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ABSTRACTBackground: Cyclosporine A (CsA) and regular doses of recombinant human thrombopoietin (rhTPO) can accelerate platelet recovery in patients with non-severe aplastic anemia (NSAA). However, it is unclear whether CsA plus rhTPO at a higher dose can further increase the efficacy.Methods: Data from patients with newly diagnosed NSAA, who had been treated with CsA in combination with different doses of rhTPO between February 2021 and August 2021 at Peking Union Medical College Hospital, were reviewed. All the enrolled patients had been treated with CsA at 3–5 mg/(kg/d), and patients were further classified into high-dose (with rhTPO 30000U qd × 14 days for 2 months) group or regular-dose (with rhTPO 15000U qd × 7days for 3 months) group. The treatment response and therapy-related adverse events were compared.Results: 36 patients including 16 (44.4%) in the high-dose and 20 (55.6%) in the regular-dose group were enrolled. The baseline characteristics were compatible between the two groups. The platelet counts were significantly higher at 1/3/6 months in the high-dose group (p = 0.028, 0.0063 and p = 0.040, respectively). The high-dose group had a significantly shorter time to platelet transfusion independence ([1 (0.5–6) months vs 2.5 (1–12) months, p = 0.040]). There was no significant difference in overall response and complete response rate between the two groups at 1/3/6/12 months (p > 0.05). Treatment-related morbidities were similar between the two groups (p > 0.05).Conclusions: Adding a higher dose of rhTPO can further accelerate platelet recovery and platelet transfusion independence in patients with newly diagnosed NSAA.

Abstract The intricacy of diseases, shaped by intrinsic processes like immune system exhaustion and hyperactivation, highlights the potential of immune renormalization as a promising strategy in disease treatment. In recent years, our primary focus has centered on γδ T cell-based immunotherapy, particularly pioneering the use of allogeneic Vδ2+ γδ T cells for treating late-stage solid tumors and tuberculosis patients. However, we recognize untapped potential and optimization opportunities to fully harness γδ T cell effector functions in immunotherapy. This review aims to thoroughly examine γδ T cell immunology and its role in diseases. Initially, we elucidate functional differences between γδ T cells and their αβ T cell counterparts. We also provide an overview of major milestones in γδ T cell research since their discovery in 1984. Furthermore, we delve into the intricate biological processes governing their origin, development, fate decisions, and T cell receptor (TCR) rearrangement within the thymus. By examining the mechanisms underlying the anti-tumor functions of distinct γδ T cell subtypes based on γδTCR structure or cytokine release, we emphasize the importance of accurate subtyping in understanding γδ T cell function. We also explore the microenvironment-dependent functions of γδ T cell subsets, particularly in infectious diseases, autoimmune conditions, hematological malignancies, and solid tumors. Finally, we propose future strategies for utilizing allogeneic γδ T cells in tumor immunotherapy. Through this comprehensive review, we aim to provide readers with a holistic understanding of the molecular fundamentals and translational research frontiers of γδ T cells, ultimately contributing to further advancements in harnessing the therapeutic potential of γδ T cells.

Abstract This trial compared eltrombopag (EPAG)+tacrolimus and EPAG monotherapy in patients with refractory/relapsed acquired aplastic anaemia (AA). Patients with refractory/relapsed AA were randomly assigned to receive either EPAG+tacrolimus or EPAG monotherapy at a ratio of 2:1. Patient response, safety, clonal evolution and survival were compared. In total, 114 patients were included in the analysis, with 76 patients receiving EPAG+tacrolimus and 38 receiving EPAG only. With a median follow-up of 18 (6–24) months, the overall response rate (ORR) for patients treated with EPAG+tacrolimus and EPAG alone was 38.2% vs. 31.6% (P = 0.490) at the 3rd month, 61.8% vs. 39.5% (P = 0.024) at the 6th month, 64.5% vs. 47.1% (P = 0.097) at the 12th month, and 60.5% vs. 34.2% (P = 0.008) at the last follow-up. The rate of each adverse event, overall survival curves (P = 0.635) and clonal evolution rate (P = 1.000) were comparable between the groups. A post hoc subgroup analysis showed that EPAG+tacrolimus could have advantage over EPAG monotherapy in terms of the ORR at the 6th month (P = 0.030)/last follow-up (P = 0.013) and the cumulative relapse-free survival (RFS) curves (P = 0.048) in patients

Numerous studies have discussed the therapeutic outcomes of using cell therapy or acupuncture to treat peripheral artery disease (PAD). However, there are no long-term studies on the safety and efficacy of transplanting peripheral blood mononuclear cells (PBMNCs) via acupoints to treat PAD. We first reviewed the short-term and long-term clinical results of PAD patients treated with PBMNCs through intramuscular non-acupoint transplantation (control group; n = 45) or intramuscular acupoint transplantation (acupoint group; n = 45) at a single university hospital general medical center between December 2002 and September 2022. Pain intensity (assessed with the verbal rating scale [VRS] score) in the acupoint group was considerably lower than that in the control group at month 1 (mean ± standard deviation [SD]: 1.29 ± 0.96 vs 1.76 ± 0.82; P = 0.016) and month 3 (mean ± SD: 1.27 ± 0.90 vs 1.61 ± 0.86; P = 0.042). We observed significant improvement of VRS score (P < .001 for all) and ankle-brachial index (ABI; P < .001 for all) from baseline in both groups at months 1, 3, 6, 12, 36, and 60. The 10-year cumulative rate of major amputation–free survival (MAFS) was higher in the acupoint group as compared to the control group (81.9%, 95% confidence interval [CI]: 71.3%–94.1% vs 78.5%, 95% CI: 66.7%–92.3%; P = 0.768). Compared with the routine injection method, intramuscular transplantation of PBMNCs via selected acupoints could significantly decrease the short-term pain intensity in patients with PAD, which remains an option for consideration.

Background: Chronic non-bacterial prostatitis (CNP), one of the most common chronic diseases in urology, leads to pain in the prostate and dysuria, critically affecting the physical or mental health of patients. However, there are no standard treatment approaches for the treatment of CNP in the clinic. Although the clinical application of Bushen Daozhuo granule (BSDZG) offers hope to CNP patients in China, the mechanisms of BSDZG in treating CNP are still not entirely clear. Hence, we aimed to investigate the novel therapeutic mechanisms of BSDZG on CNP.Methods: In this study, we first assayed the prostate index of rats and then determined the anti-inflammatory and anti-apoptotic effects of BSDZG on CNP in vivo and in vitro by employing ELISA kits and TUNEL staining. Next, we investigated whether the anti-inflammatory and anti-apoptotic mechanisms of BSDZG on prostate protein-induced rats and lipopolysaccharide (LPS) induced RWPE-1 cells were related to the AKT, p38 MAPK, and NF-κB pathways with the help of Western blot. Finally, the influence of BSDZG on the interaction between the p38 MAPK and NF-κB pathway in LPS-induced RWPE-1 cells was explored by adopting dehydrocorydaline (DHC, p38 MAPK activator) with the help of ELISA kits and Western blot.Results:In vivo, BSDZG effectively reduced the prostate index. In vivo and in vitro, BSDZG dramatically declined the level of two pro-inflammatory cytokines, TNF-α and IL-1β, as well as the apoptosis rate. Moreover, in vivo and in vitro, BSDZG memorably upregulated the expression level of p-AKT, and substantially downregulated the expression level of p-p38 MAPK and NF-κB2. The activation of p38 MAPK significantly reversed the moderation effects of BSDZG on the level of TNF-α and IL-1β, as well as the expression level of p-p38 MAPK and NF-κB2 in vitro.Conclusion: To sum up, the in vivo and in vitro therapeutic mechanisms of BSDZG on CNP were reflected as the anti-inflammation and anti-apoptosis that was formed by inhibiting the level of pro-inflammatory cytokines, TNF-α and IL-1β, to regulate the AKT, p38 MAPK, and NF-κB pathways, and the anti-inflammatory effect of BSDZG was realized by suppressing the p38 MAPK pathway to inhibit the downstream NF-κB pathway.

AbstractObjective Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease characterized by chronic complement-mediated hemolysis. The concentrated outbreak of coronavirus disease 2019 (COVID-19) in China after 6 December 2022, provided an opportunity to observe the disease course of PNH during an active Omicron infection epidemic.Patients and method Patients diagnosed with PNH at Peking Union Medical College Hospital (PUMCH) before 6 December 2022, were followed up until 10 April 2023. Clinical data related to coronavirus infection and hemolysis were recorded. Factors influencing the infection and severity rate of Omicron, as well as hemolysis provocation, were analyzed.Results In total, 131 patients with PNH were included in this retrospective analysis; 87.8% were infected with Omicron. Among them, 15.7% met the criteria for severity, and 1 patient died (0.87%). No protective factors were identified against Omicron infections. However, patients with severe Omicron infection (n = 18) had a lower vaccination rate than those with non-severe infection (n = 97; p = 0.015). Among those infected (n = 115) with Omicron, there was a significant increase in lactate dehydrogenase (LDH) levels compared with those in the uninfected group (n = 16, p = 0.000). Patients with severe infections (n = 18) had even higher LDH increase rates than those without severe infections (n = 97; p = 0.002). 10 (37.0%) patients treated with complement inhibitors developed breakthrough hemolysis (BTH). Patients treated with complement inhibitors (n = 27) exhibited less severe hemolysis than treatment-naïve patients (n = 104; p = 0.003).Conclusions Omicron infection exacerbates hemolytic attacks in patients with PNH. Vaccination helps mitigate the severity of Omicron infection, and using complement inhibitors reduces hemolysis exacerbation.

AbstractBackground Some patients with warm autoimmune haemolytic anaemia (wAIHA) or Evans syndrome (ES) have no response to glucocorticoid or relapse. Recent studies found that sirolimus was effective in autoimmune cytopenia with a low relapse rate.Methods Data from patients with refractory/relapsed wAIHA and ES in Peking Union Medical College Hospital from July 2016 to May 2022 who had been treated with sirolimus for at least 6 months and followed up for at least 12 months were collected retrospectively. Baseline and follow-up clinical data were recorded and the rate of complete response (CR), partial response (PR) at different time points, adverse events, relapse, outcomes, and factors that may affect the efficacy and relapse were analyzed.Results There were 44 patients enrolled, with 9 (20.5%) males and a median age of 44 (range: 18–86) years. 37 (84.1%) patients were diagnosed as wAIHA, and 7 (15.9%) as ES. Patients were treated with sirolimus for a median of 23 (range: 6–80) months and followed up for a median of 25 (range: 12–80) months. 35 (79.5%) patients responded to sirolimus, and 25 (56.8%) patients achieved an optimal response of CR. Mucositis (11.4%), infection (9.1%), and alanine aminotransferase elevation (9.1%) were the most common adverse events. 5/35 patients (14.3%) relapsed at a median of 19 (range: 15–50) months. Patients with a higher sirolimus plasma trough concentration had a higher overall response (OR) and CR rate (p = 0.009, 0.011, respectively). At the time of enrolment, patients were divided into two subgroups that relapsed or refractory to glucocorticoid, and the former had poorer relapse-free survival (p = 0.032) than the other group.Conclusion Sirolimus is effective for patients with primary refractory/relapsed wAIHA and ES, with a low relapse rate and mild side effects. Patients with a higher sirolimus plasma trough concentration had a higher OR and CR rate, and patients who relapsed to glucocorticoid treatment had poorer relapse-free survival than those who were refractory.

Background: Eltrombopag (ELT), a thrombopoietin receptor agonist (TPO-RA), has been approved for relapsed/refractory aplastic anemia (AA). However, data on avatrombopag (AVA), another TPO-RA, are limited, and the comparisons between the two TPO-RAs are lacking. Objectives: We aimed to compare the efficacy and safety between ELT and AVA in relapsed/refractory AA patients. Design: In this retrospective study, patients with relapsed/refractory AA who had been treated with ELT ( N = 45) or AVA ( N = 30) alone and had compatible baseline hematological parameters were compared. Methods: Data from patients diagnosed with acquired AA were retrospectively collected. All patients were refractory/relapsed to standard immunosuppressive therapy (IST) for at least 6 months before ELT or AVA. Patients had to be treated with ELT or AVA alone for at least 6 months before evaluation if they did not respond. Baseline characteristics, overall response (OR), complete response (CR), relapse, adverse events, and factors that may affect efficacy were analyzed. Results: Of the 75 patients enrolled, 45 received ELT and 30 received AVA. Patients with AVA had a higher percentage of abnormal liver or renal function than those with ELT ( p = 0.036). No significant difference was found in the OR/CR rate in the first/second/third/sixth month between the two cohorts ( p > 0.05). Patients treated with AVA had a shorter median time to response than those treated with ELT ( p = 0.012) and had a higher platelet level in the second month ( p = 0.041). AVA had fewer adverse events than ELT ( p = 0.046). Under compatible follow-up time ( p = 0.463), no difference was found between the ELT and AVA cohorts in relapse ( p = 1.000) or clone evolution ( p = 0.637). No predictive factors for OR and CR in the sixth month were found for either ELT or AVA. Conclusion: With worse liver or renal function, AVA had a similar OR/CR rate but a shorter median time to response and fewer adverse events for patients with relapsed/refractory AA.

PurposeRecent studies have revealed the contrasting prognostic roles of body mass index (BMI) and tumor location in colorectal cancer (CRC). Given that right- and left-sided CRC may exhibit inverse effects on outcome and body weight, the present study aimed to examine whether the prognostic value of BMI and tumor location could be reciprocally stratified.MethodsThis prospective, observational study recruited 4,086 patients diagnosed with stage III CRC from five independent clinical centers in China. The association of patients’ outcomes with BMI and tumor location was evaluated hierarchically by Kaplan–Meier and Cox proportional-hazards models.ResultsAlthough BMI was not associated with overall outcome, the association was significantly modified by tumor location. Among left-sided tumors, obesity and overweight were significantly associated with adverse overall survival (OS) and disease-specific survival (DSS). In contrast, among right-sided tumors, overweight was significantly associated with more favorable OS and DSS compared with the normal-weight group. The association of survival with tumor location did not reach statistical significance. However, hierarchical analysis by BMI revealed that left-sided tumors were associated with more favorable outcomes in the normal-weight group, while there was no statistically significant difference in the overweight or obese group.ConclusionsBMI and tumor location may have opposing effects on CRC prognosis, when stratified by each other, after adjusting for other known prognostic factors. These findings are the first to show the interactive prognostic impact of BMI and tumor location, which could be relevant to the stratification of patient management.

Vehicle crashes are a leading cause of death in the United States. Curvature in local roadways has been identified as one of the most significant factors that lead to fatal crashes. Given the large number of local roads and their relatively low traffic volume - compared with interstates or freeways - most local roads may not receive priorities in the first phase of highway upgrades, and critical locations, e.g., sharp curves (vertical and/or horizontal), in the network may be a deadly threat for both advanced autonomous vehicles and conventional vehicles. Furthermore, identifying local roadway curvatures presents various obstacles, such as high budgets and lack of survey data. To fill this gap, this study offers a low-cost approach to constructing three-dimensional geometric profiles for local roads in a relatively large study area using open-source data. Given these profiles, critical road segments, including extreme horizontal and vertical curves and their combinations, can be identified. This study re-classifies the local road segments into 20 sub-categories based on the calculated vertical grades and curve radii and incorporates those segments into a zero-inflated native binomial model for crash occurrence. Model results showed that grades or curves were associated with decreased crash frequency compared with straight and flat roads. However, segments with larger horizontal curve radii and low grades were found to be associated with increased crash frequency. Further implications are discussed in the paper.

Apostasia shenzhenica is a terrestrial orchid, which belongs to Apostasioideae (Orchidaceae). Here, we determined the complete plastid genome of A. shenzhenica using the Illumina reads in an effort to provide genomic resources useful for its conservation and evolutionary biology study. It has a circular molecular length of 153,164 bp and contained 109 genes, including 75 protein-coding genes, 4 rRNA genes, and 30 tRNA genes. Phylogenetic analysis indicated that A. shenzhenica was closely related to A. wallichii and embedded in Apostasioideae.

Driver perception-reaction time and ability to sustain attention decrease as drivers become drowsy. The consequences of drowsy driving crashes are often worse on interstate highways due to the relatively high travel speeds typical on such facilities. To address the problem of driver fatigue, rest areas are often located along interstates and other long-distance highways to serve as public facilities at which motorists can take a break from driving. This paper explores the relationship between a range of crash factors and the injury severity outcomes of drowsy driving crashes on interstates in Alabama. The crash outcomes were examined in relation to interstate rest area locations. Findings from the study establish that severe injury crashes were more likely to be recorded on interstates that did not have any public rest areas. In addition, drowsy driving crashes that occurred more than 16.1 km (10 mi) away from a public rest area and those that occurred after a driver passed a rest area were more likely to record severe injuries. Other factors that were found to be associated with drowsy driving crash outcomes include unlit roadway conditions, driver gender and age, seatbelt use, location attributes of the crash site, and some temporal factors. Drowsy driving crashes involving out-of-state drivers were also found to have higher chances of recording severe injuries. Increased driver education and public campaigns are recommended as strategies to reduce drowsy driving-related crashes. While drivers should be encouraged to utilize rest areas, state officials should ensure adequate security and sanitation as well as provide amenities to make rest areas more attractive to motorists. [ABSTRACT FROM AUTHOR]

To improve the salt tolerance of grape seeds and seedlings under salt stress, this study was conducted including two control groups (CK, S) and five experimental groups (S + Si40, S + Si60, S + Si80, S + C90, S + Si40 + C90), and the physiological characteristics of grape seed germination and seedlings were studied using 40, 60, and 80 μg/mL of nano-silica treatments and by mixing 40 μg/mL of nano-silica with 90 μg/mL of multi-walled carbon nanotubes (MWCNTs), respectively. The combined treatment of 40 μg/mL nano-silica and 90 μg/mL MWCNTs resulted in the best rate of growth in grape seeds and root length and an increased germination rate when compared with the other concentrations. The combined treatment reduced the MDA content in the grape seedling leaves and increased the activities of superoxide (SOD), peroxidase (POD), catalase (CAT), dehydroascorbate reductase (DHAR), monodehydroascorbate reductase (MDHAR), ascorbate peroxidase (APX), glutathione-s-transferase (GT), and glutathione reductase (GR). In addition, the scavenging activity of DPPH· was also maintained by the combined treatment. In conclusion, a combined treatment with 40 μg/mL nano-silica and 90 μg/mL MWCNTs significantly increased the reduction capacity through the direct and indirect antioxidant systems (AsA-GSH cycle) and maintained a high antioxidant capacity of grape seedlings under salt stress.

This paper elaborates the cone–hemispherical gypsum particle breakages under normal contact with different particle shape parameters (contact diameter d, cone angle θ and sphere diameter D) and proposes a simple quantitative approach to discriminate breakage modes. The effects of the particle shape parameters on particle breakage are investigated through analyzing breakage processes, breakage modes and force–displacement curves. Three breakage modes are formed during the breakage experiments: peeling, peeling–splitting and splitting, corresponding to three different normal force–displacement curves. The formation of a conical core is deemed as the precondition for particle splitting. The particle breakage mode transfers from peeling to splitting with the increase in contact diameter d and cone angle θ, but a decrease in sphere diameter D. The critical normal force Fcr is positively linearly related to contact diameter d and cone angle θ, but the relationship between Fcr and sphere diameter D heavily depends on the breakage mode. Furthermore, the critical contact diameter dcr described by cone angle θ and sphere diameter D is proposed to discriminate breakage modes of the cone–hemispherical gypsum particles.

Novel poly(tetrafluoroethylene) (PTFE) hollow fiber membranes were successfully fabricated by electrospinning, with ultrafine fibrous PTFE membranes as separation layers, while a porous glassfiber braided tube served as the supporting matrix. During this process, PTFE/poly(vinylalcohol) (PVA) ultrafine fibrous membranes were electrospun while covering the porous glassfiber braided tube; then, the nascent PTFE/PVA hollow fiber membrane was obtained. In the following sintering process, the spinning carrier PVA decomposed; meanwhile, the ultrafine fibrous PTFE membrane shrank inward so as to further integrate with the supporting matrix. Therefore, the ultrafine fibrous PTFE membranes had excellent interface bonding strength with the supporting matrix. Moreover, the obtained ultrafine fibrous PTFE hollow fiber membrane exhibited superior performances in terms of strong hydrophobicity (CA > 140°), high porosity (>70%), and sharp pore size distribution. The comprehensive properties indicated that the ultrafine fibrous PTFE hollow fiber membranes could have potentially useful applications in membrane contactors (MC), especially membrane distillation (MD) in harsh water environments.

Poly(vinylidene fluoride-hexafluoropropylene) (PVDF-HFP) porous membranes are fabricated via thermally induced phase separation (TIPS) with mixed diluent (dibutyl phthalate (DBP)/dioctyl phthalate (DOP)). The effects of mixed diluent are discussed in detail in term of morphology, mean pore size, selective wettability, etc. The results show that the membrane structure changes from spherulitic to bicontinuous with the change of DBP/DOP ratio. It is also found that the degree of crystallization decreases with the decrease of DBP/DOP ratio in mixed diluent. When liquid–liquid (L-L) phase separation precedes solid–liquid (S-L) phase separation, the obtained membranes have outstanding hydrophobicity and lipophilicity, excellent mechanical property. Additionally, the PVDF-HFP hybrid membranes are prepared with silica (SiO2) particles and the effect of SiO2 content on structure and properties is discussed. It is found that the PVDF-HFP hybrid membrane with 2 wt % SiO2 (M3-S2) has better properties and higher filtration rate and separation efficiency for surfactant-stabilized water-in-oil emulsion separation. Moreover, the membrane M3-S2 also exhibits excellent antifouling performance for long-running.