Radical Deoxygenative Three-Component Reaction of Alcohols, Aryl Alkenes, and Cyanopyridines.

We report herein a deoxygenative radical multicomponent reaction involving alcohols, aryl alkenes, and cyanopyridine under photoredox conditions. This method is photoredox-neutral, suitable for late-stage modification, and compatible with a wide array of alcohols as alkyl radical sources, including primary, secondary, and tertiary alcohols. This reaction comprises a radical relay mechanism encompassing the Giese addition of aryl alkenes by alkyl radicals, followed by the decyanative pyridination of benzyl radicals.

Improving iPSC Differentiation Using a Nanodot Platform.

Differentiation of induced pluripotent stem cells (iPSCs) is an extremely complex process that has proven difficult to study. In this research, we utilized nanotopography to elucidate details regarding iPSC differentiation by developing a nanodot platform consisting of nanodot arrays of increasing diameter. Subjecting iPSCs cultured on the nanodot platform to a cardiomyocyte (CM) differentiation protocol revealed several significant gene expression profiles that were associated with poor differentiation. The observed expression trends were used to select existing small-molecule drugs capable of modulating differentiation efficiency. BRD K98 was repurposed to inhibit CM differentiation, while iPSCs treated with NSC-663284, carmofur, and KPT-330 all exhibited significant increases in not only CM marker expression but also spontaneous beating, suggesting improved CM differentiation. In addition, quantitative polymerase chain reaction was performed to determine the gene regulation responsible for modulating differentiation efficiency. Multiple genes involved in extracellular matrix remodeling were correlated with a CM differentiation efficiency, while genes involved in the cell cycle exhibited contrasting expression trends that warrant further studies. The results suggest that expression profiles determined via short time-series expression miner analysis of nanodot-cultured iPSC differentiation can not only reveal drugs capable of enhancing differentiation efficiency but also highlight crucial sets of genes related to processes such as extracellular matrix remodeling and the cell cycle that can be targeted for further investigation. Our findings confirm that the nanodot platform can be used to reveal complex mechanisms behind iPSC differentiation and could be an indispensable tool for optimizing iPSC technology for clinical applications.

Drug repositioning via Multi-view Representation Learning with Heterogeneous Graph Neural Network.

Exploring simple and efficient computational methods for drug repositioning has emerged as a popular and compelling topic in the realm of comprehensive drug development. The crux of this technology lies in identifying potential drug-disease associations, which can effectively mitigate the burdens caused by the exorbitant costs and lengthy periods of conventional drugs development. However, current computational drug repositioning methods face challenges in accurately predicting drug-disease associations. These challenges include only considering drugs and diseases to construct a heterogeneous graph without including other biological nodes associated with the disease or drug for a more comprehensive heterogeneous graph, as well as not fully utilizing the local structure of heterogeneous graphs and rich semantic features. To address these problems, we propose a Multi-view Representation Learning method (MRLHGNN) with Heterogeneous Graph Neural Network for drug repositioning. This method is based on a collection of data from multiple biological entities associated with drugs or diseases. It consists of a view-specific feature aggregation module with meta-paths and auto multi-view fusion encoder. To better utilize local structural and semantic information from specific views in heterogeneous graph, MRLHGNN employs a feature aggregation model with variable-length meta-paths to expand the local receptive field. Additionally, it utilizes a transformerbased semantic aggregation module to aggregate semantic features across different view-specific graphs. Finally, potential drug-disease associations are obtained through a multi-view fusion decoder with an attention mechanism. Cross-validation experiments demonstrate the effectiveness and interpretability of the MRLHGNN in comparison to nine state-of-the-art approaches. Case studies further reveal that MRLHGNN can serve as a powerful tool for drug repositioning.

Primary Arthrodesis with Retrograde Hindfoot Nail for Elderly Patients with Tibia Pilon Fractures and Psychiatric Illness.

BACKGROUND: Management of tibial pilon fracture in elderly patients with psychiatric illness remains challenging for orthopedic doctors because of patients' poor bone quality and inability for self-care. This study aimed to ascertain the viability and reliability of primary arthrodesis by using retrograde hindfoot nail for these difficult cases. METHODS: We retrospectively reviewed eight elderly consecutive patients (age older than 65 years) with tibial pilon fractures and psychiatric illness from January of 2012 to December of 2019 in our institute. Primary tibiotalocalcaneal arthrodesis with retrograde hindfoot nail was used as a definitive procedure. The bone union time, wound complication rate, ankle alignment, necessity for narcotic agents, and ambulation status were evaluated. RESULTS: The average length of follow-up was 22.25 months (range, 15-36 months). Additional bone grafting surgery was performed for one patient because of fusion-site nonunion 6 months postoperatively. Another patient required debridement and removal of posterior calcaneal screw because of implant prominence and local infection. Osseous union with angular deformity less than 10° was achieved in all patients finally. The average bone union time was 6.6 months (range, 4-12 months). In terms of walking ability, six patients were capable of outdoor ambulation (classes 2 and 3). Two patients required oral pain medication at the final visit. CONCLUSIONS: The current study involved only a small number of patients, and two of the eight cases encountered undesired complications (one local infection and one bone nonunion); however, we believe that our method may serve as a valuable alternative for the treatment of tibial pilon fractures in elderly patients with psychiatric illness, considering the specificity of this fragile population.

Human platelet lysate-cultured adipose-derived stem cell sheets promote angiogenesis and accelerate wound healing via CCL5 modulation.

BACKGROUND: A rising population faces challenges with healing-impaired cutaneous wounds, often leading to physical disabilities. Adipose-derived stem cells (ASCs), specifically in the cell sheet format, have emerged as a promising remedy for impaired wound healing. Human platelet lysate (HPL) provides an attractive alternative to fetal bovine serum (FBS) for culturing clinical-grade ASCs. However, the potential of HPL sheets in promoting wound healing has not been fully investigated. This study aimed to explore the anti-fibrotic and pro-angiogenic capabilities of HPL-cultured ASC sheets and delve into the molecular mechanism. METHODS: A rat burn model was utilized to evaluate the efficacy of HPL-cultured ASC sheets in promoting wound healing. ASC sheets were fabricated with HPL, and those with FBS were included for comparison. Various analyses were conducted to assess the impact of HPL sheets on wound healing. Histological examination of wound tissues provided insights into aspects such as wound closure, collagen deposition, and overall tissue regeneration. Immunofluorescence was employed to assess the presence and distribution of transplanted ASCs after treatment. Further in vitro studies were conducted to decipher the specific factors in HPL sheets contributing to angiogenesis. RESULTS: HPL-cultured ASC sheets significantly accelerated wound closure, fostering ample and organized collagen deposition in the neo-dermis. Significantly more retained ASCs were observed in wound tissues treated with HPL sheets compared to the FBS counterparts. Moreover, HPL sheets mitigated macrophage recruitment and decreased subsequent wound tissue fibrosis in vivo. Immunohistochemistry also indicated enhanced angiogenesis in the HPL sheet group. The in vitro analyses showed upregulation of C-C motif chemokine ligand 5 (CCL5) and angiogenin in HPL sheets, including both gene expression and protein secretion. Culturing endothelial cells in the conditioned media compared to media supplemented with CCL5 or angiogenin suggested a correlation between CCL5 and the pro-angiogenic effect of HPL sheets. Additionally, through neutralizing antibody experiments, we further validated the crucial role of CCL5 in HPL sheet-mediated angiogenesis in vitro. CONCLUSIONS: The present study underscores CCL5 as an essential factor in the pro-angiogenic effect of HPL-cultured ASC sheets during the wound healing process. These findings highlight the potential of HPL-cultured ASC sheets as a promising therapeutic option for healing-impaired cutaneous wounds in clinical settings. Furthermore, the mechanism exploration yields valuable information for optimizing regenerative strategies with ASC products. BRIEF ACKNOWLEDGMENT: This research was supported by the National Science and Technology Council, Taiwan (NSTC112-2321-B-002-018), National Taiwan University Hospital (111C-007), and E-Da Hospital-National Taiwan University Hospital Joint Research Program (111-EDN0001, 112-EDN0002).

Dorsal spanning plating for complex carpometacarpal fracture-dislocations: a retrospective case series.

We studied the outcome of dorsal spanning plate for complex carpometacarpal fracture-dislocation management as a feasible option in nine patients, even on delayed presentation with substantial metacarpal shortening. However, patients must be informed about the need for plate removal.

Dislodgment Effects of Different Cage Arrangements in Posterior Lumbar Interbody Fusion: A Finite Element Study.

The vertebral cage has been widely used in posterior lumbar interbody fusion. The risk of cage dislodgment is high for patients undergoing lumbar fusion surgery. Therefore, the main objective of this study was to use a lumbar fusion model to investigate the effects of cage dislodgment on different cage arrangements after PLIF. Finite element analysis was used to compare three PEEK cage placements, together with the fibula-type cage, with respect to the four kinds of lumbar movements. The results revealed that a horizontal cage arrangement could provide a better ability to resist cage dislodgment. Overall lumbar flexion movements were confirmed to produce a greater amount of cage slip than the other three lumbar movements. The lower part of the lumbar fusion segment could create a greater amount of cage dislodgment for all of the lumbar movements. Using an autograft with a fibula as a vertebral cage cannot effectively reduce cage dislodgment. Considering the maximum movement type in lumbar flexion, we suggest that a horizontal arrangement of the PEEK cage might be considered when a single PEEK cage is placed in the fusion segment, as doing so can effectively reduce the extent of cage dislodgment.

Assessment of Thermal Osteonecrosis during Bone Drilling Using a Three-Dimensional Finite Element Model.

Bone drilling is a common procedure used to create pilot holes for inserting screws to secure implants for fracture fixation. However, this process can increase bone temperature and the excessive heat can lead to cell death and thermal osteonecrosis, potentially causing early fixation failure or complications. We applied a three-dimensional dynamic elastoplastic finite element model to evaluate the propagation and distribution of heat during bone drilling and assess the thermally affected zone (TAZ) that may lead to thermal necrosis. This model investigates the parameters influencing bone temperature during bone drilling, including drill diameter, rotational speed, feed force, and predrilled hole. The results indicate that our FE model is sufficiently accurate in predicting the temperature rise effect during bone drilling. The maximum temperature decreases exponentially with radial distance. When the feed forces are 40 and 60 N, the maximum temperature does not exceed 45 °C. However, with feed forces of 10 and 20 N, both the maximum temperatures exceed 45 °C within a radial distance of 0.2 mm, indicating a high-risk zone for potential thermal osteonecrosis. With the two-stage drilling procedure, where a 2.5 mm pilot hole is predrilled, the maximum temperature can be reduced by 14 °C. This suggests that higher feed force and rotational speed and/or using a two-stage drilling process could mitigate bone temperature elevation and reduce the risk of thermal osteonecrosis during bone drilling.

Nerve Bypass Surgery for Spinal Cord Reconstruction.

OBJECTIVE: Spinal cord injury (SCI) is a devastating condition that significantly decreases the patient's quality of life. Therefore, treatments that can facilitate nerve regeneration, reduce complications, and increase quality of life are valuable for these patients. In this study, we aimed to assess nerve bypass surgery's feasibility and clinical outcomes by transferring the intercostal nerves into the spinal cord. METHODS: Eight patients with complete thoracic SCI and delayed presentation more than a year after the injury were analyzed retrospectively. All patients underwent nerve bypass surgery with the transfer of 2 pairs of intercostal nerves from proximal to the injury site to the anterolateral spinal cord, followed by duraplasty with fascia grafting to close the dura. RESULTS: Six of the 8 (75%) patients demonstrated motor and sensory improvements, based on the American SCI Association score. Three patients demonstrated a limited recovery of motor function that could be independently triggered without ICN initiation. Five patients demonstrated evidence of cerebrospinal fluid leakage after surgery; however, only 1 patient complained of a headache. CONCLUSIONS: Spinal cord bypass surgery is a potential reconstruction method to treat chronic complete thoracic SCI with functional improvements, and is worth further investigation.

Application of whole exome sequencing in the diagnosis of muscular disorders: a study of Taiwanese pediatric patients.

Background: Muscular dystrophies and congenital myopathies encompass various inherited muscular disorders that present diagnostic challenges due to clinical complexity and genetic heterogeneity. Methods: This study aimed to investigate the use of whole exome sequencing (WES) in diagnosing muscular disorders in pediatric patients in Taiwan. Out of 161 pediatric patients suspected to have genetic/inherited myopathies, 115 received a molecular diagnosis through conventional tests, single gene testing, and gene panels. The remaining 46 patients were divided into three groups: Group 1 (multiplex ligation-dependent probe amplification-negative Duchenne muscular dystrophy) with three patients (6.5%), Group 2 (various forms of muscular dystrophies) with 21 patients (45.7%), and Group 3 (congenital myopathies) with 22 patients (47.8%). Results: WES analysis of these groups found pathogenic variants in 100.0% (3/3), 57.1% (12/21), and 68.2% (15/22) of patients in Groups 1 to 3, respectively. WES had a diagnostic yield of 65.2% (30 patients out of 46), detecting 30 pathogenic or potentially pathogenic variants across 28 genes. Conclusion: WES enables the diagnosis of rare diseases with symptoms and characteristics similar to congenital myopathies and muscular dystrophies, such as muscle weakness. Consequently, this approach facilitates targeted therapy implementation and appropriate genetic counseling.

Illuminating the Genetic Basis of Congenital Heart Disease in Patients with Kabuki Syndrome.

Congenital heart defects (CHDs) affect a substantial proportion of patients with Kabuki syndrome. However, the prevalence and type of CHD and the genotype-phenotype correlations in Asian populations are not fully elucidated. This study performed a retrospective analysis of 23 Taiwanese patients with molecularly confirmed Kabuki syndrome. Twenty-two patients presented with pathogenic variants in the KMT2D gene. Comprehensive clinical assessments were performed. A literature review was conducted to summarize the spectrum of CHDs in patients with Kabuki syndrome. In total, 16 (73.9%) of 22 patients with pathogenic KMT2D variants had CHDs. The most common types of CHD were atrial septal defects (37.5%), ventricular septal defects (18.8%), coarctation of the aorta (18.8%), bicuspid aortic valve (12.5%), persistent left superior vena cava (12.5%), mitral valve prolapse (12.5%), mitral regurgitation (12.5%), and patent ductus arteriosus (12.5%). Other cardiac abnormalities were less common. Further, there were no clear genotype-phenotype correlations found. A literature review revealed similar patterns of CHDs, with a predominance of left-sided obstructive lesions and septal defects. In conclusion, the most common types of CHDs in Taiwanese patients with Kabuki syndrome who presented with KMT2D mutations are left-sided obstructive lesions and septal defects.

Interim Use of Antibiotic-Loaded Cement Spacer for Patients with Infected Cervical Fusion.

OBJECTIVE: The management of postoperative deep infection after anterior cervical discectomy and fusion (ACDF) remains challenging for spine surgeons. Our institution uses handmade antibiotic-loaded cement spacers to treat these complex cases. This study aimed to determine the efficacy and feasibility of this treatment. METHODS: This study included 4 patients with deep cervical spine infections after ACDF who underwent our treatment between March 2012 and January 2022. Patients' laboratory data, visual analog scale scores, comorbidities, complications, and neurological status were recorded. Their clinical conditions were also evaluated based on the Neck Disability Index, Japanese Orthopaedic Association score, and Odom criteria. RESULTS: Infection eradication was achieved in all patients after treatment. The average preoperative visual analog scale score was 7.5 (range: 7-8); this decreased to 1.25 (range: 1-2) at 1 year postoperatively. None of the patients experienced severe complications, such as neurological deterioration or bone graft dislodgement. The Neck Disability Index improved from a preoperative value of 54% (range: 48-60%) to 6% (range: 4-8%) at 1 year postoperatively. The Japanese Orthopaedic Association score improved from a preoperative score of 10.25 (range: 10-11)-14.75 (range: 14-16) at 1 year postoperatively. All patients achieved excellent outcomes based on Odom criteria at 1 year postoperatively. CONCLUSIONS: Good clinical outcomes were achieved in this study. Although 2-stage surgery is required, this technique could be an alternative for patients with postoperative deep infection after ACDF.

Understanding synchronous regulating effects of starch-protein interactions on starch digestion and retrogradation under thermal shear processing.

Although starch-protein interactions have been widely used to regulate starch digestibility and retrogradation during food processings, their synchronous regulating effects on both properties still remain largely unexplored. The effects of interactions with pea protein (PP) under thermal shear processing on the digestion and retrogradation properties of modified chestnut starch were investigated. Results show that thermal shear processing broke starch multi-scale structure, leading to the reduction in molar mass, short-range ordered structure, crystallinity, and starch compactness, in turn increasing starch digestibility and accelerating starch retrogradation. However, PP molecules would interact with chestnut starch through hydrogen bonding to form the starch-protein complexes during thermal shear processing, which caused an increased resistant starch. These starch-protein interactions also inhibited the formation of short-range, long-range ordered structure, aggregate structure during storage, causing a reduced degree of retrogradation. The results provided new insights into the synchronously regulating effects of starch-protein interactions under thermal shear processing on starch digestion and retrogradation, which would facilitate the development of starch-based foods with high nutrition and quality.

Quantitative DNA Methylation Analysis and Epigenotype-Phenotype Correlations in Taiwanese Patients with Silver-Russell Syndrome.

Background: Silver-Russell syndrome (SRS; OMIM #180860) is a clinically and genetically heterogeneous imprinting disorder characterized by prenatal and postnatal growth failure. The aim of this study was to identify the epigenotype-phenotype correlations in these patients using quantitative DNA methylation analysis. Methods: One hundred and eighty-three subjects clinically suspected of having SRS were referred for diagnostic testing by the methylation profiling of H19-associated imprinting center (IC) 1 and imprinted PEG1/MEST regions using methylation-specific high-resolution melting analysis and methylation quantification with the MassARRAY assay. Correlations between quantitative DNA methylation status and clinical manifestations of the subjects according to the Netchine-Harbison (N-H) clinical scoring system for SRS were analyzed. Results: Among the 183 subjects, 90 had a clinical diagnosis of SRS [N-H score ≥ 4 (maximum = 6)] and 93 had an SRS score < 4. Molecular lesions were detected in 41% (37/90) of the subjects with a clinical diagnosis of SRS, compared with 3% (3/93) of those with an N-H score < 4. The IC1 methylation level was negatively correlated with the N-H score. The molecular diagnosis rate was positively correlated with the N-H score. Thirty-one subjects had IC1 hypomethylation (IC1 methylation level <35% by the MassARRAY assay), seven had maternal uniparental disomy 7, and two had pathogenic copy number variants. Among the 90 subjects with an N-H score ≥ 4, the IC1 methylation level was significantly different between those with or without some clinical SRS features, including birth length ≤ 10th centile, relative macrocephaly at birth, normal cognitive development, body asymmetry, clinodactyly of the fifth finger, and genital abnormalities. Conclusions: This study confirmed the suitability of the N-H clinical scoring system as clinical diagnostic criteria for SRS. Quantitative DNA methylation analysis using the MassARRAY assay can improve the detection of epigenotype-phenotype correlations, further promoting better genetic counseling and multidisciplinary management for these patients.

Incidence, risk factors, and a prognostic nomogram for distant metastasis in endometrial cancer: A SEER-based study.

OBJECTIVE: To evaluate the metastatic pattern, identify the risk factors, and establish a nomogram for predicting prognosis of endometrial cancer (EC) with distant metastasis. METHODS: A retrospective cohort study of women diagnosed with EC was conducted according to the Surveillance, Epidemiology, and End Results (SEER) database during 2010-2017. Multivariate logistic analysis and Cox analysis were performed to identify the risk factors in promoting distant metastasis and predictors associated with overall survival (OS) in this particular subpopulation. A nomogram was then constructed and validated by the concordance index (C-index), the area under the receiver operating characteristic curve (AUC), calibration plots, and decision curve analysis. RESULTS: A total of 2799 cases of distant metastasis in EC patients were identified, with an overall incidence rate of 3.74% from 2010 to 2017. Black race, unmarried status, non-endometrioid histologic types, and grade IV were significant risk factors for distant metastasis in EC patients. Meanwhile, race, histology, grade, metastasis status, surgery, lymphadenectomy, and chemotherapy were identified as independent prognostic factors for OS. A nomogram to predict 1-, 3-, and 5-year OS was established, and presented favorable accuracy and clinical applicability. Patients were further divided into high- and low-risk groups according to the model. CONCLUSION: The nomogram was developed as a highly accurate, individualized tool to better predict the prognosis of EC patients with distant metastasis, which would help clinicians to identify high-risk patients, and adjust and tailor their treatment strategies.

Isoliquiritigenin inhibits apoptosis and ameliorates oxidative stress in rheumatoid arthritis chondrocytes through the Nrf2/HO-1-mediated pathway.

Rheumatoid arthritis (RA) is a chronic inflammatory condition known for its irreversible destructive impact on the joints. Chondrocytes play a pivotal role in the production and maintenance of the cartilage matrix. However, the presence of inflammatory cytokines can hinder chondrocyte proliferation and promote apoptosis. Isoliquiritigenin (ISL), a flavonoid, potentially exerts protective effects against various inflammatory diseases. However, its specific role in regulating the nuclear factor E2-associated factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway in chondrocytes in RA remains unclear. To investigate this, this study used human chondrocytes and Sprague-Dawley rats to construct in vitro and in vivo RA models, respectively. The study findings reveal that cytokines markedly induced oxidative stress, the activation of matrix metalloproteinases, and apoptosis both in vitro and in vivo. Notably, ISL treatment significantly mitigated these effects. Moreover, Nrf2 or HO-1 inhibitors reversed the protective effects of ISL, attenuated the expression of Nrf2/HO-1 and peroxisome proliferator-activated receptor gamma-coactivator-1α, and promoted chondrocyte apoptosis. This finding indicates that ISL primarily targets the Nrf2/HO-1 pathway in RA chondrocytes. Moreover, ISL treatment led to improved behavior scores, reduced paw thickness, and mitigated joint damage as well as ameliorated oxidative stress in skeletal muscles in an RA rat model. In conclusion, this study highlights the pivotal role of the Nrf2/HO-1 pathway in the protective effects of ISL and demonstrates the potential of ISL as a treatment option for RA.

Surgical reconstructions for adult brachial plexus injuries. Part II: Treatments for total arm type.

Brachial plexus injuries (BPI) contribute not only to physical dysfunction but also to socioeconomic aspects and psychological disability. Patients with total arm-type BPI will lose not only the shoulder and elbow function but also the hand function, making reconstruction particularly challenging. Reconstructive procedures commonly include nerve repair, grafting, neurotization (nerve transfer), tendon transfer and free functional muscle transfer (FFMT). Although it is difficult to achieve prehensile hand function, most of patients with total arm-type BPI can be treated with satisfied outcomes. In addition to surgical techniques, comprehensive rehabilitation is another important factor for successful outcomes, and efficient communication can help to boost patient morale and eliminate uncertainty.

First 100 total hip arthroplasties performed by a young surgeon using the direct anterior approach: learning curve and complications.

INTRODUCTION: Most of the reported discussions about the learning curve for the direct anterior approach (DAA) in total hip arthroplasty (THA) have been by experienced surgeons. The study's aim was to describe the learning curve, short-term outcomes, complications, and adaptations to the DAA used in the first 100 THA cases experienced by a young surgeon who had received DAA training for trauma surgeries. MATERIALS AND METHODS: This retrospective study summarizes the first 100 consecutive cases experienced by a young surgeon who performed the unilateral DAA for THA between 2019 and 2021. Cumulative sum (CUSUM) analysis was performed to evaluate the learning curve on the basis of operative time and overall complications. The demographics data, short-term outcomes, and complications of the first 50 and second 50 cases were compared. RESULTS: The CUSUM curve declined after 49 and 55 cases, measured by operative time and overall complications, respectively. The median operative time (104 vs. 80 min) and intraoperative fluoroscopic time (38 vs. 12 s) increased significantly in the first 50 cases compared with the times in the second 50 cases. Complications tended to occur in the first 50 cases (12% vs. 6%), and the overall rate was 9%. Major complications all occurred in the first 50 cases, with a rate of 4%. Only one case, which involved a complicated periprosthetic fracture around the stem that extended to the tip, required the intervention of a senior surgeon. CONCLUSIONS: Even after receiving training on the DAA for trauma surgeries, the young surgeon experienced a steep learning curve and more complications in the first 50 cases. The DAA for THA is a technically demanding procedure and may require guidance from an experienced surgeon to manage unexpected complications.