Combined effects of aquifer heterogeneity and subsurface dam on nitrate contamination in coastal aquifers.

Subsurface dams are effective for seawater intrusion mitigation, yet they can cause upstream nitrate accumulation. This research examines the interplay between subsurface dam construction and aquifer layering on nitrate pollution in coastal settings, employing numerical models to simulate density-driven flow and reactive transport. The study reveals that while subsurface dams are adept at curbing seawater intrusion, they inadvertently broaden the nitrate accumulation zone, especially when a low-K layer is present. Heterogeneous aquifers see more pronounced nitrate accumulation from subsurface dams. This effect is pronounced as it influences dissolved organic carbon dynamics, with a notable retreat inland correlating with the expansion of the nitrate pollution plume. A critical finding is that controlling seawater intrusion via dam height adjustment within the Effective Damming Region effectively reduces nitrate levels and bolsters freshwater output. However, exceeding the critical threshold-where the dam surpasses the low-K layer's bottom-results in a substantial shift in nitrate concentration, underscoring the need for precise dam height calibration to avoid aggravating nitrate pollution. This study's innovative contribution lies in its quantification of the nuanced effects of subsurface dams in stratified aquifers, providing an empirical basis for dam design that considers the layered complexities of coastal aquifers. The insights offer a valuable framework for managing nitrate contamination, thus informing sustainable coastal groundwater management and protection strategies.

Barriers to prophylactic treatment among patients with haemophilia A in Shandong Province, China: a qualitative study.

BACKGROUND: Haemophilia A is a rare, hereditary haemorrhagic disease that manifests as induced spontaneous bleeding and leads to disability or premature death in severe cases. Prophylactic treatment is optimal for patients to prevent uncontrolled bleeding and reduce the severity of the injury. However, little is known about the use of prophylactic treatment among patients with haemophilia A in China, especially barriers that predispose them to low or non-adherence. In this study, we explore the barriers to the prophylactic treatment of patients with haemophilia A. METHOD: We used personal interviews and focus groups to collect the data and analysed the data through thematic analysis. Purposive sampling was employed to recruit our participants. We continued recruiting participants until data saturation was reached from the thematic analysis. Ultimately, we obtained 37 participants, among whom 19 participated in personal interviews and 18 participated in focus groups (i.e., 3 focus groups with 6 participants each). RESULTS: Three themes and nine subthemes were identified from the thematic analysis. Nine subthemes (i.e., perceived barriers) emerged from the analysis, which were further clustered into three themes: (1) poor primary health care, (2) inadequate financial support, and (3) a lack of patient-centred care. CONCLUSION: The findings presented in this descriptive qualitative study offer a unique view of Chinese patients with haemophilia A and their barriers to prophylactic treatment. Our findings not only provide an in-depth understanding of barriers to prophylactic treatment encountered by Chinese patients with haemophilia A but also address the urgent need to strengthen primary care, provide adequate financial support, and establish patient-centred care for these suffering patients.

Quantifying Benefit-Risk Trade-Offs Toward Prophylactic Treatment Among Adult Patients With Hemophilia A in China: Discrete Choice Experiment Study.

BACKGROUND: Hemophilia A is a chronic condition that requires meticulous treatment and management. Patient preferences for prophylactic treatment can substantially influence adherence, outcomes, and quality of life, yet these preferences remain underexplored, particularly in China. OBJECTIVE: This study aimed to investigate the preferences for prophylactic treatment among Chinese adult patients with hemophilia A without inhibitors, considering clinical effectiveness, side effects, dosing mode, and dosing frequency. METHODS: A discrete choice experiment was used to elicit patient preferences for prophylactic treatment of hemophilia. The study was conducted across 7 provinces in China with socioeconomic and geographical diversity. Subgroup analysis was performed according to education level, geographic location, and treatment type, alongside the exploration of benefit-risk trade-offs. RESULTS: A total of 113 patients completed the discrete choice experiment questionnaire, and we included 102 responses for analysis based on predetermined exclusion criteria. The study found that patients prioritized reducing annual bleeding times and avoiding the risk of developing inhibitors over treatment process attributes. Subgroup analysis revealed that lower-educated patients and those from rural areas attached more importance to the dosing mode, likely due to barriers to self-administration. Patients demonstrated a clear understanding of benefit-risk trade-offs, exhibiting a willingness to accept an increased risk of developing inhibitors for improved clinical outcomes. CONCLUSIONS: This study provides valuable insights into the preferences of patients with hemophilia A for prophylactic treatment in China. Understanding these preferences can enhance shared decision-making between patients and clinicians, fostering personalized prophylactic treatment plans that may optimize adherence and improve clinical outcomes.

Identification of a novel mutation in the factor XIII A subunit in a patient with inherited factor XIII deficiency.

Inherited factor XIII (FXIII) deficiency is an extremely rare and under-diagnosed autosomal recessive inherited coagulopathy, which is caused by genetic defects in the F13A1 or F13B gene. More than 200 genetic mutations have been identified since the first case of inherited FXIII deficiency was reported. This study aimed to identify underlying gene mutations in a patient with inherited FXIII deficiency who presented with recurrent intracerebral hemorrhage. Levels of plasma FXIII-A antigen were measured, F13A1 and F13B genes were sequenced, mutation information was analyzed, and the mutated protein structure was predicted using bioinformatics methods. Molecular genetic analysis identified four mutations of FXIII-related genes in the proband, including three previously reported mutations inherited from his parents (c.631G>A, p.Gly210Arg and c.1687G>A, p.Gly562Arg of F13A1 gene and c.344G>A, p.Arg115His of F13B gene) and a novel spontaneous mutation of F13A1 gene (c.2063C>G, p.Ser687Cys). Molecular structural modeling demonstrated that the novel Ser687Cys mutation may cause changes in the spatial structure of FXIII-A and increase its instability. In conclusion, we identified a novel and likely pathogenic mutation of the F13A1 gene, which enriched the gene mutation spectrum of inherited FXIII deficiency. The findings may provide promising targets for diagnosis and treatment of inherited FXIII deficiency.

Behavior characteristics of bimolecular reactive transport in heterogeneous porous media.

In order to study the mechanism of bimolecular reactive solute transport in heterogeneous porous media, the chemical reaction (CuSO4 + Na2EDTA2-→CuEDTA2) was carried out by laboratory experiments and numerical simulation in heterogeneous porous media. Three different kinds of heterogeneous porous media (Sd2 = 1.72, 1.67 and 0.80 mm2) and flow rates (1.5, 2.5 and 5.0 mL/s) were considered. The increase of flow rate would promote the mixing between reactants, resulting in a greater peak value and a slighter "tailing" of product concentration, while the increase of medium heterogeneity would result in a more significant "tailing". It was found that the concentration breakthrough curves of reactant CuSO4 had a peak in the early stage of the transport, and the peak value increased with the increase of flow rate and medium heterogeneity. The concentration peak of CuSO4 was caused by the delayed mixing and reaction of reactants. The IM-ADRE (The advection-dispersion-reaction equation considering incomplete mixing) model could well simulate the experimental results. The simulation error of IM-ADRE model for the concentration peak of product was less than 6.15%, and the fitting accuracy for "tailing" increased with the increase of flow. The dispersion coefficient increased logarithmically with the increase of flow, and was negatively correlated to the heterogeneity of the medium. In addition, the dispersion coefficient of CuSO4 simulated by IM-ADRE model was one order of magnitude larger than that simulated by ADE model, indicating that the reaction promoted dispersion.

Influence of pH on bioclogging in porous media during managed aquifer recharge (MAR): Effectiveness and mechanism.

To investigate the effect of pH on bioclogging process during managed aquifer recharge, three laboratory-scale column experiments were conducted and the relative hydraulic conductivity, bacterial cell number and the concentrations of polysaccharide, protein and EPS were measured under pH 5, 7, and 9, respectively. High-throughput sequencing was also used to determine the characteristics of bacterial community under different pH conditions. The development of bioclogging was rather different for the case of pH 5. 7, and 9; i.e., the growth process and number of bacteria differed with pH. The shortest growth period and lowest number of bacteria were observed at pH 5. In addition, the difference in bacterial EPS concentration was mainly associated with the polysaccharides. The variation in pH led to different bacterial community composition and diversity. The acid-resistant Elizabethkingia and Bacillus were abundant at pH 5, while Chryseobacterium and Klebsiella had relatively high abundances at pH 7. In contrast, the basophilic Exiguobacterium accounted for >80% of the total bacterial abundance at pH 9. This work is of great significance to explore bioclogging mechanism during MAR process, and provides insights and guidances for field-based managed aquifer recharge.

Application of Gene Therapy in Hemophilia.

Gene therapy refers to introducing normal exogenous genes into target cells to correct or compensate for the diseases caused by defective and abnormal genes for the purpose of therapy. It holds out hope of a cure for single-gene genetic diseases such as thalassemia, hemophilia, etc. At present, gene therapy is performed in two ways: introducing exogenous genes, and gene editing. A great number of clinical trials of gene therapy in hemophilia have been carried out using viral vectors to introduce foreign genes into target cells. However, the production of neutralizing antibodies following injection and the inability to prepare viral vectors in large quantities limit their application. Although gene-editing methods like CRISPR avoid the above problems, the potential risks of off-target effects are still unknown. More trials and evidence are needed to elucidate the safety and accuracy of gene therapy. This paper will review the bench and clinical work of gene therapy in hemophilia in recent years, and summarize the challenges and prospects of gene therapy, so as to provide directions for future scientific research in this field.

Risk factors for inhibitors in hemophilia A based on RNA-seq and DNA methylation.

Background: The development of factor VIII (FVIII) inhibitor is a severe complication during replacement therapy for hemophilia A patients. Objectives: We investigated the potential risk factors for FVIII inhibitor formation based on genome-wide RNA-sequencing and whole-genome bisulfite sequencing analysis. Methods: RNA-sequencing and whole-genome bisulfite sequencing analysis were applied on 17 blood samples with F8 intron 22 inversion, including seven with inhibitors and 10 without. Results: Altogether, 344 mRNA transcripts and 20 long noncoding RNAs (lncRNA) transcripts were differentially expressed. Among the differentially expressed transcripts, 200 mRNAs and 12 lncRNAs were upregulated, and 144 mRNAs and eight lncRNAs were downregulated. Gene ontology enrichment analysis of differentially expressed mRNAs showed that genes involved in immune stimulation, especially those for T-cell activation, were upregulated, whereas genes involved in negative immune response regulation were downregulated. Coexpression analysis revealed that the targeted upregulated genes of differentially expressed lncRNA were similarly closely related to immune activation, especially T-cell activation. Methylation analysis showed inhibitor patients exhibited a slightly lower methylation status in the CpG islands, 5' untranslated region, and exon regions (p < 0.01). Genes with differentially methylated regions were also related to T-cell activation. Conclusions: There is an upregulation of genes involved in activation of the immune system in hemophilia A patients with inhibitors. The lncRNA and methylation modifications may play important roles in inhibitor production. These findings are potentially to reveal novel therapeutic targets for prevention and treatment of inhibitors.

Nitrate transport behavior behind subsurface dams under varying hydrological conditions.

The construction of subsurface dams for controlling seawater intrusion triggers the accumulation of nitrate upstream of a dam. This is raising the concerns about nitrate contamination in those regions of coastal aquifers that are supposed to be used as a fresh groundwater source behind a subsurface dam. Research on this subject has been mostly restricted to the use of a simplified sea boundary (e.g., static and no slope), ignoring sea level fluctuations driven by tides. In this study, the combined effect of tides and subsurface dams on nitrate pollution in upstream groundwater was examined through laboratory experiments and numerical simulations. The results revealed that the difference in the extent of nitrate contamination under various conditions (i.e., static, tidal, static with a dam, and tidal with a dam) was related to the temporal pollution behavior. In the early stage, nitrate contamination in upstream groundwater was essentially identical for different scenarios. Both tides and subsurface dams were found to increase nitrate contamination in upstream aquifers. The extent of nitrate contamination increased with higher tidal amplitudes, whereas the increment was more evident for a large tidal amplitude. The effects of tides and subsurface dams on nitrate contamination were also regulated by the locations and infiltration rates of the pollution source. Interestingly, under the joint action of tides and subsurface dams, the increment in the extent of nitrate pollution was greater than the sum of their individual effects. The increased pollutions caused by subsurface dams and tides were quantified as 9.47% and 37.22%, respectively, whereas the increased value caused by their joint action was measured as 51.10%. These findings suggest that tidal activity should not be overlooked when assessing nitrate contamination in upstream groundwater.

Novel factor VII gene mutations in six families with hereditary coagulation factor VII deficiency.

INTRODUCTION: Hereditary human coagulation factor VII (FVII) deficiency is an inherited autosomal recessive hemorrhagic disease involving mutations in the F7 gene. The sites and types of F7 mutations may influence the coagulation activities of plasma FVII (FVII: C) and severity of hemorrhage symptoms. However, the specific mutations that impact FVII activity are not completely known. METHODS: We tested the coagulation functions and plasma activities of FVII in seven patients recruited from six families with hereditary FVII deficiency and sequenced the F7 gene of the patients and their families. Then, we analyzed the genetic information from the six families and predicted the structures of the mutated proteins. RESULTS: In this study, we detected 11 F7 mutations, including four novel mutations, in which the mutations p.Phe84Ser and p.Gly156Cys encoded the Gla and EGF domains of FVII, respectively, while the mutation p.Ser339Leu encoded the recognition site of the enzymatic protein and maintained the conformation of the catalytic domain structure. Meanwhile, the mutation in the 5' untranslated region (UTR) was closely associated with the mRNA regulatory sequence. CONCLUSION: We have identified novel genetic mutations and performed pedigree analysis that shed light on the pathogenesis of hereditary human coagulation FVII deficiency and may contribute to the development of treatments for this disease.

[Congenital Fibrinogen Deficiency Caused by Novel FGG Gene Mutation].

OBJECTIVE: To detect and analyze coagulation related indexes and genotypes of a patient with congenital fibrinogen deficiency and his family members, and to investigate the possible molecular pathogenesis. METHODS: Four peripheral blood samples (proband and 3 family members) were collected and the prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen (Fg), D-Dimer and eight coagulation factor indicators were detected. All exons and flanking sequences of the FGA, FGB, and FGG genes encoding the three peptide chains of fibrinogen were sequenced and analyzed by bioinformatics. RESULTS: Among the eight coagulation factors of the proband and the elder sister, F Ⅴ and F Ⅷ were slightly higher, TT was significantly prolonged, and Fg was significantly reduced. Sequencing results showed that c.901C>T heterozygous mutation existed in the FGG gene. Bioinformatics analysis showed that the mutation changed the original protein structure and reduced the number of hydrogen bonds. CONCLUSION: The fibrinogen gamma chain c.901C>T heterozygous mutation is the main cause of congenital fibrinogen deficiency in this family. This mutation is reported for the first time at home and abroad.

Assessment of the hydrodynamics role for groundwater quality using an integration of GIS, water quality index and multivariate statistical techniques.

To explore the impact of groundwater hydrodynamics on water quality, a cost-effective geospatial model was developed using geographic information system (GIS) technology and the Dupuit assumption. Meanwhile, the groundwater quality in the Dagu River Basin was evaluated based on the water quality index (WQI) and multivariate statistical analyses. In April (dry season) and September (rainy season) 2017, the groundwater level was automatically monitored from 115 wells, and the water quality including 21 hydrochemical parameters was sampled from 37 wells. Results reveal that the WQI values varied from 35.01 to 64.74, with mean values of 51.89 and 47.87 in the rainy and dry seasons. Approximately 80% of the samples exhibited moderate water quality, with no significant difference between the rainy and dry seasons. Nitrate pollution and the integrated water quality in the central and northern regions were generally worse than that in the southern region. The Darcy velocity in the central and northern regions was relatively high with a maximum rate of 0.56 m/d, compared with the southern region. This correlation illustrates the effect of groundwater hydrodynamics on quality. The sowing of greater chemical fertilizers combined with faster groundwater movement is likely responsible for the large-scale nitrate pollution in the central and northern regions. Results also proved the accuracy of the geospatial model with a valid uncertainty. The geospatial model provides a valuable alternative for the spatial analysis of the effect of groundwater hydrodynamics on water quality.

Bleeding assessment in haemophilia carriers-High rates of bleeding after surgical abortion and intrauterine device placement: A multicentre study in China.

INTRODUCTION: An increased bleeding tendency has been shown in female haemophilia carriers compared to healthy females. Bleeding assessment tools (BATs) have mainly been performed in western cultures. It is unclear how they perform in populations with different healthcare, health/wellness concepts and awareness, as well as family planning practices. AIM: To (a) describe and compare the bleeding symptoms in carriers with healthy females, particularly for bleeding after surgical abortion and intrauterine device (IUD) placement which are performed frequently for family planning in China; (b) quantify scores of International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) and Chinese-BAT (C-BAT) developed to include surgical abortion and IUD placement as separate categories in Chinese haemophilia carriers; (c) correlate bleeding scores (BS) with factor levels. METHODS: We conducted a multicentre, cross-sectional study on obligate haemophilia carriers and healthy controls using ISTH-BAT and C-BAT. RESULTS: We enrolled 125 haemophilia carriers and 106 controls. Carriers, compared to controls, had significantly higher median BS (3 vs 1 by both ISTH-BAT and C-BAT) and lower factor level (63.5 vs 101.8 IU/dL). Bleeding after surgical abortion and IUD placement was significantly associated with carrier status. Bleeding scores from neither ISTH-BAT nor C-BAT showed significant correlation with factor levels. CONCLUSION: Haemophilia carriers in China experienced abnormal bleeding. Unique to the Chinese carriers is significant bleeding after surgical abortion (3rd highest incidence of bleeding symptom) and IUD placement (4th highest). However, both ISTH-BAT and C-BAT exhibited no correlation between BS and factor levels in this population and neither could identify carriers with low factor level (of <50 IU/dL).

[Analysis of hemophilia case information of Shandong province].

OBJECTIVE: To summarize the general condition, regional distribution, prevalence and clinical characteristics of Shandong province based on hemophilia case registry information. METHODS: A retrospective study was carried out on 1979 hemophilia patients registered at Shandong Hemophilia Registration Center. RESULTS: The 1979 cases have included 1704 hemophilia A and 275 hemophilia B patients. Hemophilia A was characterized as severe in 1021 patients (59.9%), moderate in 483 patients (28.4%), and mild in 200 patients (11.7%); while hemophilia B was characterized as severe in 125 patients (45.4%), moderate in 116 patients (42.2%), and mild in 34 patients (12.4%). The median age was 23 years (ranging from 1 month to 81 years), and most were young patients. Joint deformity occurred in 963 patients, and 948 patients had a family history of hemophilia. All counties of Shandong province had patients except for Changdao county and Fushan district of Yantai city. The prevalence of Heze city and Dongying city (3.39/100 000 and 3.05/100 000, respectively) were relatively higher. CONCLUSION: The above data revealed epidemiological and clinical characteristics of Shandong Province. Patient-centered registry system allowed a more detailed and accurate patient information, and promoted the comprehensive care of hemophilia, which also suggested the necessity for the establishment and improvement of the National Hemophilia Registry System.

[Mechanism investigation of platelet apoptosis inhibition by N-Arachidonoylethanolamine].

OBJECTIVE: To investigate the mechanism of N- Arachidonoylethanolamine (ANA) on inhibiting platelets (PLT) apoptosis under standard blood bank storage conditions. METHODS: Samples taken from collected apheresis PLT by the Amicus instrument were split into three parts. An aliquot of 0.5 µmol/L ANA were added to one part of storage PLT as the ANA group; an aliquot of 0.5 µmol/L ANA and 1 µmol/L SR141716 was added to the another part as the ANA + SR141716 group; and the third part without ANA and SR141716 as the control group. These samples were stored on a flat-bed shaker at (22 ± 2) °C for 7 days. The expression of phosphatidyl serine (PS) positive, phospho (p)-Akt, Akt, p-Bad, Bad, caspase-3, caspase-9, cytochrome C (Cyt-C) and BCL-XL interaction with Bak were detected. RESULTS: The rate of PLT PS positive in ANA group decreased significantly than that in control group[ (8.29 ± 1.44) % vs (14.24 ± 2.47) %, P<0.05]. The release of Cyt-C from mitochondria to cytosol in ANA group decreased significantly compared with control group[ (3.29 ± 1.44) % vs (15.24 ± 3.40) %, P<0.05]. Also the expressions of p-Akt and p-Bad in ANA group increased significantly than those in control group[ (71.33 ± 10.26) % vs (35.00 ± 6.00) %, P<0.05; (39.00 ± 9.64) % vs (10.33 ± 1.53) %, P<0.05, respectively]. Higher amounts of Bak protein were co-precipitated with BCL-XL in ANA group than that in control group (about 2.6 fold, P<0.05). The expressions of cleaved caspase- 9 and caspase- 3 in ANA group decreased significantly than those in control group[ (9.63 ± 1.47) % vs (23.24 ± 2.47) %, P<0.05; (6.30 ± 1.40) % vs (13.20 ± 2.50) %, P<0.05, respectively]. There were no significantly changes between ANA+SR141716 and control groups (P>0.05). CONCLUSION: ANA protected PLTs from apoptosis as a result of inhibiting the release of Cyt-C from mitochondria to cytosol by modifying the expressions of apoptosis-relative proteins.

[Detection of hemophilia A carrier by Fâ §:C/vWFAg ratio].

OBJECTIVE: To determine the cut-off value for coagulation factor Ⅷ activity (FⅧ:C) to von Willebrand factor antigen (vWFAg) ratio which can classify obligatory carriers of hemophilia A and normal females, and assess its feasibility to diagnose suspected carriers in affected families through comparison with the method of gene diagnosis. METHODS: FⅧ:C assay was carried out by a one-stage method in both obligatory carriers and normal females. vWF antigen was measured with ELISA assay. The FⅧ:C/vWF ratio was calculated. Statistic analysis was carried out to determine the cut-off value which can classify the two groups. The ratio was then used to diagnose suspected carriers from families affected with hemophilia A. The results were compared with that by long distance polymerase chain reaction, genetic linkage analysis and/or direct sequencing. RESULTS: The FⅧ:C/vWFAg value for 90.6% of obligatory carriers was under 0.82. Should 0.82 be selected as the cut-off value to diagnose the 42 suspected carriers, most of them can be readily diagnosed. The results were all in agreement with that of genetic analysis. CONCLUSION: Cut-off value of FⅧ:C/vWFAg may be used for initial diagnose of the suspected carriers from families affected with hemophilia A. The method is quite convenient and reliable.

Differentiation of lymphatic endothelial cells from bone marrow mesenchymal stem cells with VEGFs.

Although there have been many experimental studies demonstrating that bone marrow-derived mesenchymal stem cells (MSCs) have the potential to differentiate into mesenchymal tissues such as osteocytes, chondrocytes, and adipocytes in vivo and in vitro, little information is available regarding their potential to differentiate into lymphatic endothelial cells. Therefore, we chose to investigate differentiation of MSCs into lymphatic endothelial cells using stimulation with members of the vascular endothelial growth factor (VEGFs) family. Rat MSCs were isolated from bone marrow aspirate of Sprague-Dawley rats as previously described and characterized with flow cytometry for surface markers CD14, CD34, CD29, and CD90. Purified MSCs were plated and cultured in the presence of VEGF-A, VEGF-C, or the combination of both for 10 days. We examined the cells for Prox-1 and LYVE-1 by immunocytochemistry, RT-PCR, and Western blot analysis. Results demonstrated that compared to controls, cell differentiated with VEGF-A, VEGF-C and VEGF-A+VEGF-C expressed Prox-1 and LYVE-1. Our results indicate that MSCs induced by VEGFs are capable of differentiating into lymphatic endothelial-like cells in vitro, and this response has the potential to make them attractive candidates for the development of autologous tissue grafts for future therapy.