FUBP3 mediates the amyloid-ß-induced neuronal NLRP3 expression.

JOURNAL/nrgr/04.03/01300535-202507000-00028/figure1/v/2024-09-09T124005Z/r/image-tiff Alzheimer's disease is characterized by deposition of amyloid-ß, which forms extracellular neuritic plaques, and accumulation of hyperphosphorylated tau, which aggregates to form intraneuronal neurofibrillary tangles, in the brain. The NLRP3 inflammasome may play a role in the transition from amyloid-ß deposition to tau phosphorylation and aggregation. Because NLRP3 is primarily found in brain microglia, and tau is predominantly located in neurons, it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines. Here, we found that neurons also express NLRP3 in vitro and in vivo, and that neuronal NLRP3 regulates tau phosphorylation. Using biochemical methods, we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons. In primary neurons and the neuroblastoma cell line Neuro2A, FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-ß is present. In the brains of aged wild-type mice and a mouse model of Alzheimer's disease, FUBP3 expression was markedly increased in cortical neurons. Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses. We also found that FUBP3 trimmed the 5' end of DNA fragments that it bound, implying that FUBP3 functions in stress-induced responses. These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-ß-to-phospho-tau transition than microglial NLRP3, and that amyloid-ß fundamentally alters the regulatory mechanism of NLRP3 expression in neurons. Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice, FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.

Topical frankincense treatment for frostbite based on microcirculation improvements.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese traditional medicine frankincense, which can promote blood circulation, is often used to treat skin lesions, including frostbite. AIM OF THE STUDY: To explore the properties of frankincense oil extract (FOE) and its active ingredients and their effect on frostbite wound recovery as an approach to understand the mechanism associated with microcirculation-improvement therapy. MATERIALS AND METHODS: The microcirculation-improving effects of FOE and its active ingredients were evaluated using liquid nitrogen-induced frostbite animal models. The rewarming capacity of FOE on the skin was determined through infrared detection, and frostbite wound healing was evaluated following haematoxylin and eosin (H&E) staining and fibre analysis. Moreover, related factors were examined to determine the anti-apoptotic, anti-inflammatory, and microcirculatory properties of FOE and its active ingredients on affected tissue in the context of frostbite. RESULTS: FOE and its active ingredients rapidly rewarmed wound tissue after frostbite by increasing the temperature. Moreover, these treatments improved wound healing and restored skin structure through collagen and elastin fibre remodelling. In addition, they exerted anti-apoptotic effects by decreasing the number of apoptotic cells, reducing caspase-3 expression, and eliciting anti-inflammatory effects by decreasing COX-2 and ß-catenin expression. They also improved microcirculatory disorders by decreasing HIF-1α expression and increasing CD31 expression. CONCLUSIONS: FOE and its active components can effectively treat frostbite by enhancing microcirculation, inhibiting the infiltration of inflammatory cells, decreasing cell apoptosis, and exerting antinociceptive effects. These findings highlight FOE as a new treatment option for frostbite, providing patients with an effective therapeutic strategy.

Global, regional, and national burden of preterm birth, 1990-2021: a systematic analysis from the global burden of disease study 2021.

Background: Preterm birth and its complications are leading causes of mortality among children under five years of age. Given the increasing burden of preterm birth on neonatal mortality and long-term health outcomes worldwide, a comprehensive global analysis is essential to guide effective public health interventions and policies. This study aims to assess the burden of preterm birth at the global, regional, and national levels. Methods: Using data from the Global Burden of Disease (GBD) 2021 database, this study analysed trends in age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), and disability-adjusted life-years (DALYs) as primary outcomes for preterm birth from 1990 to 2021 at global, regional, and national levels. Data were assessed using joinpoint regression analysis, decomposition analysis, and the health inequality concentration index. Findings: Globally, the incidence, mortality and DALYs due to preterm birth have shown a declining trend, but ASIR started to increase in 2016. Males were more commonly born preterm than females (12329075.82, 95% uncertainty interval [UI]: 12192632.55-12464605.4 vs. 9224694.94, 95% UI: 9113876.1-9330107.89). Changes in DALYs were primarily due to epidemiological change (111.97%) and population (-21.59%). Low Socio-demographic Index (SDI) regions increased in annual incidence cases (43.1%, 95% UI: 40.17-46.09), while high SDI regions decreased in annual incidence cases (-9.6%, 95% UI: -11.45 to -7.79). The highest annual mortality and DALYs respectively occurred in sub-Saharan Africa (295490.66, 95% UI: 241762.78-353624.41) and South Asia (32760273.93, 95% UI: 27295547.76-39070225.69). Western sub-Saharan Africa showed the largest increase in annual incidence (98.95%, 95% UI: 94.77 to 103.09), and Australasia had the lowest annual mortality (287.18, 95% UI: 244.26-339.42) and DALYs (61081.4, 95% UI: 50897.33-73069.96). Western sub-Saharan Africa also had the highest ASMR (21.57, 95% confidence interval [CI]: 17.9-25.89). The highest ASIR (543.78, 95% CI: 535.11-553.21) and age-standardized DALYs (2064.65, 95% CI: 1717.27-2473.36) both occurred in South Asia, while the lowest ASIR and age-standardized DALYs were seen in East Asia (147.31, 95% CI: 144.22-150.85) and High-income Asia Pacific (143.32, 95% CI: 117.9-167.25). India, Nigeria, and Pakistan ranked highest globally in terms of annual incidence cases, mortality, and DALYs, while the lowest annual incidence, mortality and DALYs respectively occurred in Tokelau (2.34, 95% UI: 2.12-2.56), San Marino (0.04, 95% UI: 0.02-0.07) and Tokelau (17.22, 95% UI: 11.11-24.95). Interpretation: While the global burden of preterm birth has decreased, significant disparities persist, especially in low SDI regions. There is a need for more refined policies and preventive measures to effectively address preterm birth. Funding: No funds, grants, or other support was received.

Low brain-derived neurotrophic factor and high vascular cell adhesion molecule-1 levels are associated with chronic kidney disease in patients with type 2 diabetes mellitus.

Background: Patients with type 2 diabetes mellitus (DM) have a high prevalence of chronic kidney disease (CKD). Energy imbalance and inflammation may be involved in the pathogenesis of CKD. We examined the effects of brain-derived neurotrophic factor (BDNF) and vascular cell adhesion molecule-1 (VCAM-1) on CKD in patients with type 2 DM. Methods: Patients with type 2 DM were enrolled for this cross-sectional study. Fasting serum was prepared to measure the BDNF and VCAM-1 levels. An estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 was used as the criterion for identifying patients with CKD. Results: Of the 548 enrolled participants, 156 had CKD. Patients with CKD exhibited significantly lower BDNF (median of 21.4 ng/mL, interquartile range [IQR]: 17.0-27.0 ng/mL vs. median of 25.9 ng/mL, IQR: 21.0-30.4 ng/mL, P <0.001) and higher VCAM-1 (median of 917 ng/mL, IQR: 761-1172 ng/mL vs. median of 669 ng/mL, IQR: 552-857 ng/mL, P <0.001) levels than those without CKD. Serum BDNF levels were inversely correlated with VCAM-1 levels (Spearman's rank correlation coefficient = -0.210, P <0.001). The patients were divided into four subgroups based on median BDNF and VCAM-1 levels (24.88 ng/mL and 750 ng/mL, respectively). Notably, patients in the high VCAM-1 and low BDNF group had the highest prevalence (50%) of CKD. Multivariate logistic regression revealed a significantly higher odds ratio (OR) of CKD in the high VCAM-1 and low BDNF group (OR = 3.885, 95% CI: 1.766-8.547, P <0.001), followed by that in the high VCAM-1 and high BDNF group (OR = 3.099, 95% CI: 1.373-6.992, P =0.006) compared with that in the low VCAM-1 and high BDNF group. However, the risk of CKD in the low VCAM-1 and low BDNF group was not significantly different from that in the low VCAM-1 and high BDNF group (P =0.266). Conclusion: CKD in patients with type 2 DM is associated with low serum BDNF and high VCAM-1 levels. BDNF and VCAM-1 have a synergistic effect on CKD. Thus, BDNF and VCAM-1 can be potential biomarkers for CKD risk stratification in patients with type 2 DM.

Optimize Vancomycin Dose in Surgical Ward Patients with Augmented Renal Clearance Determined by Chronic Kidney Disease Epidemiology Collaboration Equation.

Background: In the field of postoperative care, infections caused by Gram-positive bacteria pose a major clinical challenge. Vancomycin is a key therapeutic agent whose efficacy is greatly influenced by renal function, particularly by augmented renal clearance (ARC). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) is an easy and commonly used method to predict ARC; however, it is not well studied to determine vancomycin dose. In this study, we examined the effectiveness of the CKD-EPI equation in determining ARC and optimizing the dose of vancomycin for surgical ward patients. Methodology: A retrospective observational study was conducted to examine 158 surgical ward patients receiving vancomycin. Data on demographics, medical history, and vancomycin dosing were collected. Renal function was evaluated using the CKD-EPI equation, with ARC defined as eGFR ≥ 96.5 mL/min/1.73 m2. Vancomycin pharmacokinetics were calculated using the ClinCalc tool. Results: ARC was in 54% of the patients. Compared with patients without ARC, those with ARC were younger and had lower serum creatinine levels. They also required higher vancomycin doses but had lower trough concentrations and 24-hour area-under-the-curve values. A significant correlation was observed between eGFR and vancomycin clearance, with eGFR > 96.5 mL/min/1.73 m2 necessitating higher vancomycin doses (>45 mg/kg/day) to achieve the desired area under the curve to minimum inhibitory concentration ratio. Conclusion: For surgical ward patients with CKD-EPI eGFR ≥ 96.5 mL/min/1.73 m2, a vancomycin dosage of >45 mg/kg/day may be recommended to reach effective therapeutic levels. Overall, this study emphasizes the importance of tailoring vancomycin therapy depending on renal function to ensure efficacy and mitigate the risk of antimicrobial resistance in surgical ward patients.

Acquisition and reconstruction with motion suppression DWI enhance image quality in nasopharyngeal carcinoma patients: Non-echo-planar DWI comparison with single-shot echo-planar DWI.

PURPOSE: To evaluate the impact of application acquisition and reconstruction with motion suppression (ARMS) technology on improving the image quality of diffusion-weighted Imaging (DWI) for nasopharyngeal carcinoma (NPC), compared to single-shot echo-planar imaging (SS-EPI). METHODS: A total of 90 patients with NPC underwent MR examination, including ARMS DWI and SS-EPI DWI sequences. Both DWI sequences were acquired with b-values 0 and 800 s/mm2. Two radiologists evaluated the visibility of the lesion, geometric distortion, and overall image quality of the two DWI sequences. Signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), geometric distortion degree, and apparent diffusion coefficient (ADC) values of the nasopharyngeal lesions were assessed and compared for two sequences. The Wilcoxon signed-rank test was used to compare the quantitative and qualitative parameters of the two sequences. RESULTS: The lesion visibility, geometric distortion, and overall image quality scores were significantly higher in ARMS DWI (all P<0.001). Four small-sized lesions were not visible and four lesions were partially visible in the SS-EPI DWI sequence. Lesion detection rate of ARMS DWI is 100 %, while that of SS-EPI is 95.56 %, P<0.043. The mismatch distance between the fusion images of ARMS DWI and T2WI was smaller than that of SS-EPI DWI and T2WI (all P<0.001). The SNR and CNR of ARMS DWI were lower than that of SS-EPI DWI (114.48 ± 37.89 vs. 202.61 ± 78.84, P<0.001 and 1.81 ± 1.84 vs. 3.29 ± 3.71, P<0.003) while the ADC value was higher (839.19 ± 138.44 × 10-6 mm2/s vs. 788.82 ± 110.96 × 10-6 mm2/s, P<0.002). CONCLUSION: ARMS DWI improves the image quality by reducing geometric distortion and magnetic susceptibility artifacts. ARMS DWI is superior to SS-EPI DWI for diagnosing small-sized nasopharyngeal lesions, although it has lower SNR and CNR.

A Thin Polymer Layer Enables Peptide-Polycation Complexes with Ultrahigh Efficient Encapsulation.

A monolayer encapsulation is a new opportunity for engineering a system with high drug loading, but immobilizing polymer molecules on the surface of individual peptide nanoparticles is still an ongoing challenge. Herein, an individual peptide nanoparticle encapsulation strategy is proposed via surface adsorption, in which peptide molecules undergo granulation and subsequently aggregate with polymer molecules, forming a network via electrostatic interactions. Under the water phase, surplus polymer molecules dissolve, leading to a single nanoparticle encapsulation with a core-shell structure. As expected, the dense interfacial layer on the peptide nanoparticle surface achieves a superior loading degree of up to 95.4%. What's more, once the core-shell structure is established, the peptide mass fraction in individual encapsulation always exceeds 90% even under fierce external force. Following the individual nanoparticle encapsulation, the insulin-polycation complex (InsNp@PEI) reduces the inflammation from polymer and displays an effective glycemic control in type 1 diabetes. Overall, the newly developed single surface decoration encapsulates peptides with ultrahigh efficiency and opens up the possibility for further encapsulation.

Blastic plasmacytoid dendritic cell neoplasm: Two case reports.

BACKGROUND: Blastic plasmacytoid dendritic cell tumor (BPDCN) is a rare and highly invasive lymphohematopoietic tumor that originates from plasmacytoid dendritic cells. BPDCN has an extremely poor prognosis. Skin lesions are usually the first manifestation of BPDCN, although the tumor may also invade the bone marrow, lymph nodes, peripheral blood, and other parts of the body, leading to several other manifestations, requiring further differentiation through skin biopsy and immunohistochemistry. CASE SUMMARY: In the present paper, the cases of 2 patients diagnosed with BPDCN are discussed. The immunohistochemistry analysis of these 2 patients revealed positivity for CD4, CD56, and CD123. Currently, no standard chemotherapy regimen is available for BPDCN. Therefore, intensive therapy for acute lymphoblastic leukemia was applied as the treatment method for these 2 cases. CONCLUSION: Although allogeneic bone marrow transplantation could be further effective in prolonging the median survival the ultimate prognosis was unfavorable. Future treatment modalities tailored for elderly patients will help prolong survival.

On-demand removable hydrogel film derived from gallic acid-phycocyanin and polyvinyl alcohol for fruit preservation.

Postharvest spoilage of fruits accounts for significant losses ranging between 20 %-30 %, leading to considerable resource wastage and economic downturns. The development of an effective fresh-keeping packaging material is of paramount importance. This study introduces an innovative on-demand removable active fruit fresh-keeping film (GPP), created by embedding a GP (gallic acid-phycocyanin) fiber mesh hydrogel with functional properties into a polyvinyl alcohol (PVA) matrix. The resultant GPP hydrogel-based film demonstrates outstanding UV and water vapor barrier capabilities, mechanical stability, resistance to external mechanical stress, universal surface adhesion, antibacterial efficacy, and on-demand removal attributes, while being devoid of potential toxicity hazards. Utilizing grapes and blueberries as representative fruits, it is shown that the GPP hydrogel film significantly preserves the fruits' hardness, pH, total soluble solids content (TSS), and minimizes the rate of weight loss, thereby prolonging the shelf life to 13 days for grapes and 20 days for blueberries at ambient temperature. These results underscore the potential of this hydrogel-based film as an invaluable material for fruit preservation within the food industry.

Flexible Soft X-Ray Image Sensors based on Metal Halide Perovskites With High Quantum Efficiency.

Soft X-ray imaging is a powerful tool to explore the structure of cells, probe material with nanometer resolution, and investigate the energetic phenomena in the universe. Conventional soft X-ray image sensors are by and large Si-based charge coupled devices that suffer from low frame rates, complex fabrication processes, mechanical inflexibility, and required cooling below -60 °C. Here, a soft X-ray photodiode is reported based on low-cost metal halide perovskite with comparable performance to commercial Si-based device. Nanothrough network electrode minimized the optical loss due to the shadowing of insensitive layers, while a multidimensional perovskite heterojunction is generated to reduce the photo-generated carrier loss. This strategy promoted a record quantum efficiency of 8 × 103% without cooling, several orders of magnitude greater than the previously achieved. Flexible and curved soft X-ray imaging arrays are fabricated based on this high-performance device structure, demonstrating stable soft X-ray response and sharp imaging capabilities. This work highlights the low-cost and efficient perovskite photodiode as a strong candidate for the next-generation soft X-ray image sensors.

A random survival forest-based pathomics signature classifies immunotherapy prognosis and profiles TIME and genomics in ES-SCLC patients.

BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with high mortality, and only a limited subset of extensive-stage SCLC (ES-SCLC) patients demonstrate prolonged survival under chemoimmunotherapy, which warrants the exploration of reliable biomarkers. Herein, we built a machine learning-based model using pathomics features extracted from hematoxylin and eosin (H&E)-stained images to classify prognosis and explore its potential association with genomics and TIME. METHODS: We retrospectively recruited ES-SCLC patients receiving first-line chemoimmunotherapy at Nanjing Jinling Hospital between April 2020 and August 2023. Digital H&E-stained whole-slide images were acquired, and targeted next-generation sequencing, programmed death ligand-1 staining, and multiplex immunohistochemical staining for immune cells were performed on a subset of patients. A random survival forest (RSF) model encompassing clinical and pathomics features was established to predict overall survival. The function of putative genes was assessed via single-cell RNA sequencing. RESULTS AND CONCLUSION: During the median follow-up period of 12.12 months, 118 ES-SCLC patients receiving first-line immunotherapy were recruited. The RSF model utilizing three pathomics features and liver metastases, bone metastases, smoking status, and lactate dehydrogenase, could predict the survival of first-line chemoimmunotherapy in patients with ES-SCLC with favorable discrimination and calibration. Underlyingly, the higher RSF-Score potentially indicated more infiltration of CD8+ T cells in the stroma as well as a greater probability of MCL-1 amplification and EP300 mutation. At the single-cell level, MCL-1 was associated with TNFA-NFKB signaling and apoptosis-related processes. Hopefully, this noninvasive model could act as a biomarker for immunotherapy, potentially facilitating precision medicine in the management of ES-SCLC.

Nucleos(t)ide analogs to treat patients with positive hepatitis B virus deoxyribonucleic acid and normal alanine transaminase: protocol for an open-label single-center randomized parallel controlled trial.

BACKGROUND: Direct high-quality evidence remains absent on the benefits of HBeAg-negative chronic hepatitis B patients (CHB) with normal alanine transaminase (ALT) and positive HBV DNA after nucleos(t)ide analogs (NAs) treatment. METHODS: This is a single-center, open-label, randomized parallel controlled trial with a follow-up duration of 96 weeks. An estimated 300 patients will be recruited at West China Hospital of Sichuan University, China. After stratified by serum HBV DNA (< 2000 vs. ≥ 2000 IU/ml), eligible patients will be randomized (allocation ratio 1:1) to receive either antiviral therapy (the treatment group) or regular examination alone (the control group). The primary outcomes are rates of virological response and changes in the levels of serum HBV pregenomic RNA (pgRNA) and scores of health-related qualities of life. DISCUSSION: This randomized controlled trial focuses on HBeAg-negative patients with normal ALT, including those of the inactive carrier phase and the grey zone, whose antiviral treatment remains controversial. Additionally, a health-related quality of life scale is introduced to comprehensively estimate the benefit of antiviral treatment apart from virological response and adverse liver events. Meaningfully, the study findings will provide high-quality and direct evidence for optimal clinical management in such populations. TRIAL REGISTRATION: This trial was registered with the Chinese Clinical Trial Registry (ChiCTR2300069391) on 15 March 2023.

Tumor-associated lymphatic vessel density is a reliable biomarker for prognosis of esophageal cancer after radical resection: a systemic review and meta-analysis.

Purpose: To explore whether tumor-associated lymphatic vessel density (LVD) could be a biomarker for the prognosis of patients with esophageal cancer after radical resection. Methods: A systematic literature search was performed through PubMed, EMBASE, Wanfang Data, and Cochrane Library from the inception of databases until March 19, 2024. The selected studies investigated overall survival (OS) and/or recurrence-free survival (RFS) of patients with esophageal cancer with different levels of LVD after radical resection. The OS and RFS data were pooled as hazard ratios (HR) and 95% confidential interval (CI). Furthermore, the standardized mean differences (SMDs) and 95% CI were aggregated to evaluate the correlation between LVD and clinicopathological features. Results: A total of 10 retrospective studies of 1,201 patients were finally included for the meta-analysis. Patients with esophageal cancer with a high level of LVD exhibited worse OS (HR 1.65, 95% CI 1.18 to 2.31) and RFS (HR 1.57, 95% CI 1.09 to 2.26) than those with a low level of LVD. Subgroup analysis of different pathological subtypes revealed that patients with esophageal adenocarcinoma with a high level of LVD had significantly worse RFS (HR 2.84, 95% CI 1.61 to 5.02) than those with a low level of LVD; while patients with esophageal squamous cell carcinoma with a high level of LVD had similar OS (HR 1.52, 95% CI 0.93 to 2.47) and RFS (HR 1.03, 95% CI 0.72 to 1.48) to those with a low level of LVD. Furthermore, tumors with lymph node metastasis had significantly higher levels of LVD than those without lymph node metastasis (SMD = 1.11, 95% CI 0.54 to 1.67). Tumors at the stages III-IV had significantly higher levels of LVD than those at the stages I-II (SMD = 1.62, 95% CI 0.90 to 2.34). Conclusion: A high level of LVD in tumor was associated with worse survival of patients with esophageal cancer after radical resection, especially in patients with esophageal adenocarcinoma. Tumor-associated LVD is a new parameter that should be measured in postoperative pathology for predicting the prognosis of patients with esophageal cancer. Systematic review registration: https://www.crd.york.ac.uk/prospero/ PROSPERO, identifier CRD42024553766.

Kanamycin promotes biofilm viability of MRSA strains showing extremely high resistance to kanamycin.

Staphylococcus aureus is widely distributed in environment and can cause various human infection and food poisoning cases. Also, this pathogen is a typical biofilm former, which further complicates its pathogenicity. Antibiotics have been widely used to eliminate pathogenic bacteria, but their indiscriminate use has also led to the widespread emergence of drug-resistant bacteria, such as Methicillin-Resistant Staphylococcus aureus (MRSA). In this study, the effect of antibiotics on biofilm formation of MRSA strains 875 and 184 was explored. Firstly, MRSA 875 belongs to SCCmec type IV, ST239, carrying the atl, icaA, icaD, icaBC, and aap genes, and MRSA 184 belongs to SCCmec type II, ST5, carrying the atl, icaD, icaBC, aap, and agr genes. Then, a total of 8 antibiotics have been selected, including kanamycin, gentamycin, cipprofloxacin, erythromycin, meropenem, penicillin G, tetracycline, vancomycin. Minimum inhibitory concentrations (MICs) of each antibiotic were determined, and MIC of MRSA 875 and 184 to kanamycin/gentamicin are 2048/64 µg/mL and 2048/4 µg/mL, respectively. A total of 10 concentrations, ranging from 1/128 to 4 MIC with 2-fold, were used to study biofilm formation. Biofilm biomass and viability were determined during different phases, including initial adhesion (8 h), proliferation (16 h), accumulation (24 h) and maturation (48 h). Importantly, kanamycin at specific concentrations showed significant promotion of biofilm biomass and biofilm viability, with none of such observation acquired from other antibiotics. This study provides scientific basis and new research ideas for the quality control technology of microorganisms and safety prevention of MRSA.

Clinic transfers and engagement in HIV care during the perinatal period across a network of healthcare centers in Lilongwe, Malawi.

INTRODUCTION: Disengagement from HIV care during the perinatal period remains a challenge. Improving engagement in HIV care requires monitoring engagement across multiple indicators, including retention in HIV care, visit adherence, clinic transfers, and viral suppression to support improved clinical and programmatic outcomes. METHODS: We enrolled a prospective cohort of pregnant WHIV across a network of five urban clinics in Lilongwe, Malawi from February 2020-February 2021. WHIV were followed from their first antenatal care visit through 9 months postpartum across all study sites using biometric fingerprint scanning. Study visits occurred at enrollment into antenatal care, 6 weeks', 6 months, and 9 months postpartum. In addition, all usual care HIV visits were captured via medical records. Participants who missed a study visit or usual care visit were traced. We evaluated determinants of multiple indicators of engagement in care, including retention in HIV care (attending a scheduled visit or self-reported recent visit when traced), HIV visit adherence (missed scheduled HIV visits and HIV visit coverage), clinic transfers, and viral load suppression (< 1000 copies/mL) using modified Poisson regression and sub-distributional hazard ratios to account for competing events of death and loss-to-follow-up. Associations between clinic transfer and subsequent indicators of engagement in HIV care were evaluated using generalized estimating equations. RESULTS: Among 399 participants, 81% were on ART at baseline. Retention in HIV care was 87% at 6 weeks postpartum, 77% at 6 months postpartum and 89% at 9 months postpartum. At 9 months postpartum, 91% of participants were virally suppressed, 81% had missed a scheduled HIV visit, and 19% had transferred clinics. WHIV who transferred clinics were most likely to miss their subsequent scheduled HIV visit by ≥ 30 days. Transferring clinics was not associated with unsuppressed viral load or non-retention at 9 months postpartum. CONCLUSIONS: In a cohort of WHIV, retention and viral load suppression were high in the perinatal period, but missed HIV visits and clinic transfers were common. Transferring clinics was associated with an increased likelihood of missing a subsequent HIV visit. Clinic transfers may be important indicators of disruptions in clinical care for WHIV in the perinatal period.

Sulforaphane acts through the NFE2L2/AMPK signaling pathway to protect boar spermatozoa from cryoinjury by activating antioxidant defenses.

During cryopreservation, a substantial portion of spermatozoa undergoes apoptosis due to cryoinjury, resulting in decreased fertility. Boar spermatozoa are highly sensitive to temperature, with low temperature triggering reactive oxygen species (ROS) generation, leading to oxidative stress and apoptosis. Sulforaphane (SFN), a potent natural compound found in cruciferous vegetables, is efficacious in mitigating oxidative stress. We here supplemented different SFN concentrations (0, 1.25, 2.5, 5, 10, and 20 µM) into the freezing extender to explore its effect on boar sperm during cryopreservation and determine the optimal SFN concentration. Supplementation of 5 µM SFN exhibited the highest sperm motility, motion performance, plasma membrane integrity, acrosome integrity, and antioxidant properties (total antioxidant capacity (T-AOC) and antioxidant enzyme activity) after freezing and thawing. Then, RT group, C group and C + SFN group were established to explore the effect of SFN on the cryopreservation-induced sperm apoptosis level and fertilizing capacity of post-thawed sperms. SFN effectively rescued the apoptosis and fertilizing capacity of post-thawed sperms. Mechanistically, SFN activated the redox-sensitive nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) by promoting adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. This activation improved antioxidant defenses, ultimately improving cryoinjury in boar spermatozoa. In summary, SFN suppressed cryopreservation-induced apoptosis of spermatozoa by activating antioxidant defenses and the AMPK/NFE2L2 signaling pathway. These findings suggest a novel approach for augmenting the cryoprotective efficiency and spermatozoa fertility after cryopreservation.

Altered cortical functional networks in Wilson's disease: A resting-state electroencephalogram study.

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD.

Thrombectomy for patients with a large infarct core: a study-level meta-analysis with trial sequential analysis.

Background: The effectiveness and safety of endovascular treatment compared with medical management alone regarding outcomes for patients with a large infarct core remain uncertain. Objectives: To juxtapose the clinical outcomes of thrombectomy versus the best medical care in patients with a large infarct core. Design: Systematic review and meta-analysis. Data sources and methods: We conducted searches in PubMed, Cochrane, and Embase for articles published up until November 8, 2023. Randomized trials were selected for inclusion if they encompassed patients with large vessel occlusion and sizable strokes receiving thrombectomy. The primary outcome was functional outcomes at 3 months after pooling data using random-effects modeling. Safety outcomes included mortality at 3 months, symptomatic intracranial hemorrhage (SICH), and decompressive craniectomy. We performed a trial sequential analysis to balance type I and II errors. Results: From 904 citations, we identified six randomized trials, involving a cohort of 1897 patients with a large ischemic region. Of these, 953 individuals underwent endovascular thrombectomy. At 3 months, thrombectomy was significantly correlated with better neurological prognosis, as evidenced by the increased odds of good functional outcomes (odds ratio (OR), 2.90; 95% confidence interval (CI), 2.08-4.05) and favorable functional outcomes (OR, 2.40; 95% CI, 1.86-3.09). Mortality rates did not demonstrably diminish as a consequence of the endovascular management (OR, 0.78; 95% CI, 0.58-1.06). However, the incidence of SICH was greater in the thrombectomy group compared to those with only medical treatment (5.5% vs 3.2%; OR, 1.77; 95% CI, 1.11-2.83). The application of trial sequential analysis yielded definitive evidence regarding favorable function outcomes and a shift in the distribution of modified Rankin scale scores at 3 months; however, others remained inconclusive. Conclusion: The results from most of the included trials display consistency. Meta-analysis of these six randomized trials offers high-quality evidence that thrombectomy significantly mitigates disability in patients with a large infarction, while also increasing the risk of SICH. Trial registration: PROSPERO, CRD42023480359.

Intestinal flora and inflammatory bowel disease: Causal relationships and predictive models.

Background: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is significantly influenced by intestinal flora. Understanding the genetic and microbiotic interplay is crucial for IBD prediction and treatment. Methods: We used Mendelian randomization (MR), transcriptomic analysis, and machine learning techniques, integrating data from the MiBioGen Consortium and various GWAS datasets. SNPs associated with intestinal flora were mapped to genes, with LASSO regression refining gene selection. Differentially expressed genes (DEGs) and immune infiltration patterns were identified through transcriptomic analysis. Six machine learning models were used for predictive modeling. Findings: MR analysis identified 25 gut microbiota classifications causally related to IBD. SNP mapping and gene expression analysis highlighted 24 significant genes. Drug target MR and colocalization validated these genes' causal relationships with IBD. Key pathways identified included the PI3K-Akt signaling pathway and epithelial-mesenchymal transition. Immune infiltration analysis revealed distinct patterns between high and low LASSO score groups. Machine learning models demonstrated high predictive value, with soft voting enhancing reliability. Interpretation: By integrating MR, transcriptomic analysis, and sophisticated machine learning approaches, this study elucidates the causal relationships between intestinal flora and IBD. The application of machine learning not only enhanced predictive modeling but also offered new insights into IBD pathogenesis, highlighted potential therapeutic targets, and established a robust framework for predicting IBD onset.