Factors affecting delays in seeking treatment among malaria patients during the pre-certification phase in China.

BACKGROUND: Delays in malaria treatment can not only lead to severe and even life-threatening complications, but also foster transmission, putting more people at risk of infection. This study aimed to investigate the factors influencing treatment delays among malaria patients and their health-seeking behaviour. METHODS: The medical records of 494 patients diagnosed with malaria from 6 different malaria-endemic provinces in China were analysed. A bivariate and multivariable regression model was used to investigate the association between delays in seeking treatment and various factors. A Sankey diagram was used to visualize the trajectories of malaria patients seeking medical care. Total treatment delays were categorized as patient delays and doctor delays. RESULTS: The incidence of total delays in seeking malaria treatment was 81.6%, of which 28.4% were delayed by patients alone and 34.8% by doctors alone. The median time from the onset of symptoms to the initial healthcare consultation was 1 day. The median time from the initial healthcare consultation to the conclusive diagnosis was 2 day. After being subjected to multiple logistic regression analysis, living in central China was less likely to experience patient delays (OR = 0.43, 95% CI 0.24-0.78). The factors significantly associated with the lower likelihood of doctor delays included: age between 30 to 49 (OR = 0.43, 95% CI 0.23-0.81), being single/divorce/separated (OR = 0.48, 95% CI 0.24-0.95), first visiting a county-level health institution (OR = 0.25, 95% CI 0.14-0.45), first visiting a prefectural health institution (OR = 0.06, 95% CI 0.03-0.12) and first visiting a provincial health institution (OR = 0.05, 95%CI 0.02-0.12). Conversely, individuals with mixed infections (OR = 2.04, 95% CI 1.02-4.08) and those experiencing periodic symptoms (OR = 1.71, 95% CI 1.00-2.92) might face increased doctor delays. Furthermore, higher financial burden and complications were found to be associated with patient delays. Doctor delays, in addition to incurring these two consequences, were associated with longer hospital stays. CONCLUSION: There was a substantial delay in access to health care for malaria patients before China was certified malaria free. Region, marital status, periodic symptoms and the level of health institutions were factors contributing to delays in treatment-seeking among malaria patients.

Hemorrhage induced by antithrombotic agents: new insights from a real-world pharmacovigilance study.

BACKGROUND: Hemorrhage represents the most common and serious side effect of antithrombotic agents. Many studies have compared the risk of bleeding between different antithrombotic agents, but analysis of time-to-onset for hemorrhage induced by these drugs is yet sparse. METHODS: We conducted a retrospective study based on the adverse drug reaction reports on antithrombotic agents collected by the Henan Adverse Drug Reaction Monitoring Center. We assessed the reporting odds ratio to determine the disproportionate reporting signals for bleeding and the Weibull shape parameter was used to evaluate the time-to-onset data. RESULTS: In the signal detection, crude low molecular weight heparin-hemorrhage was found as a positive signal. The hemorrhage for most antithrombotic agents was random failure profiles. In particular, the hazard of hemorrhage decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole. CONCLUSION: We found that the risk of bleeding in patients taking Crude low molecular weight heparins was significantly higher compared to other antithrombotic agents, but with a small magnificence, which may be attributed to the severely irrational use of this medication under improper management. Statistics in days, results showed that the risk of bleeding decreased over time for warfarin and clopidogrel and increased for alteplase, nadroparin, and dipyridamole.

A New Design for Forearm Skin Flaps for Areas that Do not Require Additional Grafting.

Forearm skin flaps are widely used to reconstruct oral cancer due to their advantages, such as vascular stability, simple preparation, and a high success rate. However, traditional forearm skin flaps have shortcomings: the donor site requires grafting, which increases surgical trauma by creating a second surgical area, and the scarring at the donor site significantly affects the esthetics of the forearm. Therefore, we have designed a new ^-shaped radial forearm skin flap, in which the flap is designed as 2 semi-elliptical subunits. After the flap is harvested, these 2 subunits are joined, and the reserved skin at the donor site is directly sutured to the outer part of the donor site. The area of the ^-shaped radial forearm skin flap can be as large as that prepared with traditional forearm skin flaps, and there is no need for grafting at the donor site. This avoids additional trauma to the donor site after surgery, significantly reduces related complications, and enhances the esthetic outcome. This paper reports a case of a cheek cancer (carcinoma of the buccal mucosa) patient (T3N0M0), where the flap survived postoperatively, and both the surgical site and donor site healed in the first phase. The patient has no sensory or functional impairments; swallowing and speech functions are satisfactory.

Analysis of factors that promote the participation of patients with chronic diseases in shared decision making on medication: a cross-sectional survey in Hubei Province, China.

BACKGROUND: Shared decision making (SDM) improves the health status of patients with chronic diseases, especially in the condition of poly-medicated patients. This study aims to find the factors associated with participation of patients with chronic diseases in SDM on medication. METHODS: A total of 1,196 patients with chronic diseases were selected in Hubei Province of China using cluster sampling methods. The random forest method was applied to rank the importance of independent variables by Mean Decrease Gini and out-of- bag (OOB) curve. Multivariate logistic regression was used to explore the independent variables' effect direction and relative hazard. RESULTS: In this study, 5.18% of patients used patient-directed decision making (PDM, a decision-making model led by patients), 37.79% of patients used SDM (a collaborative decision-making model by patients and doctors), and 57.02% of patients used doctor-directed decision making (DDM, or paternalistic decision making, a decision-making model led by doctors). The random forest analysis demonstrated that the top 5 important factors were age, education, exercise, disease course, and medication knowledge. The OOB curve showed that the error rate reached minimum when top 5 variables in importance ranking composed an optimal variable combination. In multivariate logistic regression, we chose SDM as a reference group, and identified medication knowledge (OR = 2.737, 95%CI = 1.524 ~ 4.916) as the influencing factor between PDM and SDM. Meanwhile, the influencing factors between DDM and SDM were age (OR = 0.636, 95%CI = 0.439 ~ 0.921), education (OR = 1.536, 95%CI = 1.122 ~ 2.103), exercise (OR = 1.443, 95%CI = 1.109 ~ 1.877), disease course (OR = 0.750, 95%CI = 0.584 ~ 0.964), and medication knowledge (OR = 1.446, 95%CI = 1.120 ~ 1.867). CONCLUSION: Most Chinese patients with chronic diseases used DDM during their medication decision-making, and some patients used PDM and SDM. The participation in SDM should be taken seriously among elderly patients with lower education levels. The SDM promotion should focus on transformation of patients' traditional perception and enhance their medication knowledge.

LncRNA AGAP2 antisense RNA 1 stabilized by insulin-like growth factor 2 mRNA binding protein 3 promotes macrophage M2 polarization in clear cell renal cell carcinoma through regulation of the microRNA-9-5p/THBS2/PI3K-Akt pathway.

BACKGROUND: Increasing evidence highlights the potential role of long non-coding RNAs (lncRNAs) in the biological behaviors of renal cell carcinoma (RCC). Here, we explored the mechanism of AGAP2-AS1 in the occurrence and development of clear cell RCC (ccRCC) involving IGF2BP3/miR-9-5p/THBS2. METHODS: The expressions of AGAP2-AS1, IGF2BP3, miR-9-5p, and THBS2 and their relationship were analyzed by bioinformatics. The targeting relationship between AGAP2-AS1 and miR-9-5p and between miR-9-5p and THBS2 was evaluated with their effect on cell biological behaviors and macrophage polarization assayed. Finally, we tested the effect of AGAP2-AS1 on ccRCC tumor formation in xenograft tumors. RESULTS: IGF2BP3 could stabilize AGAP2-AS1 through m6A modification. AGAP2-AS1 was highly expressed in ccRCC tissues and cells. The lentivirus-mediated intervention of AGAP2-AS1 induced malignant behaviors of ccRCC cells and led to M2 polarization of macrophages. In addition, THBS2 promoted M2 polarization of macrophages by activating the PI3K/AKT signaling pathway. AGAP2-AS1 could directly bind with miR-9-5p and promote the expression of THBS2 downstream of miR-9-5p. These results were further verified by in vivo experiments. CONCLUSION: AGAP2-AS1 stabilized by IGF2BP3 competitively binds to miR-9-5p to up-regulate THBS2, activating the PI3K/AKT signaling pathway and inducing macrophage M2 polarization, thus facilitating the development of RCC.

Anterior column realignment via a minimally invasive hybrid approach in adult spinal deformity surgery: a short-term retrospective study.

BACKGROUND: Anterior column realignment (ACR) is a novel surgical method for correcting spinal sagittal balance. meanwhile, oblique lumbar interbody fusion (OLIF) and anterior lumbar interbody fusion (ALIF) are considered minimally invasive surgical methods through natural anatomical space. This study aimed to explore the corrective effects and clinical outcomes of OLIF or ALIF combined with ACR technology in patients with adult spinal deformity (ASD). METHODS: We retrospectively analyzed patients with sagittal imbalance who received OLIF and/or ALIF and ACR treatment from 2018 to 2021. Surgical time and intraoperative bleeding volume are recorded, the corrective effect is determined by the intervertebral space angle (IVA), lumbar lordosis (LL), the sagittal vertical axis (SVA), clinical outcome is evaluated by preoperative and final follow-up visual analog pain score (VAS), Japanese orthopedic association scores (JOA) and complications. RESULTS: Sixty-four patients were enrolled in the study, average age of 65.1(range, 47-82) years. All patients completed 173 fusion segments, for 150 segments of ACR surgery. The operation time of ALIF-ACR was 50.4 ± 22.1 min; The intraoperative bleeding volume was 50.2 ± 23.6 ml. The operation time and intraoperative bleeding volume of single-segment OLIF-ACR was 66.2 ± 19.4 min and 70.2 ± 31.6 ml. At the follow-up of 6 months after surgery, the intervertebral space angle correction for OLIF-ACR and ALIF-ACR is 9.2° and 12.2°, the preoperative and postoperative lumbar lordosis were 16.7° ± 6.4°and 47.1° ± 3.6° (p < 0.001), VAS and JOA scores were improved from 6.8 to 1.8 and 7.8 to 22.1 respectively, statistically significant differences were observed in these parameters. The incidence of surgical related complications is 29.69%, but without serious complications. CONCLUSION: ACR via a minimally invasive hybrid approach for ASD has significant advantages in restoring local intervertebral space angulation and correcting the overall sagittal balance. Simultaneously, it can achieve good clinical outcomes and fewer surgical complications.

In situ click chemistry-based discovery of 1,2,3-triazole-derived diarylpyrimidines as novel HIV-1 NNRTIs by exploiting the tolerant region I in binding pocket.

HIV-1 reverse transcriptase (RT) is considered as one of the most significant targets for the anti-HIV-1 drug design due to their determined mechanism and well-decoded crystal structure. As a part of our continuous efforts towards the development of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) by exploiting the tolerant region I of NNRTIs binding pocket (NNIBP), the miniaturized parallel synthesis via CuAAC click chemistry reaction followed by in situ biological screening have been performed in this work. The in situ enzyme inhibition screening results showed that 14 compounds exhibited higher or equivalent inhibitory activity compared to the lead K-5a2 and ETR. Anti-HIV-1 activity results indicated that C1N51 displayed the most potent activity (EC50 = 0.01-0.26 µM) against wild-type and a panel of NNRTIs-resistant strains. Moreover, the molecular simulation demonstrated that the newly introduced triazole ring could develop new hydrogen bonds with Lys103 and Pro236, which explained the feasibility of introducing triazole in the tolerant region I of the RT binding pocket.

Culture and identification of neonatal rat brain-derived neural stem cells.

BACKGROUND: Timing of passaging, passage number, passaging approaches and methods for cell identification are critical factors influencing the quality of neural stem cells (NSCs) culture. How to effectively culture and identify NSCs is a continuous interest in NSCs study while these factors are comprehensively considered. AIM: To establish a simplified and efficient method for culture and identification of neonatal rat brain-derived NSCs. METHODS: First, curved tip operating scissors were used to dissect brain tissues from new born rats (2 to 3 d) and the brain tissues were cut into approximately 1 mm3 sections. Filter the single cell suspension through a nylon mesh (200-mesh) and culture the sections in suspensions. Passaging was conducted with TrypLTM Express combined with mechanical tapping and pipetting techniques. Second, identify the 5th generation of passaged NSCs as well as the revived NSCs from cryopreservation. BrdU incorporation method was used to detect self-renew and proliferation capabilities of cells. Different NSCs specific antibodies (anti-nestin, NF200, NSE and GFAP antibodies) were used to identify NSCs specific surface markers and muti-differentiation capabilities by immunofluorescence staining. RESULTS: Brain derived cells from newborn rats (2 to 3 d) proliferate and aggregate into spherical-shaped clusters with sustained continuous and stable passaging. When BrdU was incorporated into the 5th generation of passaged cells, positive BrdU cells and nestin cells were observed by immunofluorescence staining. After induction of dissociation using 5% fetal bovine serum, positive NF200, NSE and GFAP cells were observed by immunofluorescence staining. CONCLUSION: This is a simplified and efficient method for neonatal rat brain-derived neural stem cell culture and identification.

A diagnostic model for differentiating tuberculous spondylitis from pyogenic spondylitis: a retrospective case-control study.

The purpose of this study was to describe and compare the clinical data, laboratory examination and imaging examination of tuberculous spondylitis (TS) and pyogenic spondylitis (PS), and to provide ideas for diagnosis and treatment intervention. The patients with TS or PS diagnosed by pathology who first occurred in our hospital from September 2018 to November 2021 were studied retrospectively. The clinical data, laboratory results and imaging findings of the two groups were analyzed and compared. The diagnostic model was constructed by binary logistic regression. In addition, an external validation group was used to verify the effectiveness of the diagnostic model. A total of 112 patients were included, including 65 cases of TS with an average age of 49 ± 15 years, 47 cases of PS with an average of 56 ± 10 years. The PS group had a significantly older age than the TS group (P = 0.005). In laboratory examination, there were significant differences in WBC, neutrophil (N), lymphocyte (L), ESR, CRP, fibrinogen (FIB), serum albumin (A) and sodium (Na). The difference was also statistically significant in the comparison of imaging examinations at epidural abscesses, paravertebral abscesses, spinal cord compression, involvement of cervical, lumbar and thoracic vertebrae. This study constructed a diagnostic model, which was Y (value of TS > 0.5, value of PS < 0.5) = 1.251 * X1 (thoracic vertebrae involved = 1, thoracic vertebrae uninvolved = 0) + 2.021 * X2 (paravertebral abscesses = 1, no paravertebral abscess = 0) + 2.432 * X3 (spinal cord compression = 1, no spinal cord compression = 0) + 0.18 * X4 (value of serum A)-4.209 * X5 (cervical vertebrae involved = 1, cervical vertebrae uninvolved = 0)-0.02 * X6 (value of ESR)-0.806 * X7 (value of FIB)-3.36. Furthermore, the diagnostic model was validated using an external validation group, indicating a certain value in diagnosing TS and PS. This study puts forward a diagnostic model for the diagnosis of TS and PS in spinal infection for the first time, which has potential guiding value in the diagnosis of them and provides a certain reference for clinical work.

Is shared decision-making a determinant of polypharmacy in older patients with chronic disease? A cross-sectional study in Hubei Province, China.

BACKGROUND: Shared decision-making(SDM) is recognized as an important means of managing polypharmacy among older people with chronic diseases. However, no studies have quantitatively measured the effect of SDM on polypharmacy. The objective of this study was to compare the impact of SDM and other factors on polypharmacy in inpatients and community patients. Additionally, the study aimed to compare the impact of different decision types on polypharmacy in community patients. METHODS: This is a population-based multicenter retrospective study conducted in Hubei Province, China. A cluster sampling approach was used to recruit 536 chronic disease inpatients from March to April 2019, and 849 community patients were recruited from April to June 2021. Propensity score weighting was used to control the confounding variables and determine the net effect of SDM on polypharmacy. RESULTS: Among the 536 hospitalized patients, the prevalence of polypharmacy was 56.3%. A high level of SDM was significantly associated with a lower risk of polypharmacy. Patients with chronic illnesses aged 76 years and older and with an annual family income of 24,001-36,000 yuan were associated with a lower likelihood of polypharmacy (p < 0.05). Multimorbidity was often accompanied by the occurrence of multiple medication use. Among 849 community patients, the prevalence of polypharmacy was 21.8%. Among types of decision-making, informed and paternalistic decision-making showed a higher likelihood of polypharmacy compared with shared decision-making (P < 0.05). Male, older patients over 76 years of age, urban residents, annual household income of 12,001-24,000 yuan, and multimorbidity were associated with higher likelihood of polypharmacy (P < 0.05). Patients with an annual household income of 24,001-36,000 yuan, 36,001 yuan or more, and good medication compliance showed a lower likelihood of polypharmacy (P < 0.05). CONCLUSIONS: The prevalence of polypharmacy is high among China's older population with chronic disease who should be paid more atthention by the healthcare providers. Additionaly, encouraging the patients' attendance in SDM, reducing paternalistic and informed decision-making during prescribing, improving patient medication compliance, and increasing the promotion and guidance of rational medication use for patients are essential to reduce polypharmacy in Chinese chronic disease patients.

Using Time Trade-Off Values to Estimate EQ-5D-Y Value Sets: An Exploratory Study.

OBJECTIVES: The published international EQ-5D-Y-3L valuation protocol does not recommend the composite time trade-off (cTTO) method as the primary valuation method because of 2 major concerns. First, the cTTO method was shown to generate high values. Second, the cTTO method is not as feasible for valuing children's health as other established methods. This study aimed to explore the feasibility of using cTTO values alone to estimate EQ-5D-Y-3L value sets. METHODS: We analyzed the cTTO data derived from the recently completed Chinese EQ-5D-Y-3L valuation study in which a total of 28 health states were valued. We assessed the feasibility of the cTTO tasks in terms of survey completion time and participant-reported difficulty of understanding the task, differentiating the health states, and deciding the answer. We also examined the data distribution characteristics and modeled the data using different models. RESULTS: In total, 418 participants completed the cTTO interview. On average, participants took approximately 35.70 minutes (SD 12.42) to complete the interview and made 13.21 moves (SD 9.00) in the cTTO tasks. There were 74.16%, 59.33%, and 11.48% of participants indicated that it was easy to understand the cTTO tasks, easy to differentiate between the health states, and difficult to decide on an indifference point, respectively. The data distribution was smooth, and a random-effects model performed the best in terms of coefficient significance, monotonicity, and predictive accuracy. CONCLUSION: Our finding suggests that estimating EQ-5D-Y-3L value sets using cTTO data alone is feasible and therefore could be considered as an option in future valuation studies for EQ-5D-Y-3L.

Ambient fine particulate matter and cardiopulmonary health risks in China.

ABSTRACT: In China, the level of ambient fine particulate matter (PM 2.5 ) pollution far exceeds the air quality standards recommended by the World Health Organization. Moreover, the health effects of PM 2.5 exposure have become a major public health issue. More than half of PM 2.5 -related excess deaths are caused by cardiopulmonary disease, which has become a major health risk associated with PM 2.5 pollution. In this review, we discussed the latest epidemiological advances relating to the health effects of PM 2.5 on cardiopulmonary diseases in China, including studies relating to the effects of PM 2.5 on mortality, morbidity, and risk factors for cardiovascular and respiratory diseases. These data provided important evidence to highlight the cardiopulmonary risk associated with PM 2.5 across the world. In the future, further studies need to be carried out to investigate the specific relationship between the constituents and sources of PM 2.5 and cardiopulmonary disease. These studies provided scientific evidence for precise reduction measurement of pollution sources and public health risks. It is also necessary to identify effective biomarkers and elucidate the biological mechanisms and pathways involved; this may help us to take steps to reduce PM 2.5 pollution and reduce the incidence of cardiopulmonary disease.

Meshed neuronal mitochondrial networks empowered by AI-powered classifiers and immersive VR reconstruction.

Mitochondrial networks are defined as a continuous matrix lumen, but the morphological feature of neuronal mitochondrial networks is not clear due to the lack of suitable analysis techniques. The aim of the present study is to develop a framework to capture and analyze the neuronal mitochondrial networks by using 4-step process composed of 2D and 3D observation, primary and secondary virtual reality (VR) analysis, with the help of artificial intelligence (AI)-powered Aivia segmentation an classifiers. In order to fulfill this purpose, we first generated the PCs-Mito-GFP mice, in which green fluorescence protein (GFP) could be expressed on the outer mitochondrial membrane specifically on the cerebellar Purkinje cells (PCs), thus all mitochondria in the giant neuronal soma, complex dendritic arborization trees and long projection axons of Purkinje cells could be easily detected under a laser scanning confocal microscope. The 4-step process resolved the complicated neuronal mitochondrial networks into discrete neuronal mitochondrial meshes. Second, we measured the two parameters of the neuronal mitochondrial meshes, and the results showed that the surface area (µm2) of mitochondrial meshes was the biggest in dendritic trees (45.30 ± 53.21), the smallest in granular-like axons (3.99 ± 1.82), and moderate in soma (27.81 ± 22.22) and silk-like axons (17.50 ± 15.19). These values showed statistically different among different subcellular locations. The volume (µm3) of mitochondrial meshes was the biggest in dendritic trees (9.97 ± 12.34), the smallest in granular-like axons (0.43 ± 0.25), and moderate in soma (6.26 ± 6.46) and silk-like axons (3.52 ± 4.29). These values showed significantly different among different subcellular locations. Finally, we found both the surface area and the volume of mitochondrial meshes in dendritic trees and soma within the Purkinje cells in PCs-Mito-GFP mice after receiving the training with the simulating long-term pilot flight concentrating increased significantly. The precise reconstruction of neuronal mitochondrial networks is extremely laborious, the present 4-step workflow powered by artificial intelligence and virtual reality reconstruction could successfully address these challenges.

A cofunctional grouping-based approach for non-redundant feature gene selection in unannotated single-cell RNA-seq analysis.

Feature gene selection has significant impact on the performance of cell clustering in single-cell RNA sequencing (scRNA-seq) analysis. A well-rounded feature selection (FS) method should consider relevance, redundancy and complementarity of the features. Yet most existing FS methods focus on gene relevance to the cell types but neglect redundancy and complementarity, which undermines the cell clustering performance. We develop a novel computational method GeneClust to select feature genes for scRNA-seq cell clustering. GeneClust groups genes based on their expression profiles, then selects genes with the aim of maximizing relevance, minimizing redundancy and preserving complementarity. It can work as a plug-in tool for FS with any existing cell clustering method. Extensive benchmark results demonstrate that GeneClust significantly improve the clustering performance. Moreover, GeneClust can group cofunctional genes in biological process and pathway into clusters, thus providing a means of investigating gene interactions and identifying potential genes relevant to biological characteristics of the dataset. GeneClust is freely available at https://github.com/ToryDeng/scGeneClust.

A berberine induced disassembly towards zwitterionic surfactant as mimicking cell membrane for light-scattering sensing and logic devices.

A label-free light-scattering sensor for berberine determination was developed based on Gemini zwitterionic surfactant as logic devices. Amphiphilic phosphodiesters quaternary ammonium nanoparticles (PQANPs) with bionic phosphate ester structure were selected as a model for mimicking cell membrane. PQANPs self-assembled and formed the micelle structure, emitting strong light-scattering signal. Interestingly, the addition of berberine induced remarkable decrease of light-scattering attribute to its interfering behavior of PQANPs aggregation. Disassembly of PQANPs could be triggered due to electrostatic interaction and hydrophobic force between PQANPs and berberine. The berberine attached to the PQANPs surface and generated nanocomposites, resulting in significant reduce of light-scattering signal. Hence, it generated a strong light-scattering signal variation according to the change of the concentration of target. Our proposed light-scattering on-off sensor could be applied for berberine detection with detection limit of 27 nM. Moreover, a logic gate system was constructed based on PQANPs sensor with berberine and the interfering substances as the inputs and the light-scattering intensity as an output, which could hold great potential application in future clinical diagnosis and drug analysis.

Changes of adjacent segment biomechanics after anterior cervical interbody fusion with different profile design plate: single- versus double-level.

Low-profile angle-stable spacer Zero-P is claimed to reduce the morbidity associated with traditional plate and cage construct (PCC). Both Zero-P and PCC could achieve comparable mid- and long-term clinical and radiological outcomes in anterior cervical discectomy and fusion (ACDF). It is not clear whether Zero-P can reduce the incidence of adjacent segment degeneration (ASD), especially in multi-segmental fusion. This study aimed to test the effect of fusion level with Zero-P versus with PCC on adjacent-segment biomechanics in ACDF. A three-dimensional finite element (FE) model of an intact C2-T1 segment was built and validated. Six single- or double-level instrumented conditions were modeled from this intact FE model using Zero-P or the standard PCC. The biomechanical responses of adjacent segments at the cephalad and caudal levels of the operation level were assessed in terms of range of motion (ROM), stresses in the endplate and disc, loads in the facets. When comparing the increase of adjacent-segment motion in single-level PCC fusion versus Zero-P fusion, a significantly larger increase was found in double-level fusion condition. The fold changes of PCC versus Zero-P of intradiscal and endplate stress, and facet load at adjacent levels in the double-level fusion spine were significantly larger than that in the single-level fusion spine during the sagittal, the transverse, and the frontal plane motion. The increased value of biomechanical features was greater at above segment than that at below. The fold changes of PCC versus Zero-P at adjacent segment were most notable in flexion and extension movement. Low-profile device could decrease adjacent segment biomechanical burden compared to traditional PCC in ACDF, especially in double-level surgery. Zero-P could be a good alternative for traditional PCC in ACDF. Further clinical/in vivo studies will be necessary to explore the approaches selected for this study is warranted.

Identification of "dual-site"-binding diarylpyrimidines targeting both NNIBP and the NNRTI adjacent site of the HIV-1 reverse transcriptase.

Here, we reported a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP). The anti-HIV-1 activity results demonstrated that compound 9e (EC50 = 2.04-61.1 nM) displayed robust potencies against a panel of HIV-1 NNRTIs-resistant strains, being comparable to that of etravirine (ETR). Moreover, 9e displayed much lower cytotoxicity (CC50 = 59.2 µM) and higher SI values (4605) toward wild-type HIV-1 strain. The HIV-1 RT enzyme inhibitory activity clarified the binding target of 9e was HIV-1 RT (IC50 = 0.019 µM). Furthermore, the molecular modeling study was also investigated to give a reasonable explanation of the preliminary SARs. Further test indicated that 9e possessed significantly improved water solubility under pH 7.0 and 7.4 conditions. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features. Consequently, compound 9e showed the highest activity and low cytotoxicity, which could be used as a lead for further modification to obtain potent HIV-1 NNRTIs.

Disubstituted pyrimidine-5-carboxamide derivatives as novel HIV-1 NNRTIs: Crystallographic overlay-based molecular design, synthesis, and biological evaluation.

Herein, via crystallographic overlay-based molecular hybridization strategy, a series of disubstituted pyrimidine-5-carboxamide derivatives were designed by introducing an amide moiety to the central core of the lead etravirine. All the newly synthesized compounds were evaluated for their anti-HIV-1 potencies in MT-4 cells using the MTT method. Most of the synthesized compounds displayed promising antiviral activities against the wild-type (IIIB) and a panel of HIV-1 NNRTIs-resistant strains. Especially, 21c exhibited the most potent activity (EC50 = 0.009-0.065 µM) against HIV-1 IIIB, L100I, K103N, Y181C, Y188L, and RES056, being comparable to those of etravirine. The inhibitory activity to reverse transcriptase (RT) was evaluated by ELISA method, and the target of the compounds was proved to be RT. Moreover, the molecular docking was investigated to clarify the binding mode of 21c with RT. Overall, the results demonstrated that 21c could serve as a lead for further modification to develop novel HIV-1 NNRTIs.

Ferroptosis patterns and tumor microenvironment infiltration characterization in esophageal squamous cell cancer.

Background: Esophageal Squamous Cell Cancer (ESCC) is an aggressive disease associated with a poor prognosis. As a newly defined form of regulated cell death, ferroptosis plays a crucial role in cancer development and treatment and might be a promising therapeutic target. However, the expression patterns of ferroptosis-related genes (FRGs) in ESCC remain to be systematically analyzed. Methods: First, we retrieved the transcriptional profile of ESCC from TCGA and GEO datasets (GSE47404, GSE23400, and GSE53625) and performed unsupervised clustering to identify different ferroptosis patterns. Then, we used the ssGSEA algorithm to estimate the immune cell infiltration of these patterns and explored the differences in immune cell abundance. Common genes among patterns were finally identified as signature genes of ferroptosis patterns. Results: Herein, we depicted the multi-omics landscape of FRGs through integrated bioinformatics analysis and identified three ESCC subtypes with distinct immune characteristics: clusters A-C. Cluster C was abundant in CD8+ T cells and other immune cell infiltration, while cluster A was immune-barren. By comparing the differently expressed genes between clusters of diverse datasets, we defined a gene signature for each cluster and successfully validated it in the TCGA-ESCC dataset. Conclusion: We provided a comprehensive insight into the expression pattern of ferroptosis genes and their interaction with immune cell infiltration. Additionally, we established a gene signature to define the ferroptosis patterns, which might be used to predict the response to immunotherapy.

Availability and Affordability of Therapeutic Monoclonal Antibodies After the New Medical Reform in Hubei Province, China.

OBJECTIVE: In 2017, China launched a new round of medical reform (NMR) to address the inaccessibility of high-priced drugs for patients with serious diseases. This study explored the impact of the NMR on the accessibility and affordability of high-priced monoclonal antibodies (mAbs), and the effective promotion policies after the NMR. METHODS: We used a standard method developed by the World Health Organization to conduct two surveys on the availability of mAbs and their prices before and after the NMR in the public hospitals in Hubei province, China. By interviewing hospital pharmacy experts, we identified the potential value of the current NMR in improving the access to therapeutic mAbs. RESULTS: The average availability of 13 mAbs increased by 8.1% in the surveyed hospitals of Hubei province after the NMR. The median unit price of 10 mAbs dropped by 34.3%. The average affordability of a treatment cycle of 10 mAbs dropped from 680 days to 298 days of the disposable daily income for a middle-income resident (56.2% reduction). The drug price negotiation of medical insurance inclusion and the promotion of consistent evaluation of generic and original drugs could effectively promote the accessibility of mAbs. However, the zero markup of drug pricing and the limit on the proportion of drug revenues in public hospitals showed certain negative effects on the availability of mAbs. CONCLUSION: Not all current NMR policies play a positive role in promoting the accessibility of mAbs. To further improve the accessibility of mAbs in the future in China, it is therefore critical to increase the investment in independent research and development of high-quality mAbs, establish localized guidelines for the rational use of mAbs in clinical practice, and have a cost-sharing mechanism for high-priced drugs with multiple stakeholders.