Cost-Effectiveness Analysis of Bezlotoxumab Added to Standard of Care Versus Standard of Care Alone for the Prevention of Recurrent Clostridium difficile Infection in High-Risk Patients in Spain

Introduction Clostridium difficile infection (CDI) is the major cause of infectious nosocomial diarrhoea and is associated with considerable morbidity, mortality and economic impact. Bezlotoxumab administered in combination with standard of care (SoC) antibiotic therapy prevents recurrent CDI. This study assessed the cost-effectiveness of bezlotoxumab added to SoC, compared to SoC alone, to prevent the recurrence of CDI in high-risk patients from the Spanish National Health System perspective. Methods A Markov model was used to simulate the natural history of CDI over a lifetime horizon in five populations of patients at high risk of CDI recurrence according to MODIFY trials: (1) ≥ 65 years old; (2) severe CDI; (3) immunocompromised; (4) ≥ 1 CDI episode in the previous 6 months; and (5) ≥ 65 years old and with ≥ 1 CDI episode in the previous 6 months. The incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. Deterministic (DSA) and probabilistic sensitivity analyses (PSA) were performed. Results In all patient populations (from 1 to 5), bezlotoxumab added to SoC reduced CDI recurrence compared to SoC alone by 26.4, 19.5, 21.2, 26.6 and 39.7%, respectively. The resulting ICERs for the respective subgroups were €12,724, €17,495, €9545, €7386, and €4378. The model parameters with highest impact on the ICER were recurrence rate (first), mortality, and utility values. The probability that bezlotoxumab was cost-effective at a willingness-to-pay threshold of €21,000/QALY was 85.5%, 54.1%, 86.0%, 94.5%, 99.6%, respectively. Conclusion The results suggest that bezlotoxumab added to SoC compared to SoC alone is a cost-effective treatment to prevent the recurrence of CDI in high-risk patients. The influence of changes in model parameters on DSA results was higher in patients  ≥ 65 years old, with severe CDI and immunocompromised. Additionally, PSA estimated that the probability of cost-effectiveness exceeded 85% in most subgroups

Estimating Causal Effects using a Multi-task Deep Ensemble

A number of methods have been proposed for causal effect estimation, yet few have demonstrated efficacy in handling data with complex structures, such as images. To fill this gap, we propose Causal Multi-task Deep Ensemble (CMDE), a novel framework that learns both shared and group-specific information from the study population. We provide proofs demonstrating equivalency of CDME to a multi-task Gaussian process (GP) with a coregionalization kernel a priori. Compared to multi-task GP, CMDE efficiently handles high-dimensional and multi-modal covariates and provides pointwise uncertainty estimates of causal effects. We evaluate our method across various types of datasets and tasks and find that CMDE outperforms state-of-the-art methods on a majority of these tasks.Comment: 18 pages, 7 figures, 3 tables, published at the 40th International Conference on Machine Learning (ICML 2023

Heat shock protein 27 is a potential indicator for response to YangZheng XiaoJi and chemotherapy agents in cancer cells

Heat shock protein 27 (HSP27) is a member of the heat shock protein family which has been linked to tumour progression and, most interestingly, to chemotherapy resistance in cancer patients. The present study examined the potential interplay between HSP27 and YangZheng XiaoJi, a traditional Chinese medicine used in cancer treatment. A range of cell lines from different tumour types including pancreatic, lung, gastric, colorectal, breast, prostate and ovarian cancer (both wild-type and resistant) were used. Levels and activation of HSP27 and its potential associated signalling pathways were evaluated by protein array and western blotting. Knockdown of HSP27 in cancer cells was achieved using siRNA. Localisation and co-localisation of HSP27 and other proteins were carried out by immunofluorescence. Cell growth and migration were evaluated in their response to a range of chemotherapeutic agents. The present study first identified, by way of protein array, that YangZheng XiaoJi was able to inhibit the phosphorylation of HSP27 protein in cancer cells. We further demonstrated that HSP27, which is co-localised with caspase-9, can be blocked from localising in focal adhesions and co-localising with caspase-9 by YangZheng XiaoJi. The study also demonstrated that YangZheng XiaoJi was able to sensitise cancer cells including those cells that were resistant to chemotherapy, to chemotherapeutic agents. Finally, knocking down HSP27 markedly reduced the migration of cancer cells and increased the sensitivity of cancer cells to the inhibitory effect on cellular migration by YangZheng XiaoJi. YangZheng XiaoJi can act as an agent in first sensitising cancer cells to chemotherapy and secondly to overcome, to some degree, chemoresistance when used in an appropriate fashion in patients who have active HSP2

Effect of Piezo1 on osteogenic differentiation of mouse bone marrow mesenchymal stem cells C3H10T1/2 based on CRISPR/Cas9

Objective·To investigate the effect of Piezo1 on osteogenic differentiation of mouse mesenchymal stem cells C3H10T1/2 cell line based on CRISPR/Cas9 system that can achieve stable gene knockout.Methods·According to the principle of CRISPR/Cas9 target design principle, two single guide RNAs (sgRNAs) were designed to construct lentivirus expressing Cas9 and lentivirus expressing sgRNA by using Lenti-Cas9-GFP and Lenti-U6-sgRNA-mCherry vectors. After the C3H101/2 cells were transfected with two types of lentiviruses, flow cytometry was used to screen mCherry- and GFP-positive cells. The monoclonal cells were selected, and amplified by PCR and agarose gel electrophoresis, and finally the monoclonal cell line with Piezo1 gene fragment knocked out was obtained. Sequencing, quantitative realtime PCR (qPCR) and immunofluorescence were performed to verify the the knockout efficiency of the constructed Piezol knockout C3H10T1/2 cells (CPK). CCK-8 assay was used to detect the effect of knocking out Piezo1 on cell proliferation; in vitro osteogenic induction differentiation was performed on successfully constructed Piezo1 gene knockout cells, and alkaline phosphatase (ALP) staining and alizarin red staining were used to investigate the effect of Piezo1 on osteogenic ability.Results·Positive clone was obtained in bacterial fluid of monoclonal cell lines with Piezol knocked out after PCR amplification and agarose gel electrophoresis. Sequencing analysis showed that a stop condon TGA was produced in exon 4 of Piezo1 gene in advance, so that the protein could not be translated correctly. qPCR verified that Piezo1 gene in CPK was inhibited at mRNA level; Immunofluorescence showed that the knockout efficiency of Piezo1 gene in CPK was high, which basically hindered the expression of Piezo1 in cells. CCK-8 assay showed that the cell proliferation ability decreased after knocking out Piezo1 (P<0.05); The results of ALP staining and alizarin red staining showed that the osteogenic ability of cells decreased after knocking out Piezo1(P<0.05). The mRNA expression levels of osteogenetic-related genes such as α 1 type Ⅰ collagen (Col1a1), Runt-related transcription factor 2 (Runx-2), osterix (Osx) and alkaline phosphatase (Alp) in CPK decreased significantly (all P<0.05).Conclusion·Piezo1 knockout C3H10T1/2 cells based on CRISPR/Cas9 system is constructed successfully and the osteogenic activity of stable Piezo1 knockout cell line is hindered significantly

The clinical and biological implications of the focal adhesion kinase pathway in ShenLingLan mediated suppression of cellular migration of ovarian cancer cells

The incidence of ovarian cancer in the UK has increased by almost twenty percent since the 1970’s and the majority of cases are not diagnosed until the late stages, when metastasis is more likely to have occurred. Focal Adhesion Kinase (FAK) is one of the key protein complexes which is integral to cell migration and has been linked to a variety of solid tumours. ShenLingLan (SLDM) is a traditional herbal medicine which has been formulated for the treatment of solid tumours. This study aimed to establish the impact of SLDM on FAK in ovarian cancer cells in vitro and transcript levels of FAK in an ovarian cancer cohort. FAK and paxillin phosphorylation events stimulated by SLDM treatment were identified using a Kinexus™ antibody based protein array. The impact of SLDM on cell attachment and migration was evaluated using Electric cell-substrate impedance sensing (ECIS), whilst the changes in focal adhesion complex localisation were assessed using immunofluorescence. In an ovarian cancer cohort, differences in FAK and paxillin transcript levels were assessed against key clinical parameters such as differentiation, stage and survival outcome. SLDM treatment of ovarian cancer cells in vitro resulted in the suppression of FAK and paxillin phosphorylation at several sites, which appeared to manifest as decreased cellular attachment and migration in a range of immortalised ovarian cancer cells. Increased FAK and paxillin transcript copies were observed in high grade and poorly differentiated ovarian tumours as well as in tumours from patients with ovarian cancer related incidence. SLDM has a profound effect on the migratory and adhesive properties of ovarian cancer cells, potentially via inhibitory effects on the activation of the FAK pathway, which is aberrant in clinical ovarian cancers

Original Article Neuroprotective effect of functionalized multi-walled carbon nanotubes on spinal cord injury in rats

Abstract: Traumatic injuries to the brain and spinal cord affect a large percentage of the world&apos;s population. However, there are currently no effective treatments for these central nervous system (CNS) injuries. In our study, we evaluated the neuroprotective role of functionalized multi-walled carbon nanotubes (MWCNTs) carrying brain derived neurotrophic factor (BNDF), nogo-66 receptor (NgR) and Ras homolog gene family member A (RhoA) in spinal cord injury (SCI). Our results showed that transfection into rat cortical neurons with BDNF-DNA significantly elevated the expression of BDNF both in vitro and in vivo. Meanwhile, transfection with NgR-siRNA and RhoA-siRNA resulted in an obvious down-regulation of NgR and RhoA in neuron cells and in injured spinal cords. In addition, the functionalized MWCNTs carrying BDNF-DNA, NgR-siRNA and RhoA-siRNA exhibited remarkable therapeutic effects on injured spinal cord. Taken together, our study demonstrates that functionalized MWCNTs have a potential therapeutic application on repair and regeneration of the CNS

The odontoblastic differentiation of dental mesenchymal stem cells: molecular regulation mechanism and related genetic syndromes

Dental mesenchymal stem cells (DMSCs) are multipotent progenitor cells that can differentiate into multiple lineages including odontoblasts, osteoblasts, chondrocytes, neural cells, myocytes, cardiomyocytes, adipocytes, endothelial cells, melanocytes, and hepatocytes. Odontoblastic differentiation of DMSCs is pivotal in dentinogenesis, a delicate and dynamic process regulated at the molecular level by signaling pathways, transcription factors, and posttranscriptional and epigenetic regulation. Mutations or dysregulation of related genes may contribute to genetic diseases with dentin defects caused by impaired odontoblastic differentiation, including tricho-dento-osseous (TDO) syndrome, X-linked hypophosphatemic rickets (XLH), Raine syndrome (RS), hypophosphatasia (HPP), Schimke immuno-osseous dysplasia (SIOD), and Elsahy-Waters syndrome (EWS). Herein, recent progress in the molecular regulation of the odontoblastic differentiation of DMSCs is summarized. In addition, genetic syndromes associated with disorders of odontoblastic differentiation of DMSCs are discussed. An improved understanding of the molecular regulation and related genetic syndromes may help clinicians better understand the etiology and pathogenesis of dentin lesions in systematic diseases and identify novel treatment targets

Fruit quality assessment based on mineral elements and juice properties in nine citrus cultivars

IntroductionCitrus fruit is considered a superfood due to its multiple nutritional functions and health benefits. Quantitative analysis of the numerous quality characteristics of citrus fruit is required to promote its sustainable production and industrial utilization. However, little information is available on the comprehensive quality assessment of various fruit quality indicators in different citrus cultivars.MethodsA total of nine different fresh citrus fruits containing seeds were collected as the experimental materials. The objectives of this study were: (i) to determine the morphological and juice properties of citrus fruits, (ii) to measure the mineral elements in the peel, pulp, and seeds, and (iii) to evaluate the fruit quality index (FQI) using the integrated quality index (IQI) and the Nemoro quality index (NQI) methods.ResultsThere were significant differences in fruit quality characteristics, including morphological, mineral, and juice quality, among the investigated citrus cultivars. The proportion of pulp biomass was the highest, followed by that of peel and seeds. N and Cu had the highest and lowest concentrations, respectively, among the measured elements across all citrus fruits, and the amounts of N, P, Mg, Cu, and Zn in seeds, K and Al in pulp, and Ca, Fe, and Mn in peel were the highest, dramatically affecting the accumulation of minerals in the whole fruit and their distribution in various fruit parts. Additionally, Ningmeng fruits had the highest vitamin C and titratable acidity (TA) but the lowest total soluble solids (TSS) and total phenolic (TP) contents, resulting in the lowest TSS/TA and pH values. In contrast, Jinju fruits had the highest TSS and TP contents. Based on the mineral element and juice quality parameters, principal component analysis showed that the citrus fruits were well separated into four groups, and the dendrogram also showed four clusters with different distances. The FQI range based on the IQI method (FQIIQI) and NQI method (FQINQI) was 0.382-0.590 and 0.106-0.245, respectively, and a positive relationship between FQIIQI and FQINQI was observed.ConclusionOur results highlight the great differences in mineral and juice characteristics among fruit parts, which mediated fruit quality. The strategy of fruit quality assessment using the FQI can be expanded for targeted utilization in the citrus industry