The study aims to analyze the safety and effectiveness of endovascular treatment for complicated symptomatic spontaneous isolated superior mesenteric artery dissection (SISMAD). This is a retrospective study of 93 patients undergoing endovascular treatment for symptomatic SISMAD from June 2019 to June 2024. The primary outcomes were the cumulative complete remodeling (ie, true lumen dilated with false lumen disappeared) rate and dissection-related mortality. Secondary outcomes included re-intervention, bare stent patency, and adverse events. Patients (n = 93; mean age, 58 years; 91.4% men) were included in the study. Abdominal pain was the most common symptom (94.6%). The cumulative complete remodeling rates at 6, 12, 36, and 60 months postoperatively were 71.0%, 78.2%, 86.3%, and 86.3%, respectively. In the cases treated with stent assisted coiling, 100% patients achieved complete remodeling, compared with 84.1% in the cases treated with stent alone, with statistically significant difference (P < .001). The rate of adverse events and early re-intervention was 6.5% (6/93) and 5.4% (5/93). The median follow-up time was 27 months (range 6-64), and there was 1 case of late re-intervention, 1 case of stent occlusion, and no dissection-related deaths. Endovascular treatment showed a satisfactory outcome in treating symptomatic SISMAD, with a good cumulative complete remodeling rate.
The retina is a complex sensory neural tissue composed of six major types of neurons and one type of glial cell. The cell fate specification of retinal cells is tightly governed by intrinsic factors and extrinsic microenvironmental cues. Among the key regulators directing retinal cell fate differentiation is a group of bHLH family transcription factors (TFs). Our previous work demonstrated that the bHLH TF Ngn3 exhibits robust potential to induce retinogenesis in both distantly related fibroblasts in vitro and late retinal progenitor cells (RPCs) in vivo. However, the underlying molecular mechanisms remain largely elusive. In this study, we combined immunohistological examination and RNA-seq and ATAC-seq analyses to investigate the cellular and molecular mechanisms governing Ngn3-driven retinogenesis in late RPCs. Our results revealed that Ngn3 overexpression promotes premature cell cycle exit in late RPCs and remodels their transcriptomic and epigenomic landscape towards a state favoring rod photoreceptor and RGC differentiation. Furthermore, cross-comparison with Ngn3-overexpressing fibroblasts in vitro revealed cell-type-specific mechanisms underlying Ngn3-mediated neuronal fate reprogramming. These findings advance our understanding of Ngn family-mediated retinal cell fate regulation and provide a mechanistic framework for optimizing Ngn3-based retinal regeneration strategies for the treatment of retinal degeneration diseases.
Background/Objectives: Respiratory failure in late pregnancy represents a complex and high-risk clinical scenario due to physiological adaptations during pregnancy that reduce maternal respiratory reserve, with tightly coupled maternal and foetal outcomes. This review aims to synthesise current evidence on epidemiology, maternal-foetal physiology, and management strategies for respiratory failure in late gestation. Methods: This narrative review integrates contemporary literature, national surveillance data, physiological principles, and expert consensus to summarise the causes, clinical implications, and management of respiratory failure in pregnancy. Results: Respiratory failure in pregnancy arises from diverse obstetric and non-obstetric conditions, including pneumonia, asthma, pulmonary embolism, cardiogenic pulmonary oedema, and ARDS. Maternal hypoxaemia is strongly associated with foetal compromise. Management requires pregnancy-specific ventilatory targets, avoidance of permissive hypercapnia, cautious use of non-invasive and invasive ventilation, and safe implementation of prone or semi-prone positioning. ECMO use has expanded, with maternal survival improving to approximately 75%, although optimal anticoagulation and timing of delivery remain uncertain. Conclusions: Effective management of respiratory failure in late pregnancy requires early recognition, multidisciplinary coordination, and adaptation of respiratory support to maternal-foetal physiology. Despite improvements in critical care and ECMO outcomes, key evidence gaps persist, underscoring the need for integrated maternal critical care pathways and further research to optimise outcomes for both mother and baby.
Vitamin K is a fat-soluble vitamin essential for the activation of vitamin K-dependent proteins involved in coagulation and other physiological processes. Neonates are particularly vulnerable to vitamin K deficiency due to limited placental transfer, low hepatic stores, immature liver function, and insufficient dietary intake, especially in exclusively breastfed infants. This review summarizes the biochemistry and pharmacokinetics of vitamin K, focusing on their role in the pathogenesis of late vitamin K deficiency bleeding (VKDB), including intracranial hemorrhage in early infancy. The limitations of conventional coagulation tests are discussed, highlighting the importance of functional biomarkers such as PIVKA-II (Proteins Induced by Vitamin K Absence or Antagonist-II) for the early detection of subclinical deficiency. Despite effective prophylaxis at birth, late VKDB cases still occur, likely due to declining vitamin K levels over time and nutritional factors. These findings underscore the need for prolonged vitamin K supplementation following adequate prophylaxis at birth, particularly to protect high-risk newborns from late VKDB. Strategies may include vitamin K-containing multivitamin supplementation in preterm infants, as well as daily oral vitamin K supplementation (150 µg/day) in exclusively breastfed infants, in order to ensure adequate vitamin K status during early infancy.
To evaluate the real-world effectiveness of a pro re nata (PRN) anti-vascular endothelial growth factor (anti-VEGF) regimen for neovascular age-related macular degeneration (nAMD) during 2019-2021 at Kuopio University Hospital, including the COVID-19 pandemic period. This retrospective study included 107 patients (162 eyes) treated with intravitreal anti-VEGF injections for nAMD. The included eyes were not treatment-naive at study entry but had received anti-VEGF treatment before 2019. Annual injection numbers, drug choice (bevacizumab or aflibercept 2 mg), central retinal thickness (CRT), and visual acuity (VA) were analyzed from diagnosis through 2021 using independent-sample t-tests. The mean number of injections in the first treatment year was 6.79 ± 2.32. During 2019-2021, annual means were 5.09 ± 2.33, 5.40 ± 2.10, and 4.96 ± 2.11, respectively. Bevacizumab-treated eyes received significantly more injections than aflibercept-treated eyes across all years (p < 0.01 for 2019; p < 0.05 for 2020-2021). Mean VA declined from 70 ± 57 ETDRS letters at diagnosis to 62 ± 57 ETDRS letters by late 2021 (p < 0.0001). In the aflibercept-only subgroup, the decline was smaller and not significant (68 ETDRS letters ± 55 ETDRS letters to 66 ± 56 ETDRS letters; p > 0.27). CRT decreased significantly from 388.4 ± 139.4 µm at diagnosis to 320.8 ± 114.7 µm in 2019 and remained stable thereafter (p < 0.0001 vs. baseline; p > 0.5 between years). The PRN regimen maintained anatomical outcomes but resulted in gradual visual decline, likely due to fewer injections, particularly during the COVID-19 period. Aflibercept required fewer injections without compromising outcomes. Transitioning toward a treat-and-extend protocol may enhance visual stability and cost-effectiveness in nAMD care.
Depressive and anxiety disorders are prevalent, impactful conditions that are rising globally. Antidepressants showed limited efficacy and side effects, highlighting the need for alternatives. Intermittent fasting (IF) has emerged as a potential nutritional strategy to improve mood-related symptoms (MRSs). To evaluate differences in anxiety and depression between adults practising IF and those following a regular eating pattern (REP), exploring variations within IF groups, comparing early IF (EIF; morning/afternoon feeding), late IF (LIF; afternoon/evening feeding) and REP groups, and between sexes. A cross-sectional study (May 2024-May 2025) employed an anonymous 41-question online survey distributed globally, including the Hospital Anxiety and Depression Scale (HADS) questionnaire to assess anxiety and depression. Data from 302 healthy participants aged 18-65 (88 male, 214 female) were analysed using IBM SPSS Statistics. A two-way ANOVA examined the effects of sex and eating patterns on anxiety and depression. Participants included 214/302 (70.9%) in the REP and 88/302 (29.1%) in the IF group, with 22/302 (7.2%) in the EIF and 66/302 (21.9%) in the LIF group. Females reported significantly higher mean anxiety than males (p = 0.047). The IF group reported significantly lower anxiety (p = 0.031) and depression (p = 0.022) than the REP group. Our findings suggest an association between IF and reduced anxiety and depression. Further research is needed to elucidate the IF-MRSs relationship, explore sex-specific approaches and optimal dietary strategies to improve MRSs.
Natural products are complex chemical molecules produced by organisms to carry out a wide range of functions. The remarkable chemical diversity of these compounds arises from the diversity of the biosynthetic gene clusters (BGCs) that encode the enzymes responsible for their biosynthesis. In the present mini-review, we explore the processes that drive late-stage diversification of BGCs, where small changes generate highly similar yet distinct compounds. We consider examples of non-modular and modular BGCs and discuss the mechanisms behind their diversification, such as enzyme promiscuity, point mutations, and recombination. Then, we use a fitness landscape concept borrowed from the field of evolutionary biology to consider how these mechanisms allow BGCs to explore the chemical space of possible molecules and illustrate why recombination is such a powerful mechanism for natural product diversification in modular systems. Lastly, we argue that the framework of fitness landscapes could help understand the expected bioactivity of unknown natural products.
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Nowadays, hypertension has become an emerging health issue in both children and adolescents. The prevalence of hypertension is increased gradually past decades by decades. Now, hypertension is not a noncommunicable disease, but it is a lifestyle disease which arises not in adulthood but initially arises in early childhood in both developed and developing countries. A school-based cross-sectional study was carried out among 1770 school-going adolescents of aged 15-19 years from schools of Meerut urban area. The school list was obtained from Internet, and schools were selected by simple random sampling. All the students of class 9th to 12th from selected school were covered. Statistical tests like Chi-square test were applied, and P < 0.05 was taken as statistically significant. The prevalence of hypertension in adolescents was found to be 12.8%. The study revealed that the highest percentage was found in nonvegetarians (18.8%) in the age group 18-19 years (15.73%), more in males (14.9%) and also higher in Muslim religion (22.4%), which was found statistically significant. Percentages of smokers, alcoholic, and tobacco chewers were higher among hypertensive students, and this association was statistically significant (P < 0.05). The association between dietary habits was not found significant. Almost nearly 13% of the school children had high blood pressure. Hypertension was found to be significant with age, gender, type of diet, religion, and consumption of pulses. Blood pressure measurements should be included in daily examination as part of the care of children.
ObjectivesThis study aimed to evaluate hematological inflammatory indices in patients with knee osteoarthritis and to investigate their association with radiographic disease severity. It also assessed whether these indices may have adjunctive value in distinguishing early-stage from late-stage osteoarthritis.MethodsThis retrospective study included 2176 patients diagnosed with knee osteoarthritis between January 1, 2023, and July 1, 2025. Patients aged 50-90 years with primary knee osteoarthritis and an available complete blood count (CBC) were included. Age, gender, Kellgren-Lawrence (KL) stage, neutrophil, lymphocyte, monocyte, and platelet counts were recorded. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), monocyte to lymphocyte ratio (MLR), systemic immune inflammation index (SII), systemic inflammation response index (SIRI), and pan-immune inflammation value (PIV) were calculated. Receiver operating characteristic (ROC) analysis and multivariable binary logistic regression adjusted for age and gender were performed.ResultsNLR (p < 0.001), MLR (p < 0.001), SII (p < 0.001), SIRI (p < 0.001), and PIV (p < 0.001) were significantly higher in patients with late-stage osteoarthritis, whereas PLR did not differ significantly between groups (p = 0.061). ROC analysis showed that NLR, MLR, SII, SIRI, and PIV had statistically significant but poor to modest discriminatory ability for late-stage osteoarthritis. Although SIRI showed the highest AUC among the evaluated indices, its performance remained within the modest range, and none of the markers demonstrated clinically meaningful discriminatory ability. In multivariable binary logistic regression analysis adjusted for age and gender, NLR, MLR, SII, SIRI, and PIV remained associated after adjustment for age and gender with late-stage osteoarthritis.ConclusionNLR, MLR, SII, SIRI, and PIV were associated with greater radiographic severity in knee osteoarthritis. Among the investigated biomarkers, SIRI, PIV, and SII showed relatively better discriminatory performance than the other indices; however, the overall ability of all markers to distinguish early-stage from late-stage osteoarthritis was limited. These findings suggest that CBC-derived inflammatory indices may serve as inexpensive adjunctive markers of radiographic severity, but they should not be used as stand-alone tools in clinical decision-making.
Background: Experimental studies indicated that maternal choline and betaine status have the potential to alter fetal growth, but epidemiological data remain sparse. Objective: We aimed to investigate the association of maternal and cord blood choline and betaine concentrations with birthweight outcomes. Methods: This prospective cohort study involved 988 mother-infant dyads from Hebei and Shandong provinces. Plasma concentrations of choline and betaine in maternal late pregnancy and cord blood were quantified using ultra-performance liquid chromatography-mass spectrometry. Multivariable linear or logistic regression was performed to examine their association with continuous or binary birthweight outcomes. Results: Maternal plasma choline and betaine concentrations in late pregnancy (median [interquartile range]; 12.34 [10.13, 14.78] and 14.99 [12.01, 18.36] μmol/L) were significantly lower than those in cord blood (29.98 [24.74, 35.93] and 31.14 [25.56, 37.28] μmol/L). Each 1 μmol/L increase of late-pregnancy and cord blood betaine concentrations were associated with 9.87 g (95% confidence interval [CI]: -16.08, -3.66 g) and 5.29 g (95% CI: -8.52, -2.06 g) lower birthweight, respectively. Compared with the lowest quintile, the highest quintiles of late-pregnancy and cord blood betaine concentrations were associated with lower risks of large-for-gestational-age (adjusted odds ratios [ORs] = 0.47 [95% CI: 0.24, 0.90] and 0.31 [95% CI: 0.17, 0.56]) and macrosomia (adjusted ORs = 0.12 [95% CI: 0.03, 0.43] and 0.15 [95% CI: 0.05, 0.40]). These associations, particularly for cord blood, persisted and appeared more pronounced in pregnancies with maternal overweight/obesity or gestational diabetes mellitus (GDM), but the interaction effect did not reach statistical significance. No significant associations were observed for choline in any periods. Conclusions: Higher plasma concentrations of betaine in maternal late-pregnancy and cord blood were associated with lower birthweight. These findings emphasize the importance of sufficient betaine status during pregnancy, especially among mothers with obesity or GDM.
Elderly patients exhibit heightened susceptibility to postoperative complications following general anesthesia and surgery, yet the molecular mechanisms driving this age-dependent vulnerability remain poorly defined. We performed RNA sequencing on olfactory bulb (OB), hippocampus (HI), lung, and spleen from young (3-month, m), late middle-aged (17 m), and geriatric (27 m) male C57BL/6 mice 24 h after 2 h of exposure to isoflurane anesthesia and laparotomy (ISO/OP). Short-term ISO/OP elicited pronounced, age-dependent transcriptional remodeling across tissues. Late middle-aged mice exhibited robust activation of stress- and metabolism-associated pathways in the OB and HI, accompanied by suppression of lipid, synaptic, and structural maintenance programs. In contrast, young adults displayed limited responses, characterized by modest and adaptive synaptic remodeling in the HI. Peripheral organs showed a parallel age-dependent divergence. Late middle-aged mice exhibited amplified immune and inflammatory signaling in the lung and spleen alongside suppression of structural, regulatory, and metabolic homeostatic programs, whereas young adults demonstrated attenuated, metabolically adaptive transcriptional responses. Circulating extracellular vesicles (EVs) mirrored tissue-level shifts, indicating a systemic transition from adaptive plasticity in 3 m to stress and immune dominant signaling by 17 m. Geriatric mice displayed a distinct response pattern, characterized by activation of stress and detoxification programs in brain tissues, altered circadian gene expression in lung and spleen, and extensive remodeling of EV protein cargo enriched for inflammatory and growth factor-related signatures. Together, these findings indicate that late middle-age is associated with amplified peri-anesthetic biological reactivity across central and peripheral systems, suggesting an under-recognized window for perioperative risk stratification and preventative intervention.
In advanced estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the combination of cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) is the standard of care for treatment in the first-line setting. While CDK4/6i were initially developed to induce cell cycle arrest, it is evident that CDK4/6i also have the potential to regulate the tumor immune microenvironment. Here, we characterize the baseline immune landscape and the immunomodulatory effects of abemaciclib and ET in advanced breast cancer tumors. We used single-cell RNA-sequencing of CD45-enriched cells to investigate the impact of the CDK4/6i, abemaciclib, and ET on the transcriptome of immune cell populations in 13 matched-pair advanced and metastatic ER+/HER2- breast tumor biopsies. We tested the association of immune cell population gene signatures with survival in publicly available datasets. We profiled 170,798 cells from bone, breast, lymph node, and liver biopsies. We find that expression of genes associated with interferon response are downregulated in many T cell populations. Expression of genes associated with antigen presentation were upregulated in tumor-associated macrophages (TAMs) and dendritic cells following treatment. The relative proportion of TREM2+ TAMs decreases following treatment with abemaciclib and ET in late progressors and lower expression of the TREM2+ TAM signature is associated with improved overall survival in breast cancer patients. Our data reveal heterogeneous lymphoid and myeloid subpopulations in advanced and metastatic breast tumors that are associated with late progression on abemaciclib and ET and overall survival in breast cancer patients.
Reduced responsiveness to hearing one's own name is a core early behavioral predictor of autism spectrum disorder (ASD). This behavioral maker reflects atypicalities in self-related and social auditory processing, that are foundational to the development of social communication. To better understand the underlying neural mechanism of this alteration, the current study investigated neural correlates of auditory own-name processing in a sample of toddlers with ASD and typically developing (TD) controls using an auditory novelty oddball paradigm. Participants included 54 toddlers (30 ASD, 24 TD; 2-4 years) who passively listened to five auditory stimuli consisted of pure tones (500Hz and 1000Hz) and name types (self, familiar and stranger names). An auditory novelty oddball paradigm was utilized to assess neural response to standard and deviant stimuli, as well as to the different name types. Event-related potentials (ERPs) were recorded to measure neural activity during the stimulus processing. Compared to TD controls, autistic toddlers showed reduced late MMN to deviant tones that was infrequently presented relative to standard tones; Analysis of ERP components during own-name processing revealed atypical neural response pattern: autistic toddlers exhibited enhanced central P3a coupled with decreased LDN amplitudes to one's own-name relative to other names, and lack of parietal LPP effect typically observed in response to one's own-name. Our findings provide insight into the neural mechanisms underlying altered own-name processing in toddlers with ASD. These results suggest preserved early attentional capture of self-relevant salience, but atypical higher-order cognitive functioning during self-related and social auditory processing in toddlers with ASD.
Hip arthroscopy is increasingly used in the management of femoroacetabular impingement syndrome (FAIS), yet the definition of treatment failure remains unsettled. In response to the recent study by Mygind-Klavsen et al., we argue that conversion to total hip arthroplasty (THA), although clinically important, is a late and highly selective endpoint that does not capture the broader spectrum of unsuccessful hip preservation. Patients who remain symptomatic, fail to achieve clinically meaningful improvement, or undergo revision without THA are not represented by arthroplasty conversion alone. We further question whether conventional radiographic variables such as alpha angle, lateral joint-space width, and Tönnis grade are sufficient to explain failure in a condition as structurally and biologically heterogeneous as femoroacetabular impingement syndrome. Recent evidence suggests that cartilage status, composite risk stratification, and technique-related factors may be more informative for long-term survivorship than conventional morphology alone. Finally, the long registry period analysed in the target article spans different technical eras, raising the possibility that treatment-era effects were conflated with patient-related risk. In our view, the study provides a useful registry-based estimate of THA conversion after hip arthroscopy, but its findings should not be interpreted as establishing the dominant determinants of failure in contemporary hip-preservation practice.
Smartphone-based cognitive behavioral therapy (CBT) programs offer accessible interventions for subthreshold depression, yet engagement needed for meaningful benefit remains unclear. We examined how lesson and worksheet engagement relate to depressive symptom improvements in a behavioral activation (BA) intervention, accounting for time-varying confounders. This secondary analysis included 298 adults assigned to the BA arm of the RESiLIENT trial, a randomized controlled trial in Japan. Lesson and worksheet completion were treated as time-varying exposures, each yielding four engagement patterns: minimal (Few-Few), early (Many-Few), late (Few-Many), and consistently high (Many-Many). Outcomes were depressive symptom changes measured by the Patient Health Questionnaire-9 (PHQ-9) at weeks 6 and 26. We applied the parametric g-formula to estimate counterfactual PHQ-9 changes under each pattern, adjusting for baseline and time-varying confounders. Early lesson engagement during weeks 0-3 was associated with larger PHQ-9 reductions at both weeks 6 and 26, even when later engagement declined (Many-Few vs. Few-Few: week 6: -1.47 [95% CI -2.52 to -0.53]; week 26: -1.27 [-2.53 to -0.17]). In contrast, higher worksheet engagement was linked to improved PHQ-9 at week 6, with maximal benefit among consistently high engagers (Many-Many vs. Few-Few: -1.25 [-2.17 to -0.44]) and late engagers (Few-Many vs. Few-Few: -1.18 [-2.20 to -0.08]), but not persist to week 26. Greater engagement with smartphone-delivered BA is associated with larger symptom reductions. Early lesson engagement drives sustained benefit, whereas worksheet engagement did not persist. These findings may guide digital CBT design by emphasizing early lesson completion alongside concurrent skill practice.
This experimental study aimed to evaluate the effects of crocin on wound healing and fibrosis in vocal fold injury. Thirty-six male Wistar Albino rats were randomly divided into 3 groups: a sham group, a local crocin treatment group, and a systemic crocin treatment group. In the study, all rats underwent injury to their right vocal folds. Six rats from each group were randomly sacrificed on the 5th and 30th days after surgery. Tissue samples were evaluated for lamina propria thickness, inflammation severity, epithelial regeneration, edema, hyaluronic acid, collagen, elastin, and the cytokines TGF-β1, FGF2, and HGF. In the early phase, less inflammation, more epithelial regeneration, and lamina propria were observed in the systemic treatment group compared to the sham group. In the late phase, Compared to the sham group, both the systemic and local treatment groups showed higher values in lamina propria thickness, elastin, and HGF measurements, while collagen levels were significantly decreased. Furthermore, in the systemic group, TGF-β1 decreased in the late period, while hyaluronic acid and FGF2 levels remained high. When the groups were evaluated within themselves, inflammation and edema were observed to decrease more significantly in the late period in all groups. Hyaluronic acid decreased significantly in the sham and local treatment groups, while this decrease was limited in the systemic treatment group. Lamina propria thickness increased significantly in the treatment groups on day 30 compared to day 5. Crocin treatment applied using different methods has shown positive effects on various parameters, wound healing, and fibrosis reduction in the early and late periods after vocal fold injury. However, more extensive preclinical and clinical studies are needed to determine the efficacy and applicability of this treatment.
African swine fever (ASF) is a highly contagious and lethal disease caused by African swine fever virus (ASFV), with a mortality rate approaching up to 100%. At present, the functions of multiple genes of ASFV remain to be elucidated. In this study, we demonstrate that pD345L is a late-expressed viral protein and localizes to the viral factory. The recombinant strain JX23-02ΔD345L was obtained from the genotype Ⅰ/Ⅱ strain JX23-02. In vitro assays demonstrated that the deletion of D345L remarkably impairs viral replication. Further analyses revealed that JX23-02ΔD345L significantly upregulated pro-inflammatory cytokines (IL-1β, TNF-α) and IFN pathway components in PAMs, induced pyroptosis, apoptosis, and interferon responses. In vivo animal experiments demonstrated that the JX23-02ΔD345L strain was completely attenuated in pigs, failing to induce any typical clinical signs of ASF even with a high-dose inoculation. Moreover, a single immunization with JX23-02ΔD345L can elicit specific humoral and cellular immune responses against ASFV, conferring 80% protection against intramuscular challenge with the homologous strain JX23-02 and 60% protection against heterologous strain SY18. These results reveal D345L as a crucial virulence-related gene for ASFV pathogenesis, which is highly correlated with viral replication and the host antiviral response. Furthermore, JX23-02ΔD345L represented a candidate for the development of effective and safe ASFV vaccines. This finding provides a foundation for the research on ASFV and offers an important target and evidence for vaccine development.