Which infertility treatment pathway is most cost-effective for women with polycystic ovary syndrome (PCOS)-related infertility in centres with expertise in oocyte in vitro maturation (IVM)? Cost-effectiveness analysis of treatment pathways for PCOS-related infertility using a Markov decision-analytic model. Real-life data from 517 anovulatory PCOS patients treated between January 2018 and January 2023 at a Belgian tertiary infertility clinic informed model parameters and defined the treatment-as-usual (TAU) strategy. Five pathways including incremental cycles of letrozole, low-dose gonadotropins, assisted reproductive technology (ART) after conventional ovarian stimulation (COS) or IVM were modelled and compared to TAU. Patients transitioned between treatment cycles, resulting in ongoing pregnancy or drop-out over a 24-month horizon. Costs were assessed from healthcare and societal perspectives, including direct and indirect costs. Incremental cost-effectiveness ratios (ICERs) were calculated, with sensitivity analyses performed. Ongoing pregnancy rates (OPR) after the first, fourth, and sixth letrozole cycles were 16.1%, 41.6%, and 45.7%, with minimal gain beyond 4 cycles. Deterministic analysis identified two cost-effective pathways: (a) 4 cycles of letrozole followed by 2 cycles of low-dose gonadotropins and COS, and (b) 4 cycles of letrozole followed by 2 cycles of low-dose gonadotropins, 1 cycle of IVM, and COS, with ICERs of -€8174 and -€10,805 from the healthcare perspective, and -€11,494 and -€14,083 from the societal perspective, respectively. Incorporating IVM as second-line would require a 25.7% relative OPR increase from IVM, to become the most cost-effective pathway. Probabilistic sensitivity analyses confirmed robustness. This model highlights the role of IVM as a valuable component of PCOS infertility treatment in centres of expertise, with potential for greater impact as culture systems advance.
We sought to evaluate oxidative changes in premature infants receiving 100% oxygen compared with 30% during deferred cord clamping (DCC). Premature infants born at 220/7 to 286/7 weeks received DCC in conjunction with either 30% (LO Group) or 100% (HI Group) oxygen. Blood was extracted from a preserved umbilical segment and a postnatal sample was collected from umbilical vascular lines within two hours of birth. Reduced-to-oxidized glutathione (GSH/GSSG) ratios were analyzed using liquid chromatography coupled to tandem mass spectrometry. Sixty-eight infants had data available for analysis. The median (IQR) gestational age of infants was 264/7 (246/7, 282/7) weeks in both groups. Among infants receiving 100% versus 30% oxygen, median (IQR) GSH/GSSG ratio were not statistically different in arterial cord blood [7.5 (0.6, 290) vs 37 (1.1, 265), p = 0.52] or venous cord blood [8.4 (2,50) vs 76 (5, 210), p = 0.12] or postnatal samples [14 (2, 290) vs 8 (2, 280), p = 0.98)]. Briefly providing 30% vs. 100% oxygen for 90 seconds during DCC showed no significant difference in GSH/GSSG ratios, but redox effects remain unclear given variability, sample size and limited power. Further studies are needed to ascertain potential oxidative damage during neonatal resuscitation and deferred cord clamping. THIS TRIAL IS REGISTERED ON CLINICALTRIALS. NCT04413097 IMPACT: The effect of oxygen administration during deferred cord clamping on redox status is unclear due to large variability in GSH and GSSG values and small sample size. These data provide some insights about umbilical arterial and venous oxygen levels and the effect of placenta on GSH/GSSG in preterm infants. Further basic and clinical studies are needed to better ascertain the potential for oxidative damage during neonatal resuscitation and deferred cord clamping.
Depression and anxiety are common mental disorders with substantial public health burden, yet the relative contributions of potentially modifiable physiological, psychosocial, and female-specific reproductive factors to their development remain incompletely understood, particularly across sex and age groups. We aimed to examine the associations of these factors with incident depression and anxiety in women and men and to estimate their population attributable fractions (PAFs). This prospective cohort study included 87,648 participants from the UK Biobank (44,383 women and 43,265 men) recruited between 2006 and 2010 and followed for a median of 13.7 years. Incident depression and anxiety were defined as the first recorded ICD-10 diagnosis or new-onset symptom positivity during follow-up among participants free of the respective condition at baseline. Sex-stratified Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and individual and combined PAFs were calculated separately in women and men. During follow-up, 5.65% of women and 4.21% of men developed depression, while 6.02% and 3.60% developed anxiety, respectively. Psychosocial factors contributed the largest population burden in both sexes. Neuroticism symptoms had the largest PAFs for depression (women: HR 2.61, 95% CI: 2.36, 2.88; PAF 48.61%, 95% CI: 44.71%, 52.68%; men: HR 3.50, 95% CI: 3.07, 3.98; PAF 59.93%, 95% CI: 55.41%, 64.13%) and anxiety (women: HR 2.82, 95% CI: 2.56, 3.11; PAF 51.75%, 95% CI: 47.93%, 55.68%; men: HR 2.94, 95% CI: 2.58, 3.36; PAF 53.80%, 95% CI: 48.89%, 58.62%). The additive combined PAF of psychosocial factors was 61.17% in women and 66.90% in men for depression, and 59.98% and 56.80% for anxiety. Among physiological factors, obesity contributed the largest PAF for depression in both sexes, while chronic inflammation was associated with both outcomes in both sexes. In women, reproductive factors provided additional contributions, with hormone replacement therapy showing the largest PAFs for depression (HR 1.48, 95% CI: 1.34, 1.62; PAF 13.43%, 95% CI: 10.15%, 16.84%) and anxiety (HR 1.32, 95% CI: 1.20, 1.44; PAF 9.43%, 95% CI: 6.38%, 12.80%). Age-stratified analyses showed that psychosocial contributions remained substantial across age groups, whereas physiological and reproductive contributions were more pronounced in later life. When all factors were considered jointly, the overall additive combined PAFs were 67.54% in women and 69.71% in men for depression, and 61.23% and 57.82% for anxiety. These findings support sex-informed and life course-oriented prevention strategies for depression and anxiety.
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In this prospective study, we evaluated the performance of thoracoabdominal photon-counting detector computed tomography (PCD-CT) for breast cancer assessment with MRI as reference standard and iodine uptake as a potential marker for breast cancer subtyping. 75 women (mean age: 55.8 ± 13.9 years [SD]) with 79 newly diagnosed breast cancers and indication for staging CT received a prone-positioned contrast-enhanced thoracoabdominal PCD-CT and a breast MRI. Cancer visibility (median 1/1/1, IQR 0/1/1) and image quality (median 1/1/1, IQR 0/0/0) were rated excellent in PCD-CT on a 4-point Likert scale (1 = excellent, 4 = poor). Cancer size in PCD-CT correlated significantly with MRI (p < 0.001). Diagnostic accuracy was good for T-stage (pooled accuracy 0.814), focality (0.772), axillary (0.822) and internal mammary lymph nodes (0.981), moderate for ductal carcinoma in situ (0.591). A significantly lower maximum iodine uptake was revealed in cancer with ductal carcinoma in situ (p = 0.027), a significantly lower mean iodine uptake in triple negative cancers (p = 0.003). Thoracoabdominal PCD-CT demonstrated excellent cancer visibility with convincing results for assessing cancer size, T-stage, and lymph node status. Iodine uptake shows promising associations with triple negative breast cancer.
Apoptosis plays a paramount role in endometriosis pathogenesis. This process may be disrupted in endometrial stromal cells (ESCs) of women with endometriosis, causing them to continue developing in ectopic locations. This study investigates the role of apoptosis in endometriosis by comparing the protein expression of Fas (CD95) and Fas ligand (FasL) in ESCs of women with endometriosis to that of healthy controls. Additionally, it examines the gene expression levels of Fas and FasL in peritoneal fluid mononuclear cells (PFMCs) and peripheral blood mononuclear cells (PBMCs) from both groups. Lastly, it assesses the levels of soluble FasL (sFasL) released by ESCs and PFMCs. ESCs were isolated from ectopic (n = 11) and eutopic samples (n = 17) of endometriosis patients and control (n = 10), alongside peritoneal fluid and blood samples from 10 patients and 10 controls. Using Western blot, Fas and FasL protein expression were assessed in ectopic endometrial stromal cells (EESCs), eutopic endometrial stromal cells (EuESCs), and control endometrial stromal cells (CESCs). Additionally, quantitative real-time PCR was used to evaluate Fas and FasL gene expression in PFMCs and PBMCs. Lastly, an enzyme-linked immunosorbent assay (ELISA) was conducted to assess the concentration of sFasL molecules in the supernatants of EESCs, EuESCs, CESCs, and PFMCs. Importantly, Fas protein levels in EESCs and EuESCs were lower than in CESCs (p < 0.01). Conversely, FasL protein levels were elevated in EESCs compared to both EuESCs and CESCs (p < 0.01 and p < 0.05, respectively). Additionally, patients with endometriosis exhibited higher Fas gene expression in PFMCs (p < 0.05) and lower expression in PBMCs (p < 0.01) compared to controls, along with reduced FasL expression in PFMCs (p < 0.01). Moreover, the concentration of sFasL molecules released from EESCs was significantly higher compared to EuESCs (p < 0.01) and CESCs (p < 0.05). All in all, our findings shed light on the understanding of the involvement of the Fas/FasL pathway in endometriosis pathogenesis.
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Breast density is a breast cancer risk factor. The accurate quantification of breast density requires reliable segmentation of dense tissue in mammograms, but it is a challenging task due to large variations in tissue appearance across hospitals and imaging devices. We propose MammoDenseSegNet, a new deep encoder-decoder convolutional neural network designed to enhance segmentation performance through two complementary modules: a) Adaptive dual attention module, which captures long-range spatial and channel interdependencies to provide focused attention on relevant dense tissue areas regardless of their location; and b) Multi kernel receptive field module, which enlarges the network's receptive field at the bottleneck layer to aggregate multi-scale contextual features. Additionally, a multi-scale dice loss with deep supervision guides learning across decoder levels to improve robustness. We evaluated MammoDenseSegNet on two public digital mammogram datasets (VinDR-Mammo and EMBED) and one private dataset, spanning a variety of breast densities and imaging artifacts in a total of 1499 images from 606 women. Statistical analysis was done using generalized linear models accounting for correlation among images from the same women and adjusting for potential confounders (proc genmod, proc mixed, SAS v.9.4, SAS Institute, Cary, NC). MammoDenseSegNet demonstrated consistently high performance across various conditions (with Recall ranging from 0.64 to 0.90 and Dice from 0.63 to 0.91) and significantly (p < 0.001) outperformed the publicly available state-of-the-art algorithm based on the VGG16 (with Recall from 0.04 to 0.91 and Dice from 0.06 to 0.82 across the same conditions). The improvement was largest for low-density tissue, where the baseline algorithm practically fails (with the mean Recall of 0.14 and Dice of 0.16) while MammoDenseSegNet remained clinically useful (with the mean Recall of 0.66 and Dice of 0.63).
Hepatitis C virus self-testing (HCVST) has emerged as a potential strategy to expand testing among key populations. We assessed the feasibility of HCVST in cisgender men-who-have-sex-with-men (cis-MSM) and transgender women (TGW) on pre-exposure prophylaxis (PrEP). This cross-sectional study included cis-MSM or TGW attending a PrEP consultation in Rio de Janeiro (Brazil). Participants performed HCVST using blood-based and oral-fluid kits on the same day under observation. Difficulties, errors and assistance during HCVST were recorded. Re-reading and re-testing concordance [Kappa(k)] and values/preferences were assessed. A total of 250 participants (88% cis-MSM, age = 34 [IQR,28-41] years, 42% with high education level) were included. The main steps where participants requested assistance (95%CI) for blood-based HCVST were to add buffer [35.6%(29.9-41.8)] and to collect blood sample with the dropper [34.0%(28.4-40.1)]. The main error during oral fluid HCVST was incorrect collection of oral fluid [29.6% (95%CI,24.2-35.6)]. A total of 62.4% (95%CI,56.2-68.2) and 28.8% (95%CI,23.5-34.8) participants needed assistance in at least one step of blood-based and oral fluid HCVST, respectively. Lower education level was associated with higher odds of needing assistance for blood-based HCVST [aOR = 2.07 (95%CI,1.99-3.59),p = 0.009]. Re-reading and re-testing k-indexes were 0.92 and 0.89 for blood-based, and 1.00 and 0.75 for oral fluid HCVST, respectively. More than 95% of people felt safe; would repeat or would recommend HCVST. A total of 46.4% (95%CI,40.3-52.6) preferred oral fluid versus 36.4% (95%CI,30.6-42.6) who preferred blood-based. A relatively high proportion of participants needed assistance, especially for blood-based HCVST. Despite these challenges, high re-reading and re-testing agreements were observed and HCVST was well-accepted.
Impaired ventricular-arterial coupling (VAC) is associated with adverse health outcomes. However, the predictive values of VAC calculated by different non-invasive methods remain uncertain. We aimed to assess prognostic values of VAC calculated as the ratio between arterial elastance (Ea) and left ventricular end-systolic elastance (Ees) and between carotid-femoral pulse wave velocity (PWV) and global longitudinal strain (GLS). In 3634 Atherosclerosis Risk In Communities study participants (57.4% women; mean age, 75.1 years), Cox proportional hazard models were constructed to determine associations of VAC metrics with heart failure (HF) and all-cause mortality. Risk prediction models were employed to examine prediction improvement of VAC beyond established risk factors. Over approximately 6.3 years (median), 316 participants experienced HF, and 482 died. The hazard ratios of HF related to 1-SD increment in VAC metrics were 1.28 (95% CI, 1.18-1.38; P < 0.001) for Ea/Ees and 1.40 (1.27-1.54; P < 0.001) for PWV/GLS with adjustments applied for potential confounders. PWV/GLS was the only VAC parameter associated with mortality (adjusted HR, 1.18; 1.08-1.28; P < 0.001). PWV/GLS was observed to have stronger associations with all outcomes in individuals aged ≤74 years than those aged >74 years (P for interaction ≤0.034). The addition of VAC maker to the conventional risk factors improved risk prediction for incident HF (P ≤ 0.010) assessed by C statistics, net reclassification improvement, and integrated discrimination improvement for Ea/Ees (0.702, 22.4%, and 1.40%) and for PWV/GLS (0.701, 22.1%, and 1.46%). In the general population, impaired VAC was associated with a higher risk of incident HF and total mortality.
Café-au-lait macules (CALMs) are relatively common in clinical manifestations, mostly present with 1 to 3. Multiple CALMs are unusual and may reveal underlying hereditary diseases. This article summarizes clinical features and diagnostic criteria of some CALMs-related syndromes, aiming at enhancing clinicians' awareness of CALMs, improving the early diagnosis and intervention, and reducing or preventing the occurrence of severe complications. 牛奶咖啡斑在临床上发生率较高，一般人群皮损多为1~3个，多发的咖啡斑是相对少见的，可能提示潜在的遗传性疾病。本文梳理了相关综合征的临床特点及诊断标准，以期提高临床对咖啡斑相关疾病的认知，提高早期诊断率，尽早干预，减少和预防严重并发症的出现。.
Pseudomembranous colitis due to Clostridioides difficile infection (CDI) is a serious complication of antibiotic therapy and hospitalization that can progress to toxic megacolon, necessitating emergency colectomy. Patients undergoing pancreaticoduodenectomy (PD) are particularly at high risk due to biliary obstruction, recurrent cholangitis, broad-spectrum antibiotic exposure, and prolonged postoperative stays. We report the case of an elderly woman with multiple cardiovascular comorbidities and recent CDI who underwent PD for pancreatic ductal adenocarcinoma (PDAC). Prior to surgery, she had an endoscopic retrograde cholangiopancreatography (ERCP) with duodenobiliary (DB) stent placement due to obstructive jaundice, and biopsies confirmed PDAC. Intravenous cefotaxime was initiated because of signs of acute cholangitis. She subsequently developed CDI and completed treatment with oral vancomycin, which was discontinued only 11 days before the PD. Standard prophylaxis with cefazolin was administered prior to surgery. On postoperative day (POD) 1, empirical antibiotic therapy with cefotaxime was initiated. By POD 3, she developed profuse watery diarrhea, fever, and leukocytosis, with confirmed recurrent CDI. Despite prompt fidaxomicin therapy and intensive care, she rapidly deteriorated. Computed tomography (CT) revealed severe pancolitis and toxic megacolon. Emergency subtotal colectomy with end ileostomy was performed, and histopathological examination confirmed the diagnosis. She eventually stabilized but remained frail, and the tumor board recommended best supportive care instead of adjuvant chemotherapy due to the disease stage and the severe course of CDI. This case underscores the need for early CDI testing in postoperative diarrhea following PD and for cautious perioperative antibiotic strategies in patients with recent CDI, as broad-spectrum antibiotics may precipitate fulminant recurrence.
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To explore what works for whom, how and why when implementing women's sexual and reproductive health interventions in prisons to understand the barriers and facilitators to implementation and to generate recommendations for policymakers. Realist review using the Realist And Meta-narrative Evidence Synthesis: Evolving Standards guidelines. We systematically searched Ovid MEDLINE, Global Health, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL) and the American Psychological Association (APA) PsycINFO databases and hand-searched unpublished literature and reference lists, January-June 2025. Primary studies of implementing women's sexual and/or reproductive health interventions, including those addressing sexually transmitted infections, cervical health, breast screening, contraception and women's health holistically. Study populations included people in prisons that detain women in high-income countries. We extracted and analysed data relating to implementation processes using a grounded theory approach and retroductive inference to articulate cross-case Intervention-Context-Actor-Mechanism-Outcome configurations (ICAMOCs) and refine programme theory. We discussed findings in relation to existing theories from the literature to elicit recommendations for policymakers. Of 4617 deduplicated records, 26 met the inclusion criteria. Ten ICAMOCs were constructed from cross-case analyses, grouped into three themes: (1) planning (teaming, team leadership, assessing needs and capacity, tailoring and planning), (2) doing (piloting, standardisation and support, trauma-informed engagement and peer advocacy) and (3) sustaining (evaluation-adaptation cycles). The ICAMOCs indicated three overarching mechanisms as being key to effective implementation, namely, perceived utility of the intervention, motivation and empowerment. For women's sexual and reproductive health interventions to be effective in prisons, everyone involved in implementation needs to perceive the intervention's benefit and be both motivated and empowered to take action. We recommend policymakers build a resilient and empowered delivery workforce, invest in research partnerships to increase awareness and understanding and promote trauma-informed approaches to women's healthcare in prisons.
This study advances current discourse by introducing a novel analytic framework-the global quest for genital beauty-to clarify how sociocultural ideals of vulva appearance shape motivations, meanings, and policy responses surrounding female genital cutting (FGC) and female genital cosmetic surgery (FGCS). Using a theory‑informed narrative synthesis of literature published between 2015 and August 2025 across PubMed, Scopus, and Web of Science, supplemented by seminal theoretical works and agency reports. The analysis demonstrates that although FGC and FGCS arise within distinct sociocultural systems, both are influenced by gendered expectations about bodily propriety and aesthetic norms. The review identifies substantial variations within each category: FGC encompasses procedures with differing degrees of tissue alteration and risk, while FGCS includes a growing array of elective cosmetic interventions shaped by media, pornography, and clinical marketing. An estimated 230 million women and girls in countries with available survey data have undergone FGC, requiring a 27‑fold acceleration in progress to meet the 2030 Sustainable Development Goal target, while clinical organizations report rising demands for FGCS despite limited evidence of benefit and acknowledged risks. By applying the genital beauty framework, this study reframes the comparison between FGC and FGCS, highlighting both their divergences and their shared entanglement with globalized beauty norms. This perspective supports more precise ethical, clinical, and policy guidance, including rights‑based strategies to accelerate abandonment of FGC and reduce non‑therapeutic demand for FGCS through regulation, norm‑change interventions, and education about genital diversity.
Natural products (NPs) including herbal teas are widely consumed in Malaysia but lack stringent regulation. Naturally occurring phytochemicals including estragole (genotoxic), aristolochic acids (AAs; Group 1 carcinogen) and certain pyrrolizidine alkaloids (PAs; Group 2B carcinogen) pose severe hepatotoxic and nephrotoxic risk. An integrated risk assessment using the Margin of Exposure (MOE) and the RISK21 framework was applied to 90 NPs (30 per compound). The samples were identified through National Pharmaceutical Regulatory Agency (NPRA) QUEST3 + database and analyzed using validated UPLC-DAD and LC-MS methods. Estragole, AAs, and PAs were detected in 30% (55.0-418.0 µg/g), 16.7% (8.7-2256.3 µg/g), and 36.7% (0.02-21.1 µg/g) of samples, respectively. Lifetime exposure to estragole and AAs, and eight PA-positive samples, resulted in MOE values < 10 000, indicating high priority for risk management. RISK21 characterization placed AAs in the red zone, representing unacceptable risk. Notably, half of estragole-positive products targeted women's health, raising concerns for vulnerable populations, including potential neonatal exposure via breast milk. Furthermore, simultaneous product use may result in potential cumulative effects. Malaysians face significant long-term health risks from toxic phytochemicals in NPs, particularly AAs. The integrated framework provides a critical decision-support tool to strengthen regulatory oversight and enforce stricter quality control.
To quantify systemic exposure to budesonide following intratracheal administration; evaluate the impact of intratracheal budesonide on blood glucocorticoid activity (cortisol plus betamethasone as cortisol equivalents); and relate the latter to outcomes. Sub-study of the PLUSS randomized trial(ACTRN12617000322336) of intratracheal budesonide with surfactant versus surfactant alone. Among 63 infants enrolled at Kidz First Neonatal Care, Auckland, systemic exposure to intratracheal budesonide was low, and cortisol equivalents were similar between intervention groups at 36-48 h (adjusted-ratio-geometric-means = 1.16, 95% CI 0.52-2.57). Antenatal betamethasone <24 h before birth contributed to neonatal blood glucocorticoid activity for up to 24-48 h. Infants above the upper tertile for cortisol equivalents at <60 h, compared with those below the lower tertile, had increased likelihood of severe intraventricular hemorrhage and possibly death. Systemic exposure to intratracheal budesonide has little to no effect on cortisol equivalents at 36-48 h. High glucocorticoid activity after birth may be associated with poorer neonatal outcomes.
Health inequalities by sex/gender, migration, education and income persist across Europe, yet intersectionality-informed research on how these social positions jointly shape self-rated health (SRH) remains limited. We conducted a cross-sectional analysis of the German National Cohort (NAKO; n=179 861). Sex/gender, education and income were combined with three migration characteristics (any migration, Turkish and ethnic German resettler backgrounds) into three 16-strata exposure variables. We used Poisson regression with robust SEs to estimate adjusted frequencies and relative risks of poor SRH, adjusting for age, household size and study site. Departures from additivity were assessed using two-, three-, four-way and total relative excess risk due to interaction (RERI). Poor SRH followed a social gradient. Adjusted frequency of poor SRH generally increased with each additional marginalised social position, from 6.3% (95% CI 5.5% to 7.2%) among high education and income migrant men to 22.6% (95% CI 21.3% to 23.8%) among low education and income migrant women. Adjusted frequencies were highest among participants with Turkish background. Joint exposure to female sex/gender, migration and low education and income was associated with risk of poor SRH beyond the sum of individual effects. Total RERIs for four-way intersections were 1.10 (95% CI 0.83 to 1.37) for any migration, 3.09 (95% CI 2.02 to 4.15) for Turkish and 1.62 (95% CI 0.84 to 2.41) for ethnic German resettler backgrounds. SRH in Germany exhibits pronounced intersectional inequalities. Individuals occupying multiple marginalised social positions experienced a disproportionate burden of poor SRH, highlighting the importance of intersectionality in population health monitoring.
Emerging evidence suggests a critical role of the tumor microenvironment (TME) in breast cancer (BC) development and outcomes, yet factors that modify the TME are poorly understood. We investigated the relationship between BC etiological factors and the tumor and TME using 110 histological features of the epithelium, stroma, and immune infiltration, computationally quantified in 3724 H&E slides from three prospective cohort studies. Age, race, hormonal, and lifestyle factors were associated with features of the breast TME. Menopausal hormone therapy was associated with epithelial and stromal features found in less aggressive tumors, while higher body mass index (BMI) was associated with two histological features not captured by grade, and both were associated with poor prognosis. These two features mediated the BMI and BC-specific mortality association by 18.1%. Our findings provide novel insights into the role of etiological factors on the TME including modifiable factors that have implications for prevention and outcomes.