Microneedle-mediated drug delivery for neurological diseases.

Neurological disorders, including brain injury, brain tumors, and neurodegenerative diseases, rank as the second leading cause of death worldwide. Exploring effective new treatments for neurological disorders has long been a hot research issue in clinical practice. Recently, microneedles (MNs) have attracted much attention due to their designation as a "painless and non-invasive" novel transdermal delivery method, characterized by their biocompatibility and sustainability. The advantages of MNs open an avenue for potential therapeutic interventions targeting neurological disorders. This review presents a concise overview of progress in the field of MNs, with highlights on the application in the treatment of neurological disorders. Notably, trends in the development of MNs and future challenges are also discussed.

Fine-tuning large language models for chemical text mining.

Extracting knowledge from complex and diverse chemical texts is a pivotal task for both experimental and computational chemists. The task is still considered to be extremely challenging due to the complexity of the chemical language and scientific literature. This study explored the power of fine-tuned large language models (LLMs) on five intricate chemical text mining tasks: compound entity recognition, reaction role labelling, metal-organic framework (MOF) synthesis information extraction, nuclear magnetic resonance spectroscopy (NMR) data extraction, and the conversion of reaction paragraphs to action sequences. The fine-tuned LLMs demonstrated impressive performance, significantly reducing the need for repetitive and extensive prompt engineering experiments. For comparison, we guided ChatGPT (GPT-3.5-turbo) and GPT-4 with prompt engineering and fine-tuned GPT-3.5-turbo as well as other open-source LLMs such as Mistral, Llama3, Llama2, T5, and BART. The results showed that the fine-tuned ChatGPT models excelled in all tasks. They achieved exact accuracy levels ranging from 69% to 95% on these tasks with minimal annotated data. They even outperformed those task-adaptive pre-training and fine-tuning models that were based on a significantly larger amount of in-domain data. Notably, fine-tuned Mistral and Llama3 show competitive abilities. Given their versatility, robustness, and low-code capability, leveraging fine-tuned LLMs as flexible and effective toolkits for automated data acquisition could revolutionize chemical knowledge extraction.

In silico off-target profiling for enhanced drug safety assessment.

Ensuring drug safety in the early stages of drug development is crucial to avoid costly failures in subsequent phases. However, the economic burden associated with detecting drug off-targets and potential side effects through in vitro safety screening and animal testing is substantial. Drug off-target interactions, along with the adverse drug reactions they induce, are significant factors affecting drug safety. To assess the liability of candidate drugs, we developed an artificial intelligence model for the precise prediction of compound off-target interactions, leveraging multi-task graph neural networks. The outcomes of off-target predictions can serve as representations for compounds, enabling the differentiation of drugs under various ATC codes and the classification of compound toxicity. Furthermore, the predicted off-target profiles are employed in adverse drug reaction (ADR) enrichment analysis, facilitating the inference of potential ADRs for a drug. Using the withdrawn drug Pergolide as an example, we elucidate the mechanisms underlying ADRs at the target level, contributing to the exploration of the potential clinical relevance of newly predicted off-target interactions. Overall, our work facilitates the early assessment of compound safety/toxicity based on off-target identification, deduces potential ADRs of drugs, and ultimately promotes the secure development of drugs.

3D-printed Personalized Porous Acetabular Component to Reconstruct Extensive Acetabular Bone Defects in Primary Hip Arthroplasty.

OBJECTIVE: Management of extensive acetabular bone defects in total hip arthroplasty (THA) remains challenging. This study aims to investigate the feasibility and preliminary outcomes of 3D-printed personalized porous acetabular components for the reconstruction of acetabular defects in primary THA. METHODS: This retrospective study involved seven patients who received 3D-printed acetabular components in primary THA between July 2018 and March 2021. Preoperatively, acetabular bone defects were evaluated by referencing the Paprosky classification. There were two "Paprosky type IIIA" defects and five "Paprosky type IIIB" defects. The acetabular components were custom-made for each patient to reconstruct the extensive acetabular defects. The hip function was assessed according to the Harris hip score (HHS). Clinical and radiographic outcomes were assessed. RESULTS: The average follow-up period was 40 months, ranging from 26 to 57 months. There were no patients lost to follow-up. The HHS improved from 44 (range: 33-53) before the operation to 88 (range: 79-93) at the final follow-up. Postoperative X-rays showed that the 3D-printed personalized components were properly fitted with the acetabulum. The average center of rotation (COR) discrepancy was 2.3 mm horizontally and 2.1 mm vertically, respectively. Tomosynthesis-Shimadzu metal artifact reduction technology images showed that the implant was in close contact with the host bone. Moreover, no complications were observed during the follow-up period, including loosening, dislocation, or component protrusion. CONCLUSION: The implantation of 3D-printed personalized acetabular components showed accurate reconstruction, stable mechanical support, and favorable function at short-term follow-up. This may be a viable alternative method for reconstructing extensive acetabular defects in THA.

Nanosilicate-reinforced GelMA-PEGDA hydrogel promotes angiogenesis for bone regeneration.

Bone tissue engineering has emerged as a pivotal field addressing the critical clinical needs of bone fractures. This study focused on developing multi-composite hydrogels by synergizing biocompatible GelMA macromolecules with synthetic PEGDA and reinforcing them with nanosilicates (SN). The incorporation of SN introduces crucial trace elements such as silicon, magnesium, and lithium, promoting both angiogenesis and osteogenesis. Characterizations revealed that PEGDA significantly reinforced the composite hydrogels' stability, while SN further enhanced the mechanical integrity of the GelMA-PEGDA-SN (GPS) hydrogels. Cell studies designated that GPS improved cell proliferation and migration, angiogenic VEGF/eNOS expression and osteogenic differentiation. In vivo experiments showed that GPS hydrogels effectively enhanced calvarial bone healing, with the GPS-2 formulation (2 % SN) displaying superior bone coverage and increased vascular formation. Assessments of osteogenic formation and the angiogenic marker CD31 validated the comprehensive bone regeneration potential of GPS hydrogels. These findings highlight the significant promise of GPS hydrogels in fostering bone healing with promoted angiogenesis.

3D-Printed custom-made hemipelvic endoprosthetic reconstruction following periacetabular tumor resection: utilizing a novel classification system.

BACKGROUND: Customized 3D-printed pelvic implants with a porous structure have revolutionized periacetabular pelvic defect reconstruction after tumor resection, offering improved osteointegration, long-term stability, and anatomical fit. However, the lack of an established classification system hampers implementation and progress. METHODS: We formulated a novel classification system based on pelvic defect morphology and 3D-printed hemipelvis endoprostheses. It integrates surgical approach, osteotomy guide plate and prosthesis design, postoperative rehabilitation plans, and perioperative processes. RESULTS: Retrospectively analyzing 60 patients (31 males, 29 females), we classified them into Type A (15 patients: Aa = 6, Ab = 9), Type B (27 patients: Ba = 15, Bb = 12), Type C (17 patients). All underwent customized osteotomy guide plate-assisted tumor resection and 3D-printed hemipelvic endoprosthesis reconstruction. Follow-up duration was median 36.5 ± 15.0 months (range, 6 to 74 months). The mean operating time was 430.0 ± 106.7 min, intraoperative blood loss 2018.3 ± 1305.6 ml, transfusion volume 2510.0 ± 1778.1 ml. Complications occurred in 13 patients (21.7%), including poor wound healing (10.0%), deep prosthesis infection (6.7%), hip dislocation (3.3%), screw fracture (1.7%), and interface loosening (1.7%). VAS score improved from 5.5 ± 1.4 to 1.7 ± 1.3, MSTS-93 score from 14.8 ± 2.5 to 23.0 ± 5.6. Implant osseointegration success rate was 98.5% (128/130), with one Type Ba patient experiencing distal prosthesis loosening. CONCLUSION: The West China classification may supplement the Enneking and Dunham classification, enhancing interdisciplinary communication and surgical outcomes. However, further validation and wider adoption are required to confirm clinical effectiveness.

Efficacy and safety of anlotinib in patients with desmoid fibromatosis: a retrospective analysis.

Introduction: Desmoid fibromatosis is an aggressive fibroblastic neoplasm with a high propensity for local recurrence. Targeted therapy for Desmoid fibromatosis represents a novel avenue in systemic treatment. Anlotinib, a novel multitargeted angiogenesis inhibitor, represents a novel approach for targeted therapy. Therefore, this study aims to assess the efficacy and safety of anlotinib in patients with Desmoid fibromatosis. Methods: We retrospectively gathered the clinical medical records of Desmoid fibromatosis patients who underwent anlotinib treatment between June 2019 and November 2023 at our center. Anlotinib was initiated at a daily dose of 12 mg and adjusted based on drug-related toxicity. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors 1.1 criteria. Progression-free survival served as the primary endpoint and was analyzed utilizing the Kaplan-Meier method. Results: In total, sixty-six consecutive patients were enrolled. No patients achieved a complete response; however, fourteen patients (21.21%) exhibited a partial response, while forty-six patients (70%) experienced disease stability. Progressive disease was observed in 6 patients (9.10%), and the progression-free survival rates at 12 and 36months were 89.71% and 82.81%, respectively. The disease control rate was 90.91%, while the objective response rate was 21.21%. Conclusion: Anlotinib proves effective in managing recurrent and symptomatic patients with Desmoid fibromatosis. However, the toxicity profile of anlotinib presents a higher risk of Hand-Foot Skin Reaction and hypertension. Therefore, given that 41.67% of patients were subjected to dose adjustments associated with the initial dose of 12 mg, implementing dosage reductions may help balance efficacy with side effects.

Three-dimensional printed custom-made modular talus prosthesis in patients with talus malignant tumor resection.

BACKGROUND: Talar malignant tumor is extremely rare. Currently, there are several alternative management options for talus malignant tumor including below-knee amputation, tibio-calcaneal arthrodesis, and homogenous bone transplant while their shortcomings limited the clinical application. Three-dimensional (3D) printed total talus prosthesis in talus lesion was reported as a useful method to reconstruct talus, however, most researches are case reports and its clinical effect remains unclear. Therefore, the current study was to explore the application of 3D printed custom-made modular prosthesis in talus malignant tumor. METHODS: We retrospectively analyzed the patients who received the 3D printed custom-made modular prosthesis treatment due to talus malignant tumor in our hospital from February 2016 to December 2021. The patient's clinical data such as oncology outcome, operation time, and volume of blood loss were recorded. The limb function was evaluated with the Musculoskeletal Tumor Society 93 (MSTS-93) score, The American Orthopedic Foot and Ankle Society (AOFAS) score; the ankle joint ranges of motion as well as the leg length discrepancy were evaluated. Plain radiography and Tomosynthesis-Shimadzu Metal Artefact Reduction Technology (T-SMART) were used to evaluate the position of prosthesis and the osseointegration. Postoperative complications were recorded. RESULTS: The average patients' age and the follow-up period were respectively 31.5 ± 13.1 years; and 54.8 months (range 26-72). The medium operation time was 2.4 ± 0.5 h; the intraoperative blood loss was 131.7 ± 121.4 ml. The mean MSTS-93 and AOFAS score was 26.8 and 88.5 respectively. The average plantar flexion, dorsiflexion, varus, and valgus were 32.5, 9.2, 10.8, and 5.8 degree respectively. One patient had delayed postoperative wound healing. There was no leg length discrepancy observed in any patient and good osseointegration was observed on the interface between the bone and talus prosthesis in all subjects. CONCLUSION: The modular structure of the prosthesis developed in this study seems to be convenient for prosthesis implantation and screws distribution. And the combination of solid and porous structure improves the initial stability and promotes bone integration. Therefore, 3D printed custom-made modular talus prosthesis could be an alternative option for talus reconstruction in talus malignant tumor patients.

Is 3D-printed self-stabilizing endoprosthesis reconstruction without supplemental fixation following total sacrectomy a viable approach for sacral tumours?

PURPOSE: The spinopelvic reconstruction poses significant challenges following total sacrectomy in patients with malignant or aggressive benign bone tumours encompassing the entire sacrum. In this study, we aim to assess the functional outcomes and complications of an integrated 3D-printed sacral endoprostheses featuring a self-stabilizing design, eliminating the requirement for supplemental fixation. METHODS: We retrospectively analyzed patients with sacral tumours who underwent total sacrectomy followed by reconstruction with 3D-printed self-stabilizing endoprosthesis. Clinically, we evaluated functional outcomes using the 1993 version of the musculoskeletal tumour society (MSTS-93) score. Perioperative and postoperative complications were also documented. RESULTS: 10 patients met final inclusion criteria. The median age was 49 years (range, 31-64 years). The median follow-up time was 26.5 months (range, 15-47 months). Median postoperative functional MSTS-93 was 22.5 (range, 13-25). The median operation time was 399.5 min (305-576 min), and the median intraoperative blood loss was and 3200 ml (2400-7800 ml). Complications include wound dehiscence in one patient, bowel, bladder, and sexual dysfunction in four patients, cerebrospinal fluid leak in one patient, and tumour recurrence in one patient. There were no mechanical complications related to the endoprosthesis at the last follow-up. CONCLUSION: The utilization of 3D-printed self-stabilizing endoprosthesis proved to be a viable approach, yielding satisfactory short-term outcomes in patients undergoing total sacral reconstruction without supplemental fixation.

Artemisinic acid attenuates osteoclast formation and titanium particle-induced osteolysis via inhibition of RANKL-induced ROS accumulation and MAPK and NF-κB signaling pathways.

Periprosthetic osteolysis (PPO) is the most common cause of joint arthroplasty failure. Its progression involves both biological and mechanical factors. Osteoclastogenesis induced by wear from debris-cell interactions, ultimately leading to excessive bone erosion, is considered the primary cause of PPO; therefore, targeting osteoclasts is a promising treatment approach. Currently available drugs have various side effects and limitations. Artemisinic acid (ArA) is a sesquiterpene isolated from the traditional herb Artemisia annua L. that has various pharmacological effects, such as antimalarial, anti-inflammatory, and antioxidant activities. Therefore, this study was aimed at investigating the effect of ArA on osteoclast formation and bone resorption function in vitro, as well as wear particle-induced osteolysis in vivo, and to explore its molecular mechanism of action. Here, we report that ArA inhibits RANKL-stimulated osteoclast formation and function. Mechanistically, ArA suppresses intracellular reactive oxygen species levels by activating the antioxidant response via nuclear factor erythroid-2-related factor 2 (Nrf2) pathway upregulation. It also inhibits the mitogen-activated kinases (MAPK) and nuclear factor-κB (NF-κB) pathways, as well as the transcription and expression of NFATc1 and c-Fos. In vivo experiments demonstrated that ArA reduces osteoclast formation and alleviates titanium particle-induced calvarial osteolysis. Collectively, our study highlights that ArA, with its osteoprotective and antioxidant effects, is a promising therapeutic agent for preventing and treating PPO and other osteoclast-mediated osteolytic diseases.

Advanced Pelvic Girdle Reconstruction with three dimensional-printed Custom Hemipelvic Endoprostheses following Pelvic Tumour Resection.

PURPOSE: Resection of pelvic bone tumours and subsequent pelvic girdle reconstruction pose formidable challenges due to the intricate anatomy, weight-bearing demands, and significant defects. 3D-printed implants have improved pelvic girdle reconstruction by enabling precise resections with customized guides, offering tailored solutions for diverse bone defect morphology, and integrating porous surface structures to promote osseointegration. Our study aims to evaluate the long-term efficacy and feasibility of 3D-printed hemipelvic reconstruction following resection of malignant pelvic tumours. METHODS: A retrospective review was conducted on 96 patients with primary pelvic malignancies who underwent pelvic girdle reconstruction using 3D-printed custom hemipelvic endoprostheses between January 2017 and May 2022. Follow-up duration was median 48.1 ± 17.9 months (range, 6 to 76 months). Demographic data, imaging examinations, surgical outcomes, and oncological evaluations were extracted and analyzed. The primary endpoints included oncological outcomes and functional status assessed by the Musculoskeletal Tumor Society (MSTS-93) score. Secondary endpoints comprised surgical duration, intraoperative bleeding, pain control and complications. RESULTS: In 96 patients, 70 patients (72.9%) remained disease-free, 15 (15.6%) had local recurrence, and 11 (11.4%) succumbed to metastatic disease. Postoperatively, function improved with MSTS-93 score increasing from 12.2 ± 2.0 to 23.8 ± 3.8. The mean operating time was 275.1 ± 94.0 min, and the mean intraoperative blood loss was 1896.9 ± 801.1 ml. Pain was well-managed, resulting in substantial improvements in VAS score (5.3 ± 1.8 to 1.4 ± 1.1). Complications occurred in 13 patients (13.5%), including poor wound healing (6.3%), deep prosthesis infection (4.2%), hip dislocation (2.1%), screw fracture (1.0%), and interface loosening (1.0%). Additionally, all patients achieved precise implantation of customized prosthetics according to preoperative plans. T-SMART revealed excellent integration at the prosthesis-bone interface for all patients. CONCLUSION: The use of a 3D-printed custom hemipelvic endoprosthesis, characterized by anatomically designed contours and a porous biomimetic surface structure, offers a potential option for pelvic girdle reconstruction following internal hemipelvectomy in primary pelvic tumor treatment. Initial results demonstrate stable fixation and satisfactory mid-term functional and radiographic outcomes.

Biomimetic design and clinical application of Ti-6Al-4V lattice hemipelvis prosthesis for pelvic reconstruction.

OBJECTIVE: This study aims to biomimetic design a new 3D-printed lattice hemipelvis prosthesis and evaluate its clinical efficiency for pelvic reconstruction following tumor resection, focusing on feasibility, osseointegration, and patient outcomes. METHODS: From May 2020 to October 2021, twelve patients with pelvic tumors underwent tumor resection and subsequently received 3D-printed lattice hemipelvis prostheses for pelvic reconstruction. The prosthesis was strategically incorporated with lattice structures and solid to optimize mechanical performance and osseointegration. The pore size and porosity were analyzed. Patient outcomes were assessed through a combination of clinical and radiological evaluations. RESULTS: Multiple pore sizes were observed in irregular porous structures, with a wide distribution range (approximately 300-900 µm). The average follow-up of 34.7 months, ranging 26 from to 43 months. One patient with Ewing sarcoma died of pulmonary metastasis 33 months after surgery while others were alive at the last follow-up. Postoperative radiographs showed that the prosthesis's position was consistent with the preoperative planning. T-SMART images showed that the host bone was in close and tight contact with the prosthesis with no gaps at the interface. The average MSTS score was 21 at the last follow-up, ranging from 18 to 24. There was no complication requiring revision surgery or removal of the 3D-printed hemipelvis prosthesis, such as infection, screw breakage, and prosthesis loosening. CONCLUSION: The newly designed 3D-printed lattice hemipelvis prosthesis created multiple pore sizes with a wide distribution range and resulted in good osteointegration and favorable limb function.

Transcriptomic and cellular decoding of scaffolds-induced suture mesenchyme regeneration.

Precise orchestration of cell fate determination underlies the success of scaffold-based skeletal regeneration. Despite extensive studies on mineralized parenchymal tissue rebuilding, regenerating and maintaining undifferentiated mesenchyme within calvarial bone remain very challenging with limited advances yet. Current knowledge has evidenced the indispensability of rebuilding suture mesenchymal stem cell niches to avoid severe brain or even systematic damage. But to date, the absence of promising therapeutic biomaterials/scaffolds remains. The reason lies in the shortage of fundamental knowledge and methodological evidence to understand the cellular fate regulations of scaffolds. To address these issues, in this study, we systematically investigated the cellular fate determinations and transcriptomic mechanisms by distinct types of commonly used calvarial scaffolds. Our data elucidated the natural processes without scaffold transplantation and demonstrated how different scaffolds altered in vivo cellular responses. A feasible scaffold, polylactic acid electrospinning membrane (PLA), was next identified to precisely control mesenchymal ingrowth and self-renewal to rebuild non-osteogenic suture-like tissue at the defect center, meanwhile supporting proper osteointegration with defect bony edges. Especially, transcriptome analysis and cellular mechanisms underlying the well-orchestrated cell fate determination of PLA were deciphered. This study for the first time cellularly decoded the fate regulations of scaffolds in suture-bony composite defect healing, offering clinicians potential choices for regenerating such complicated injuries.

Advancements in Photothermal Therapy Using Near-Infrared Light for Bone Tumors.

Bone tumors, particularly osteosarcoma, are prevalent among children and adolescents. This ailment has emerged as the second most frequent cause of cancer-related mortality in adolescents. Conventional treatment methods comprise extensive surgical resection, radiotherapy, and chemotherapy. Consequently, the management of bone tumors and bone regeneration poses significant clinical challenges. Photothermal tumor therapy has attracted considerable attention owing to its minimal invasiveness and high selectivity. However, key challenges have limited its widespread clinical use. Enhancing the tumor specificity of photosensitizers through targeting or localized activation holds potential for better outcomes with fewer adverse effects. Combinations with chemotherapies or immunotherapies also present avenues for improvement. In this review, we provide an overview of the most recent strategies aimed at overcoming the limitations of photothermal therapy (PTT), along with current research directions in the context of bone tumors, including (1) target strategies, (2) photothermal therapy combined with multiple therapies (immunotherapies, chemotherapies, and chemodynamic therapies, magnetic, and photodynamic therapies), and (3) bifunctional scaffolds for photothermal therapy and bone regeneration. We delve into the pros and cons of these combination methods and explore current research focal points. Lastly, we address the challenges and prospects of photothermal combination therapy.

Characterization of an exopolysaccharide synthesized by Lacticaseibacillus rhamnosus B6 and its immunomodulatory activity in vitro.

An exopolysaccharide, designated F1, was purified from the fermented milk by Lacticaseibacillus rhamnosus strain B6 (CGMCC No. 13310). F1, with the weight average molecular weight of 1.577 × 106 Da, is consisted of rhamnose, glucose and galactose in a molar ratio of 3.7:1.5: 1. The backbone included 1,3-linked Rha, 1,2,3-linked Rha, 1,2-linked Glc and 1,3-linked Glc residues, with the branching point located at O2 position of 1,2,3-linked Rha residue, and the branch chain composed of terminal linked galactose residue with a pyruvate substituent. F1 could significantly stimulate the phagocytic activity and TNF-α expression in RAW 264.7 macrophages in a dose-dependent manner, and the release of NO at 200 µg/mL as well. F1 at 200 µg/mL could stimulate the expression of the pro-inflammatory cytokine encoding genes including TNF-α and iNOS, but with a negligible upregulating effect on the mRNA expression of IL-10. F1 could up-regulate the expression of NF-κBp65 and skew macrophage polarization towards M1 phenotype. These results suggest F1 elicit an immunomodulatory effect through the NF-κB signaling pathway.

Pay Attention to the Osteochondromas in Fibrodysplasia Ossificans Progressiva.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare disease characterized by malformation of the bilateral great toes and progressive heterotopic ossification. The clinical features of FOP occur due to dysfunction of the bone morphogenetic protein (BMP) signaling pathway induced by the mutant activin A type I receptor/activin-like kinase-2 (ACVR1/ALK2) which contributes to the clinical features in FOP. Dysregulation of the BMP signaling pathway causes the development of osteochondroma. Poor awareness of the association between FOP and osteochondromas always results in misdiagnosis and unnecessary invasive operation. CASE PRESENTATION: In this study, we present a case of classical FOP involving osteochondroma. An 18-year-old male adolescent, born with deformity of bilateral big toes, complained multiple masses on his back for 1 year. The mass initially emerged with a tough texture and did not cause pain. It was misdiagnosed as an osteochondroma. After two surgeries, the masses became hard and spread around the entire back region. Meanwhile, extensive heterotopic ossification was observed around the back, neck, hip, knee, ribs, and mandible during follow-up. Osteochondromas were observed around the bilateral knees. No abnormalities were observed in the laboratory blood test results. Whole exome sequencing revealed missense mutation of ACVR1/ALK2 (c.617G > A; p.R206H) in the patient and confirmed the diagnosis of FOP. CONCLUSION: In summary, classical FOP always behaves as a bilateral deformity of the big toes, as well as progressive ectopic ossification and osteochondromas in the distal femur and proximal tibia. An understanding of the association between osteochondromas and FOP aids in diagnosis and avoids unnecessary invasive management in patients.

3D-Printed Personalized Lattice Implant as an Innovative Strategy to Reconstruct Geographic Defects in Load-Bearing Bones.

OBJECTIVE: Geographic defect reconstruction in load-bearing bones presents formidable challenges for orthopaedic surgeon. The use of 3D-printed personalized implants presents a compelling opportunity to address this issue. This study aims to design, manufacture, and evaluate 3D-printed personalized implants with irregular lattice porous structures for geographic defect reconstruction in load-bearing bones, focusing on feasibility, osseointegration, and patient outcomes. METHODS: This retrospective study involved seven patients who received 3D-printed personalized lattice implants for the reconstruction of geographic defects in load-bearing bones. Personalized implants were customized for each patient. Randomized dodecahedron unit cells were incorporated within the implants to create the porous structure. The pore size and porosity were analyzed. Patient outcomes were assessed through a combination of clinical and radiological evaluations. Tomosynthesis-Shimadzu metal artifact reduction technology (T-SMART) was utilized to evaluate osseointegration. Functional outcomes were assessed according to the Musculoskeletal Tumor Society (MSTS) 93 score. RESULTS: Multiple pore sizes were observed in porous structures of the implant, with a wide distribution range (approximately 300-900 um). The porosity analysis results showed that the average porosity of irregular porous structures was around 75.03%. The average follow-up time was 38.4 months, ranging from 25 to 50 months. Postoperative X-rays showed that the implants matched the geographic bone defect well. Osseointegration assessments according to T-SMART images indicated a high degree of bone-to-implant contact, along with favorable bone density around the implants. Patient outcomes assessments revealed significant improvements in functional outcomes, with the average MSTS score of 27.3 (range, 26-29). There was no implant-related complication, such as aseptic loosening or structure failure. CONCLUSION: 3D-printed personalized lattice implants offer an innovative and promising strategy for geographic defect reconstruction in load-bearing bones. This approach has the potential to match the unique contours and geometry of the geographic bone defect and facilitate osteointegration.

Application of ensemble learning for predicting GABAA receptor agonists.

BACKGROUND: Over the past few decades, agonists binding to the benzodiazepine site of the GABAA receptor have been successfully developed as clinical drugs. Different modulators (agonist, antagonist, and reverse agonist) bound to benzodiazepine sites exhibit different or even opposite pharmacological effects, however, their structures are so similar that it is difficult to distinguish them based solely on molecular skeleton. This study aims to develop classification models for predicting the agonists. METHODS: 306 agonists or non-agonists were collected from literature. Six machine learning algorithms including RF, XGBoost, AdaBoost, GBoost, SVM, and ANN algorithms were employed for model development. Using six descriptors including 1D/2D Descriptors, ECFP4, 2D-Pharmacophore, MACCS, PubChem, and Estate fingerprint to characterize chemical structures. The model interpretability was explored by SHAP method. RESULTS: The best model demonstrated an AUC value of 0.905 and an MCC value of 0.808 for the test set. The PubMac-based model (PubMac-GB) achieved best AUC values of 0.935 for test set. The SHAP analysis results emphasized that MaccsFP62, ECFP_624, ECFP_724, and PubchemFP213 were the crucial molecular features. Applicability domain analysis was also performed to determine reliable prediction boundaries for the model. The PubMac-GB model was applied to virtual screening for potential GABAA agonists and the top 100 compounds were given. CONCLUSION: Overall, our ensemble learning-based model (PubMac-GB) achieved comparable performance and would be helpful in effectively identifying agonists of GABAA receptors.

Microbiome and metabolome dysbiosis analysis in impaired glucose tolerance for the prediction of progression to diabetes mellitus.

Gut microbiota and circulating metabolite dysbiosis predate important pathological changes in glucose metabolic disorders; however, comprehensive studies on impaired glucose tolerance (IGT), a diabetes mellitus (DM) precursor, are lacking. Here, we perform metagenomic sequencing and metabolomics on 47 pairs of individuals with IGT and newly diagnosed DM and 46 controls with normal glucose tolerance (NGT); patients with IGT are followed up after 4 years for progression to DM. Analysis of baseline data reveals significant differences in gut microbiota and serum metabolites among the IGT, DM, and NGT groups. In addition, 13 types of gut microbiota and 17 types of circulating metabolites showed significant differences at baseline before IGT progressed to DM, including higher levels of Eggerthella unclassified, Coprobacillus unclassified, Clostridium ramosum, L-valine, L-norleucine, and L-isoleucine, and lower levels of Eubacterium eligens, Bacteroides faecis, Lachnospiraceae bacterium 3_1_46FAA, Alistipes senegalensis, Megaspaera elsdenii, Clostridium perfringens, α-linolenic acid, 10E,12Z-octadecadienoic acid, and dodecanoic acid. A random forest model based on differential intestinal microbiota and circulating metabolites can predict the progression from IGT to DM (AUC = 0.87). These results suggest that microbiome and metabolome dysbiosis occur in individuals with IGT and have important predictive values and potential for intervention in preventing IGT from progressing to DM.

The Involvement of Lactic Acid Bacteria and Their Exopolysaccharides in the Biosorption and Detoxication of Heavy Metals in the Gut.

Heavy metal pollution has become one of the most important global environmental issues. The human health risk posed by heavy metals encountered through the food chain and occupational and environmental exposure is increasing, resulting in a series of serious diseases. Ingested heavy metals might disturb the function of the gut barrier and cause toxicity to organs or tissues in other sites of the body. Probiotics, including some lactic acid bacteria (LAB), can be used as an alternative strategy to detoxify heavy metals in the host body due to their safety and effectiveness. Exopolysaccharides (EPS) produced by LAB possess varied chemical structures and functional properties and take part in the adsorption of heavy metals via keeping the producing cells vigorous. The main objective of this paper was to summarize the roles of LAB and their EPS in the adsorption and detoxification of heavy metals in the gut. Accumulated evidence has demonstrated that microbial EPS play a pivotal role in heavy metal biosorption. Specifically, EPS-producing LAB have been reported to show superior absorption, tolerance, and efficient abatement of the toxicity of heavy metals in vitro and/or in vivo to non-EPS-producing species. The mechanisms underlying EPS-metal binding are mainly related to the negatively charged acidic groups and unique steric structure on the surface of EPS. However, whether the enriched heavy metals on the bacterial cell surface increase toxicity to local mammal cells or tissues in the intestine and whether they are released during excretion remain to be elucidated.