Aim: improve the effectiveness of treatment for patients with COPD in the acute phase with clinical and laboratory manifestations of endogenous intoxication by including carbon or organosilicon sorbents in complex therapy. Materials and Methods: To evaluate the effectiveness of enterosorption therapy in the complex treatment of patients with COPD in the acute phase with clinical and laboratory manifestations of endogenous intoxication, patients were divided into three groups according to severity. The first group consisted of 34 patients (21.9%) with mild bronchial obstruction (GOLD 1), the second group included 64 patients (41.3%) with moderate bronchial obstruction (GOLD 2), and the third group included 57 patients (36.8%) with severe bronchial obstruction (GOLD 3). The control group consisted of 20 healthy people aged 40 to 78 years. The following exclusion criteria were used: the presence of diabetes mellitus, acute coronary syndrome, previous myocardial infarction, rheumatological pathology, oncological and infectious diseases, acute inflammatory processes of any localization in patients. Results: COPD in the exacerbation phase is accompanied by clinical and laboratory manifestations of endotoxicosis, more pronounced in patients with severe broncho-obstruction. This is manifested by an increase in the content of endogenous intoxication indicators in blood serum (molecules of medium weight by 84% and 126% (p<0.001) and erythrocyte intoxication index by 86% (p<0.001)). There is a direct correlation of mean strength between the severity of the disease and the level of MSM254 and MSM280 (r=0.496 and r=0.557, p<0.01) and weak strength - with an erythrocyte index of intoxication (r=0.253, p<0.01). COPD in the exacerbation phase is accompanied by the activation of free radical processes, most pronounced in patients with severe broncho-obstruction, manifested by a probable increase in malondialdehyde - by 116% (p<0.001) and a decrease in the activity of superoxide dismutase - by 59% (p<0.01) compared to the control. There is a direct mean strength correlation between severity and malondialdehyde levels (r=0.486, p<0.01) and inverse with serum superoxide dismutase (r=-0.500, p<0.01). MDA content in blood serum increases, SOD activity decreases with increasing age of patients. Conclusions: COPD exacerbation accompanied by clinical and laboratory manifestations of endogenous intoxication, namely increasing concentrations of malondialdehyde and superoxide dismutase activity decrease depending on the severity and age of bronchial patients. With the progression of the disease also increases the content of interleukin 1β and 10, tumor necrosis factor α, circulating immune complexes, immunoglobulin E and reduced lysozyme activity in serum, in proportion to the increase in the severity of the disease. The use in treatment of 10-day course enterosorbtsiynoyi therapy using carbon (karbolaynu) or silicone (enterosgel) enterosorbent in treatment of patients with COPD exacerbation is accompanied by a decrease in clinical and laboratory manifestations of endotoxemia, such as cough, shortness of breath, discharge of phlegm, weakness and significant reduction of the average molecular weight and erythrocyte intoxication index, malondialdehyde, interleukins, immunoglobulin E and circulating immune complexes and increased activity of SOD and content of lysozyme in serum.
Autistic people with communication support needs can benefit from the use of augmentative and alternative communication. While research has considered the use of AAC to supplement communication and improve communication effectiveness, less is known about other potential outcomes across the lifespan such as wellbeing and social interaction. The aim of this systematic review was to synthesise current research regarding the use of AAC for autistic adults and children; exploring how AAC supports the individual's communication, adaptive functioning and quality of life. A systematic search was conducted across six databases; PsychINFO, Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Scopus, Educational Resources Information Centre (ERIC), and Google Scholar. Eligibility criteria included experimental design, peer-reviewed publications and papers published in English after 2013. Relevant papers were exported to Covidence; screening, full text review and data extraction were conducted in duplicate and quality appraisal was completed for all papers using the Scientific Merit Rating Scales (SMRS). Included studies were grouped by age, intervention types, AAC types and reported outcomes, and described qualitatively. The 69 included papers focused on a range of AAC types. The majority investigated speech-generating devices and low-tech picture exchange. Most used behavioural intervention techniques. Most papers focused only on children, with only three papers investigating outcomes of AAC use with adults. The results were largely descriptions of proximal outcomes, such as simple requests, with few considering generalisation of skills or distal outcomes such as quality of life. The quality of the papers was generally low, with limitations in study design and diagnostic ascertainment noted. AAC has the potential to be an important support for autistic people, however, evidence regarding the impact on the broad range of communication functions and quality of life is very limited. A greater focus on the impact of AAC on these areas is needed in both research and practice along with a stronger focus on adults and a greater range of AAC types. PROSPERO number: CRD42023473247 WHAT THIS PAPER ADDS: What is already known on this subject The use of augmentative and alternative communication (AAC) with autistic adults and children is an established practice. Previous research has shown some effectiveness related to the specific goals being studied but it has centred mostly on children, and most research has focused on making requests, rather than broad communication or life outcomes. What this paper adds to existing knowledge This study explores the literature about autism and AAC and seeks to specifically examine the range of outcomes reported. We found that most of the research on this topic continues to focus on children, aided rather than unaided communication, and on outcomes related directly to the intervention, such as making requests. Very few studies included measures of generalisation or considered broader outcomes of AAC supports, such as quality of life, or enhanced social interactions. What are the potential or actual clinical implications of this work? Clinicians and researchers should consider the potential for broader impacts of AAC and ensure that goals focus on skills beyond immediate functions to areas such as quality of life, well-being, learning and employment, and the development of social relationships. Clinicians and researchers should also ensure that AAC interventions are offered to not only children, but also to autistic adults who may benefit from communication supports.
Objective: To evaluate the screening efficiency of gene DNA methylation testing, p16 staining, human papillomavirus (HPV) genotyping, and liquid-based cytology (LBC), and their combined strategies in self-collected high-risk HPV (HR-HPV) positive individuals. Methods: This study analyzed a subset of data from a free self-sampling cervical cancer screening program conducted in Baise, Guangxi Zhuang Autonomous Region (from May 2023 to April 2024). HR-HPV positive self-collected cases with complete data and quality control were included. Using the triage strategy recommended by the 2019 American Society for Colposcopy and Cervical Pathology (ASCCP) risk-based management guideline and the Chinese cervical cancer screening guideline [ie, HPV16/18 positivity and (or) LBC of atypical squamous cell of undetermined significance (ASCUS) or worse] as reference standard, the sensitivity, specificity, colposcopy referral rate, and the number needed to colposcopy (NNC) of various secondary triage approaches were assessed. Results: (1) A total of 777 HR-HPV positive women with complete data were analyzed. (2) Methylation positivity was significantly higher in high-risk group HPV16/18 (20.5%, 25/122) and high-intermediate-risk group HPV31/33/35/45/52/58 (17.2%, 66/381) than that in the low-risk group HPV39/51/56/59/66/68 (9.6%, 26/371; χ²=8.85 and χ²=7.59, P=0.003 and P=0.006). (3) Methylation positivity of cervical intraepithelial neoplasia (CIN)Ⅲ and cervical cancer cases (67.5%, 27/40) was significantly higher than CINⅠ cases (12.9%, 31/240), and CINⅡ cases (16.4%, 12/73), with statistically significant differences (P<0.05). The p16 positivity increased with lesion severity in all pairwise comparisons (P≤0.005 after correction). (4) When the guideline-recommended triage strategy [HPV16/18 positivity and (or) LBC≥ASCUS] was applied to this study population, using colposcopy-directed biopsy pathology as the reference standard, the sensitivity and specificity for detecting CINⅡ+ and CINⅢ+ were 69.03%, 65.21%, and 95.00%, 63.23%, respectively; the colposcopy referral rate was 39.77% (309/777), and NNC was 3.96 for CINⅡ+ and 8.13 for CINⅢ+. (5) Methylation performance: for CINⅡ+, sensitivity was 34.51% and specificity was 88.25%; for CINⅢ+, sensitivity was 67.50% and specificity was 87.79%. (6) p16 performance: the sensitivity for detecting CINⅡ+ and CINⅢ+ were 72.57% and 92.50%, respectively, which did not differ significantly from the guideline-recommended strategy (all P>0.05), whereas the specificity for CINⅡ+ and CINⅢ+ were 68.67% and 65.60%, respectively, similar to the guideline-recommended strategy (all P>0.05). The colposcopy referral rate was lower with p16 testing alone compared with the guideline-recommended strategy [37.32% (290/777) vs 39.77%; P>0.05]. (7) Combined strategy 3a achieved a sensitivity of 63.72% for detecting CINⅡ+, which was similar to the guideline-recommended strategy (P=0.109), and a sensitivity of 95.00% for detecting CINⅢ+, identical to that of the guideline-recommended strategy. The specificity of strategy 3a for CINⅡ+and CINⅢ+ were 70.18% and 68.52%, respectively, both significantly higher than those of the guideline-recommended strategy (χ²=9.75 and 12.56, all P<0.01). The colposcopy referral rate for strategy 3a was significantly lower than that of the guideline-recommended strategy [34.75% (270/777) vs 39.77%; P<0.001], with corresponding NNC of 3.75 for CINⅡ+ and 7.11 for CINⅢ+. Strategy 5a showed a sensitivity of 64.60% for detecting CINⅡ+, which was not significantly different from that of the guideline-recommended strategy (64.60% vs 69.03%; χ²=3.20, P=0.074), and a sensitivity of 95.00% for CINⅢ+, identical to that of the guideline-recommended strategy. The specificity of strategy 5a for CINⅡ+ and CINⅢ+ were 75.30% and 73.00%, respectively, both significantly higher than the guideline-recommended strategy (both P<0.001). NNC for strategy 5a was 3.25 for CINⅡ+ and 6.24 for CINⅢ+, both lower than those of the guideline-recommended strategy (3.96 and 8.13, respectively). The colposcopy referral rate for strategy 5a was also significantly lower than that of the guideline-recommended strategy [30.50% (237/777) vs 39.77%; χ²=70.01, P<0.001]. Conclusions: Among self-collected, high-risk HPV-positive individuals, combined triage strategies that integrate HPV genotyping with cytology, p16 staining and methylation testing, specifically strategy 3a and 5a, offer comparable sensitivity with superior specificity and lower referral rates versus co-testing for detecting CINⅡ+ and CINⅢ+. 目的： 评价基因甲基化检测、p16染色、人乳头状瘤病毒（HPV）分型检测、子宫颈液基细胞学检查及其联合方案，对阴道自取样高危型HPV（HR-HPV）阳性人群的分流效率。 方法： 前瞻性选取2023年5月至2024年4月北京大学深圳医院在广西壮族自治区百色地区开展的自取样子宫颈癌免费筛查项目的部分数据，纳入结果齐全并通过质控的自取样HR-HPV阳性妇女共777例，以2019年美国阴道镜和子宫颈病理学会（ASCCP）基于风险的子宫颈癌筛查结果异常和癌前病变的管理指南及中国子宫颈筛查指南推荐的HPV16/18阳性和（或）细胞学检查结果≥未明确诊断意义的不典型鳞状上皮细胞（ASCUS）分流方案（简称：指南推荐方案）应用在本研究人群中的敏感度、特异度、阴道镜转诊率及需行阴道镜数量（NNC）为参照，比较基因甲基化检测、p16染色、HPV分型检测、子宫颈液基细胞学检查及其联合方案在自取样HR-HPV阳性人群中的分流效能。 结果： 高风险的HPV16/18阳性受试者的基因甲基化阳性率高于低风险的HPV39/51/56/59/66/68阳性者［分别为20.5%（25/122）、9.6%（26/271）；χ²=8.85，P=0.003］，高~中风险的HPV31/33/35/45/52/58阳性受试者的基因甲基化阳性率高于低风险的HPV39/51/56/59/66/68阳性者［分别为17.2%（66/381）、9.6%；χ²=7.59，P=0.006］；子宫颈上皮内瘤变（CIN）Ⅲ和子宫颈癌受试者的甲基化阳性率（67.5%，27/40）显著高于CINⅠ（12.9%，31/240）和CINⅡ（16.4%，12/73），差异有统计学意义（P<0.05）。p16阳性率随子宫颈病变级别升高而显著增加（校正P≤0.005）。以子宫颈活检病理检查结果作为标准，应用指南推荐方案作为分流方案时，诊断CINⅡ+、CINⅢ+的敏感度及特异度分别为69.03%、65.21%和95.00%、63.23%，阴道镜转诊率为39.77%（309/777），NNC分别为3.96、8.13例；基因甲基化检测分流方案诊断CINⅡ+、CINⅢ+的敏感度和特异度分别为34.51%、88.25%和67.50%、87.79%；p16分流方案诊断CINⅡ+、CINⅢ+的敏感度分别为72.57%、92.50%，与指南推荐方案相近（P均>0.05），特异度分别为68.67%、65.60%，与指南推荐方案相当（P均>0.05），且阴道镜转诊率低［分别为37.32%（290/777）、39.77%；P>0.05］。在联合分流方案中，3a方案诊断CINⅡ+的敏感度为63.72%，与指南推荐方案（69.03%）相近（P=0.109），诊断CINⅢ+的敏感度与指南推荐方案一致，均为95.00%，特异度分别为70.18%和68.52%，均高于指南推荐方案（χ2值分别为9.75、12.56，P均<0.01），阴道镜转诊率低于指南推荐方案［分别为34.75%（270/777）、39.77%；P<0.001］，NNC分别为3.75和7.11例；5a方案诊断CINⅡ+的敏感度为64.60%，低于指南推荐方案（χ2=3.20，P=0.074），诊断CINⅢ+的敏感度为95.00%，与指南推荐方案一致，特异度分别为75.30%和73.00%，均高于指南推荐方案（P均<0.001），NNC分别为3.25和6.24例，低于指南推荐方案（分别为3.96和8.13例），阴道镜转诊率低于指南推荐方案［分别为30.50%（237/777）、39.77%；χ2=70.01，P<0.001］。 结论： 在自取样HR-HPV阳性人群中，HPV分型检测结合细胞学检查、p16染色、基因甲基化检测的联合分流方案——3a方案及5a方案，在诊断CINⅡ+、CINⅢ+时可获得与指南推荐方案相近的敏感度、显著更高的特异度及更低的阴道镜转诊率。.
Clinical utility and dynamics of plasma biomarkers in early-onset dementia remain underexplored. To investigate plasma biomarker trajectories and their associations with clinical outcomes in early-onset Alzheimer disease (EOAD) and frontotemporal dementia (FTD). This multicenter, prospective cohort study analyzed participants in phase 1 of the Longitudinal Study of Early-onset Dementia and Family Members (LEAF), which was conducted from April 2021 through December 2023 in 34 centers across South Korea. Patients with β-amyloid-positive EOAD and FTD were included and underwent annual blood sampling and clinical assessment, within a follow-up period of approximately 2 years. Data were analyzed between June 2025 and March 2026. Levels of plasma phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) biomarkers were analyzed using assays. (1) Associations of baseline biomarkers with clinical outcomes (assessed with the Mini-Mental State Examination [MMSE] and the Clinical Dementia Rating-Sum of Boxes [CDR-SB] for the EOAD group, or the frontotemporal lobar degeneration [FTLD]-modified CDR-SB for the FTD group), (2) biomarker trajectories, and (3) association of biomarker level changes and clinical outcomes. A total of 322 participants with p-tau217, GFAP, and NfL analyses were stratified into the EOAD or FTD group based on their diagnosis. The EOAD group (n = 245) had a mean (SD) age of 61.8 (5.4) years and included 163 females (66.5%), while the FTD group (n = 77) had a mean (SD) age of 65.1 (7.3) years and included 45 females (62.3%). In the EOAD group, higher log2-transformed baseline p-tau217, GFAP, and NfL were each associated with faster decline in the MMSE score (association estimate [SE], -0.390 [0.127], P = .002; -0.775 [0.164], P < .001; and -0.679 [0.182], P < .001, respectively) and the CDR-SB score (estimate [SE], 0.401 [0.099], P < .001; 0.535 [0.126], P < .001; and 0.693 [0.122], P < .001, respectively). In the FTD group, GFAP and NfL were associated with MMSE decline (estimate [SE], -2.118 [0.566], P < .001 and -2.360 [0.428], P < .001, respectively), whereas p-tau217 was not (estimate [SE], 0.071 [0.418], P = .87). No biomarker was associated with FTLD-modified CDR-SB score change. Longitudinally, all mean (SD) biomarker levels increased in the EOAD group (p-tau217: 0.253 [0.077] pg/mL, P = .001; GFAP: 0.173 [0.040] pg/mL, P < .001; NfL: 0.149 [0.045] pg/mL, P = .001), whereas in the FTD group, only NfL level showed an upward pattern (0.251 [0.127] pg/mL, P = .05). Annualized biomarker changes were associated with worsening clinical outcomes in the EOAD group, but not in the FTD group. GFAP and NfL level increases were associated with MMSE score decline (estimate [SE], -0.005 [0.002], P = .007 and -0.010 [0.003], P = .001, respectively), while p-tau217 level increases were associated with CDR-SB score worsening (estimate [SE], 0.072 [0.024], P = .003) in the EOAD group. In this cohort study of patients with EOAD and FTD, baseline p-tau217, GFAP, and NfL were consistently associated with clinical outcomes in the EOAD group, whereas GFAP and NfL were associated with cognition only in the FTD group. These findings demonstrate distinct characteristics of plasma biomarkers in EOAD and FTD, supporting their potential utility for risk stratification.
Sickle cell disease (SCD) is a severe, inherited hemoglobin disorder characterized by chronic hemolysis, vaso-occlusive crises (VOCs), and systemic inflammation. Hydroxyurea is the standard conventional pharmacotherapy for SCD, but it has certain limitations, necessitating the need to explore other safe and effective treatment options for SCD. Ayurveda interventions offer a potential therapeutic approach complementary to conventional medicine for SCD management, with anti-inflammatory, immunomodulatory, and hematopoietic properties. This randomized controlled trial will evaluate the efficacy and safety of an Ayurvedic therapeutic regimen as an adjunct to hydroxyurea in SCD management, assessing its impact on hematological parameters, inflammatory biomarkers, VOC frequency, and overall quality of life. A PROBE (Prospective, Randomized, Open-Label, Blinded End Point) study will be conducted on individuals of any gender aged 18 years or older and diagnosed with SCD (with hemoglobin S levels more than 60% and a history of at least 1 VOC per year over the past 3 y). Individuals with acute VOC or any severe infection requiring hospitalization, a history of significant comorbidities, or hematopoietic stem cell transplantation will not be considered. The study will be conducted at the All India Institute of Medical Sciences, Bhopal, India. A total of 100 participants will undergo random assignment in a 1:1 ratio to receive either an Ayurveda regimen (Dadimadi Ghrita, Punarnavadi Mandura, and Vasaguduchyadi Kwatha) as an add-on to hydroxyurea or hydroxyurea alone for 8 months. The primary outcome will be a change in hemoglobin electrophoresis parameters (hemoglobin S, fetal hemoglobin, and adult hemoglobin) and the frequency of VOC episodes over 8 months. The secondary outcome measures include changes in the levels of proinflammatory markers (interleukin-6, interleukin-8, C-reactive protein, and transforming growth factor-β) and lactate dehydrogenase, frequency of hospitalization for VOCs and blood transfusions, and health-related quality of life (Short Form-8 Health Survey questionnaire). Safety will be evaluated by recording the incidence of adverse events and changes in liver and kidney function tests from baseline. The recruitment of study participants was initiated on November 1, 2023. By the second week of February 2025, 83 participants had been enrolled in the study. The final study is expected to be complete by December 31, 2025. We will start the analysis of the study outcomes in February 2026, and the publication of the final results is expected by August 2026. This randomized controlled trial protocol outlines a rigorous study design aimed to explore the potential benefits of an integrated therapeutic regimen comprising Ayurveda interventions and standard conventional care in the long-term management of SCD through validated clinical and laboratory parameters. The outcomes of this study can address the needs and challenges associated with SCD management and inform future management protocols.
Oligometastatic cancer is characterised by a low volume of metastases to a small number of anatomical sites. However, evaluating the impact of metastases-directed therapies (MDTs) on overall survival or quality of life is often challenging. Current clinical trials use a wide range of primary endpoints that might not be validated or suited to MDT. To address this issue, we did a systematic review of international trial registries, alongside a Delphi consensus process involving 30 experts and five patient representatives. The aim was to identify preferred primary endpoints for MDT trials in oligometastatic disease, regardless of tumour type. Overall survival and progression-free survival were the most frequently used endpoints across the 121 comparative trials reviewed. Over four Delphi consensus rounds, overall survival had the highest level of agreement, although its limitations as a sole endpoint were emphasised. In addition to the widely used progression-free survival endpoint, polymetastatic progression-free survival and start-or-switch of systemic therapy-free survival also reached consensus, particularly for trials integrating systemic therapies. Both polymetastatic progression-free survival and systemic therapy-free survival permit repeat MDT without classifying it as treatment failure. Patient representatives highlighted the importance of time-to-deterioration of quality of life. This consensus supports overall survival as a primary endpoint and, in addition to progression-free survival, recommends polymetastatic progression-free survival and systemic therapy-free survival, especially in combination with systemic therapies. Adopting these endpoints will make MDT trials more relevant, comparable, and patient-centred, thereby empowering future clinical and policy decisions.
Knee osteoarthritis (KOA) is a degenerative joint condition characterized by progressive cartilage deterioration and chronic pain, leading to functional impairment. Bone marrow-derived orthobiologics, such as bone marrow aspirate clot (BMA-clot) and bone marrow aspirate concentrate (BMAC), have emerged as promising regenerative therapies. Despite their growing clinical use, no randomized clinical trials to date have directly compared the efficacy and safety of these two approaches in patients with KOA, leaving a gap in the current evidence base. This study aimed to compare the efficacy and safety of intra-articularBMA-clot and BMAC in patients with moderate to severe KOA over a 12-month follow-up period. In this prospective, randomized, double-blind clinical trial, patients aged 50-80 years with Kellgren-Lawrence grade 3-4 KOA were enrolled. Participants received thr ee monthly intra-articular injections of eitherBMA-clot or BMAC. The primary outcome was functional improvement assessed by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included pain reduction (Visual Analog Scale) and quality of life (Short Form-36, SF-36). Adverse events were monitored, and data were analysed using mixed-effectsmodels. Both treatments resulted in significant improvements in pain, function, and quality of life throughout the 12-month period. Clinical outcomes between the BMA-clot and BMAC groups were not statistically different. The incidence of adverse events was low, with no serious complications observed. Intra-articular administration of BMA-clot and BMAC appears to be safe and effective for the management of moderate to severe KOA, providing sustained symptom relief and functional gains over a 12-month period. Given its simpler preparation and lower cost, BMA-clot may represent a more accessible therapeutic option in clinical settings.
The 5-year survival rate of early-stage hepatocellular carcinoma (HCC) patients remains only 60%, largely due to the inability to achieve ultra-early detection and safe, minimally invasive intervention of its premalignant precursor-high-grade dysplastic nodules (HGDN). Current clinical practice faces an unresolved dilemma: conventional imaging has limited sensitivity for HGDN, no standardized minimally invasive intervention exists, and no integrated platform enables synchronous detection, boundary localization and on-demand intervention, despite HGDN 80.8% 5-year HCC progression rate. To address these core challenges, we developed a multifunctional dual-hairpin DNA polydopamine nano-system (H/R@PDA-GC) targeting miRNA-224, a biomarker consistently upregulated during HGDN malignant transformation.This system enables specific detection of miRNA-224 with an ultra-low limit of detection (LOD) of 0.068 pM. Clinically, there is a 3-5-year natural history window from HGDN formation to clinically diagnosable early HCC; thus, this system provides a potential technical tool for the ultra-early warning of HCC at the precancerous stage. It simultaneously activates near-infrared fluorescence for targeted imaging of HGDN to precisely delineate lesion boundaries, and leverages its efficient photothermal conversion capability to achieve effective ablation of HGDN in validated murine models. Both cellular and animal studies confirmed its good in vitro and short-term in vivo biocompatibility, significant anti-inflammatory and antioxidant effects, and therapeutic efficacy, addressing the dual clinical needs of ultra-early detection and safe intervention of premalignant lesions. Consequently, H/R@PDA-GC provides an integrated theranostic strategy, which has potential clinical value for reducing the risk of HCC progression, and lays a foundation for ultra-early intervention of HCC precancerous lesions.Clinical trial number. Not applicable.
To identify the continuous dose-response relationship between the duration of premature rupture of membranes (PROM) and the probability of neonatal and maternal infectious morbidity. This meta-analysis and systematic review synthesise data from 15 studies worldwide involving more than 70,000 mother-neonate pairs. A two-step random-effects model of PROM duration as a continuous dose, using restricted cubic splines, was used to estimate specific risk thresholds. The analysis established a progressive, non-linear escalation of risk. The onset of statistical risks at 16 hours is the early-onset pneumonia (Adjusted OR 1.86, 95% CI: 1.152.99). At the age of 18 hours, the incidence of culture-proven sepsis in neonates was 4.0%, and the odds ratio for maternal fever was significantly higher (AOR 36.6). The analysis of the ROC curves revealed a critical mathematical pivot point at 37 hours, after which complications escalate exponentially. Latency greater than 48 hours was the most significant independent predictor of culture-proven sepsis, with an increased risk of 8.2 (p < 0.001). Histologic chorioamnionitis was detected in 39% of mothers, and in many cases, they are clinically silent. Considerable heterogeneity (I2 > 60%) was mainly caused by gestational age disparities in cohorts of extremely preterm and term babies. PROM latency risk is not a threat but accelerates with time. Although 18 hours will be an acceptable early warning level, the range of 37 to 48 hours is a high-risk period that needs aggressive treatment. International guidelines need to be reviewed to reflect this non-linear trend, especially regarding pregnancy, where the risks of delivery are low compared to the rising risk of latency.
Although histological criteria underpin current classification, accurate risk stratification, particularly for borderline and malignant tumours, remains challenging. We analysed a 20-year institutional series of phyllodes tumours (PTs), integrating clinicopathological data with long-term clinical outcomes. Histological features were extracted from original pathology reports, with slide re-review where archival material was available. Among 111 PTs, 80% were benign, 11% borderline and 9% malignant. The follow-up ranged from 0 to 20 years, with 11.3, 10.3 and 7.6 years for benign, borderline and malignant PT, respectively. Most patients underwent local excision; mastectomy was performed in 22% of malignant PT. Final positive margins were identified in 18% of benign, 8% of borderline and none of the malignant tumours. Adjuvant radiotherapy was administered in 18% of borderline and 67% of malignant PT. Local recurrence occurred in 3%, 11% and 22% of benign, borderline and malignant tumours, respectively. Distant metastases were observed exclusively in malignant PTs (33%, 3/9 cases), two of which were preceded by local recurrence. Notably, two of the three metastatic malignant PTs showed either ≤10 mitoses/10 high-power field or <marked stromal atypia and lack of stromal overgrowth, which are required for diagnosis of malignant PT per WHO 5th edition recommendation. The low event rate precluded robust multivariable analysis. Our results highlight the biological heterogeneity of malignant PTs and the limitations of rigid histological thresholds. These findings underscore the need for collaborative, multi-institutional prospective studies with standardised tumour sampling and reporting and molecular correlation to refine clinically meaningful risk stratification in PT.
Cognitive-communication disorders are pervasive following traumatic brain injury (TBI), disrupting communication at the level of discourse and social interaction. Discourse impairments impact functioning across major life domains, such as work and social relationships, and overall quality of life. Problems with discourse affect all severity levels of TBI and persist over time. Veterans may experience even greater functional decline due to comorbid health conditions (eg, posttraumatic stress disorder, pain). The functional impact and chronicity of discourse impairments following TBI underscore the importance of treating these impairments. This study aims to (1) develop, refine, and manualize a treatment protocol targeting narrative discourse-Talking About Life Experiences (TALE)-in people with TBI and (2) evaluate the feasibility of the TALE discourse treatment in a pilot randomized controlled trial (RCT). This is a stage 1a (phase 1) and stage 1b (phase 2) treatment development study aligned with the Stage Model of Behavioral Therapies Research. All participants will be individuals with TBI and communication difficulties. In the treatment development phase (phase 1), 5-10 participants will be recruited to obtain key stakeholder feedback for treatment refinement. In the feasibility pilot phase (phase 2), 40 participants with TBI and communication difficulty will be randomized to receive the TALE intervention or treatment as usual. We will obtain information on the tolerability, acceptability, and feasibility of recruitment for the TALE intervention, as well as preliminary data on treatment delivery, assessment methods, and treatment effects. Assessments will be conducted at baseline, posttreatment, and at 1-month follow-up and will include measures of discourse ability, cognition, mental health, pain, functional communication, and daily functioning. Feedback regarding assessment and treatment will also be collected via surveys and exit interviews. This study was funded in October 2021. Recruitment for phase 1 began on September 26, 2022. Seven participants were enrolled. Phase 1 concluded on November 17, 2023. Recruitment for phase 2 began on November 27, 2023. Thirty-four participants were enrolled. Data collection was completed on November 3, 2025. Data analysis has been conducted concurrently with data collection and is expected to continue until early-mid 2026. Results are expected to be published in peer-reviewed journals in late 2026 and early 2027. Stakeholder feedback from the phase 1 treatment development trial will facilitate refinement of the TALE protocol in preparation for the phase 2 feasibility pilot RCT. Results from phase 2 will be used to determine the tolerability, acceptability, and feasibility of methods. Findings from this study will inform the development and implementation of a future fully powered RCT evaluating treatment efficacy. ClinicalTrials.gov NCT05008419; https://clinicaltrials.gov/ct2/show/NCT05008419. DERR1-10.2196/86329.
Oropharyngeal squamous cell carcinoma (OPSCC) accounts for a substantial proportion of head and neck cancers, with a rising incidence largely driven by human papillomavirus (HPV) infection. Despite advances in multimodal treatment, disease recurrence remains common and limits long-term survival, highlighting the need for reliable biomarkers to guide prognosis and treatment. This review summarizes recent advances in biomarker development in OPSCC across multiple biological domains. We examined molecular biomarkers, including genomic alterations, DNA methylation, and non-coding RNAs; protein biomarkers associated with oncogenic signaling, cell-cycle regulation, apoptosis, inflammation, and angiogenesis; as well as circulating biomarkers such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosome-derived RNA. Among currently available biomarkers, p16, PD-L1, and circulating HPV DNA demonstrate the strongest clinical applicability, particularly for risk stratification and post-treatment surveillance. Emerging evidence also supports the use of combined biomarker panels to improve prediction of treatment response to radiotherapy, chemotherapy, and immunotherapy. However, many candidate biomarkers show inconsistent performance due to methodological variability, limited sensitivity and specificity, and insufficient prospective validation. While several biomarkers show promise in OPSCC, further standardization of detection methods and large-scale prospective studies are required. Integration of multi-omics data with computational approaches, including artificial intelligence, may facilitate the development of robust and clinically actionable predictive models, ultimately enabling more personalized management and earlier detection of recurrence.
We evaluated the clinical impact of textbook outcome (TO) in patients with stage I gastric cancer (GC) who underwent minimally invasive surgery (MIS). Moreover, we identified the risk factors associated with achieving TO in these patients. Patients were selected from the database of the Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital between 2005 and 2025. Our definition of TO comprised 10 items: complete (potentially curative) resection, R0 resection, retrieval of more than 16 lymph nodes, no intraoperative complications, no severe postoperative complications (Clavien-Dindo grade III or higher), no reintervention after surgery, no unplanned ICU/HCU admission, no readmission within 30 days after discharge, no prolonged hospital stay (defined as more than 21 days after surgery), and no mortality within 30 days after surgery. We analyzed 889 patients who underwent MIS and were pathologically diagnosed with stage I GC. Among them, 621 patients (69.8%) achieved TO, whereas 268 patients (30.2%) did not. The most frequent reason for failure to achieve TO was prolonged hospital stay (>21 days after surgery) (17.5%), followed by postoperative surgical complications (15.4%). In the multivariate analysis, age [odds ratio (OR)=1.619), BMI (OR=1.849), and type of gastrectomy (OR=1.674) were identified as independent risk factors for failure to achieve TO. The 5-year overall survival (OS) rate was 97.5% in patients who achieved TO and 94.7% in those who did not, showing a significant difference between the two groups (p=0.041). The TO achievement rate was approximately 70%, and failure to achieve TO was associated with age, preoperative BMI, and type of gastrectomy. Achievement of TO was associated not only with favorable short-term outcomes but also with improved long-term oncological outcomes.
Brucellosis in dogs, caused by Brucella canis, is a zoonotic disease often underdiagnosed because of diagnostic challenges and subclinical infection. Bacterial culture, the reference standard, is impractical and has limited sensitivity because of intermittent or low-grade bacteremia. Accurate point-of-care (POC) testing could facilitate timely management and infection control. Evaluate the diagnostic performance of 3 POC lateral flow assays for detection of B. canis antibodies in dogs, using the Canine Brucella Multiplex (CBM) assay as the reference serologic assay. Fifty serum samples from 50 client-owned dogs submitted for B. canis serology. Samples were classified as CBM-positive (n = 10; culture-positive dogs) or CBM-negative (n = 40; healthy dogs undergoing export testing). Assays were run in duplicate and independently interpreted by 2 observers. Positive percent agreement (PPA), negative percent agreement (NPA), and inter-reader agreement were calculated relative to CBM. The Anigen Rapid C.Brucella Ab assay demonstrated 90.0% PPA (95% CI, 55.5-99.8) and 100% NPA (95% CI, 91.1-100). The FASTest® BRUCELLA canis assay demonstrated 100% PPA (95% CI, 69.1-100) and 92.5% NPA (95% CI, 79.6-98.4). The Canine Brucella LPS Antibody Rapid Test demonstrated 0% PPA (95% CI, 0-30.9) and 97.5% NPA (95% CI, 86.8-99.9). Inter-reader agreement was almost perfect for all assays (κ = 0.81-1.00). The Anigen Rapid C.Brucella Ab and FASTest® BRUCELLA canis assays showed good agreement with the CBM assay and may be useful rule out tests in dogs with clinical signs compatible with brucellosis. In low prevalence settings, positive results require confirmatory testing, and false negatives remain possible.
Small intestinal adenocarcinoma (SIA) is a rare cancer with a poor prognosis. Optimal treatment strategies are unclear as biological understanding of the disease is limited and randomized controlled trials are lacking. Current management is based on protocols for other gastrointestinal cancers. Therefore, the AdenoCarcinoma of the Small Intestine (ACSI) cohort was initiated, a subcohort of the nationwide Prospective Dutch ColoRectal Cancer cohort (PLCRC) study. The ACSI cohort aims to provide a large-scale, prospective SIA cohort, where clinical and molecular data will be combined to improve knowledge on tumor biology, treatment responsiveness, disease outcome and patient reported outcomes (PROs). Patient/material and methods: All adult SIA patients in the Netherlands are eligible for inclusion. Nationwide inclusion is facilitated by 68 hospitals. Clinical data are collected, as well as optional PROs, pathology- and blood samples. Until June 2025, 143 patients have been enrolled. Data of the first 105 patients show a median age of 65 years (interquartile range 58-73) at diagnosis with a slight male predominance (60%). Most tumors are located in the duodenum (57%) and 27% of patients present with stage IV disease, with a majority having single-site metastases (64%). Primary tumor resection is performed in 80%, while systemic treatment is administered in 42%. Four patients did not receive any anti-tumor treatment (14%). Mismatch repair deficiency is detected in 28% of patients. The ACSI cohort enables structured national collection of clinical data, tumor samples and PROs of SIA patients. These data provide a valuable source for further research and improvement of care for this patient group.
Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, whereas its molecular and cellular mechanisms remain poorly understood. This study aimed to characterize the cellular heterogeneity of FCD and investigate the function of ferroptosis in FCD pathogenesis. Single-nucleus RNA sequencing was carried out on epileptogenic cortical tissues from 18 patients with FCD and 6 perilesional control samples with normal histology. Data were analysed using uniform manifold approximation and projection for dimensionality reduction and visualization. Differentially expressed genes (DEGs) were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. UCell scoring and gene set enrichment analysis (GSEA) were applied to assess pathway activity. Expression levels of ferroptosis-related genes (FRGs) were validated by immunofluorescence, and biochemical assays quantified the levels of superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA) and lipid peroxides (LPO). A total of 170 747 nuclei were profiled, resolving five major cell types, including inhibitory neurons, excitatory neurons, astrocytes, microglia and oligodendrocytes. DEGs across these populations were significantly enriched in ferroptosis and oxidative stress-associated pathways. UCell and GSEA highlighted remarkable alterations in ferroptosis, apoptosis and oxidative stress, particularly in inhibitory neurons and astrocytes. Immunofluorescence confirmed upregulation of key FRGs, including ferritin light chain, ferritin heavy chain 1, poly rC binding protein 1, microtubule-associated protein 1 light chain 3B and prion protein-encoding gene, in FCD tissues. Concordantly, biochemical assays demonstrated reduced SOD and GSH levels, alongside elevated MDA and LPO levels, confirming the transcriptional and histological findings. The results indicated that ferroptosis may play a notable role or act as a concurrent mechanism in the pathogenesis of FCD, potentially contributing to the neuronal and glial dysfunction and epileptogenesis. Integrating transcriptomic, histological and biochemical data, this study demonstrated that targeting ferroptosis-related pathways may hold promise as a potential therapeutic strategy for FCD, providing new insights into the molecular mechanisms underlying this condition. This study pioneers the first single-nucleus transcriptomic atlas for Focal Cortical Dysplasia (FCD) types I and II, deciphering the cellular heterogeneity across five major brain cell types within the epileptogenic cortex. Through integrated multi-omics analysis, it reveals for the first time a significant association between the ferroptosis pathway and FCD pathogenesis. We identify and validate ferroptosis-related genes (e.g., FTH1, FTL, PCBP1) as potential biomarkers and therapeutic targets, supported by congruent biochemical evidence of oxidative stress in this drug-resistant epilepsy.
Human flora-associated (HFA) mice are often used to simulate the structure of human intestinal microbiota and to study the causal relationships between diseases and gut microbiota. However, several factors affect the colonization efficiency of human microbiota in germ-free (GF) mice, and the differential effects of gavage and lower gut transplantation on colonization are still unclear. In this study, we explored the reproducibility of the recipient-to-donor gut microbiota community structure and function under different transplantation routes and the differences in microbial colonization between recipients via gavage transplantation (GT_mice group) and lower gut transplantation (LGT_mice group). High-throughput sequencing of the metagenome was performed on the feces of each subject, and the composition of microbiome of each group was analyzed. As expected, the introduction of human fecal microbiota into GF mice via lower gut transplantation had a high transfer efficiency, which was evident from the similar species community structure to that of the donor (Adonis R2=0.713 960 for LGT_mice group‒donor group; Adonis R2=0.774 095 for GT_mice group‒donor group) and a higher bacterial colonization rate. The findings provide unique insights into improving the accuracy of constructing humanized microbiota transplantation models, aiding our understanding of the relationships between the human gut microbiota and disease. 人类菌群相关（HFA）小鼠常被用于模拟人类肠道微生物群结构，以探索疾病与肠道微生物群间的因果关系。然而，人类微生物群在无菌小鼠中的定植效率受多种因素影响，且灌胃和灌肠移植两种途径的定植效果差异尚待阐明。本研究探讨了不同移植途径对受体与供体间肠道微生物的群落结构和功能的重现性的影响，并比较了灌胃（上消化道移植，GT_mice组）和灌肠（下消化道移植，LGT_mice组）两种菌群移植方式在受体小鼠中微生物定植差异。我们通过对每个受体的粪便进行高通量宏基因组测序，并分析各组微生物组组成。结果显示，通过下消化道移植将人类粪便微生物群引入无菌小鼠具有较高的转移效率，这不仅体现在其物种群落结构与供体相似度较高（Adonis分析结果:LGT_mice组-供体组，Adonis R2=0.713 960;GT_mice组-供体组，Adonis R2=0.774 095），也表现为更高的细菌定植率。上述发现为提高人源化微生物群移植模型的构建准确性提供了新见解，有助于加深对人类肠道微生物群与疾病关联机制的理解。.
Intervertebral disk degeneration (IDD) is a degenerative disease mainly characterized by intervertebral disk tissue senescence and collagen loss. The role of hsa_circ_0036763 in IDD remains incompletely understood. The clinical value of hsa_circ_0036763 was explored by retrospectively analyzing the serum samples of 120 IDD patients through ROC curve, Kaplan-Meier curve, and Cox proportional hazards analysis. The severity of IDD was distinguished through the modified Pfirrmann grading system. The downstream regulatory mechanism (miR-4741/RGSL1) of hsa_circ_0036763 was mined through the miRDB and TargetScan databases, and their targeting relationships were demonstrated by the dual-luciferase reporter and RNA pull-down assays. The IL-1β-induced senescent nucleus pulposus cells (NPCs) were used to evaluate the potential role of hsa_circ_0036763/miR-4741/RGSL1 axis in IDD progression. Serum hsa_circ_0036763 expression was negatively correlated with the modified Pfirrmann grade of IDD patients (r = -0.675). Its low expression predicted a higher risk of IDD recurrence (HR = 0.252, p = 0.002). Hsa_circ_0036763 sponged miR-4741, thereby relieving its inhibition on RGSL1 expression. Exogenous overexpression of hsa_circ_0036763 alleviated the senescence, collagen loss, and oxidative stress in IL-1β-induced NPCs, which were reversed by co-transfection of miR-4741 mimics and silencing of RGSL1. Hsa_circ_0036763 may serve as a prognostic marker for IDD and participates in IDD-related NPC degeneration by regulating miR-4741/RGSL1.
Lung cancer remains a major global public health challenge, with lung adenocarcinoma being the most prevalent histologic subtype. Rosuvastatin, a widely used lipid-lowering agent, has recently attracted attention for its potential antitumor properties. This study investigates the underlying mechanisms and therapeutic potential of rosuvastatin in lung cancer. The effects of rosuvastatin were evaluated in lung adenocarcinoma cell lines using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine (EdU) incorporation, Transwell migration and invasion assays, wound-healing assays, and flow cytometry for apoptosis analysis. RNA sequencing identified cell-cycle signaling pathways as the primary targets of rosuvastatin. Analysis of survival curves and differential gene expression between tumor and adjacent non-tumor tissues using public databases, including the Human Protein Atlas, Gene Expression Profiling Interactive Analysis (GEPIA), and Tumor Immune Estimation Resource (TIMER), suggested that polo-like kinase 1 (PLK1) may be a key target mediating the antitumor effects of rosuvastatin. Western blotting and quantitative reverse transcription polymerase chain reaction (qRT-PCR) were used to confirm the differential expression of PLK1 and related cell-cycle proteins in lung adenocarcinoma cells following treatment with different doses of rosuvastatin. Furthermore, rescue experiments with PLK1 knockdown were performed to verify its role in the mechanism of rosuvastatin. A subcutaneous mouse xenograft model was established in vivo to assess the antitumor activity of rosuvastatin via PLK1 inhibition. Rosuvastatin exerted significant antitumor effects against lung adenocarcinoma both in vitro and in vivo. Mechanistic studies indicated that its anticancer activity is mainly mediated by downregulating PLK1 expression. By suppressing PLK1 expression, rosuvastatin inhibited cancer cell proliferation, migration, and invasion. These findings support the potential of rosuvastatin as a therapeutic agent for lung cancer, although further studies are needed to confirm its clinical utility.
Dravet syndrome (DS) is a rare and severe childhood-onset developmental epileptic encephalopathy caused primarily by mutations in the sodium channel gene SCN1A. Animal models have undeniably advanced our understanding of DS, but they still do not fully capture its clinical heterogeneity, highlighting the need for complementary human in vitro systems. Here, we generated induced pluripotent stem cells (iPSCs) from urine epithelial cells of three DS patients carrying distinct SCN1A variants and differentiated them into neural stem cells (NSCs) and early-stage neurospheres. Clinical severity was assessed using the DANCE checklist, and molecular phenotypes were characterized through isobaric quantitative proteomics. Comparative analyses identified differences in protein abundance across patient-derived lines, with distinct molecular patterns associated with clinical severity measures. The patient-derived lines exhibited variability in protein groups related to synaptic organization, mitochondrial processes, and RNA processing, reflecting interindividual molecular differences within the cohort. These findings establish patient-derived neurospheres as a scalable human model for investigating molecular variability in DS. This approach provides a framework to explore disease heterogeneity and provides a foundation for future studies linking molecular profiles to clinical variability in DS.