higher follicular output rate (59.4% vs. 52.8%) and follicle-to-oocyte index (82.6% vs. 70.9%). In fresh transfers, ongoing pregnancy was higher with LHP per started cycle (18.3% vs. 9.4%) and per embryo transfer (30.4% vs. 15.5%), with a similar trend per oocyte retrieval (18.5% vs. 10.4%). In multivariable logistic regression analyses, LH priming remained independently associated with ongoing pregnancy after adjustment for age, body mass index, and anti-Müllerian hormone, with consistent effect estimates across models (odds ratio range 2.20-2.41). Combined first-transfer ongoing pregnancy, defined as the fresh transfer or, when no fresh transfer occurred, the first subsequent frozen embryo transfer derived from the same stimulation cycle, also showed a favorable trend (29.7% vs. 17.0%). On updated follow-up, all pregnancies that had reached the ongoing stage in both groups resulted in live birth. In low-prognosis women, a COC-based recombinant luteinizing hormone priming protocol within a high-dose antagonist framework was associated with improved follicular efficiency, fewer pre-retrieval suspensions, and higher ongoing pregnancy rates in fresh cycles. Prospective studies are warranted to confirm these findings and better define patient selection.
Climate change and anthropogenic ignitions are intensifying wildfire frequency worldwide, elevating the risk of freshwater contamination by ash. In water, dissolved ash releases ions and other toxic constituents that increase pH and alter physicochemical conditions, while suspended ash particles may impose mechanical stress, disrupt behavior, and increase exposure through ingestion. However, the relative contributions of these distinct ash exposure pathways to ecological toxicity remain poorly understood. Here, we investigated whether wildfire ash alters crustacean behavior and whether suspended macroparticles and ash-induced pH shifts differentially shape these responses. The freshwater crab Aegla jarai and the cladoceran Daphnia magna were exposed to aqueous ash extracts without suspended macroparticles (dissolved fraction) or containing suspended macroparticles (dissolved plus particulate fractions), alongside a control. For D. magna, treatments with and without pH correction disentangled intrinsic ash toxicity from the effects of alkalinization. In A. jarai, ash did not affect agonistic responsiveness, refuge use, or food consumption. However, locomotor activity increased during the food detection test, particularly in treatments containing macroparticles, consistent with reduced search efficiency without impairing ingestion. In contrast, D. magna exhibited concentration-dependent immobilization (a proxy for mortality), intensified by elevated pH and the presence of macroparticles. Effects on distance traveled were weaker and mainly associated with pH shifts. Together, these findings show that wildfire ash affects freshwater crustaceans through chemical and physical pathways. Ash-induced pH shifts primarily drive ash toxicity, while suspended macroparticles amplify this effect, underscoring the need to consider both dissolved and particulate fractions in postwildfire risk assessments.
Neutron crystallography was used to determine a 2.5-Å resolution all-atom structure of macrophage migration inhibitory factor (MIF) interacting with 3-(4-hydroxyphenyl)-pyruvate (HPP). MIF is a pro-inflammatory, pro-tumorigenic protein that may be an attractive therapeutic target. MIF catalyzes the interconversion of the keto and enol forms of HPP by a tautomerase reaction. Although HPP is evidently not a physiological substrate of MIF, many compounds that inhibit this activity in enzymatic assays have been found also to inhibit physiological activities of MIF. Therefore, the MIF-catalyzed HPP tautomerization reaction is used in initial screening of compounds in the search for inhibitors of MIF physiological activity. The neutron diffraction-derived crystal structure reveals the position of a water molecule involved in the tautomerization reaction, and also confirms the charged state of lysine-32 in the active site. The structure confirms the previously proposed catalytic mechanism of MIF, with the N-terminal Pro-1 abstracting a proton to generate an HPP enolate intermediate which is subsequently protonated. The structure reported herein reveals that this proton is supplied by a neighboring water molecule. Along with the neutron structure, a room-temperature synchrotron x-ray crystal structure reveals a covalent adduct between HPP and MIF. While this adduct is a result of radiation-induced chemistry, its formation confirms the catalytic role of the active site residue because a covalent complex could only form if the reactive carbon of the substrate is correctly positioned by the enzyme.
This study estimates the cost of managing infertility, including intrauterine insemination (IUI) from health system perspective in India. This was a retrospective cross-sectional microcosting study using mixed approach. Unit costs were estimated at the cost-centre level based on average resource utilisation and aggregated by facility type and cause of infertility. The cost data was collected for the year 2022-2023 and adjusted for inflation in 2025. The study was conducted at five healthcare facilities providing infertility services, of which three were public and two were private hospitals situated in different parts of country. The cost data was collected from different departments of hospitals. To determine the service utilisation, 100 infertility patients were enrolled at each hospital. Patients undergoing infertility treatment (including IUI) for five selected causes of infertility and willing to participate in the study were included. The cost of providing infertility treatment for 1 year was the primary outcome measure. The share of different cost-components in the total cost was the secondary outcome measure. The one-year health system cost of infertility management ranged from INR 5515 (USD 63) to INR 15 139 (USD 173). Median costs were generally higher in public hospitals compared to private hospitals. Outpatient consultations contributed about two-thirds of total costs. The mean cost of one IUI cycle ranged from INR 8272 (USD 94) to INR 8887 (USD 101). This first-of-its-kind study provides robust evidence on the health system cost of infertility management in India. The findings highlight significant cost variations by infertility cause and facility type, underscoring the need for inclusion of infertility services, particularly IUI, within public health financing packages. These results offer a foundation for future cost-effectiveness analyses and policy decisions related to infertility treatment in India.
To identify the specific support needs of Black women navigating infertility care and generate strategies to improve access, patient experience, and outcomes. Mixed-methods observational study SUBJECTS: Black women aged 18-45 years in the US who were currently seeking or had recently sought infertility care EXPOSURE: Online survey and semi-structured interviews MAIN OUTCOME MEASURE: Quantitative data on demographics and fertility care experiences; qualitative data on perceived support needs and recommended solutions RESULTS: 176 women responded to the online survey; of these, 41 women provided consent to participate in semi-structured interviews with the study team. Most participants (74.3%) were 35-45 years of age, married or partnered, held an advanced degree, worked full-time, and had insurance that covered some or all fertility services. 25.5% of participants reported feeling under-supported by friends, family, doctors, or others during their infertility journey, with 31.3% identifying this lack of support as a barrier to initiating treatment. Participants described feelings of loneliness and isolation, with few affirming spaces or communities to find resources and connect with other Black women with infertility. They also shared examples of racism, discrimination, and a lack of compassionate care that led to dismissal of health concerns and delays in referral to reproductive endocrinologists that complicated their infertility journeys. Study participants provided several suggestions for clinics and providers to improve the support of Black women seeking infertility care, from enhancing patient-centered care to increasing access to Black reproductive medicine and mental health providers. Understanding the specific support needs of Black women seeking infertility care will inform patient-centered, compassionate, and culturally responsive care that improves the patient's experience and outcomes.
Pollinators are declining globally due to anthropogenic pressures, such as intensive grazing and nutrient enrichment. Yet, their combined effects on pollinators and plant-pollinator interactions remain poorly understood, particularly in the Arctic. Here, we experimentally tested how grazing exclusion and nutrient addition shape flower-visiting insect communities and interaction networks in a high-productivity montane and a low-productivity tundra grassland, in northern Fennoscandia. Grazing exclusion emerged as the primary driver across both grasslands, increasing flower-visitor family richness, diversity, and the number of plant-pollinator interactions. These effects were especially strong in the tundra grassland, where resource limitation is more pronounced. In contrast, nutrient addition had weaker and more context-dependent effects, enhancing flower-visitor richness and the number of interactions mainly in the tundra grassland and particularly when combined with grazing exclusion. At both sites, grazing exclusion and nutrient addition altered community composition, with the strongest shifts occurring under their combined effects. Despite large effects on interaction numbers, network structure responded more subtly. Weighted connectance declined with grazing exclusion, especially in the tundra, indicating that interactions became more concentrated on a subset of plant species where floral resources were abundant. In contrast, network specialization (H2') and nestedness showed limited responses to experimental treatments, suggesting relatively stable interaction organization. Overall, our results demonstrate that grazing strongly regulates pollinator communities and interaction networks in Arctic grasslands, while nutrient enrichment plays a secondary, context-dependent role. The pronounced sensitivity of tundra grasslands highlights their vulnerability to environmental change and underscores the importance of managing grazing pressure to sustain pollination processes in Arctic ecosystems.
To explore the associations of early-pregnancy alanine aminotransferase (ALT), aspartate aminotransferase (AST), and γ-glutamyl transferase (GGT) with gestational diabetes mellitus (GDM) risk, and to examine the statistical interdependencies among these enzymes in relation to GDM. This retrospective cohort included 9,077 singleton pregnancies. Multivariate logistic regression was used to examine the associations of ALT, AST, and GGT with GDM. Statistical mediation models (PROCESS Macro Model 4) assessed whether the association of ln-ALT and ln-AST with GDM could be statistically accounted for by ln-GGT. Stratified analyses by ln-ALT quartiles examined whether the negative association of ln-AST (observed after adjustment for other enzymes) varied across levels of hepatocellular injury. Moderated mediation analysis (PROCESS Macro Model 58) examined whether age, pre-pregnancy BMI, or gestational age at sampling modified the observed associations. All models were adjusted for prespecified covariates. In regression analyses, ln-GGT showed the strongest association with GDM (aOR 1.514-1.640, all P < 0.001). ln-ALT was associated with GDM in the single-enzyme model (P = 0.016) but was attenuated after ln-GGT adjustment (P = 0.801). ln-AST showed no association in the single-enzyme model (P = 0.982) but demonstrated a negative association after co-adjustment (aOR 0.494-0.738, P < 0.05). Mediation analysis indicated that the association of ln-ALT with GDM was largely accounted for by ln-GGT (indirect effect β=0.1754, 95% CI 0.0986-0.2527). ln-AST demonstrated contrasting statistical associations: a positive indirect component via ln-GGT (indirect effect β=0.2797, 95% CI 0.1770-0.3815) and a negative direct association (β=-0.3041, P = 0.037). Stratification by ln-ALT quartiles showed that the negative association of ln-AST was statistically significant only in quartiles 3-4. BMI positively, and gestational age negatively, modified the associations between ALT/AST and GGT (all P < 0.001). Early-pregnancy hepatic enzymes and GDM exhibit a GGT-focused interdependent association pattern: the association of ALT with GDM is largely accounted for by GGT, whereas AST demonstrates contrasting statistical associations-a positive indirect component via GGT and a negative direct association. This descriptive framework offers one potential statistical account for heterogeneous observational findings; prospective and experimental studies are needed to validate these patterns.
This case presents a patient in her early 30s who had a heterotopic caesarean scar pregnancy following spontaneous conception. This is a rare presentation, so the literature is limited on diagnosis, management and outcomes. In this case, both the caesarean scar heterotopic and the intrauterine pregnancies were alive. The patient successfully underwent surgical management of heterotopic pregnancy. Given the rarity of this presentation, a detailed description of the management is important. Due to the global increase in caesarean section rates and assisted reproductive technologies, more research is required to establish guidelines on investigation and management of heterotopic caesarean scar pregnancy.
This review critically reflects on the use of immunocrit in neonatal piglets as an indicator of passive immunity status. Under intensive production conditions and with the development of hyperprolific sow lines, reliable techniques are required to objectively assess the success of passive immunity transfer to the piglets. The immunocrit is a cost-effective indirect method for assessing immunoglobulin concentration in serum or plasma samples obtained 12-48 h after the birth of the first piglet, by using the principle of protein precipitation. Reduced growth performance, delayed development, greater vulnerability to illness, and higher pre-weaning mortality are all consistently associated with low immunocrit readings. Higher numbers, on the other hand, indicate effective immunoglobulin absorption and better long-term productivity. Various management strategies, including split suckling, cross-fostering, and farrowing system design, directly influence immunocrit values by affecting colostrum intake and competition among piglets. Certain interventions, such as oxytocin administration or anti-inflammatory treatments, may influence colostrum composition or farrowing conditions, but they do not always result in appreciable changes in immunocrit levels. Its usefulness, quickness, and field application make it an important tool in contemporary swine production, even though it lacks the analytical precision of enzyme-linked immunosorbent assay and radial immunodiffusion that quantify individual immunoglobulin isotypes, such immunoglobulin G. For herd level interpretations the immunocrit results should be complementary to the evaluation of the farrowing and colostrum management practices, the sow diet and the handling of the piglets in supporting corrective measures prenatally.
South American camelids (SAC), including llamas (Lama glama) and alpacas (Vicugna pacos), exhibit distinctive reproductive features, such as induced ovulation and highly viscous seminal plasma (SP), that complicate conventional semen collection and objective sperm evaluation. Consequently, spermatozoa recovered from the cauda epididymis or through surgical vas deferens deviation (VDD) have become valuable alternatives for research and germplasm preservation. These sperm sources also provide a unique opportunity to investigate sperm physiology in the absence of SP. This review critically compares the functional characteristics of ejaculated, epididymal and VDD-derived spermatozoa and examines how methodological variables, including collection procedures, post-mortem interval, tissue handling and surgical protocols, contribute to variability among studies. Current evidence indicates that many functional differences observed among sperm sources, particularly in motility and plasma membrane functionality, are largely associated with the presence or absence of SP rather than intrinsic differences in sperm quality. These findings support a reinterpretation of SP as a physiological regulator of sperm quiescence, membrane stability and functional competence rather than merely a technical obstacle. We also review advanced analytical approaches, including flow cytometry and imaging flow cytometry, highlighting their potential to improve the evaluation of camelid sperm physiology and cryobiology, while summarizing current evidence on the developmental competence of sperm from different anatomical sources for in vitro embryo production. Overall, this review provides an updated synthesis of the literature, identifies major methodological limitations and highlights priorities for future research to advance reproductive biotechnologies in SAC.
Oocyte meiotic maturation requires highly asymmetric cell division, governed by spindle migration and actin cap formation. However, the upstream mechanisms that regulate the precise coordination of these events remain unclear. This study aimed to elucidate the role of PARP7, a mono-ADP-ribosyltransferase, in regulating actin cytoskeletal dynamics and chromosomal stability during mouse oocyte meiosis. Metabolomic profiling was performed to assess NAD+ dynamics during meiosis. PARP7 expression and localisation were analysed using genetic knockdown and pharmacological inhibition approaches. Multi-omics analyses were performed to identify PARP7 targets and map MARylation sites within the motor domain. Protein stability was evaluated following PARP7 suppression and site-directed mutagenesis. PARP7 was identified as the most abundant PARP family member in oocytes and localised to the actin cap during anaphase I. PARP7 inhibition disrupted meiotic progression, resulting in cytokinesis failure, aberrant polar body extrusion, and increased aneuploidy. These defects were attributed to impaired actin cap formation. MYH9 was identified as a PARP7 target, and MARylation was found to be critical for its stability; loss of this modification accelerated MYH9 degradation. PARP7-mediated MARylation stabilises MYH9 to maintain actin cap integrity and chromosomal segregation in mouse oocytes. These findings provide novel insights into the aetiology of oocyte aneuploidy and age-related reproductive decline.
The relationship between clomiphene citrate (CC) dosing regimens and adverse reproductive outcomes has not been fully elucidated, both with and without use of in vitro fertilisation (IVF). We aimed to study the association between cumulative CC dose and perinatal outcomes among fresh autologous IVF cycles. Retrospective cohort study. We included all fresh autologous IVF embryo transfer cycles performed in the US fertility clinics during 2004-2021 using CC for ovulation induction. We used robust Poisson regression models to estimate adjusted risk ratios (aRRs) and 95% CIs for associations between four categories of CC dose (<500 mg, 500-749 mg, 750-999 mg and ≥1000 mg) and perinatal outcomes of interest. 21 004 fresh autologous embryo transfer cycles using CC. The primary outcome measures included biochemical pregnancy, clinical pregnancy, spontaneous abortion, stillbirth, live birth, multiple birth and preterm delivery. Among fresh autologous embryo transfer cycles using CC, 21.3% used <500 mg, 67.8% used 500-749 mg, 7.2% used 750-999 mg and 3.7% used ≥1000 mg. After adjustment, rates of spontaneous abortion were higher for patients using 500-749 mg (11.8%; aRR, 1.12; 95% CI 1.02 to 1.25) and 750-999 mg of CC (14.4%; aRR, 1.38; 95% CI 1.18 to 1.62) than for those using <500 mg (10.3%). The ≥1000 mg group had a three-fold higher rate of stillbirth than the <500 mg group, but these estimates were imprecise (0.7% vs 0.2%; aRR, 3.31; 95% CI 0.88 to 12.40). Multiple birth risk was significantly higher among all CC dosage categories compared with the <500 mg group. Our findings extend previous findings on the association between CC exposure and adverse perinatal outcomes by demonstrating a dose-dependent relationship.
Multimodal large language models are increasingly used in radiological diagnosis, but their performance has not been systematically evaluated across volumetric (3D) imaging, real-world clinical versus public teaching cases, and bilingual contexts. The aim of the study is to develop a bilingual radiology benchmark and characterize the diagnostic performance of state-of-the-art multimodal large language models across input modality, clinical setting (public teaching vs routine clinical), disease rarity, and clinical-history language and to disentangle linguistic from clinical-content effects through a cross-linguistic control experiment. We constructed RadM-Bench, comprising 720 cases evenly distributed across 9 radiological subspecialties: 360 English public teaching cases enriched in rare diseases (RadEdu) and 360 Chinese routine clinical cases (RealClin). In total, 4 proprietary models (GPT-4o, O3, Gemini-2-Flash, and Gemini-2.5-Flash-Thinking) and 6 open-source models (Qwen2.5-VL-72B/7B, InternVL3-78B/8B, Llama-4-Scout-17B-16E, and MedGemma-4B) were evaluated under 4 input conditions: clinical history alone, history with radiologist-selected 2D key images, and history with volumetric data sampled at 2 and 10 frames per second (fps). Each response was scored on a 4-tier 0-3 diagnostic-quality rubric by 2 board-certified radiologists blinded to model identity. Mean scores with bias-corrected and accelerated bootstrap 95% CIs are reported. To disentangle language from clinical content, all 360 RealClin histories were translated into English and re-evaluated, with paired comparisons by Wilcoxon signed-rank tests and Benjamini-Hochberg false-discovery-rate correction. Mean performance remained below 1.5 on the 0-3 scale for all 10 models on both datasets. Adding radiologist-selected 2D key images to clinical history improved performance in all 10 models (+19.8% to +139.2%). In RealClin at fps=10, all 8 evaluable models scored lower with volumetric input than with the 2D-image baseline (-5.3% to -31.4%); MedGemma-4B and Llama-4-Scout-17B-16E could only be evaluated at fps=2 due to context-window and graphics processing unit-memory constraints. At fps=2, a total of 8 out of 10 models declined (-6.8% to -28.6%), while Qwen2.5-VL-7B and InternVL3-8B showed marginal improvements (+2.4% and +2.1%). Cross-dataset transfer diverged by model category: proprietary models declined from RadEdu to RealClin (eg, O3 with images: 1.14 to 0.79), whereas Chinese-centric open-source models improved (eg, InternVL3-78B: 0.48 to 0.75). The rare-disease premium observed in 9 out of 10 models in RadEdu reversed in RealClin, where common-disease scores exceeded rare-disease scores in 7 out of 10 models under history-only input. Translating RealClin histories into English produced a numerical decrease in mean score for all 10 models, which were statistically significant in 9 out of 10 models after false discovery rate correction, excluding a Chinese-language penalty. Within the scope of this benchmark, multimodal inputs improved performance over clinical history alone, but performance gaps remain in volumetric data processing and cross-context generalization, with mean diagnostic performance across the 10 evaluated models remaining below clinically actionable levels on both datasets.
To systematically evaluate the evidence on the contraceptive efficacy, cycle control, safety, and selected noncontraceptive effects of estetrol 15 mg/drospirenone 3 mg (E4/DRSP) and to assess certainty of evidence by outcome using the GRADE approach. A systematic review was conducted in accordance with PRISMA 2020. PubMed/MEDLINE, Scopus, and Google Scholar were searched for eligible studies published through February 2026. Clinical trials and comparative studies evaluating E4/DRSP in women of reproductive age were included. Outcomes were grouped into contraceptive efficacy, bleeding/cycle control, safety and tolerability, hemostatic and endocrine-metabolic effects, ovarian suppression, and noncontraceptive clinical outcomes. Risk of bias was assessed using design-specific tools, and certainty of evidence was graded by outcome. A total of 25 eligible publications/study reports were included, comprising phase 2 dose-finding studies, pivotal phase 3 contraceptive trials, pooled analyses, mechanistic comparator studies, adolescent data, and indication-specific studies. E4/DRSP demonstrated robust contraceptive efficacy, predictable bleeding patterns, and an acceptable tolerability profile. Across mechanistic studies, E4/DRSP showed less pronounced hemostatic and endocrine-metabolic effects than ethinyl estradiol-containing comparators. The most consistent biological differentiation of E4/DRSP was observed for APC resistance and thrombin-generation endpoints, which were less affected than with EE-containing comparators. The strongest noncontraceptive evidence was observed for dysmenorrhea, supported by a randomized, double-blind, placebo-controlled trial. Certainty of evidence was moderate for contraceptive efficacy, cycle control, common adverse events, and surrogate hemostatic/metabolic outcomes; high for dysmenorrhea versus placebo; low for endometriosis-related and menstrual symptom outcomes; and very low for clinical thromboembolic risk. E4/DRSP is an effective combined oral contraceptive with favorable cycle control and a consistent biologic profile suggesting lower hepatic/hemostatic impact than ethinyl estradiol-containing formulations. However, current evidence does not establish comparative thromboembolic safety, which requires dedicated postauthorization and real-world comparative studies.
Artificial intelligence (AI)-based language models are increasingly explored as tools for interpreting and applying clinical guideline recommendations. In urology, the European Association of Urology (EAU) recently introduced a guideline-specific chatbot; however, its comparative performance relative to contemporary general-purpose large language models (LLMs) remains unclear. In this structured comparative study, five AI systems-the EAU Guidelines Bot, ChatGPT-5, Gemini 2.5 Pro, Copilot - Smart GPT-5, and Perplexity Pro-were evaluated using 13 clinical questions derived directly from strongly recommended statements in the EAU erectile dysfunction (ED) guidelines. Responses were independently assessed by three senior reviewers across five predefined domains: relevance, clarity, structure, clinical utility, and factual accuracy, using a 5-point Likert scale. The primary outcome of the study was the composite performance score, which was calculated as the mean of the five domain scores. Inter-rater reliability was calculated using ICC(2,k), and differences among models were analyzed with the Friedman test followed by Holm-adjusted Wilcoxon post-hoc comparisons. Significant performance differences were observed across all domains (all p < 0.001). The highest composite scores were observed for Gemini 2.5 Pro [4.60 (4.40-4.73)] and the EAU Guidelines Bot [4.53 (4.47-4.80)], followed by ChatGPT-5 [4.27 (4.07-4.47)]. Lower composite scores were observed for Copilot - Smart GPT-5 [3.73 (3.40-3.87)] and Perplexity Pro [3.60 (3.47-3.80)]. Domain-level analysis showed consistently high median scores (≥ 4) for factual accuracy among top-performing models, whereas variability was more pronounced in clarity, structure, and clinical utility. These findings suggest that both guideline-specific systems and advanced general-purpose LLMs may generate responses broadly consistent with guideline-based recommendations in structured ED scenarios. However, variability across domains-particularly in structure and clinical utility-and modest differences in composite performance suggest that these models should be interpreted as supportive tools rather than definitive clinical decision-making systems, requiring further validation in real-world settings.
Endometriosis is characterized by inflammation and fibrosis, in which cytokines and cytokine-macrophage interactions serve as critical mediators. However, the specific mechanisms that initiate the fibrotic cascade in endometriosis remain poorly defined. Spatial transcriptomics (ST) and cellular interaction analyses were performed on human specimens of endometriotic lesions and normal endometrium. An endometriosis mouse model was used to evaluate the effect of IL-17 C neutralization with the MOR106 antibody on ectopic lesion growth and fibrosis. In vitro experiments were conducted to explore the role of IL-17 C in macrophage polarization and extracellular matrix (ECM) production by endometrial stromal cells (ESCs). IL-17RE expression was significantly upregulated in endometriotic tissues compared with normal endometrium and correlated with endometriosis fibrosis. IL-17 C levels were markedly higher in patient-derived tissues and peritoneal fluid. In a mouse model of endometriosis, neutralization of IL-17 C with the MOR106 antibody inhibited ectopic lesion growth and alleviated fibrosis in both eutopic and ectopic endometrium. Importantly, MOR106 selectively reduced CD206 + M2 macrophage infiltration in lesions without significantly altering the M1 macrophage population, suggesting that IL-17 C primarily drives M2-like macrophage accumulation in vivo. In vitro, IL-17 C promoted macrophage polarization toward a pro-fibrotic M2-like phenotype, and these IL-17 C-induced M2 macrophages enhanced ECM production by ESCs via activation of the MAPK/ERK pathway. Targeting the IL-17 C/IL-17RE axis provides a promising novel therapeutic strategy for mitigating fibrosis in endometriosis.