Avatrombopag as alternative therapy for severe aplastic anemia patients who are intolerant or unresponsive to eltrombopag.

Introduction: Eltrombopag (EPAG), a thrombopoietin receptor agonist, was approved for the treatment of severe aplastic anemia (SAA) combined with immunosuppressive therapy (IST). However, EPAG contains a typical biphenyl structure, which causes liver function damage. Methods: Twenty patients with SAA who were intolerant or refractory to EPAG were enrolled in a multicenter prospective registry of the Chinese Eastern Collaboration Group of Anemia (ChiCTR2100045895) from October 2020 to June 2023. Results: Eight patients who were ineffective to EPAG, six with kidney impairment, and nine with abnormal liver function (two with concomitant liver and kidney impairment) were converted to avatrombopag (AVA) therapy with the median duration of AVA treatment was 6 (3-24) months. 17 cases (85%) achieved trilineage hematological response (HR): complete remission (CR) in 3 cases (15%), good partial remission (GPR) in 4 cases (20%), partial remission (PR) in 10 cases (50%), and no response (NR) in 3 cases (15%). The median time to response was 1.7 (0.5-6.9) months, with 16 cases (94%) achieving response within six months and 17 cases (100%) within 12 months. 9 cases (50%) achieved transfusion independence. AVA converted treatment was associated with higher neutrophil counts (0.8×109/L vs 2.2×109/L, p=0.0003), platelet counts (11×109/L vs 39×109/L, p=0.0008), hemoglobin count (59g/L vs 98g/L, p=0.0002), red cell count (1.06×1012/L vs 2.97×1012/L, p=0.001), and absolute reticulocyte count (31.99 ×109/L vs 67.05×109/L p=0.0004) were all significantly elevated compared with the pre-treatment level. After the conversion to AVA therapy, liver and kidney function indexes were maintained within the normal range, no AVA related grade 2 or higher adverse events occurred, and no thrombotic events occurred. Conclusion: The conversion to AVA was an optimal choice for patients with SAA who were EPAG intolerant or refractory. Clinical trial registration: http://www.chictr.org.cn/showproj.html?proj=125480, identifier ChiCTR2100045895.

Cadherin 17 Nanobody-Mediated Near-Infrared-II Fluorescence Imaging-Guided Surgery and Immunotoxin Delivery for Colorectal Cancer.

Surgery and targeted therapy are of equal importance for colorectal cancer (CRC) treatment. However, complete CRC tumor resection remains challenging, and new targeted agents are also needed for efficient CRC treatment. Cadherin 17 (CDH17) is a membrane protein that is highly expressed in CRC and, therefore, is an ideal target for imaging-guided surgery and therapeutics. This study utilizes CDH17 nanobody (E8-Nb) with the near-infrared (NIR) fluorescent dye IRDye800CW to construct a NIR-II fluorescent probe, E8-Nb-IR800CW, and a Pseudomonas exotoxin (PE)-based immunotoxin, E8-Nb-PE38, to evaluate their performance for CRC imaging, imaging-guided precise tumor excision, and antitumor effects. Our results show that E8-Nb-IR800CW efficiently recognizes CDH17 in CRC cells and tumor tissues, produces high-quality NIR-II images for CRC tumors, and enables precise tumor removal guided by NIR-II imaging. Additionally, fluorescent imaging confirms the targeting ability and specificity of the immunotoxin toward CDH17-positive tumors, providing the direct visible evidence for immunotoxin therapy. E8-Nb-PE38 immunotoxin markedly delays the growth of CRC through the induction of apoptosis and immunogenic cell death (ICD) in multiple CRC tumor models. Furthermore, E8-Nb-PE38 combined with 5-FU exerts synergistically antitumor effects and extends survival. This study highlights CDH17 as a promising target for CRC imaging, imaging-guided surgery, and drug delivery. Nanobodies targeting CDH17 hold great potential to construct NIR-II fluorescent probes for surgery navigation, and PE-based toxins fused with CDH17 nanobodies represent a novel therapeutic strategy for CRC treatment. Further investigation is warranted to validate these findings for potential clinical translation.

Safety of different concentrations of glycerine enema for meconium evacuation in preterm infants: study protocol for a randomised controlled trial.

INTRODUCTION: Various approaches are employed to expedite the passage of meconium in preterm infants within the neonatal intensive care unit (NICU), with glycerine enemas being the most frequently used. Due to the potential risk of high osmolality-induced harm to the intestinal mucosa, diluted glycerine enema solutions are commonly used in clinical practice. The challenge lies in the current lack of knowledge regarding the safest and most effective concentration of glycerine enema. This research aims to ascertain the safety of different concentrations of glycerine enema solution in preterm infants. METHODS AND ANALYSIS: This study protocol is for a single-centre, two-arm, parallel-group, double-blind and non-inferiority randomised controlled trial. Participants will be recruited from a NICU in a teriary class A hospital in China, and eligible infants will be randomly allocated to either the glycerine (mL): saline (mL) group in a 3:7 ratio or the 1:9 ratio group. The enema procedure will adhere to the standardised operational protocols. Primary outcomes encompass necrotising enterocolitis and rectal bleeding, while secondary outcomes encompass feeding parameters, meconium passage outcomes and splanchnic regional oxygen saturation. Analyses will compare the two trial arms based on an intention-to-treat allocation. ETHICS AND DISSEMINATION: This trial is approved by the ethics committee of the Medical Ethics Committee of West China Second University Hospital of Sichuan University. The results will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ChiCTR2300079199.

DeepKOA: a deep-learning model for predicting progression in knee osteoarthritis using multimodal magnetic resonance images from the osteoarthritis initiative.

Background: No investigations have thoroughly explored the feasibility of combining magnetic resonance (MR) images and deep-learning methods for predicting the progression of knee osteoarthritis (KOA). We thus aimed to develop a potential deep-learning model for predicting OA progression based on MR images for the clinical setting. Methods: A longitudinal case-control study was performed using data from the Foundation for the National Institutes of Health (FNIH), composed of progressive cases [182 osteoarthritis (OA) knees with both radiographic and pain progression for 24-48 months] and matched controls (182 OA knees not meeting the case definition). DeepKOA was developed through 3-dimensional (3D) DenseNet169 to predict KOA progression over 24-48 months based on sagittal intermediate-weighted turbo-spin echo sequences with fat-suppression (SAG-IW-TSE-FS), sagittal 3D dual-echo steady-state water excitation (SAG-3D-DESS-WE) and its axial and coronal multiplanar reformation, and their combined MR images with patient-level labels at baseline, 12, and 24 months to eventually determine the probability of progression. The classification performance of the DeepKOA was evaluated using 5-fold cross-validation. An X-ray-based model and traditional models that used clinical variables via multilayer perceptron were built. Combined models were also constructed, which integrated clinical variables with DeepKOA. The area under the curve (AUC) was used as the evaluation metric. Results: The performance of SAG-IW-TSE-FS in predicting OA progression was similar or higher to that of other single and combined sequences. The DeepKOA based on SAG-IW-TSE-FS achieved an AUC of 0.664 (95% CI: 0.585-0.743) at baseline, 0.739 (95% CI: 0.703-0.775) at 12 months, and 0.775 (95% CI: 0.686-0.865) at 24 months. The X-ray-based model achieved an AUC ranging from 0.573 to 0.613 at 3 time points. However, adding clinical variables to DeepKOA did not improve performance (P>0.05). Initial visualizations from gradient-weighted class activation mapping (Grad-CAM) indicated that the frequency with which the patellofemoral joint was highlighted increased as time progressed, which contrasted the trend observed in the tibiofemoral joint. The meniscus, the infrapatellar fat pad, and muscles posterior to the knee were highlighted to varying degrees. Conclusions: This study initially demonstrated the feasibility of DeepKOA in the prediction of KOA progression and identified the potential responsible structures which may enlighten the future development of more clinically practical methods.

High tolerance of and removal of cefazolin sodium in single-chamber microbial fuel cells operation.

Single-chamber microbial fuel cells (MFCs) have been shown to be a promising approach for cefazolin sodium (CFZS)-contaminated wastewater treatment, in terms of electricity production, high CFZS tolerance and effective CFZS removal. MFCs exposed to CFZS loadings up to 100 mg L-1, produced stable power of 18.2 ±â€¯1.1 W m-3 and a maximum power of 30.4 ±â€¯2.1 W m-3, similar to that of CFZS-free MFCs (stable power 19.4 ±â€¯0.8 W m-3 and maximum power 32.5 ±â€¯1.6 W m-3), notwithstanding a longer acclimitisation MFC activation. More anodophilic genera (i.e. Acinetobacter, Stenotrophomonas, Lysinibacillus) and antibiotic-resisting genera (i.e. Dysgonomonas) were enriched in CFZS acclimitised anodes. Both the thickness of biofilms and the duration of CFZS acclimitisation were essential for the development of high CFZS tolerance (e.g. 450 mg L-1). The inhibition of MFCs by CFZS was reversible. The present MFCs generated a CFZS removal rate of 1.2-6.8 mg L-1 h-1 without any apparent inhibition of electricity production.

Diabetes tolerogenic vaccines targeting antigen-specific inflammation.

Tolerance controls the magnitude of inflammation, and balance between beneficial and harmful effects of inflammation is crucial for organ function and survival. Inadequate tolerance leads to various inflammatory diseases. Antigen specific tolerance is ideal for inflammation control as alternative anti-inflammatory interventions are non-specific and consequently increase the risk of infection and tumorigenesis. With inherent antigen specificity, tolerogenic vaccines are potentially ideal for control of inflammation. Although the concept of tolerogenic vaccines is still in its infancy, tolerogenic mucosal vaccines and specific immuno-therapies have long been proven effective in pioneering examples. Now a body of evidence supporting the concept of tolerogenic vaccines has also accumulated. Here we comment on recent successes of the tolerogenic vaccine concept, present new evidence with a type 1 diabetes vaccine as an example and draw conclusions on the advantages and potential for inflammatory disease control at the bedside.

Amiloride enhances antigen specific CTL by faciliting HBV DNA vaccine entry into cells.

The induction of relatively weak immunity by DNA vaccines in humans can be largely attributed to the low efficiency of transduction of somatic cells. Although formulation with liposomes has been shown to enhance DNA transduction of cultured cells, little, if any, effect is observed on the transduction of somatic tissues and cells. To improve the rate of transduction, DNA vaccine delivery by gene gun and the recently developed electroporation techniques have been employed. We report here that to circumvent requirement for such equipment, amiloride, a drug that is prescribed for hypertension treatment, can accelerate plasmid entry into antigen presenting cells (APCs) both in vitro and in vivo. The combination induced APCs more dramatically in both maturation and cytokine secretion. Amiloride enhanced development of full CD8 cytolytic function including induction of high levels of antigen specific CTL and expression of IFN-γ+perforin+granzymeB+ in CD8+ T cells. Thus, amiloride is a facilitator for DNA transduction into host cells which in turn enhances the efficiency of the immune responses.

Children's vaccines do not induce cross reactivity against SARS-CoV.

In contrast with adults, children infected by severe acute respiratory syndrome-corona virus (SARS-CoV) develop milder clinical symptoms. Because of this, it is speculated that children vaccinated with various childhood vaccines might develop cross immunity against SARS-CoV. Antisera and T cells from mice immunised with various vaccines were used to determine whether they developed cross reactivity against SARS-CoV. The results showed no marked cross reactivity against SARS-CoV, which implies that the reduced symptoms among children infected by SARS-CoV may be caused by other factors.