Intraoperative Observation of the Proper Digital Nerves in Wassel-Flatt Type â £ Radial Polydactyly.

PURPOSE: The aim of the study was to present the intraoperative findings of the relevant digital nerves of the duplicated thumbs in an excision and reconstruction procedure for the Wassel-Flatt type Ⅳ radial polydactyly. METHODS: The study was conducted on patients with Wassel-Flatt type IV radial polydactyly who underwent excision and reconstruction between 2018 and 2021 at our institution. The ulnar digital nerve of the radial thumb and the radial digital nerve of the ulnar thumb were identified and traced intraoperatively. The level of the bifurcation of the nerves and abnormal findings were documented. RESULTS: A total of 123 hands in 119 patients were included in this study. In 114 hands, the bifurcation of the nerves was located within 1 cm of the metacarpophalangeal flexion crease. The radial digital nerve to the ulnar thumb was abnormally compressed in deep fascial tissue in 7 of these 114 hands. In 5 hands, the level of bifurcation was more than 1 cm proximal to the crease. No radial digital nerve to the ulnar thumb was identified in the remaining 4 hands. CONCLUSIONS: Although rare, abnormal nerve compression of the digital nerve may exist in duplicated thumbs of Wassel-Flatt type IV radial polydactyly. CLINICAL RELEVANCE: In an excision and reconstruction procedure, we suggest that the bifurcation of the nerves should be identified before the nerve to the radial thumb is excised to avoid injuring the nerve to the main ulnar thumb.

Scopoletin Reactivates Latent HIV-1 by Inducing NF-κB Expression without Global T Cell Activation.

Reversing HIV-1 latency promotes the killing of infected cells and is essential for cure strategies. However, current latency-reversing agents (LRAs) are not entirely effective and safe in activating latent viruses in patients. In this study, we investigated whether Scopoletin (6-Methoxy-7-hydroxycoumarin), an important coumarin phytoalexin found in plants with multiple pharmacological activities, can reactivate HIV-1 latency and elucidated its underlying mechanism. Using the Jurkat T cell model of HIV-1 latency, we found that Scopoletin can reactivate latent HIV-1 replication with a similar potency to Prostratin and did so in a dose- and time-dependent manner. Moreover, we provide evidence indicating that Scopoletin-induced HIV-1 reactivation involves the nuclear factor kappa B (NF-κB) signaling pathway. Importantly, Scopoletin did not have a stimulatory effect on T lymphocyte receptors or HIV-1 receptors. In conclusion, our study suggests that Scopoletin has the potential to reactivate latent HIV-1 without causing global T-cell activation, making it a promising treatment option for anti-HIV-1 latency strategies.

Pathway for biodegrading coumarin by a newly isolated Pseudomonas sp. USTB-Z.

Coumarin is widely used in personal care products and pharmaceutical industry, which leads to the release of this compound into environment as an emerging contaminant. Here, a promising strain USTB-Z for biodegrading coumarin was successfully isolated from botanical soil and characterized as a potential novel Pseudomonas sp. based on 16S rDNA sequence analysis and orthologous average nucleotide identity tool. Initial coumarin up to 800 mg/L could be completely removed by USTB-Z within 48 h at the optimal culture conditions of pH 7.3 and 30 °C, which indicates that USTB-Z has a strong capacity in coumarin biodegradation. The biodegradation products of coumarin were further investigated using HPLC and Q-TOF LC/MS, and melilotic acid and 2,3-dihydroxyphenylpropionic acid were identified. The draft genome of strain USTB-Z was sequenced by Illumina NovaSeq, and 21 CDSs for NAD (P)-dependent oxidoreductase, 43 CDSs for hydrolase, 1 CDS for FAD-depend monooxygenase, 1 CDS for 3-hydroxycinnamic acid hydroxylase, 21 CDSs for dioxygenase, and 5 CDSs for fumarylacetoacetate (FAA) hydrolase were annotated and correlated to coumarin biodegradation. The present study provides a theoretical basis and microbial resource for further research on the coumarin biodegradation.

Benzylguanidine and Galactose Double-Conjugated Chitosan Nanoparticles with Reduction Responsiveness for Targeted Delivery of Doxorubicin to CXCR 4 Positive Tumors.

Benzylguanidine, a small cationic and amphiphilic molecule, exhibits a high affinity to C-X-C chemokine receptor type 4 (CXCR 4) and a membrane penetration ability. It has not been used as a functional moiety of nanocarriers for the systemic delivery of chemotherapeutic drugs in tumor therapy. In this study, we investigated the membrane penetration of benzylguanidine-conjugated nanocarriers and their efficiency and safety for targeted delivery of doxorubicin (DOX) in CXCR 4 positive tumors. We conjugated the benzylguanidine bearing guanidinobenzoic acid onto the cystamine bismethacrylamide cross-linked chitosan-poly(methyl methacrylate) nanoparticles, which were then decorated with lactobionic acid (abbreviated as LGCC NPs). A small proportion of LGCC NPs were able to directly penetrate the plasma membrane to enter cells, thereby circumventing endocytic vesicles. The DOX-loaded LGCC NPs (LGCC NPs/DOX) displayed good stability under extracellular physiological conditions and reduction-triggered drug release under high glutathione (GSH) concentration. Moreover, LGCC NPs/DOX showed an increase in tumor-targeted cellular uptake through receptor-mediated endocytosis, enhanced endo/lysosomal escape, and a high nuclear distribution. More importantly, LGCC NPs/DOX significantly suppressed the in vitro and in vivo proliferation of CXCR 4 positive hepatocarcinoma and breast cancer. The findings provide a guideline for the combined application of benzylguanidine and other functional groups in antitumor nanomedicines.

Whole genome sequencing of pairwise human subjects reveals DNA mutations specific to developmental dysplasia of the hip.

Developmental dysplasia of the hip (DDH) is a common congenital malformation characterized by mismatch in shape between the femoral head and acetabulum, and leads to hip dysplasia. To date, the pathogenesis of DDH is poorly understood and may involve multiple factors, including genetic predisposition. However, comprehensive genetic analysis has not been applied to investigate a genetic component of DDH. In the present study, 10 pairs of healthy fathers and DDH daughters were enrolled to identify genetic hallmarks of DDH using high throughput whole genome sequencing. The DDH-specific DNA mutations were found in each patient. Overall 1344 genes contained DDH-specific mutations. Functional enrichment analysis showed that these genes played important roles in the cytoskeleton, microtubule cytoskeleton, sarcoplasm and microtubule associated complex. These functions affected osteoblast and osteoclast development. Therefore, we proposed that the DDH-specific mutations might affect bone development, and caused DDH. Our pairwise high throughput sequencing results comprehensively delineated genetic hallmarks of DDH. Further research into the biological impact of these mutations may inform the development of DDH diagnostic tools and allow neonatal gene screening.

Force Field Benchmark of Amino Acids. 2. Partition Coefficients between Water and Organic Solvents.

The partitioning of amino acids between water and apolar environments is of vital importance in protein function and drug delivery. Here we present an extensive benchmark for octanol/water (log Poct), chloroform/water (log Pclf), and cyclohexane/water (log Pchx) partition coefficients of neutral amino acid side chain analogues (SCAs) with Amber families of ff99SB-ILDN, ff03, ff14SB, fb15, and ff15ipq, CHARMM 27, GROMOS 53A6, and OPLS-AA/L force fields. A root-mean-square error (RMSE) of 0.4-1.3 log units from experiment is observed for the tested FFs, of which Amber ff94 lineages of ff99SB-ILDN, ff14SB, and fb15 perform best with an RMSE and mean signed error (MSE) of about 0.5 and 0.2 log units, respectively, a performance comparable with quantum mechanical SMD calculations. This finding retains the possibility of modeling proteins in varied environments with one set of classical molecular mechanical force fields. All the FFs tend to overestimate log P, except for GROMOS 53A6 underestimating log Pclf and log Pchx. These discrepancies are mainly due to the larger overestimated solvation free energies in water (Δ Gwat) relative to that in organic solvents (Δ Goct, Δ Gclf, and Δ Gchx); for GROMOS 53A6, it is due to the underestimated Δ Gwat and Δ Goct. The latest water models of "FB" and "OPC" families paired with the recent Amber fb15 do not show an obvious improvement for Δ Gwat and log P calculations. The van der Waals interaction between amino acids and cyclohexane is found to be too strong (overestimated) systematically. Scaling protein-water interactions lead to more favorable Δ Gwat, thereby lowering log P and resulting in a better performance for Amber ff03ws, while such scaling seems a bit too much for Amber ff99SBws. This, along with our previous work ( Zhang et al. J. Chem. Inf. MODEL: 2018 , 58 , 1037 - 1052 ), may aid in the development and systematic improvements of classical force fields to model proteins in aqueous and nonaqueous phases accurately.

Force Field Benchmark of Amino Acids: I. Hydration and Diffusion in Different Water Models.

Thermodynamic and kinetic properties are of critical importance for the applicability of computational models to biomolecules such as proteins. Here we present an extensive evaluation of the Amber ff99SB-ILDN force field for modeling of hydration and diffusion of amino acids with three-site (SPC, SPC/E, SPC/Eb, and TIP3P), four-site (TIP4P, TIP4P-Ew, and TIP4P/2005), and five-site (TIP5P and TIP5P-Ew) water models. Hydration free energies (HFEs) of neutral amino acid side chain analogues have little dependence on the water model, with a root-mean-square error (RMSE) of ∼1 kcal/mol from experimental observations. On the basis of the number of interacting sites in the water model, HFEs of charged side chains can be putatively classified into three groups, of which the group of three-site models lies between those of four- and five-site water models; for each group, the water model dependence is greatly eliminated when the solvent Galvani potential is considered. Some discrepancies in the location of the first hydration peak ( RRDF) in the ion-water radial distribution function between experimental and calculated observations were detected, such as a systematic underestimation of the acetate (Asp side chain) ion. The RMSE of calculated diffusion coefficients of amino acids from experiment increases linearly with the increasing diffusion coefficients of the solvent water models at infinite dilution. TIP3P has the fastest diffusivity, in line with literature findings, while the "FB" and "OPC" water model families as well as TIP4P/2005 perform well, within a relative error of 5%, and TIP4P/2005 yields the most accurate estimate for the water diffusion coefficient. All of the tested water models overestimate amino acid diffusion coefficients by approximately 40% (TIP4P/2005) to 200% (TIP3P). Scaling of protein-water interactions with TIP4P/2005 in the Amber ff99SBws and ff03ws force fields leads to more negative HFEs but has little influence on the diffusion of amino acids. The most recent FF/water combinations of ff14SB/OPC3, ff15ipq/SPC/Eb, and fb15/TIP3P-FB do not show obvious improvements in accuracy for the tested quantities. These findings here establish a benchmark that may aid in the development and improvement of classical force fields to accurately model protein dynamics and thermodynamics.

Co-Delivery of Doxorubicin and Survivin shRNA-Expressing Plasmid Via Microenvironment-Responsive Dendritic Mesoporous Silica Nanoparticles for Synergistic Cancer Therapy.

PURPOSE: The present study is aimed at designing an appropriate co-delivery system for chemotherapeutic drugs and gene drugs with high loading capacity, on-demand release behaviors, efficient endosomal escape, and enhanced nucleic localization, thereby providing efficacious antitumor activity. METHODS: Schiff-base linked imidazole dendritic mesoporous silica nanoparticles (SL-IDMSN) were developed and employed to load doxorubicin (DOX) and survivin shRNA-expressing plasmid (iSur-pDNA) to form nanocomplexes. The nanoparticles were assessed by structural characterization, drug loading and release, cellular uptake, intracellular distribution, gene transfection, in vitro anti-proliferation of hepatoma cells, and in vivo tumor growth inhibition in H-22 tumor bearing mice. RESULTS: SL-IDMSN showed high loading capacity for both DOX and iSur-pDNA due to their hierarchical mesostructures. The cleavage of Schiff-base linkage on SL-IDMSN in the weakly acidic endosomes/lysosomes led to microenvironment-specific release of both DOX and iSur-pDNA. Meanwhile, the imidazole modification could trigger the efficient endosomal escape via proton sponge effect, thereby enhancing nuclear accumulation of iSur-pDNA and gene silencing efficiency. More importantly, these superior performances of SL-IDMSN resulted in their improved inhibitory effects on in vitro cancer cell proliferation and in vivo tumor growth. CONCLUSIONS: SL-IDMSN is a microenvironment-sensitive and biocompatible nanocarrier for the co-delivery of DOX and iSur-pDNA, which might be a promising carrier for co-delivery of chemotherapeutic drugs and gene drugs for synergistic cancer therapy.

Comparative Assessment of Computational Methods for Free Energy Calculations of Ionic Hydration.

Experimental observations for ionic hydration free energies are highly debated mainly due to the ambiguous absolute hydration free energy of proton, ΔGhyd*(H+). Hydration free energies (HFEs) of the 112 singly charged ions in the Minnesota solvation database were predicted by six methods with explicit and implicit solvent models, namely, thermodynamic integration (TI), energy representation module (ERmod), three-dimensional reference interaction site model (3D-RISM), and continuum solvation models based on the quantum mechanical charge density (SMD) and on the Poisson-Boltzmann (PB) and generalized Born (GB) theories. Taking the solvent Galvani potential of water into account, the resulting real HFEs from TI calculations for the generalized Amber force field (GAFF) modeled ions best match the experiments based on ΔGhyd*(H+) = -262.4 kcal/mol (Randles Trans. Faraday Soc . 1956 , 52 , 1573 - 1581 ), in agreement with our previous work on charged amino acids (Zhang et al. J. Phys. Chem. Lett. 2017 , 8 , 2705 - 2712 ). The examined computational methods show an accuracy of ∼7 kcal/mol for the GAFF-modeled ions, except for SMD with a higher accuracy of ∼4 kcal/mol. A biased deficiency in modeling anionic compounds by GAFF is observed with a larger standard deviation (SD) of 9 kcal/mol than that for cations (SD ∼ 4 kcal/mol). The relatively cheap ERmod and 3D-RISM methods reproduce TI results with good accuracy, although ERmod yields a systematic underestimation for cations by 9 kcal/mol; PB and GB generate relative (but not absolute) HFEs comparable to the TI predictions. Computational accuracy is found to be more limited by the accuracy of force fields rather than the models themselves.

Evaluation of Generalized Born Models for Large Scale Affinity Prediction of Cyclodextrin Host-Guest Complexes.

Binding affinity prediction with implicit solvent models remains a challenge in virtual screening for drug discovery. In order to assess the predictive power of implicit solvent models in docking techniques with Amber scoring, three generalized Born models (GBHCT, GBOBCI, and GBOBCII) available in Dock 6.7 were utilized, for determining the binding affinity of a large set of ß-cyclodextrin complexes with 75 neutral guest molecules. The results were compared to potential of mean force (PMF) free energy calculations with four GB models (GBStill, GBHCT, GBOBCI, and GBOBCII) and to experimental data. Docking results yield similar accuracy to the computationally demanding PMF method with umbrella sampling. Neither docking nor PMF calculations reproduce the experimental binding affinities, however, as indicated by a small Spearman rank order coefficient (∼0.5). The binding energies obtained from GB models were decomposed further into individual contributions of the binding partners and solvent environments and compared to explicit solvent simulations for five complexes allowing for rationalizing the difference between explicit and implicit solvent models. An important observation is that the explicit solvent screens the interaction between host and guest much stronger than GB models. In contrast, the screening in GB models is too strong in solutes, leading to overestimation of short-range interactions and too strong binding. It is difficult to envision a way of overcoming these two opposite effects.

Retrospective analysis of the radiographic indicators for peri-acetabular osteotomy of developmental dysplasia in children.

PURPOSE: Open surgery, nonsurgical positioning device and casting are mainstay treatments of developmental dysplasia of the hip (DDH). The optimal indicators for surgical interventions remain unclear. In this study, we aim to establish empirical, sensitive radiographic indicators for peri-acetabular osteotomy intervention in developmental dysplasia in Chinese children. METHODS: One hundred and three DDH patients treated in The Soochow University Children's Hospital between 2006 and 2012 were assessed; patients with known causes of neuron muscular and abnormal hip joint origin were excluded. Fifty-four suitable patients, demonstrating 71 dysplasia hips with complete clinical record and adequate X-ray films, were enrolled in this study. Patients were divided into group A (conservative interventions failed, followed by salvage peri-acetabular osteotomy) and group B (conservative treatment only); a total of 16 quantitative parameters were measured on each pelvic X-ray film. RESULTS: Among 71 hip joints measured, 29 hips of group A underwent salvage peri-acetabular osteotomy (40.8 %,) showed higher X2, Y, h, and Smith c/b (Vh) (p < 0.05). The age, c, HT, b, A2 in the group A salvage operation were statistically significantly different compared to group B patients (without salvage operations) (p < 0.05). CONCLUSIONS: Pre-operative pelvic X-ray film assessment of acetabulum lateralization markers (X2, c, HT, c/b ratio) and the superior migration measurements (Y, h, h/b ratio) are potentially valuable radiographic indicators for determining which DDH patients will require peri-acetabular osteotomy.

Effects of particle size and binding affinity for small interfering RNA on the cellular processing, intestinal permeation and anti-inflammatory efficacy of polymeric nanoparticles.

BACKGROUND: Silencing of excessive secreted tumour necrosis factor (TNF)-α from macrophages might be an effective therapy of ulcerative colitis (UC), which acquires improvements on small interfering RNA (siRNA) delivery vectors. Thus, in the present study, the effects of particle size and binding affinity of four polymeric nanoparticles on siRNA delivery for the treatment of UC were evaluated. METHODS: Galactosylated trimethyl chitosan-cysteine (GTC) nanoparticles of varying particle size and binding affinity for siRNA were prepared and TNF-α siRNA was encapsulated. Their cellular transport was investigated in murine macrophages and Caco-2 cell monolayers were utilized to analysis the intestinal permeation. Finally, in vivo anti-inflammatory efficacy was assessed in a mouse model of UC. RESULTS: Although marginal effects of particle size on the in vitro gene silencing efficiency were detected, GTC nanoparticles with a particle size of 450 nm and stronger binding affinity for siRNA showed reduced intestinal epithelial permeability and enhanced in vivo anti-inflammatory efficacy compared to those with a particle size of 200 nm. By contrast, the delivery processes were significantly affected by the binding affinity for siRNA, where smaller GTC nanoparticles (200 nm) with moderate siRNA binding strength exhibited remarkable cytoplasmic distribution and sufficient intracellular release of siRNA, as well as a sustained in vitro and in vivo gene silencing effect. CONCLUSIONS: Nanoparticles with a particle size of 450 nm or balanced binding affinity for siRNA might be preferable for the treatment of ulcerative colitis.

Exploring advantages/disadvantages and improvements in overcoming gene delivery barriers of amino acid modified trimethylated chitosan.

PURPOSE: Present study aimed at exploring advantages/disadvantages of amino acid modified trimethylated chitosan in conquering multiple gene delivery obstacles and thus providing comprehensive understandings for improved transfection efficiency. METHODS: Arginine, cysteine, and histidine modified trimethyl chitosan were synthesized and employed to self-assemble with plasmid DNA (pDNA) to form nanocomplexes, namely TRNC, TCNC, and THNC, respectively. They were assessed by structural stability, cellular uptake, endosomal escape, release behavior, nuclear localization, and in vitro and in vivo transfection efficiencies. Besides, sodium tripolyphosphate (TPP) was added into TRNC to compromise certain disadvantageous attributes for pDNA delivery. RESULTS: Optimal endosomal escape ability failed to bring in satisfactory transfection efficiency of THNC due to drawbacks in structural stability, cellular uptake, pDNA liberation, and nuclear distribution. TCNC evoked the most potent gene expression owing to multiple advantages including sufficient stability, preferable uptake, efficient pDNA release, and high nucleic accumulation. Undesirable stability and insufficient pDNA release adversely affected TRNC-mediated gene transfer. However, incorporation of TPP could improve such disadvantages and consequently resulted in enhanced transfection efficiencies. CONCLUSIONS: Coordination of multiple contributing effects to conquer all delivery obstacles was necessitated for improved transfection efficiency, which would provide insights into rational design of gene delivery vehicles.

Effects of probiotics on the growth performance and intestinal micro flora of broiler chickens.

Antibiotics have been used in poultry industry for decades to promote growth and protect animals from diseases, followed by various side effects. In efforts of searching for a better alternative, probiotic is of extensive attention. We investigated the effects of Bacillus subtitles, Rhodopseudomonas palustris, Candida utilis and Lactobacillus acidophilus as 0.1% (W/W) feed additives on broiler growth performance and intestinal microflora. The results showed the probiotics treatments significantly improved growth of broilers. Broilers supplemented with B. subtilis and L. acidophilus weighed 18.4% and 10.1% more than birds in control group at 42 days of age. Furthermore the feed conversion ratios of the birds in the two groups were also improved, decreasing 9.1% and 12.9%, respectively. Further study indicated a significant increase of cecal Lactobacilli concentration in briolers supplemented with probiotics, expecially in L. acidophilus treatment group. Meanwhile, the count of cecal Actinomyces in birds treated with probiotics was significantly lower compared with the control group. In conclusion, probiotics such as B. subtitles and L. acidophilus are good alternatives to antibiotics in promoting growth resulting from a beneficial modulation of the intestinal micro flora, which leads to increased efficiency of intestinal digestion in the host animal.

Gold nanorod-chitosan based nanocomposites for photothermal and chemoembolization therapy of breast cancer.

Gold nanorods (AuNR) have received significant attention in tumor thermo-chemotherapy. However, insufficient thermal availability limits the in vivo highly efficient applications of AuNR in photothermal therapy. In this study, we have fabricated N-isopropylacrylamide grafted O-carboxymethyl chitosan nanoparticles (NCMC NPs) with thermo-responsive properties for co-encapsulating AuNR and doxorubicin (DOX), forming AuNR@NCMC/DOX nanocomposites (NCs). As a result of the thermo- and photothermal-responsiveness, AuNR@NCMC/DOX NCs exhibited irreversible aggregation at high temperature and under near-infrared (NIR) irradiation with an increase of size to 3 µm. When AuNR@NCMC/DOX NCs reached tumor sites following intravenous administration, they were located in the tumor vessels under NIR irradiation due to an embolization effect. This response enhanced tumor targeting, on-demand release, and the thermal performance of AuNR@NCMC/DOX NCs. We have observed higher tumor accumulation of DOX and AuNR with subsequent stronger inhibition of tumor growth than that achieved without NIR irradiation. The development of AuNR-based NCs with multiple smart responsivenesses at tumors can provide a promising paradigm for solid tumor treatment via the cooperative effects of photothermal therapy and chemoembolization.

Revision of residual deformities after primary surgery for Wassel-Flatt IV-D thumb duplication using a microsurgical free lateral great toe flap.

We report the application and results of skin defect coverage using the free lateral great toe flap in revision surgery for residual postoperative deformities in Wassel-Flatt type IV-D thumb duplications. This retrospective study included five patients treated between June 2020 and September 2021 to correct angular deformity and repair the secondary skin defect. All the flaps survived. The patients were followed up for 8-12 months and all the reconstructed thumbs had a satisfactory appearance. The results of the Japanese Society for Surgery of the Hand scoring system were excellent in one patient, good in three patients and fair in one patient. The results of the Alignment, Ulnar and Radial stability, Range of motion and Aesthetical aspects (ALURRA) scoring system were good in four patients and moderate in one patient.Level of evidence: IV.

Transverse snuffbox perforator flap for a first-web contracture: an anatomical study and case report.

This cadaveric study describes a dorsal wrist transverse elliptical cutaneous flap, based on radial artery cutaneous perforators in the region of the snuffbox. The flap was then successfully used in a child with thumb hypoplasia and severe first-web contracture.

In situ customized apolipoprotein B48-enriched protein corona enhances oral gene delivery of chitosan-based nanoparticles.

The formation of protein corona (PC) is important for promoting the in vivo delivery of nanoparticles (NPs). However, PC formed in the physiological environment of oral delivery is poorly understood. Here, we engineered seven types of trimethyl chitosan-cysteine (TC) NPs, with distinct molecular weights, quaternization degrees, and thiolation degrees, to deeply investigate the influence of various PC formed in the physiological environment of oral delivery on in vivo gene delivery of polymeric NPs, further constructing the relationship between the surface characteristics of NPs and the efficacy of oral gene delivery. Our findings reveal that TC7 NPs, with high molecular weight, moderate quaternization, and high sulfhydryl content, modulate PC formation in the gastrointestinal tract, thereby reducing particle size and promoting oral delivery of gene loaded TC7 NPs. Orally delivered TC7 NPs target macrophages by in situ adsorption of apolipoprotein (Apo) B48 in intestinal tissue, leading to the improved in vivo antihepatoma efficacy via the natural tumor homing ability of macrophages. Our results suggest that efficient oral delivery of genes can be achieved through an in situ customized ApoB48-enriched PC, offering a promising modality in treating macrophage-related diseases.

Association between septic shock and tracheal injury score in intensive care unit patients with invasive ventilation: a prospective single-centre cohort study in China.

OBJECTIVES: There was no evidence regarding the relationship between septic shock and tracheal injury scores. Investigate whether septic shock was independently associated with tracheal injury scores in intensive care unit (ICU) patients with invasive ventilation. DESIGN: Prospective observational cohort study. SETTING: Our study was conducted in a Class III hospital in Hebei province, China. PARTICIPANTS: Patients over 18 years of age admitted to the ICU between 31 May 2020 and 3 May 2022 with a tracheal tube and expected to be on the tube for more than 24 hours. PRIMARY AND SECONDARY OUTCOME MEASURES: Tracheal injuries were evaluated by examining hyperaemia, ischaemia, ulcers and tracheal perforation by fiberoptic bronchoscope. Depending on the number of lesions, the lesions were further classified as moderate, severe or confluent. RESULTS: Among the 97 selected participants, the average age was 56.6±16.5 years, with approximately 64.9% being men. The results of adjusted linear regression showed that septic shock was associated with tracheal injury scores (ß: 2.99; 95% CI 0.70 to 5.29). Subgroup analysis revealed a stronger association with a duration of intubation ≥8 days (p=0.013). CONCLUSION: Patients with septic shock exhibit significantly higher tracheal injury scores compared with those without septic shock, suggesting that septic shock may serve as an independent risk factor for tracheal injury. TRIAL REGISTRATION NUMBER: ChiCTR2000037842, registered 03 September 2020. Retrospectively registered, https://www.chictr.org.cn/edit.aspx?pid=57011&htm=4.

Effective in vivo reactivation of HIV-1 latency reservoir via oral administration of EK-16A-SNEDDS.

The latent reservoir of human immunodeficiency virus (HIV) is a major obstacle in the treatment of acquired immune deficiency syndrome (AIDS). The "shock and kill" strategy has emerged as a promising approach for clearing HIV latent reservoirs. However, current latency-reversing agents (LRAs) have limitations in effectively and safely activating the latent virus and reducing the HIV latent reservoirs in clinical practice. Previously, EK-16A was extracted from Euphorbia kansui, which had the effect of interfering with the HIV-1 latent reservoir and inhibiting HIV-1 entry. Nevertheless, there is no suitable and efficient EK-16A oral formulation for in vivo delivery and clinical use. In this study, an oral EK-16A self-nanoemulsifying drug delivery system (EK-16A-SNEDDS) was proposed to "shock" the HIV-1 latent reservoir. This system aims to enhance the bioavailability and delivery of EK-16A to various organs. The composition of EK-16A-SNEDDS was optimized through self-emulsifying grading and ternary phase diagram tests. Cell models, pharmacokinetic experiments, and pharmacodynamics in HIV-1 latent cell transplant animal models suggested that EK-16A-SNEDDS could be absorbed by the gastrointestinal tract and enter the blood circulation after oral administration, thereby reaching various organs to activate latent HIV-1. The prepared EK-16A-SNEDDS demonstrated safety and efficacy, exhibited high clinical experimental potential, and may be a promising oral preparation for eliminating HIV-1 latent reservoirs.