Search Results (5,000)

Background: Obsessive–compulsive disorder (OCD) is a heterogeneous psychiatric condition with substantial heritability. Early genetic studies were often underpowered and produced limited reproducibility, but recent large-scale genomic and multi-omic approaches are beginning to elucidate the genetic architecture of OCD. Objectives: This review aims to synthesise current evidence from recent genomic and epigenomic studies on OCD and their implications for molecular pathways of pathogenesis, including endophenotypes. Methods: We reviewed peer-reviewed literature and preprints published in recent years, focusing on multiple genetic approaches, including genome-wide association studies (GWAS), whole exome sequencing (WES), whole genome sequencing (WGS), and methylome-wide association studies (MWAS). We then integrated the results with endophenotypic evidence at the biochemical, physiological, structural, functional, and executive/cognitive levels. Results: Recent large-scale genomic studies provide strong evidence of a highly polygenic contribution from common variants, while rare coding and structural variants also contribute measurably, with enriched signals in pathways relevant to neurodevelopment and, in some cohorts, early-onset presentations. Epigenomic studies have moved from scattered findings to more replicable methylation patterns, including loci influenced by nearby genetic variation and indications of sex-dependent effects. Although convergence at the single-gene level remains limited, cross-study and cross-omics signals increasingly point to biological domains involving synaptic organisation and plasticity, neurological development and chromatin regulation, immune/stress pathways, and cellular homeostasis. Conclusions: The biology of OCD risk is best represented by an integrative model combining polygenic load, contributions from rare variants, and regulatory (epigenetic) mechanisms that influence intermediate phenotypes at the circuit and cognitive levels. The current findings are not yet clinically applicable for individual diagnosis; however, they may inform future multidisciplinary research frameworks and, in the longer term, contribute to the development of more personalised approaches in OCD. Full article

Fabry disease (FD) is an X-linked systemic lysosomal storage disease caused by mutations in the galactosidase-α (GLA) gene, which encodes the α-galactosidase A (α-AGAL) enzyme. FD can lead to serious complications, including early death, if left untreated. For over 20 years, enzyme replacement therapy (ERT) based on the use of agalsidase-α and agalsidase-β has been the standard treatment for FD, alongside new molecules that have enriched the therapeutic armamentarium and others that are being tested to expand it further. Unfortunately, ERT can be associated with the formation of inhibiting antidrug antibodies (ADAs), which impact ERT clinical efficacy and have consequences affecting safety and therapeutic adherence. A group of FD specialists discussed the problem of immunogenicity in FD, analyzing the most recent literature and the strategies that are currently being used to address it. Once formed, fluctuating levels of ADAs persist and have an impact on the clinical picture and prognosis of the disease that is still the subject of lively scientific debate. The critical nature of ADAs is demonstrated by their ability to bind to the enzyme, increasing drug clearance while forming immune complexes that can build up in the tissues causing chronic inflammation that aggravates the progression of the disease and affects the onset of acute reactions after the infusion, impacting therapeutic adherence. Although similar in their therapeutic mechanism, agalsidase-α and agalsidase-β differ in their production process, with resulting differences from a pharmacokinetic and pharmacodynamic point of view and diverse immunological implications: despite showing rather overlapping efficacy outcomes, agalsidase-α demonstrates a better tolerability profile, with a lower frequency of ADAs, than agalsidase-β. Given the extreme variability of the clinical picture, it is crucial for optimal FD management that the most appropriate molecule is chosen by taking into account the unique immunological risk profile of each single patient, and particular attention should be paid to naïve subjects by periodic measurement of ADAs during therapy and cross-referencing data to correlate serological and clinical patterns. Full article

Special-shaped concrete-filled steel tube (CFST) columns are increasingly adopted as efficient vertical load-carrying members in integrated residential structural systems. However, their intrinsically nonuniform confinement promotes early local buckling and bulging of tube plates and limits deformation stability under axial compression. This study presents an experimental assessment of an L-shaped CFST column enhanced by a fully bolted threaded-rod transverse tie (RT) system, which is intended to strengthen confinement delivery and delay tube instability. Two 1500 mm-high specimens with identical cross-sectional dimensions (400 mm × 200 mm legs; 6 mm wall thickness) were fabricated using Q235 steel and C30 concrete: one conventional baseline (L1) and one RT-improved column (L2) with pre-drilled bolt holes at 150 mm spacing and installed threaded rods (10 mm nominal diameter) to provide a distributed transverse restraint. Monotonic axial compression tests were conducted under staged load control while recording the axial shortening, mid-height lateral deflection, and longitudinal and transverse steel strains. The RT detailing postponed the onset of visible local buckling, tightened the lateral deflection envelope, and increased the measured peak axial resistance from 4354 kN (L1) to 5354 kN (L2), corresponding to an increase of approximately 23%. The combined deformation and strain evidence indicates that the RT system improves the confinement effectiveness by stabilizing the tube dilation and promoting a more controlled instability evolution. Overall, the fully bolted RT approach offers a practical and fabrication-compatible pathway for enhancing the axial strength and deformation performance of L-shaped CFST columns. Full article

Background/Objective: To examine whether patients with late-onset schizophrenia (LOS) and very-late-onset schizophrenia-like psychosis (VLOS) are at a higher risk of developing dementia than patients with early-onset schizophrenia (EOS). Methods: A random sample of incident cases of patients with schizophrenia with an age of onset after age 40 (LOS) and age 60 (VLOS) was selected from a psychiatric case register covering all psychiatric services within the city of The Hague, The Netherlands, between 1997 and 2012. Schizophrenia diagnosis and age of onset were audited by systematic review of all case notes up to 2019. Patients who were initially misclassified as LOS/VLOS in the registry but, after this audit, had an age of onset before age 40, were classified as EOS. The risk of developing dementia was compared between the groups using a logistic regression model with correction for age, gender, and stroke as possible confounders. Results: Our study groups consisted of 74 patients with EOS, 81 with LOS, and 25 with VLOS. Dementia was present in 10 patients at follow-up, 7 out of 106 (6.6%) patients in the combined LOS and VLOS groups, and 3 out of 74 (4.1%) patients in the EOS group. However, after correction for confounders, logistic regression showed no statistically significant higher change in the development of dementia in LOS nor VLOS patients compared to EOS patients, nor with age of onset as a continuous variable. Conclusions: Patients with LOS and VLOS are not at a higher risk of developing dementia compared to patients with EOS. These results do not support the hypothesis that LOS and especially VLOS, are precursors of dementia. Full article

Background/Objectives: Alzheimer’s disease (AD) exhibits marked genetic heterogeneity between early-onset (EOAD) and late-onset (LOAD) forms. EOAD is typically associated with highly penetrant variants, whereas LOAD follows a polygenic architecture dominated by non-coding variation. However, the tissue-specific regulatory consequences of these variants remain insufficiently characterized. This study aimed to compare the regulatory genomic architectures underlying EOAD and LOAD using a multi-tissue integrative approach. Methods: GWAS-associated variants for EOAD and LOAD were retrieved from the GWAS Catalog using a relaxed significance threshold (p < 1 × 10⁻⁵). Variants were functionally annotated and integrated with GTEx v8 eQTL data across 13 neurologically relevant tissues and peripheral blood. Regulatory effects were evaluated using eQTL slope estimates. Basal gene expression patterns were assessed using GTEx RNA-seq data, and protein–protein interaction and functional enrichment analyses were performed using the STRING database. Results: A total of 287 variants were analyzed (32 EOAD, 255 LOAD), with minimal overlap. EOAD exhibited a highly focal regulatory profile, identifying GSE1 as the sole eQTL-regulated gene, restricted to the dorsolateral prefrontal cortex (BA9). In contrast, LOAD displayed a broad multi-tissue regulatory architecture involving APH1B, APOE, CEP63, and HAVCR2, with heterogeneous tissue-specific effects. LOAD-regulated genes converged on pathways related to γ-secretase activity, amyloid precursor protein processing, and Notch signaling, whereas GSE1-associated interactions were enriched for chromatin organization and epigenetic repression. Conclusions: EOAD and LOAD exhibit distinct regulatory genomic architectures, with EOAD characterized by focal, region-specific regulation and LOAD by widespread, tissue-dependent effects, highlighting stage-specific molecular mechanisms contributing to AD heterogeneity. Full article

Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality, most commonly arising from placental dysfunction, with increasing evidence implicating aberrant DNA methylation in its pathogenesis. To identify robust epigenetic alterations associated with FGR, we analyzed placental chorionic villi from an in-house early-onset FGR cohort and compared them with a publicly available dataset (GSE100197). DNA methylation profiling was performed using Illumina EPIC (in-house) and 450K (public) arrays, processed with identical normalization and quality-control pipelines, including adjustment for gestational age and estimation of placental cell-type composition. Differentially methylated positions (DMPs) were identified using linear regression models, revealing 10,427 DMPs in the in-house cohort and 7467 in the public dataset, with 108 shared DMPs showing consistent direction of change across both cohorts. Promoter-associated DMPs were mapped to genes involved in angiogenesis, morphogenesis, immune regulation, and transcriptional control, including EPHA1, ANGPTL6, ITGAX, BCL11B, and CYP19A1, while additional novel candidates such as SLC39A12, YEATS4, and MIR515 family members were also identified. Functional annotation suggests that these methylation changes may influence pathways essential for placental vascular development and structural organization. Overall, this cross-cohort comparison highlights reproducible epigenetic signatures of FGR and underscores the need for standardized approaches to clarify the molecular mechanisms underlying placental insufficiency. Full article

Objective: To identify risk factors for intrapartum cesarean delivery (CD) among women with obesity (BMI ≥ 30) and to evaluate whether a machine learning model (XGBoost) can improve prediction of this outcome compared with a previously developed regression-based risk score. Methods: A retrospective cohort study at a single university-affiliated tertiary medical center was conducted. All women with a pre-pregnancy BMI ≥ 30 who initiated a trial of labor between 2012 and 2024 were included. Women who underwent elective CD or had missing outcome data were excluded. Maternal, obstetric, and intrapartum characteristics were compared between women who delivered vaginally and those who required an intrapartum CD. Predictors were evaluated using extreme gradient boosting (XGBoost), and model performance was assessed using receiver operating characteristic (ROC) analysis and SHAP-based interpretability. Results: Among 146,999 women who delivered during the study period, 10,248 (7.0%) had a pre-pregnancy BMI ≥ 30. A total of 7236 obese women attempted a trial of labor, of whom 1031 (14.5%) underwent an intrapartum CD. Key predictors included limited cervical dilatation at admission, epidural anesthesia, nulliparity, maternal BMI and age, oxytocin use, birthweight, inflammatory markers (white blood count and neutrophils to lymphocytes ratio), and previous cesarean scar. The XGBoost model demonstrated excellent discriminatory ability with an AUC of 0.945 (95%CI 0.930–0.960, DeLong), and exceeded the performance of our previous regression-based score, and provided detailed insight into nonlinear effects through SHAP analysis. In a secondary analysis restricted to variables available at admission, a pre-labor model retained a strong discriminatory performance across BMI categories, supporting its applicability for early risk stratification prior to labor onset. Conclusions: A machine learning-based model accurately predicts intrapartum cesarean delivery in women with obesity and may serve as a valuable tool to support individualized counseling and delivery planning. Full article

Background/Objectives: Maternal rectovaginal carriage of Group B Streptococcus (GBS, Streptococcus agalactiae) is a major risk factor for vertical transmission and early-onset neonatal infection. Intrapartum antibiotic prophylaxis reduces early-onset disease but does not address antenatal carriage and may affect the maternal–neonatal microbiota. Microbiota-directed interventions, including probiotics, are being explored as complementary strategies. Methods: This prospective, single-centre, open-label pilot intervention study included 10 pregnant women (18–40 years) with singleton pregnancies and a positive vaginal and/or rectal GBS swab, without pre-gestational or gestational diabetes and without antibiotic use in the 4 weeks before enrolment. Participants received OMNi-BiOTiC^® FLORA plus (multi-strain lactic acid bacteria, including Lactobacillus crispatus) orally at 2 × 2 g/day from the 15th to the 34th gestational week. Microbiological swabs were obtained at qualification (12–15 weeks), mid-pregnancy (22–25 weeks), and late pregnancy (34–35 weeks). Outcomes were described descriptively. Results: Among 56 screened pregnant women, 10 were GBS-positive (17.9%) and enrolled. All participants were GBS-positive at baseline. At 22–25 weeks, 5/10 (50%) had a negative GBS result. At 34–35 weeks, 9/10 (90%) were GBS-negative, while 1/10 (10%) remained colonised. Time to first negative result ranged from 7.6 to 20.2 weeks from supplementation start (median 8.6 weeks). No recurrences (negative-to-positive transitions) were observed between the second and third sampling points. No adverse events related to supplementation were reported. In contrast, among the 46 women who were GBS-negative at screening and did not receive probiotic supplementation, 14 (30.4%) were found to be GBS-positive at routine screening performed at 35–37 weeks of gestation. Conclusions: In this pilot single-arm study, oral supplementation with a multi-strain probiotic preparation during pregnancy was associated with a time-dependent reduction in rectovaginal GBS carriage and was well tolerated. These preliminary findings support the feasibility of larger randomised controlled trials incorporating microbiome profiling and neonatal outcomes. Full article

Background/Objectives: SLC13A5 encodes a sodium–citrate cotransporter implicated in early-onset epileptic encephalopathy and metabolic brain dysfunction, yet its developmental regulation and molecular context in the human brain remain incompletely defined. Methods: Leveraging human developmental transcriptomes from the Evo-Devo resource, we delineated tissue trajectories and network context for SLC13A5 across the fetal–postnatal life. Results: In the cerebrum, SLC13A5 expression rises from late fetal stages to peak in the first postnatal year and then declines into adulthood, while cerebellar levels increase across the lifespan; liver shows a fetal decrease followed by sustained postnatal upregulation. A transcriptome-wide scan identified extensive positive and negative associations with SLC13A5, and a signed weighted gene co-expression network analysis (WGCNA) built on biweight midcorrelation placed SLC13A5 in a large module. The module eigengene tracked brain maturation (Spearman rho = 0.802, p = 8.62 × 10⁻⁶) and closely matched SLC13A5 abundance (rho = 0.884, p = 2.73 × 10⁻⁶), with a significant partial association after adjusting for developmental rank (rho = 0.672, p = 6.17 × 10⁻⁴). Functional enrichment converged on oxidative phosphorylation and mitochondria. A force-directed subnetwork of the top intramodular members (|bicor| > 0.6) positioned SLC13A5 adjacent to a densely connected nucleus including CYP46A1, ITM2B, NRGN, GABRD, FBXO2, CHCHD10, CYSTM1, and MFSD4A. Conclusions: Together, these results define a developmentally tuned, mitochondria-centered program that co-varies with SLC13A5 in the human brain across the lifespan. It may provide insights to interrogate age-dependent phenotypes and therapeutic avenues for disorders involving citrate metabolism. Full article

Colorectal cancer (CRC) is one of the leading causes of mortality worldwide, with rising cases in individuals under 50 years old, classified as early-onset CRC (EO-CRC). EO-CRC is characterized by having clinical features related to a worse prognosis and outcome. This underscores the critical need for early detection biomarkers. ncRNAs emerge as potential biomarkers for diagnosis, prognosis, and treatment response in other types of cancers. Sequencing data from the NCBI Bioproject PRJNA787417 were analyzed to identify differentially expressed miRNAs in early- and late-onset colorectal cancer (EO-CRC and LO-CRC). Differential expressions were assessed with a log fold change threshold of 1 and an adjusted p-value of 0.05. Predicted mRNA targets were identified via ENCORI and analyzed for pathway enrichment using the SHINYGO algorithm. RNA-seq analysis identified a 25-ncRNA EO-CRC signature, including hsa-miR-195 (downregulated) and hsa-miR-549a (upregulated), with enrichment analyses suggesting associations with MAPK, PI3K, VEGF, and KRAS pathways commonly linked to angiogenesis, migration, and invasion. This preliminary report highlights a 25-gene deregulated signature in EO-CRC, in which hsa-miR-195 and hsa-miR-549a emerge as biomarkers of clinical relevance, regulating key genes involved in angiogenesis, migration, and invasion. Their dysregulation could contribute to the aggressive clinical features and poor outcomes observed in EO-CRC. Full article

Background/Objectives: To assess the mental health of Chinese college students following the lifting of COVID-19 restrictions in December 2022. Methods: A three-wave cross-sectional study was conducted among students from 22 colleges in Guangdong, China, at three time points: Onset of COVID-19 (February 2020; T1; initial survey wave), during restrictions (June 2021; T2), and after restrictions (March to April 2023; T3). Participants at each wave were 164,101, 86,767, and 130,285, respectively. The standardized prevalence rates of depression, suicidal ideation (SI), anxiety, insomnia, acute stress, and fear of COVID-19 after restrictions were compared with those from the initial survey wave and restriction periods. Multivariate logistic regression was used to identify associated risk factors. Results: After restrictions were lifted, standardized prevalence rates of mental symptoms were as follows: anxiety (13.5%), depression (19.9%), insomnia (11.8%), acute stress (19.7%), fear of COVID-19 (16.2%), and suicidal ideation (31.8%). The standardized prevalence rates at T3 were higher than those at T1, with absolute increases of 10.9% for anxiety, 13.9% for depression, 9.1% for insomnia, and 23.5% for suicidal ideation. Acute stress showed a V-shaped pattern, with lower prevalence during the restriction period compared to T1, followed by an increase at T3. Fear of COVID-19 declined after the initial phase and remained stable. Students with a history of infection, those perceiving greater pandemic impact, and those who either neglected or excessively engaged in protective behaviors were at elevated risk for mental health symptoms. Conclusions: Our findings highlight the long-term adverse effects of the pandemic at the population level on Chinese college students’ mental health. Continuous monitoring, early prevention, and accessible mental health care should be prioritized in the coming years. Full article

Background/Objectives: Surgical site infection (SSI) after autologous rib cartilage microtia reconstruction is an uncommon but potentially devastating complication, as infection of the avascular cartilage framework can rapidly lead to partial or complete framework loss. Traditional management often favored aggressive debridement or framework removal, resulting in significant deformity. This study aimed to evaluate salvage-oriented management strategies and to propose a structured treatment algorithm for SSI following microtia reconstruction. Methods: A retrospective case series was conducted of patients who developed SSI after autologous rib cartilage microtia reconstruction between March 2021 and November 2025. SSI was defined by clinical and surveillance criteria requiring intervention beyond routine postoperative care. Nine patients were included. Management strategies were analyzed with respect to infection control, framework preservation, and wound healing outcomes. Results: SSI occurred at variable time points, ranging from early postoperative infection to delayed and late-onset presentations. Identified pathogens included Gram-positive cocci and multidrug-resistant Gram-negative organisms. Negative-pressure wound therapy (NPWT) was applied in all cases with wound dehiscence, persistent drainage, or cartilage exposure. Conservative staged debridement was performed only after clear demarcation of nonviable tissue. Overall auricular framework preservation was achieved in 100% of patients, with no cases requiring complete framework removal, although limited cartilage loss occurred in select cases. These outcomes demonstrate the clinical feasibility and effectiveness of salvage-oriented management across heterogeneous infection scenarios. Conclusions: SSI following autologous microtia reconstruction can be effectively salvaged without routine framework removal through a structured, timing-based algorithm emphasizing early culture-guided antimicrobial therapy, NPWT, and conservative staged intervention. This salvage-oriented approach provides a clinically relevant and reproducible framework for preserving auricular structure while minimizing morbidity, even in infections involving multidrug-resistant organisms. Full article

Background: Young-onset rheumatoid arthritis (YORA), defined by disease onset between 16–40 years, raises distinct clinical challenges related to long-term disease burden, fertility, and prolonged exposure to immunomodulatory therapy. Despite its relevance, evidence regarding treatment outcomes in this population remains limited and heterogeneous, largely due to inconsistent definitions of YORA across studies. Methods: This systematic review was conducted in accordance with the PRISMA 2020 guidelines to synthesize contemporary evidence on the efficacy and safety of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in younger rheumatoid arthritis populations. A structured search of PubMed and Embase was performed to identify studies published between 2020 and 2025 that evaluated advanced therapies in patients with young-onset rheumatoid arthritis or in rheumatoid arthritis cohorts reporting age-stratified outcomes for younger adults. Results: From the screened literature, 16 studies met the predefined inclusion criteria, including 6 studies explicitly defining YORA based on age at disease onset and 10 studies reporting outcomes in younger adult subgroups (<40–45 years). Across studies, younger patients demonstrated higher remission rates, greater reductions in disease activity, and superior treatment persistence compared with older-onset rheumatoid arthritis cohorts. Tumor necrosis factor inhibitors, interleukin-6 receptor antagonists, and Janus kinase inhibitors showed consistent clinical efficacy. Structural outcomes, reported in a limited number of studies, suggested low rates of radiographic progression in younger patients. Safety profiles were generally favorable, with infections and laboratory abnormalities representing the most reported adverse events and no age-specific safety signals being identified. Conclusions: Biologic and targeted therapies provide substantial clinical benefit in YORA and younger adult RA populations, with outcomes being generally superior to those observed in older-onset RA. However, heterogeneity in YORA definitions and limited long-term data highlight the need for prospective, age-at-onset-defined studies and extended pharmacovigilance to better inform lifelong treatment strategies. Full article

Background/Objectives: Midlife is associated with changes in body weight and fat distribution in women; however, it remains unclear whether these changes can be attributed to chronological aging, menopause, or associated lifestyle changes. The objective of this study was to compare the possible differences in body fat distribution parameters measured by regional Lunar osteodensitometry scans (DXA) between clinically healthy, BMI-matched pre- and postmenopausal women. Methods: A cross-sectional analysis of body composition parameters, such as total body, android, and gynoid fat percentage, was performed using DXA hip and lumbar scans in 171 women aged 45–55 years. Comparisons were made across 50 premenopausal (median age 47.9 (4.5) years) and 121 postmenopausal women (median age 51.7 (3.7) years), matched for median BMI (25.8 (6.7) vs. 25.6 (7.8) kg/m²). Associations between body fat outcomes and predictors were examined using multivariable linear regression. Results: No significant differences were observed between study groups in body composition parameters, including android fat percentage (%), gynoid fat%, total body fat%, or android/gynoid ratio. Unlike age, menopausal status, or years since menopause, BMI was the only significant predictor of body fat distribution. In the entire cohort, total body fat percentage showed a modest but significant positive correlation with age (ρ = 0.200, 95%CI [0.043, 0.345], p = 0.009), while the menopause onset age was positively correlated with BMI (ρ = 0.195, 95%CI [0.002, 0.369], p = 0.032). Among postmenopausal women within the first two years of menopause, the android/gynoid ratio showed a positive correlation with years of estrogen deprivation (ρ = 0.451, 95%CI [0.144, 0.707], p = 0.007). Conclusions: Age was correlated with higher total body fat %; neither age nor menopausal status was correlated with BMI. In early postmenopause, the android/gynoid ratio increased with years since menopause. The median age at menopause observed in our study was 48 years, which is lower than in other Caucasian studies. Full article

Background: Optimizing pregnancy outcomes while minimizing gonadotropin exposure and treatment burden remains a major goal in ovulation induction for intrauterine insemination (IUI), particularly for patients with polycystic ovary syndrome (PCOS) or high ovarian reserve. Sequential protocols combining early letrozole with late-onset recombinant FSH (rFSH) have been proposed to enhance efficiency while reducing medication requirements. However, real-world comparative data adjusting for baseline differences are limited. Methods: This retrospective comparative cohort study included 764 IUI cycles performed between January 2022 and October 2025. Cycles were stimulated either with conventional rFSH (n = 372) or letrozole plus late-onset rFSH (n = 392). The primary outcome was pregnancy per cycle, defined by a positive serum β-hCG. Secondary outcomes included clinical pregnancy, total gonadotropin dose, endometrial thickness, cycle cancelation, and obstetric outcomes. Confounding was addressed using multivariable logistic regression, propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and doubly robust estimation. Results: The crude pregnancy rate was higher in the letrozole plus late rFSH group compared with conventional rFSH (14.8% vs. 9.9%, p = 0.042). Women in the sequential stimulation group had higher AMH levels, higher antral follicle counts, and a higher prevalence of PCOS (32.4% vs. 16.3%, p = 0.001). After adjustment for age, ovarian reserve, and other baseline characteristics using regression, PSM, and IPTW, the stimulation protocol was not independently associated with pregnancy (adjusted OR 1.09, 95% CI 0.68–1.74; p = 0.657). Female age remained the strongest predictor of pregnancy (adjusted OR 0.70 per year increase; p < 0.001). The sequential protocol required a significantly lower total gonadotropin dose (median 375 IU vs. 750 IU; p < 0.001) while maintaining comparable cycle cancellation and safety outcomes. Conclusions: Sequential stimulation with letrozole plus late-onset rFSH achieves pregnancy outcomes comparable to conventional rFSH stimulation while significantly reducing gonadotropin requirements. After adjustment for PCOS status and ovarian reserve, the protocol itself did not independently influence pregnancy, suggesting that crude differences reflected baseline imbalances rather than true treatment effects. This approach represents a clinically efficient, gonadotropin-sparing option for IUI, particularly in patients at risk for excessive ovarian response. Full article