Original research publications

The optimal regimen for Hyperthermic IntraPEritoneal Chemotherapy (HIPEC) remains controversial. We aim to present long-term overall survival results from our phase 2 trial evaluating a concentration-based short-course regimen for ovarian cancer at the time of interval CytoReductive Surgery (iCRS). This was a multicenter, single-arm, phase 2 trial including patients with advanced ovarian cancer undergoing iCRS after neoadjuvant chemotherapy (NACT). HIPEC was administered via the closed-abdomen technique for 30 min at 41°C-43°C, comprising the use of cisplatin (25 mg/L of perfusate/m 2 , total limit 240 mg) alone, or in combination with doxorubicin (15 mg/L, total limit 90 mg). Between February 2015 and July 2019, fifteen patients were enrolled and followed for a median of 110.6 months (95% CI, 85.2 - not reached). Median overall survival was 83.9 months (95% CI, 31.3 - not reached), with a 5-year survival rate of 53.3% (95% CI, 33.2-85.6) and a restricted mean survival time truncated at 5 years of 45·6 months (95% CI, 37.2-54.0). At the time of this analysis, 13.3% were alive without disease, 13.3% remained on systemic therapy, and 73.3% had died. Concentration-based short-course HIPEC is a feasible and safe regimen for ovarian cancer patients. This approach is associated with favorable long-term overall survival, highlighting the need for head-to-head comparisons of different HIPEC regimens.

Women who experience a placental ischemic (PI) pregnancy, such as preeclampsia, have an increased risk of developing chronic kidney disease (CKD) as early as 5-20 years postpartum. The underlying mechanisms leading to this increased risk for CKD are unknown. Mechanisms that contribute to the development of CKD are hypertension and changes in renal molecular factors such as inflammation, oxidative stress, and nitric oxide (NO) bioavailability. To determine the relationship between blood pressure, renal molecular factors, and CKD in women after a PI pregnancy, we used the reduced uterine perfusion pressure model of preeclampsia in rats. In this study, two groups were utilized: normal pregnant (NP) and PI dams. At 6 weeks postpartum (∼2-3 human years), we examined the dams' blood pressure via carotid catheterization, collected the plasma to measure creatinine, and obtained the kidneys to evaluate the abundance and concentrations of renal molecular factors. PI dams exhibited an increase in blood pressure (125±3vs111±3 mmHg, p=0.002), TNF-α in the kidney cortex (81.38±1.1vs67.48±0.58 pg/mL / mg Protein, p<0.0001), and increased NO bioavailability (0.64±0.08vs0.41±0.05 µmol NO 3 /mg Protein, p=0.03) in the kidney medulla. However, serum creatinine, renal KIM-1, eNOS, NGAL, and oxidative stress did not have significant changes. In summary, PI dams have alterations in kidney inflammation and NO bioavailability, with no indications of renal dysfunction or injury. Thus, suggesting that changes in renal molecular factors may precede the onset of CKD. This study is clinically relevant, because it highlights the potential contributions of altered renal molecular factors in development of CKD postpartum.

Ovarian cancer remains a major cause of death among gynecologic malignancies because of late diagnosis, frequent recurrence, and resistance to standard chemotherapy. Drug repurposing offers a cost-effective strategy for identifying alternative therapeutic agents, but the comparative toxicodynamic effects of fenbendazole in malignant and nonmalignant ovarian cell models remain incompletely characterized. In this study, the toxicodynamic effects of fenbendazole were evaluated in malignant ovarian cell lines (OVCAR8 and A2780) and compared with those in a nonmalignant ovarian epithelial comparator (IOSE-80) using integrated in vitro approaches, with exploratory in silico analysis as supportive structural context. Fenbendazole reduced viability in ovarian cancer cells in a time- and concentration-dependent manner. At 72 h, IC 50 values were lowest in A2780, intermediate in OVCAR8, and remained above the tested concentration range in IOSE-80, yielding lower-bound selectivity indices in favor of malignant cells. Fenbendazole also increased G2/M accumulation, γ-H2AX and cleaved caspase-3 signals, and Annexin V-positive cell populations in malignant cells. These findings indicate that fenbendazole exerts preferential toxicodynamic effects in malignant ovarian cell models relative to the nonmalignant comparator used in this study. An exploratory molecular docking analysis provided limited supportive structural context for a possible tubulin-related mechanism but was not interpreted as evidence of direct target engagement.

To evaluate perioperative morbidity, factors associated with postoperative complications and documented recurrence after one-stage laparoscopic resection for multicompartment deep endometriosis. Retrospective multicentre cohort study. Two tertiary referral centres specialised in endometriosis surgery (Bern, Switzerland; Budapest, Hungary). A total of 299 consecutive patients with pathologically confirmed deep endometriosis undergoing one-stage laparoscopic resection between January 2017 and December 2025. One-stage laparoscopic resection of multicompartment deep endometriosis. Clinically relevant postoperative complications were defined as Clavien-Dindo Grade ≥ II. Multivariable logistic regression assessed associated factors. Recurrence-free survival was evaluated using Kaplan-Meier analysis in patients with an available recurrence time or censoring time. Postoperative complications occurred in 36/299 patients (12.0%), including 35/299 (11.7%) with Grade ≥ II complications and 14/299 (4.7%) with Grade ≥ IIIb complications. Greater #ENZIAN deep endometriosis anatomical extent was independently associated with clinically relevant complications (adjusted odds ratio 1.51 per additional involved compartment, 95% confidence interval 1.04-2.18). Documented recurrence occurred in 43/299 patients (14.4%) and 26/299 (8.7%) underwent reoperation for recurrence. Follow-up duration was available for 231/299 patients (77.3%). Recurrence-free survival did not differ significantly according to bowel (log-rank p = 0.431) or bladder surgical technique (p = 0.116). Greater #ENZIAN deep endometriosis anatomical extent was independently associated with clinically relevant postoperative complications following one-stage surgery for multicompartment deep endometriosis, suggesting that overall anatomical disease extent may better reflect surgical complexity than involvement of a single anatomical site. These findings support the role of anatomical disease extent in preoperative counselling and individualised surgical planning.

Although highly preventable, cervical cancer remains one of the most common malignancies among women worldwide. As part of the Global Burden of Disease study, we estimated cervical cancer incidence, mortality and disability-adjusted life-years (DALYs) across 204 countries and territories from 1990 to 2023, with forecasts to 2050. In 2023, 887,000 new cases (95% uncertainty interval 682,000-1,170,000), 369,000 deaths (292,000-475,000) and 13.3 million DALYs (10.1-17.4) were estimated globally. Age-standardized incidence rate (ASIR) and age-standardized mortality rates (ASMR) were more than four and seven times higher in low- versus high-income countries. Between 1990 and 2023, global ASIR was largely stable (-0.4% (-26.6 to 34.7)), whereas ASMR changed by -17.5% (-36.2 to 13.4). All cervical cancer DALYs were attributable to human papillomavirus infection, with tobacco use contributing 5.9% (3.2-9.3) globally. By 2050, global ASIR and ASMR are forecast to change by -12.5% (-25.7 to 3.5) and -9.0% (-21.5 to 6.6) from 2024, yet absolute cases and deaths are forecast to rise by 20.2% (4.6-38.5) and 39.3% (23.6-57.3). ASIR and ASMR are forecast to remain highest in low-income countries. Intensified action is needed to accelerate progress.

To describe the embolization technique and clinical outcomes of uterine artery embolization (UAE) for refractory postpartum hemorrhage (PPH), and to identify variables associated with clinical failure. This retrospective cohort study included 150 consecutive patients who underwent UAE for PPH at a single tertiary center (2021-2025). Clinical failure was defined as hysterectomy or repeat embolization (≥ 2 sessions). Variables associated with clinical failure were identified by univariable logistic regression and Fisher's exact test; pre-UAE transfusion was analyzed separately to assess reverse causality. Clinical success was achieved in 140/150 patients (93.3%); clinical failure occurred in 10/150 (6.7%), comprising hysterectomy in 4/10 and repeat embolization in 6/10. Uterine atony was the most common etiology (107/150, 71.3%). Additional vessel embolization was required in 47/150 patients (31.3%). In an exploratory subgroup analysis, emergency cesarean section had a higher failure rate than elective cesarean Sect. (5/32, 15.6% vs. 1/56, 1.8%; p = 0.022). On univariable analysis, higher total pRBC transfusion (OR 1.144; p = 0.003) and lower platelet count (OR 0.982; p = 0.023) were associated with clinical failure; pre-UAE transfusion was not (OR 1.168; p = 0.161), suggesting total pRBC reflects hemorrhage burden rather than antecedent risk. UAE achieved clinical success in 140/150 patients (93.3%); additional vessel embolization was required in 47/150 (31.3%). Total pRBC transfusion and platelet count were associated with clinical failure in univariable analysis; procedural variables were not. Level 4, Case Series.

Chemotherapy remains the backbone of neoadjuvant treatment for triple-negative breast cancer (TNBC), and response to chemotherapy strongly correlates with patient prognosis. However, predicting chemoresistance remains a major clinical challenge. To address this obstacle, we performed serial fine needle aspirations followed by RNA-sequencing on patient-derived xenograft (PDX) models of TNBC that were either chemoresponsive or chemoresistant. We found that these two classes of PDX models exhibited distinct transcriptional trajectories that diverged within one week of chemotherapy initiation, preceding measurable changes in tumor volume. At early time points, chemoresponsive tumors showed activation of apoptotic and cytokine-related pathways, while these changes were absent in chemoresistant models. Notably, cytokine upregulation in chemoresponsive tumors coincided with infiltration of myeloid-derived immune cells into the tumor bed within seven days of chemotherapy, indicating active microenvironment remodeling, even in mice lacking a fully intact immune system. Analysis of paired biopsies from patients with TNBC collected before treatment and within four days of the first chemotherapy dose revealed a consistent pattern: chemoresponsive tumors upregulated inflammatory pathways, whereas chemoresistant tumors showed diminished activation of these pathways. These results underscore the potential clinical value of early on-treatment tumor sampling to detect chemoresistance and guide therapeutic intervention.

Midwifery continuity of care may improve maternal mental health. Integrating this model into midwifery education may facilitate broader adoption; however, no trials examined its effects on maternal health. We aimed to assess the effect of a midwifery student's continuity of care program on fear of childbirth and postpartum depression (primary outcomes). In this trial, low-risk women at 26-29 weeks of gestation were recruited from Tabriz health centers from November 2022 to February 2023 and assigned to intervention or control groups using stratified block randomization. Twenty-five final-year midwifery students provided continuity of care (each for one to two women) from pregnancy through postpartum for the intervention group; both groups received usual care. Childbirth fear and depression were assessed using the Wijma Delivery Expectancy/Experience Questionnaire and Edinburgh Postnatal Depression Scale at baseline, and 40-50 days postpartum. Analysis of covariance, adjusted for baseline values, parity, and intended hospital type, was used to compare the groups. All 93 recruited women were analyzed; 50% were primiparous. In the intervention group (n=45), 76% attended≥6 antenatal sessions, and 64% participated in≥3 postpartum sessions provided by the students. The intervention group showed lower mean total fear of childbirth (35.8 vs. 75.8, adjusted mean difference (AMD) -43.2; 95% CI: -52.7 to -33.7) and depression scores (5.3 vs. 11.2, AMD -5.9; 95% CI: -8.1 to -3.7) than controls. The findings support further evaluation and implementation research. However, these findings should be interpreted cautiously considering the single-city design, lack of blinding, and reliance on self-reported outcomes. Iranian Registry of Clinical Trials, IRCT20100414003706N41, registered prospectively on 30 April 2022, https://www.irct.ir/search/result?query = IRCT20100414003706N41.

Evidence on the effects of maternal probiotic supplementation on postpartum mental health and neonatal outcomes in low birth weight infants remains limited. This study examined whether postpartum maternal oral supplementation with Lactobacillus paracasei 431 and Bifidobacterium lactis BB-12 (1×10⁹ CFU/day each) alleviates postpartum depression (PPD) symptoms and reduces total serum bilirubin (TSB) levels in infants weighing 1000-2000 g at birth (two primary outcomes). In this randomized, double-blind, placebo-controlled trial, women who had delivered within 48 hours and intended to breastfeed their infants received either probiotics or placebo for 42-45 days. Mothers-not infants-were the unit of randomization (stratified by twin status and birth-weight category). Postpartum depression was assessed using the Edinburgh Postnatal Depression Scale at baseline and at 42-45 days postpartum. TSB was assessed at baseline and on days 4 and 7 of the intervention. ANCOVA and repeated measures ANOVA, adjusted for baseline values and the stratification factors were used to compare the groups in terms of PPD score and TSB levels, respectively. One hundred twenty-two mothers (138 infants, including 16 sets of twins) were enrolled and randomized into two groups. After one mother dropped per group, data from 60 mothers and 69 infants in each group were analyzed. Depression scores did not differ significantly between the probiotic and placebo groups (adjusted mean difference -1.6; 95% confidence interval [CI] -3.9 to 0.69). Similarly, infant TSB levels across days 4 and 7 of the intervention showed no significant differences (0.21; 95% CI: -0.31 to 0.73). One infant death and two cases of positive blood culture occurred in each group. The maternal probiotic supplementation during breastfeeding in mothers of infants weighing 1000-2000 g at birth did not significantly affect postpartum depression or infant TSB levels. Any potential benefit of higher probiotic doses or longer intervention periods remains speculative and should be weighed against neonatal safety considerations. IRCT20100414003706N42 (registered 22 November 2022, revised 4 February 2024; https://en.irct.ir/trial/65451).

Health coaching is an innovative model of health promotion, empowering individuals to enhance self-care, make informed choices, and develop health knowledge and skills. Integrating digital technologies like mobile apps, web platforms, wearables, and artificial intelligence into health coaching enables personalized, accessible, and continuous support to improve disease management. In maternal health, digital coaching promotes healthy behaviors in nutrition, physical activity, sleep, and mental well-being. This review explores digital health coaching interventions during pregnancy and their impact on maternal and fetal outcomes. We conducted a scoping review of English-language articles from 2000 until December 2024 in PubMed, Scopus, Web of Science, IEEE, and Google Scholar. Keywords that formed the search strategy were "digital health"," health coaching ","pregnancy" along with synonyms and related terms. Thirty- one studies were included. Most interventions used smartphones, text messaging, coaching applications, virtual sessions, and wearable devices focusing on nutrition and physical activity to manage weight and gestational diabetes. Nutritionists, obstetricians, and midwives were the main contributors, using motivational interviewing, goal setting, and social cognitive theories. Outcomes showed acceptability and satisfaction in 45% of studies, feasibility in 35%, and effectiveness in lifestyle behaviors in 68%. Improvements in weight management, glycemic control, and body composition were observed in 42% of studies.10% noted benefits in maternal and newborn health. One study reported cost-effectiveness; however, some found no significant differences in gestational weight gain or diabetes. Digital health coaching in pregnancy can have favorable potential to support mothers' health and change their behavior. However, more research is needed on the most effective components, including psychological aspects and socio-economic measures.

Background: Perioperative anxiety is common in women undergoing surgery for ectopic pregnancy and may aggravate pain and delay recovery. This trial evaluated whether evidence-based nursing combined with structured psychological intervention reduces perioperative anxiety compared with routine nursing in women undergoing conservative laparoscopic surgery for tubal ectopic pregnancy. Methods: In this single-center, parallel-group randomized controlled trial, 124 women with tubal ectopic pregnancy scheduled for non-emergency conservative laparoscopic surgery were enrolled by convenience sampling and randomly assigned 1:1 to a control group (routine perioperative nursing) or an experimental group (evidence-based nursing plus structured psychological intervention). The prespecified primary outcome was the between-group difference in State Anxiety Inventory (S-AI) score on the day of discharge. Secondary outcomes were postoperative pain (Visual Analogue Scale, VAS) and short-term recovery outcomes. Results: The day-of-discharge S-AI score was lower in the experimental group than in the control group (32.61 ± 4.45 vs 38.24 ± 2.62; mean difference -5.63, 95% CI -6.92 to -4.34; P < .001), with a significant group-by-time interaction (P < .001). VAS scores at 2, 6, 12, and 24 hours after surgery were lower in the experimental group (all P < .001). First ambulation time, length of hospital stay, antibiotic use time, and menstrual recovery time were shorter in the experimental group (all P < .001). Conclusion: Evidence-based nursing combined with structured psychological intervention was associated with lower perioperative anxiety and postoperative pain and with shorter short-term recovery outcomes in women undergoing conservative laparoscopic surgery for tubal ectopic pregnancy.

Breast reconstruction is a key component of comprehensive breast cancer care, yet access remains uneven in many middle-income countries. In Brazil, federal policies have sought to expand reconstruction within the public health system (SUS), but long-term national trends remain insufficiently characterized. This study aimed to evaluate temporal trends in breast cancer-related surgical procedures and breast reconstruction hospital admissions in Brazil and to examine temporal changes associated with major federal policy measures. We conducted a nationwide ecological interrupted time-series study using administrative data from the Brazilian Hospital Information System (SIH/DATASUS) between 2008 and 2024. Annual aggregated hospital admissions for breast cancer-related surgical procedures and breast reconstruction funded by SUS were used as the unit of analysis. The primary outcome was the annual ratio of breast reconstruction hospital admissions to breast cancer-related surgical hospital admissions. Interrupted time-series analyses were performed using segmented negative-binomial regression models. Between 2008 and 2024, 312,375 hospital admissions for breast cancer-related surgical procedures and 30,049 breast reconstruction hospital admissions were recorded in the Brazilian public health system. The annual breast reconstruction admission ratio increased from 6.67% in 2008 to 19.23% in 2024, corresponding to a significant annual increase of 6.0% (p < 0.001). Temporal changes were observed following both Law No. 12,802/2013 and Ordinance No. 127/2023. Despite this increase, breast reconstruction hospital admissions remained substantially lower than breast cancer-related surgical admissions throughout the study period, and marked regional disparities persisted. Breast reconstruction hospital admissions increased substantially in Brazil's public health system between 2008 and 2024. Temporal changes coincided with major federal policy measures; however, the persistent gap between breast reconstruction and breast cancer-related surgical hospital admissions suggests continuing challenges in access to reconstructive care. Ongoing monitoring and health policies remain important to improve equitable access to breast reconstruction within SUS.

Pregnancy outcomes in frozen-thawed embryo transfer (FET) cycles are still unsatisfactory in assisted reproductive technology, and poor endometrial receptivity is a core barrier. The efficacy, effect modifiers and mechanisms of growth hormone (GH) intrauterine perfusion for FET remain unclear. This study aimed to investigate the association of GH intrauterine perfusion with pregnancy outcomes, identify key beneficiaries and preliminarily explore the potential clinical pathway for clinical precise application. A single-center retrospective cohort study was performed with 4060 FET cycles from January 2023 to December 2024. Cycles were divided into GH perfusion group and control group. One-to-one propensity score matching was used to balance 13 covariates, and 900 cycles were included. Generalized estimating equations, interaction tests, subgroup analyses, exploratory factor analysis and Bootstrap mediation analysis were adopted, and sensitivity analysis was conducted to verify result stability. Baseline covariates were well balanced after matching. The GH perfusion group had significantly higher clinical pregnancy rate and live birth rate, and lower spontaneous abortion rate. GH perfusion was independently associated with higher odds of clinical pregnancy and live birth. Patients younger than 35 years, with BMI ≥ 24 kg/m², AMH ≤ 1.1 ng/ml, thin endometrium and blastocyst transfer benefited more. Endometrial thickness-blood flow factor played a partial mediating role, and sensitivity analysis supported the robustness of results. GH intrauterine perfusion was associated with better pregnancy outcomes among FET patients in this cohort. Overweight/obese patients, those with diminished ovarian reserve or thin endometrium, and blastocyst transfer recipients appeared to gain greater relative benefit. Correlation analysis suggested this intervention might be associated with higher live birth rates through changes in endometrial thickness and blood flow profiles, while full underlying mechanisms require further investigation.

The incidence and clinical manifestations of major depressive disorder (MDD) differ between sexes. This implies distinct neuropathological mechanisms. This study aimed to investigate sex-specific brain patterns in MDD by stratifying patients according to both sex and disease course. We recruited 1170 participants (811 MDD patients and 359 healthy controls) who underwent T1-weighted and resting-state functional magnetic resonance imaging. We explored duration-stage-related, sex-specific differences in gray matter (GM), amplitude of low-frequency fluctuation (ALFF), and structural-functional coupling. We also used the structural covariance network (SCN) to assess morphological connectivity reorganization. Finally, we explored the relationship between key brain measures derived from the preceding multimodal analyses and clinical features. GM abnormalities in both sexes were observed first appeared in areas supporting sensorimotor and interoceptive functions, and later extended to areas involved in cognitive and emotional processing. Critically, we found distinct sex-specific epicentres of pathology. In male patients, the right postcentral gyrus (PoCG) exhibited early GM atrophy and decreased betweenness centrality within the SCN. In female patients, the left inferior temporal gyrus (ITG) showed early GM atrophy, increased degree centrality within the SCN, reduced ALFF values, and a two-stage evolution of structural-functional coupling with a transition lasting 3 years. Clinically, GM volumes of the right PoCG in male patients were negatively associated with insomnia-early, genital symptoms, and weight loss, while in female patients, GM volumes of the left ITG were negatively associated with depressed mood, work and interest, and psychic anxiety. This study shows a sex-specific neuropathological origin in MDD, with the left ITG serving as the core pathological area in females and the right PoCG in males. These conclusions not only advance our insight into the sex-dependent mechanisms underlying MDD but also provide a stage-informed framework for individualized interventions, suggesting that the early years of the disease may be a critical period for structure-targeted therapies.

This study aimed to characterize the physicochemical properties of exopolysaccharides (EPS) produced by vaginal Lactobacillus casei L2, Lactobacillus plantarum L4, Lactobacillus crispatus L5, and Lactobacillus rhamnosus L17 strains and to evaluate their antimicrobial, antibiofilm, anti-quorum sensing (anti-QS), and antiproliferative activities under in vitro conditions. EPS production was quantified using the phenol-sulfuric acid method, with glucose as a standard. Antimicrobial activity was assessed against selected Gram-positive and Gram-negative bacteria. Antibiofilm activity was evaluated by quantitative assays and visualized using confocal laser scanning microscopy (CLSM) and scanning electron microscopy (SEM). Anti-QS activity was determined using Chromobacterium violaceum ATCC 12,472 as an indicator strain. Antiproliferative effects were analyzed in the MDA-MB-231 breast cancer cell line. All EPS preparations exhibited varying degrees of antimicrobial and antibiofilm activity, with L17 demonstrating the strongest biofilm inhibition. EPS derived from L2 and L17 strains showed marked quorum sensing inhibitory effects. In the MDA-MB-231 cell line, EPS from L2 and L17 reduced cell viability in a dose-dependent manner, with maximal inhibition observed at 85 µg/mL. These findings demonstrate that EPS derived from vaginally derived Lactobacillus spp. species possess strain-dependent biological activities, particularly in antibiofilm effect and regulation of quorum sensing. Further structural and mechanistic studies are needed to elucidate their functional potential.

Menstrual hygiene management remains a critical public health issue, with male attitudes being key drivers of menstrual stigmatization. In male-dominated industries like construction, awareness and empathy toward menstrual hygiene are alarmingly low, perpetuating discrimination and poor health outcomes for women. This study aimed to evaluate the effectiveness of the Men for Menstruation-Care and Concern (MFM-CC) Tool on awareness toward menstrual hygiene among male construction site workers in the Mumbai Metropolitan Suburban Region of Maharashtra, India. A single-arm pre-post bio-behavioral intervention study was conducted among 482 construction workers (213 from MS East, 269 from MS West) between November 2024 and February 2025 using the novel MFM-CC Tool. The intervention comprised a standardized audiovisual health education model in the local language and a 15-item questionnaire administered pre- and post-intervention to assess awareness of menstrual hygiene. Significant improvements were observed across all awareness parameters. Awareness of monthly menstruation frequency increased from 10.0% to 97.3% ( p < .001). Recognition of sanitary pads as ideal menstrual hygiene products improved from 10.0% to 100.0%. Willingness to discuss menstrual health with female family members rose from 10.2% to 96.5%. Support for workplace menstrual health facilities increased from 19.9% to 89.2% ( p < .001). Mean awareness scores significantly improved from 2.20 ± 1.47 to 10.70 ± 0.86 ( p < .001). The MFM-CC Tool was effective in improving menstrual hygiene awareness among male construction workers and demonstrated its potential as a replicable approach for promoting male engagement in menstrual health advocacy.

Systemic combination chemotherapy for cervical cancer is often limited by poor drug solubility and high toxicity. Over the past decade, there has been growing interest in local therapy using hydrogel-based drug carriers that remain at the site of the lesion, thereby reducing side effects. However, to date, research has been limited mainly to in vitro studies. In this study, we demonstrate the use of dynamic hydrogels to ensure effective delivery of water-insoluble drugs for in vivo anti-cervical cancer therapy in a mouse model. The main structural component of the hydrogel was a non-linear poly(benzyl glycidyl ether)-poly(glyceryl glycerol ether) copolyether, which increases the solubility of the poorly water-soluble clotrimazole and nifuratel and enables reversible cross-linking, confering injectability and self-healing behavior to the hydrogel. Two-dose intratumoral implementation of hydrogel formulations resulted in a superior effect in the reduction of the tumor volume by > 90% within a 14-day therapy. Unexpectedly, 50% of the mice with induced tumors were completely cured with a hydrogel constructed of copolyethers, whose molar ratio of constitutional repeating units of GGE to BGE was equal to 2:1. The drug loading of both drugs can be a key parameter crucial for the achievement of the superior efficacy of this formulation, making it a highly therapeutic delivery system. The use of copolyethers enhanced controlled drug delivery, as evidenced by a statistically significant reduction in tumor volume (p < 0.001) compared to the efficacy of pure drugs (> 0.05). Furthermore, copolyether-based formulations provide a safer therapeutic alternative to pure drugs. This was confirmed by blood biochemical analyses, which showed no increase in LDH or CRP levels, and by histopathological evaluations of mouse livers, which demonstrated that, unlike pure clotrimazole, the formulations do not induce liver damage. The high yield point detected for hydrogel and the strong mucosal adhesion of the synthesized hydrogels up to 18.7 kPa allow the formulation to remain at the target site. Surprisingly, we observed that incorporating clotrimazole into the hydrogel significantly increased mucosal adhesion strength. Permeability investigations performed on ex vivo porcine vaginal mucosa showed a sustained permeation reaching 40% and 25% of permeated nifuratel and clotrimazole, respectively. The presented dual drug-loaded dynamic hydrogels are highly promising for clinical use in cervical cancer treatment.

Dolutegravir is central to antiretroviral therapy in pregnancy, although conventional pharmacokinetic measures cannot fully explain variability in maternal cardiometabolic outcomes or fetal exposure. This narrative review proposes an integrated omics framework linking pharmacogenomics, transcriptomics, proteomics, and metabolomics with longitudinal pharmacokinetics and clinical phenotyping. Using dolutegravir as a case study, we examine genetic determinants of drug disposition, gestational changes in molecular pathways, and emerging evidence implicating adipose dysfunction, mitochondrial metabolism, lipid remodeling, and insulin resistance. We distinguish established pharmacokinetic findings from mechanistic hypotheses requiring pregnancy-specific validation. Proposed studies combine serial maternal sampling, targeted placental and adipose investigations, and offspring follow-up, while accounting for HIV, antiretroviral backbone, gestational physiology, and environmental confounding. Prespecified analyses, analytical validation, and independent replication are essential to avoid overinterpretation. Integrated omics should complement, not replace, pharmacometrics, ultimately identifying reproducible mechanisms and clinically useful biomarkers to inform individualized monitoring and treatment strategies while preserving dolutegravir's proven virologic benefits.

To evaluate pregnancy outcomes following maternal pramipexole exposure using data from the Izmir Kâtip Celebi University Teratology Information, Training and Research Center (TERAFAR). Pregnant women exposed to pramipexole and referred to the TERAFAR between 2011 and 2025 were evaluated. Maternal demographic data, medical history, and exposure details were recorded at the initial visit; pregnancy outcomes and neonatal data were collected through postpartum telephone interviews. The primary outcome was the rate of major congenital malformations, while secondary outcomes included miscarriage, stillbirth, preterm birth, and low birth weight. A total of 11 pregnancies were evaluated. Median maternal age was 36 years, and restless legs syndrome was the primary indication in 10 of the 11 pregnancies. The median daily dose was 0.25 mg. Of the 11 pregnancies, 10 resulted in live births and one ended in miscarriage. No major congenital malformations were observed. A minor congenital anomaly (infantile hemangioma) was detected in only one premature infant. In this case series, maternal exposure to pramipexole was not associated with a consistent pattern of congenital anomalies suggestive of a teratogenic signal. Given the clinical context, the minor anomaly observed (infantile hemangioma) is more likely attributable to prematurity and maternal factors than to pramipexole exposure. Given the small sample size, findings should be interpreted with caution but may inform individualized counseling of pregnant women with inadvertent pramipexole exposure. Further studies are warranted.

Breast cancer is a highly common malignancy in women, with bone as its most frequent site of distant metastasis significantly increasing mortality risk. This study integrated single-cell RNA sequencing datasets (GSE266330 and GSE243526) to systematically characterize the tumor microenvironment across normal tissue, primary tumor, and bone metastasis in breast cancer. In total, 141 056 high-quality single cells were analyzed from an integrated cohort comprising a bone-metastasis dataset (GSE266330) and a primary/normal breast dataset (GSE243526), identifying 11 major cell types. Within the bone-metastatic cohort, we identified a macrophage subpopulation highly expressing SPP1 (Mac-SPP1) that exhibited an M2-polarized signature and elevated metabolic gene-set enrichment, and that expressed transcription factors such as HOXA9 and MAF. We also identified CD4-S100A9 and CD8-GZMK T-cell subpopulations with high cytotoxicity, high exhaustion, and metabolic reprogramming. Pseudotime analysis positioned CD4-S100A9 cells at one end of the inferred CD4+ T-cell trajectory and CD8-GZMK cells at an intermediate node along the inferred CD8+ T-cell trajectory. Cell-cell communication analysis predicted that Mac-SPP1 interacts with these T-cell subsets through the SPP1-integrin (e.g., SPP1-CD44) and CD74-MIF/COPA signaling axes. This study provides a single-cell characterization of the breast cancer bone-metastatic microenvironment, identifying an SPP1-expressing macrophage subset (Mac-SPP1) and predicting its interactions with CD4-S100A9 and CD8-GZMK T cells. Because the bone-metastatic and primary/normal specimens derive from different datasets, these findings are descriptive and cannot be attributed to metastatic progression alone and require experimental validation and confirmation in cohorts that profile primary and metastatic specimens within a single study.

To evaluate the association between hypertensive disorders of pregnancy (HDP) and neurodevelopmental outcomes among children aged approximately 36 months in a rural area of Bangladesh. The study was based on HDP cases identified within a pregnancy cohort conducted between April 2015 and March 2018. Children born to HDP-exposed mothers (n=173) and a randomly selected group of HDP-unexposed mothers (n=350) were assessed for cognitive, language and motor development using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), between November 2019 and July 2021. Multiple linear regression analysis was used to examine the associations and results were reported as adjusted mean differences in composite scores (β coefficients) with 95% CIs. Overall, children born to mothers with HDP had lower mean composite scores for cognitive (β=−1.14, 95% CI −2.06 to −0.22), language (β=−1.54, 95% CI −2.56 to −0.52) and motor (β=−2.52, 95% CI −3.95 to −1.08) development compared with children of HDP-unexposed mothers. Significant associations were also observed across several developmental subdomains. When analyses were stratified by specific HDP types, the effects were more pronounced among children exposed to chronic hypertension, whereas no significant association was detected for exposure to pre-eclampsia. HDP were associated with impaired neurocognitive development among children in a rural area of Bangladesh. The strength of these associations varied across developmental domains and by specific HDP types.

To develop a non-invasive PET/CT imaging strategy for triple-negative breast cancer (TNBC) patients by targeting Sortilin (SORT1) protein, a promising therapeutic target lacking companion diagnostics, we synthesized two novel 68 Ga-labeled peptide radiotracers, 68 Ga-FZ-SR-1 and 68 Ga-FZ-SR-2, achieving high radiochemical purity (>95%). In vitro evaluation was carried out using MDA-MB-468 (high SORT1 expression) and MDA-MB-231 (low SORT1 expression) TNBC cell lines to assess stability, binding affinity, and uptake specificity. In vivo pharmacokinetics and tumor targeting were assessed by microPET/CT imaging and ex vivo biodistribution in MDA-MB-468 and MDA-MB-231 xenografts. 68 Ga-FZ-SR-1 demonstrated slightly higher tumor-targeting efficiency and contrast-to-noise ratios compared to 68 Ga-FZ-SR-2. Moreover, 68 Ga-FZ-SR-1 exhibited favorable tumor targeting, rapid renal clearance and favorable in vivo pharmacokinetic properties, selected for further evaluation. Ex vivo histology further revealed good consistency between radiotracer accumulation and intratumoral SORT1 expression. In summary, this proof-of-concept study demonstrates the feasibility of 68 Ga-FZ-SR-1 for the noninvasive visualization of SORT1, providing an exploratory foundation for SORT1-targeted diagnostic and therapeutic strategies in TNBC.

Intrahepatic cholestasis of pregnancy (ICP) is associated with significant maternal morbidity and fetal risk. We describe a 31-year-old primiparous patient with quiescent systemic lupus erythematosus and lupus nephritis on azathioprine, hydroxychloroquine, and tacrolimus who developed generalized pruritus at 29 weeks. Workup showed markedly elevated bile acids (234 µmol/L) with mild alanine aminotransferase elevation. She was diagnosed with ICP and started on ursodiol and hydroxyzine, but symptoms persisted. Given reports of thiopurine-associated cholestasis, the medication was discontinued, and 6-methylmercaptopurine levels were found to be supratherapeutic. Within days, bile acids and pruritus improved, with normalization over three weeks. She remained asymptomatic, delivered at 36 weeks, and later resumed azathioprine without issue. We summarize 17 cases of thiopurine-associated cholestasis, typically with early onset, severe bile acid elevation, and poor response to ursodiol. This case highlights the importance of medication review, and assessment for possible secondary contributors in atypical or refractory ICP presentations.

Cervical cancer is the leading cause of cancer mortality for women in Uganda, yet fewer than a third of Ugandan women have ever been screened. Screen-and-treat programmes using visual inspection with acetic acid (VIA) are a key prevention strategy. Current guidelines recommend screening for women aged 25-49 every 3 years. However, there is limited evidence comparing the trade-offs between health gains, costs and implementation feasibility across alternative programme designs at scale. We conducted a cost-effectiveness and budget impact analysis of 30 VIA screen-and-treat cervical cancer policies using a microsimulation parameterised to represent Ugandan women aged 25-49 over a 15-year time horizon. Policies varied across three implementation dimensions: (1) screening frequency, (2) screening uptake among eligible women and (3) treatment follow-through for precancerous lesions. We estimated population-level costs, deaths averted, quality-adjusted life years (QALYs) gained and incremental cost-effectiveness ratios (ICERs). We found that, depending on screening frequency, uptake and treatment follow-through, between 13% and 50% of deaths could be averted compared with the base case (current levels). The 15-year total costs ranged from $32.9 million to $158.6 million, or $5 to $23 per eligible woman. Both incremental costs and deaths averted increased at a diminishing rate as screening intensified. Policy scenarios with lower levels of treatment were dominated by those with higher treatment follow-through, regardless of screening uptake. ICERs ranged from $88 to $313 per QALY gained, and $2219 to $6881 per death averted. The most effective and efficient policy scenarios were not simply those with the highest levels of screening or treatment, but those that optimally configured all three programme levers simultaneously. The findings revealed interactive effects of screening frequency, uptake and treatment follow-through on costs and health outcomes. These results equip Ugandan policymakers with context-specific evidence to prioritise screening policies that balance health impact, cost and implementation capacity.

To evaluate the prevalence of abnormal glucose tolerance at six weeks postpartum among women with gestational diabetes mellitus (GDM) and to evaluate the agreement between early postpartum and six-week postpartum oral glucose tolerance test (GTT). This prospective repeated-measures study included Thai women with singleton pregnancies, no pregestational diabetes, and a diagnosis of GDM. Participants were consecutively recruited upon admission to the labor and delivery unit. All participants underwent a 75 g, 2-hour GTT both during the immediate postpartum prior to hospital discharge and at six weeks postpartum. Glucose tolerance status was categorized as normal glucose tolerance and abnormal GTT. Agreement between the two testing periods was evaluated using Cohen's kappa coefficient. A total of 158 women were included in the analysis. The prevalence of abnormal glucose tolerance at six weeks postpartum was 44.9% (71/158), including impaired GTT in 66 women (41.8%) and diabetes mellitus in 5 women (3.2%). Among women with abnormal GTT at six weeks postpartum, 42.3% (30/71) had normal early postpartum results. Conversely, 44.6% (33/74) of women with abnormal early postpartum findings demonstrated normal GTT at six weeks. The Cohen's kappa coefficient was 0.197, indicating poor agreement. Agreement for diabetes mellitus diagnosis was similarly low (kappa = 0.201). Early postpartum OGTT demonstrated poor agreement with six-week postpartum testing and showed limited utility as a standalone screening strategy for postpartum dysglycemia among women with GDM. Early postpartum testing may not accurately reflect glycemic status at 6 weeks postpartum, potentially leading to misclassification.

Polycystic ovary syndrome (PCOS) is a prevalent endocrine and reproductive disorder in women of childbearing age. Chronic inflammatory status is common among PCOS patients, and numerous studies have verified that this population exhibits dysregulated inflammatory cytokines and immune cell imbalance. Such inflammatory disorders are characterized by aberrant expression of pro-inflammatory cytokines, inflammasomes and inflammatory markers. These abnormalities not only impair the female reproductive system and trigger pathological conditions including irregular menstruation and infertility, but also exert long-term adverse impacts on multiple systemic organs such as the liver and cardiovascular system. Hyperandrogenism, insulin resistance, hyperinsulinemia, obesity, gut microbiota dysbiosis and hypothalamic-pituitary-ovarian axis dysfunction observed in PCOS patients can all induce inflammatory dysregulation. In recent years, bioactive constituents of traditional Chinese medicine (TCM) have been widely adopted in the clinical management of PCOS with remarkable therapeutic efficacy. Starting from the prevalent inflammatory phenotype in women with PCOS, this review elaborates on the pathological correlation and underlying mechanisms between PCOS and inflammation. It summarizes the roles of five inflammation-related signaling pathways (NF-κB, PI3K/Akt, NLRP3, JAK/STAT, and AMPK) and the mechanisms of action of 18 TCM bioactive constituents that target these pathways in PCOS-related inflammation, providing a reference for future PCOS research directions and therapies.

Concurrent chemoradiotherapy (CCRT) remains the standard of care for locally advanced cervical cancer (LACC); however, 30-40% of patients experience recurrence, prompting evaluation of systemic treatment intensification to improve outcomes over CCRT alone. This critical review synthesizes evidence from PubMed, Embase, and the Cochrane Library up to January 2026, evaluating clinical trials of intensification strategies categorized by treatment timing: neoadjuvant, concurrent, and adjuvant modalities. Historical attempts to intensify treatment through adjuvant chemotherapy have failed to confer survival benefits with the regimens studied, often increasing toxicity without efficacy (OUTBACK). However, recent Phase III trials have reported survival benefits with specific treatment regimens. Specifically, induction chemotherapy followed by CCRT (INTERLACE) and pembrolizumab with CCRT followed by maintenance (KEYNOTE-A18) have demonstrated significant improvements in overall survival, whereas additional concurrent cytotoxic agents have not consistently improved outcomes and may increase toxicity. CCRT remains the cornerstone; intensification should follow the tested regimen, eligibility criteria, and toxicity profile. PD-L1-based selection and the independent benefit of adjuvant immunotherapy require further validation.

To develop and internally validate stage-specific models for predicting subsequent pregnancy loss in women with recurrent spontaneous abortion (RSA), and to evaluate changes in discriminatory performance associated with the sequential incorporation of sequentially available clinical, biochemical, hormonal, and environmental information. In this single-center prospective cohort study, we developed and internally validated three stage-specific models for subsequent pregnancy outcomes. The first-stage model included baseline demographic and reproductive variables; the second-stage model further incorporated preconception serum 25-hydroxyvitamin D (25(OH)D); and the third-stage model additionally included gestational age, prenatal hormonal indicators, and pregnancy-course ambient PM 2.5 and O 3 exposure metrics. Logistic regression (LR), random forest (RF), and extreme gradient boosting (XGBoost) models were developed and internally validated using repeated 10-fold cross-validation. Model performance was assessed using ROC-AUC, PR-AUC, Brier score, sensitivity, specificity, and F1 score. Among 470 women with RSA who subsequently conceived, 86 (18.3%) experienced pregnancy loss again. In RF and XGBoost models, discrimination improved most clearly after incorporating gestational age, prenatal hormonal indicators, and ambient PM 2.5 and O 3 exposure metrics, whereas the addition of preconception 25(OH)D alone provided little incremental value. In internal validation, the RF-based third-stage model achieved the highest discrimination, with a ROC-AUC of 0.935 (95% CI: 0.874~0.996). The XGBoost-based third-stage model also demonstrated improved discrimination, with a ROC-AUC of 0.870 (95% CI: 0.801~0.938). A stage-specific prediction framework integrating sequentially available clinical, biochemical, and pregnancy-course environmental information improved discrimination for subsequent pregnancy loss among women with RSA, particularly in tree-based models. These findings provide preliminary evidence that progressively incorporating information from different stages of the subsequent pregnancy may improve risk discrimination beyond baseline characteristics alone. However, these findings were derived from internal validation within a single-center cohort, and the third-stage model was limited by a reduced sample size, a small number of pregnancy-loss events, reliance on complete-case analysis, and the use of outcome-anchored environmental exposure metrics that were not available at a predefined prediction time. External validation in larger, independent cohorts and prospective evaluation using exposure windows aligned with a predefined prediction time are needed to determine the robustness and clinical utility of the framework.

Breast cancer, including subtypes with limited treatment options, remains a formidable global health challenge. While conventional therapies often suffer from severe off-target toxicity and the rapid development of drug resistance, emerging phototherapies are limited by poor tissue penetration and monotherapy inefficiency. To overcome these clinical hurdles, there is a critical need for multifunctional, multimodal therapeutic platforms. Here, we present mesoporous polydopamine-curcumin nanoparticles (MPDA-Cur) as a multimodal nanoplatform featuring pH-responsive chemotherapy alongside NIR-triggered synergistic photothermal/photodynamic therapy (PTT/PDT) and enhanced ROS generation. MPDA-Cur was synthesized via dopamine polymerization and curcumin loading, yielding spherical nanoparticles (119.21 ± 13.5 nm) with pH-dependent drug release (54.1% at pH 5.5 vs. 40.9% at pH 7.4) and enhanced reducing/phenolic redox activity. Under 808 nm NIR irradiation, MPDA-Cur generated localized hyperthermia (ΔT ≈ 30.8 °C) and increased reactive oxygen species (ROS) production, which, together with curcumin-mediated chemotherapy, resulted in approximately 70% cell death in MCF-7 cells, with Annexin V/PI staining indicating apoptosis as a major mechanism of cell death. Quantitative H₂O₂ measurement further showed that MPDA-Cur plus NIR irradiation significantly increased intracellular H₂O₂ levels relative to non-irradiated controls. The nanoplatform exhibited greater cytotoxicity toward MCF-7 cells than toward L-929 fibroblasts under the tested in vitro conditions, while L-929 viability remained >80%, and also demonstrated hemocompatibility. By integrating pH-responsive curcumin release with NIR-triggered photothermal and ROS-associated photodynamic effects, MPDA-Cur addresses several limitations of conventional monotherapies in vitro. This work establishes MPDA-Cur as a promising multifunctional platform for further preclinical investigation in multimodal breast cancer therapy.

GIM/FP/GP: [Formula: see text].