Human CD4-binding site antibody elicited by polyvalent DNA prime-protein boost vaccine neutralizes cross-clade tier-2-HIV strains.

The vaccine elicitation of HIV tier-2-neutralization antibodies has been a challenge. Here, we report the isolation and characterization of a CD4-binding site (CD4bs) specific monoclonal antibody, HmAb64, from a human volunteer immunized with a polyvalent DNA prime-protein boost HIV vaccine. HmAb64 is derived from heavy chain variable germline gene IGHV1-18 and light chain germline gene IGKV1-39. It has a third heavy chain complementarity-determining region (CDR H3) of 15 amino acids. On a cross-clade panel of 208 HIV-1 pseudo-virus strains, HmAb64 neutralized 20 (10%), including tier-2 strains from clades B, BC, C, and G. The cryo-EM structure of the antigen-binding fragment of HmAb64 in complex with a CNE40 SOSIP trimer revealed details of its recognition; HmAb64 uses both heavy and light CDR3s to recognize the CD4-binding loop, a critical component of the CD4bs. This study demonstrates that a gp120-based vaccine can elicit antibodies capable of tier 2-HIV neutralization.

I s pelvic support osteotomy (PSO) suitable for ordinary high-riding hip dysplasia?

PURPOSE: Pelvic support osteotomy (PSO) is regarded to provide pelvic stability and improve abductor function to delay or even avoid total hip arthroplasty (THA) in young patients with high-riding hip dysplasia. However, some of these patients eventually have to undergo THA. Because of the double-angulation deformity of the femur after PSO, subsequent THA is challenging. This study aimed to analyze whether PSO surgery is suitable for high-riding hip dysplasia and summarize orthopaedic strategy during THA for patients with previous PSO. METHODS: This case-control study included eight cases of THA for high-riding hip dysplasia patients with previous PSO (study group) and 24 cases of high-riding hip dysplasia patients without any hip surgical therapy (control group) by a 1:3 match (from May 2018 to January 2022). We compared demographics and joint function before and after THA between two groups and recorded all patients' preoperative imaging data, surgical procedures, postoperative imaging data, and complications. The surgical techniques for patients with previous PSO were highlighted. RESULTS: There was no statistical difference between the two groups in demographic (p > 0.05). The study group had worse hip Harris score (HHS), range of motion (ROM), visual analogue scale (VAS), and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) (p < 0.05) compared with the control group before THA. All patients had concurrent THA and osteotomy at the proximal femur, but the study group experienced longer operation time (p = 0.047) with more blood loss (p = 0.027) and higher complication rate compared with the control group (p = 0.009). At the last follow-up, the study group's HHS, ROM, VAS, and WOMAC were still worse than those in the control group. CONCLUSIONS: PSO did not improve the joint function of high-riding hip dysplasia patients but brought challenges to subsequent THA and affected the surgical outcomes. In short, we suggested that PSO is unsuitable for routine high-riding hip dysplasia patients.

The therapeutic potential of Ziziphi Spinosae Semen and Polygalae Radix in insomnia management: Insights from gut microbiota and serum metabolomics techniques.

ETHNOPHARMACOLOGICAL RELEVANCE: Ziziphi Spinosae Semen and Polygalae Radix (ZSS-PR) constitute a traditional Chinese herbal combination with notable applications in clinical and experimental settings due to their evident sedative and calming effects. Aligned with traditional Chinese medicine principles, Ziziphi Spinosae Semen supports cardiovascular health, nourishes the liver, and induces mental tranquillity. Simultaneously, Polygalae Radix elicits calming effects, fosters clear thinking, and reinstates proper coordination between the heart and kidneys. ZSS-PR is commonly employed as a therapeutic intervention for various insomnia types, demonstrating distinct clinical efficacy. Our previous study findings provide evidence that ZSS-PR administration significantly reduces sleep onset latency, increases overall sleep duration, and improves abnormal neurotransmitter levels in a murine insomnia model. AIM OF STUDY: This investigation aimed to scrutinize the intrinsic regulatory mechanism of ZSS-PR in managing insomnia using gut microbiota and serum metabolomics techniques. MATERIALS AND METHODS: Mice were given DL-4-Chlorophenylalanine to induce insomnia and then treated with ZSS-PR. The open-field test assessed the animals' spontaneous activity. Concentrations of neurotransmitters, endocrine hormones, and cytokines in the duodenum were measured using enzyme linked immunosorbent assay, and brain histopathology was evaluated with H&E staining. The impact of ZSS-PR on the metabolic profile was examined by liquid chromatography couped to high resolution mass spectrometry, and 16S rDNA sequencing was used to study the influence of ZSS-PR on the gut microbiota. Additionally, the content of short-chain fatty acids (SCFAs) was analyzed by GC-MS. Finally, correlation analysis investigated relationships between biochemical markers, metabolites, SCFAs, and gut microbiota. RESULTS: ZSS-PR treatment significantly increased movement time and distance in mice with insomnia and improved pathological impairments in the cerebral cortex and hippocampus. It also restored abnormal levels of biochemical markers in the gut of insomnia-afflicted mice, including 5-hydroxytryptamine, dopamine, gastrin, melatonin, tumour necrosis factor-α, and interleukin-1ß. Metabolomics findings showed that ZSS-PR had a significant restorative effect on 15 endogenous metabolites in mice with insomnia. Furthermore, ZSS-PR primarily influenced five metabolic pathways, such as phenylalanine, tyrosine, and tryptophan biosynthesis, glutamine, and glutamate metabolism. Additionally, gut microbiota analysis revealed notable alterations in both diversity and microbial composition after ZSS-PR treatment. These changes were primarily attributed to the relative abundances of microbiota, including Firmicutes, Bacteroidota, Fusobacteriota, Muribaculaceae_unclassified, and Ligilactobacillus. The results of SCFAs analysis demonstrated that ZSS-PR effectively restored abnormal levels of acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid, and valeric acid in insomniac mice. Subsequent correlation analysis revealed that microbiota show obvious correlations with both biochemical markers and metabolites. CONCLUSIONS: The results provide compelling evidence that ZSS-PR effectively mitigates abnormal activity, reduces cerebral pathological changes, and restores abnormal levels of neurotransmitters, endocrine hormones, and cytokines in mice with insomnia. The underlying mechanism is intricately linked to the modulation of gut microbiota and endogenous metabolic pathways.

Single-Domain Antibody-Based Protein Degrader for Synucleinopathies.

Synucleinopathies are a group of neurodegenerative diseases characterized by the accumulation of α-synuclein (α-syn) in the brain, leading to motor and neuropsychiatric symptoms. Currently, there are no known cures for synucleinopathies, and treatments mainly focus on symptom management. In this study, we developed a single-domain antibody (sdAb)-based protein degrader with features designed to enhance proteasomal degradation of α-syn. This sdAb derivative targets both α-syn and Cereblon (CRBN), a substrate-receptor for the E3-ubiquitin ligase CRL4CRBN, and thereby induces α-syn ubiquitination and proteasomal degradation. Our results indicate that this therapeutic candidate enhances proteasomal degradation of α-syn, in addition to the endogenous lysosomal degradation machinery. By promoting proteasomal degradation of α-syn, we improved clearance of α-syn in primary culture and mouse models of synucleinopathy. These findings indicate that our sdAb-based protein degrader is a promising therapeutic candidate for synucleinopathies. Considering that only a small percentage of antibodies enter the brain, more potent sdAbs with greater brain entry than whole antibodies could enhance clinical benefits of antibody-based therapies.

Glycosides constituents from Codonopsis pilosula.

A new glycoside (1) along with six known analogues (1-7) were isolated from Codonopsis pilosula collected at Shanxi in China. The structure of 1 was established based on comprehensive spectroscopic data and literature comparison. The anti-inflammatory effects of isolated compounds were further investigated in LPS-induced RAW264.7 macrophage.

Transmembrane domain-driven PD-1 dimers mediate T cell inhibition.

Programmed cell death-1 (PD-1) is a potent immune checkpoint receptor on T lymphocytes. Upon engagement by its ligands, PD-L1 or PD-L2, PD-1 inhibits T cell activation and can promote immune tolerance. Antagonism of PD-1 signaling has proven effective in cancer immunotherapy, and conversely, agonists of the receptor may have a role in treating autoimmune disease. Some immune receptors function as dimers, but PD-1 has been considered monomeric. Here, we show that PD-1 and its ligands form dimers as a consequence of transmembrane domain interactions and that propensity for dimerization correlates with the ability of PD-1 to inhibit immune responses, antitumor immunity, cytotoxic T cell function, and autoimmune tissue destruction. These observations contribute to our understanding of the PD-1 axis and how it can potentially be manipulated for improved treatment of cancer and autoimmune diseases.

Application and evaluation of artificial intelligence 3D preoperative planning software in developmental dysplasia of the hip.

BACKGROUND: Accurate preoperative planning is crucial for successful total hip arthroplasty (THA) for developmental dysplasia of the hip (DDH). The aim of this study was to compare the accuracy of an artificial intelligence-assisted three-dimensional (3D) planning system (AIHIP) with two-dimensional templates in predicting acetabular cup size in THA for DDH. METHOD: This study retrospectively analyzed image data from 103 DDH patients who had THA between May 2019 and August 2023. AIHIP was used for 3D planning, and two-dimensional (2D) templates were used by two experienced surgeons. Accuracy was assessed by comparing predicted and actual cup sizes, and potential factors affecting accuracy were analyzed, including gender, side, BMI, and dysplasia classification. RESULTS: AIHIP had higher accuracy in predicting the acetabular cup size compared to the 2D template. Within ± 0 size, AIHIP's accuracy was 84.1%, while the 2D template's was 64.0% (p < 0.05). Within ± 1 size, AIHIP's accuracy was 95.1%, while the 2D template's was 81.1% (p < 0.05). Accuracy was unaffected by gender, side, or BMI but was by DDH classification. In subgroup analysis, AIHIP's mean absolute error (0.21 ± 0.54) was significantly lower than the 2D template's (0.62 ± 0.95) for Crowe II and Crowe III (p < 0.05). CONCLUSION: AIHIP is superior to 2D templates in predicting the acetabular cup size accurately for THA in DDH patients. AIHIP may be especially beneficial for Crowe II and III DDH patients, as 2D templates may not accurately predict cup size in these cases.

Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.

Robotic-assisted total hip arthroplasty in patients with developmental dysplasia of the hip.

PURPOSES: Due to the morphological diversity of deformities, technical difficulties, improperly designed components, and so on, THA remains a challenging task in dysplastic hips, especially in highly dislocated hips. The purpose of this study was to comprehensively evaluate the clinical outcomes of robot-assisted THA in patients with DDH through a large cohort study, including the precision of acetabular cup positioning, indicators of inflammatory response, indicators of muscle damage, and complications. METHODS: We retrospectively analyzed patients with DDH who underwent THA in our prospectively constructed joint registry between August 2018 and August 2022. Finally, 147 manual THAs and 147 robotic-assisted THAs were included in the final analysis. Patient demographics, indicators of inflammation, indicators of muscle damage, operative time, Harris hip scores (HHS), and forgotten joint score (FJS) were recorded for analysis. The precision of the positioning of the acetabular component was assessed with plain radiographs. RESULTS: In the Crowe II/III groups, the reconstructed center of rotation (COR) in the robotic-assisted group was closer to the anatomical COR with less variation than the manual group (absolute horizontal distances of COR 3.5 ± 2.8 vs. 5.4 ± 4.9 mm, p < 0.05; absolute vertical distances of COR 6.4 ± 4.1 vs. 11.7 ± 8.2 mm, p = 0.001). For all Crowe subtypes, the robotic-assisted THA significantly increased the proportion of acetabular cups located in the safety zone within 5° (all p < 0.05). Interleukin-6 and creatine kinase levels were slightly lower and significantly different in the robotic-assisted group at three days postoperatively (all p < 0.05). CONCLUSIONS: Compared to the manual technique, the robot-assisted technique improved the precision and reproducibility of acetabular component positioning, particularly in DDH patients with Crowe types II/III. The robotic-assisted technique did not increase operative time, bleeding, complications, or revision rates, and had a slighter early inflammatory response and muscle damage.

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies.

Bacteria dysbiosis has been associated with an increased risk of HIV-1 transmission and acquisition. The prevalent idea is that bacteria dysbiosis compromises mucosal integrity and promotes inflammatory conditions to cause recruitment and activation of immune cells that harbor or are targeted by HIV-1. However, it is also possible that HIV-1 directly binds bacteria or bacterial products to impact virus infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The Streptococcal Siglec-like lectin SLBR-N, which is part of the fimbriae shrouding the bacteria surface and recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. Conversely, N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to broadly neutralizing antibodies targeting different regions of Env. Hence, this study highlights the potential contribution of O-glycans in promoting HIV-1 infection through the exploitation of O-glycan-binding lectins from commensal bacteria at the mucosa.

A First-Principles Study of Anion Doping in LiFePO4 Cathode Materials for Li-Ion Batteries.

Doping anions into LiFePO4 can improve the electrochemical performance of lithium-ion batteries. In this study, structures, electronic properties and Li-ion migration of anion (F- , Cl- , and S2- ) doping into LiFePO4 were systematically investigated by means of density functional theory calculations. Anion substitution for oxygen atoms leads to an expansion of the LiFePO4 lattice, significantly facilitating Li-ion diffusion. For Cl- and F- anion doped into LiFePO4 , the energy barrier of Li-ion migration gets lowered to 0.209 eV and 0.283 eV from 0.572 eV. The introduction of anions narrows the forbidden band of LiFePO4 , enhancing its electronic conductivity. This work pays a way towards the rational design of high-performance lithium-ion batteries.

Corrigendum: Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1.

[This corrects the article DOI: 10.3389/fimmu.2023.1271686.].

Human CD4-Binding Site Antibody Elicited by Polyvalent DNA Prime-Protein Boost Vaccine Neutralizes Cross-Clade Tier-2-HIV Strains.

The vaccine elicitation of HIV-neutralizing antibodies with tier-2-neutralization breadth has been a challenge. Here, we report the isolation and characteristics of a CD4-binding site specific monoclonal antibody, HmAb64, from a human volunteer immunized with a polyvalent gp120 DNA prime-protein boost vaccine. HmAb64 derived from heavy chain variable germline gene IGHV1-18, light chain germline gene IGKV1-39, and had a 3rd heavy chain complementarity determining region (CDR H3) of 15 amino acids. On a cross-clade panel of 208 HIV-1 pseudo-virus strains, HmAb64 neutralized 21 (10%), including tier-2 neutralization resistant strains from clades B, BC, C, and G. The cryo-EM structure of the antigen-binding fragment of HmAb64 bound to a conformation between prefusion closed and occluded open forms of envelope trimer, using both heavy and light CDR3s to recognize the CD4-binding loop, a critical component of the CD4-binding site. A gp120 subunit-based vaccine can thus elicit an antibody capable of tier 2-HIV neutralization.

The invasiveness of robot-assisted total hip replacement is similar to that of conventional surgery.

Robot-assisted total hip arthroplasty (R-THA) is increasingly being performed throughout the world. The invasiveness of this operation is unknown. We retrospectively reviewed the cohort of consecutive osteonecrosis of the femoral head (ONFH) patients who received primary R-THA or manual THA (M-THA) from January 2020 to January 2022 in our institution. One experienced surgeon performed all procedures. We calculated the propensity score to match similar patients in different groups by multivariate logistic regression analysis for each patient. We included confounders consisting of age, sex, body mass index (BMI), and operation time. Preoperative serum markers and Harris hip scores (HHS), postoperative serum markers at first day and third day, complications rate, postoperative HHS and Forgotten Joint Score (FJS) at 6 months after surgery of different cohorts were compared. We analyzed 218 ONFH patients treated with THA (98 R-THA patients, and 120 M-THA patients). After propensity score matching, we generated cohorts of 95 patients in R-THA and M-THA groups. We found no significant difference in preoperative serum markers and HHS. In the R-THA cohort, the PLT count was significantly lower on the postoperative day 1 (192.36 ± 41.72 × 109/L Vs 210.47 ± 72.85 × 109/L, p < 0.05). The Hb level was significantly lower on the postoperative third day in the R-THA cohort (98.52 ± 12.99 g/L Vs 104.74 ± 13.15 g/L, p < 0.05). There was no significant difference in the other serum markers between the cohorts on postoperative day 1 and 3 (p > 0.05). The FJS was significantly higher in the R-THA than M-THA group (p = 0.01). There was no significant difference in the postoperative HHS or complication rate between the groups (p > 0.05). The R-THA is not associated with a serious invasiveness compared to M-THA. Patients who underwent R-THA had a better early function compared to those who underwent M-THA.

Vaccination with immune complexes modulates the elicitation of functional antibodies against HIV-1.

Introduction: Neutralizing antibodies (Abs) are one of the immune components required to protect against viral infections. However, developing vaccines capable of eliciting neutralizing Abs effective against a broad array of HIV-1 isolates has been an arduous challenge. Objective: This study sought to test vaccines aimed to induce Abs against neutralizing epitopes at the V1V2 apex of HIV-1 envelope (Env). Methods: Four groups of rabbits received a DNA vaccine expressing the V1V2 domain of the CRF01_AE A244 strain on a trimeric 2J9C scaffold (V1V2-2J9C) along with a protein vaccine consisting of an uncleaved prefusion-optimized A244 Env trimer with V3 truncation (UFO-BG.ΔV3) or a V1V2-2J9C protein and their respective immune complexes (ICs). These IC vaccines were made using 2158, a V1V2-specific monoclonal Ab (mAb), which binds the V2i epitope in the underbelly region of V1V2 while allosterically promoting the binding of broadly neutralizing mAb PG9 to its V2 apex epitope in vitro. Results: Rabbit groups immunized with the DNA vaccine and uncomplexed or complexed UFO-BG.ΔV3 proteins (DNA/UFO-UC or IC) displayed similar profiles of Env- and V1V2-binding Abs but differed from the rabbits receiving the DNA vaccine and uncomplexed or complexed V1V2-2J9C proteins (DNA/V1V2-UC or IC), which generated more cross-reactive V1V2 Abs without detectable binding to gp120 or gp140 Env. Notably, the DNA/UFO-UC vaccine elicited neutralizing Abs against some heterologous tier 1 and tier 2 viruses from different clades, albeit at low titers and only in a fraction of animals, whereas the DNA/V1V2-UC or IC vaccines did not. In comparison with the DNA/UFO-UC group, the DNA/UFO-IC group showed a trend of higher neutralization against TH023.6 and a greater potency of V1V2-specific Ab-dependent cellular phagocytosis (ADCP) but failed to neutralize heterologous viruses. Conclusion: These data demonstrate the capacity of V1V2-2J9C-encoding DNA vaccine in combination with UFO-BG.ΔV3, but not V1V2-2J9C, protein vaccines, to elicit homologous and heterologous neutralizing activities in rabbits. The elicitation of neutralizing and ADCP activities was modulated by delivery of UFO-BG.ΔV3 complexed with V2i mAb 2158.

Short Carbon Nanotube-Based Delivery of mRNA for HIV-1 Vaccines.

Developing a safe and effective preventive for HIV-1 remains the hope for controlling the global AIDS epidemic. Recently, mRNA vaccines have emerged as a promising alternative to conventional vaccine approaches, primarily due to their rapid development and potential for low-cost manufacture. Despite the advantages of mRNA vaccines, challenges remain, especially due to the adverse effects of the delivery vehicle and low delivery efficiency. As a result, Luna Labs is developing a short carbon nanotube-based delivery platform (NanoVac) that can co-deliver mRNA and HIV-1 glycoproteins to the immune system efficiently with negligible toxicity. Surface chemistries of NanoVac were optimized to guide antigen/mRNA loading density and presentation. Multiple formulations were engineered for compatibility with both intramuscular and intranasal administration. NanoVac candidates demonstrated immunogenicity in rabbits and generated human-derived humoral and cellular responses in humanized mice (HIS). Briefly, 33% of the HIV-1-infected HIS mice vaccinated with NanoVac-mRNA was cleared of virus infection by 8-weeks post-infection. Finally, NanoVac stabilized the loaded mRNA against degradation under refrigeration for at least three months, reducing the cold chain burden for vaccine deployment.

Multiple Dynamic Bonds-Driven Integrated Cathode/Polymer Electrolyte for Stable All-Solid-State Lithium Metal Batteries.

All-solid-state lithium metal batteries (LMBs) are considered as the promising higher-energy and improved-safety energy-storage systems. Nevertheless, the electrolyte-electrodes interfacial issues due to the limited solid physical contact lead to discontinuous interfacial charge transport and large interfacial resistance, thereby suffering from unsatisfactory electrochemical performance. Herein, we construct an integrated cathode/polymer electrolyte for all-solid-state LMBs under the action of polymer chains exchange and recombination originating from multiple dynamic bonds in our well-designed dynamic supramolecular ionic conductive elastomers (DSICE) molecular structure. The DSICE acts as polymer electrolytes with excellent electrochemical performance and mechanical properties, achieving the ultrathin pure polymer electrolyte thickness (12 µm). Notably, the DSICE also functions as lithium iron phosphate (LiFePO4 , LFP) cathode binders with enhanced adhesive capability. Such well-constructed Li|DSICE|LFP-DSICE cells generate delicate electrolyte-electrodes interfacial contact at the molecular level, providing continuous Li+ transport pathways and promoting uniform Li+ deposition, further delivering superior long-term charge/discharge stability (>600 cycles, Coulombic efficiency, >99.8 %) and high capacity retention (80 % after 400 cycles). More practically, the Li|DSICE|LFP-DSICE pouch cells show stable electrochemical performance, excellent flexibility and safety under abusive tests.

Does robot-assisted surgery reduce leg length discrepancy in total hip replacement? Robot-assisted posterior approach versus direct anterior approach and manual posterior approach: a propensity score-matching study.

BACKGROUND: Advocates of robot-assisted technique argue that robots could improve leg length restoration in total hip replacement. However, there were few studies to compare the robot-assisted posterior approach (RPA) with conventional posterior approach (PA) THA and direct anterior approach (DAA) THA in LLD. This study aimed to determine whether robot-assisted techniques could significantly reduce LLD compared to manual DAA and manual PA. METHODS: We retrospectively reviewed the cohort of consecutive ONFH patients who underwent THA robot-assisted posterior, manual posterior, and manual DAA from January 2018 to December 2020 in one institution. One experienced surgeon performed all procedures. We calculated the propensity score to match similar patients in different groups by multivariate logistic regression analysis for each patient. We included confounders consisting of age at the time of surgery, sex, body mass index (BMI), and preoperative LLD. Postoperative LLD and Harris hip scores (HHS) at two years after surgery of different cohorts were compared. RESULT: We analyzed 267 ONFH patients treated with RPA, DAA, or PA (73 RPA patients, 99 DAA patients, and 95 PA patients). After propensity score matching, we generated cohorts of 40 patients in DAA and RPA groups. And we found no significant difference in postoperative LLD between RPA and DAA cohorts (4.10 ± 3.50 mm vs 4.60 ± 4.14 mm, p = 0.577) in this study. The HHS at 2 years postoperatively were 87.04 ± 7.06 vs 85.33 ± 8.34 p = 0.202. After propensity score matching, we generated cohorts of 58 patients in manual PA and RPA groups. And there were significant differences in postoperative LLD between the RPA and PA cohorts. (3.98 ± 3.27 mm vs 5.38 ± 3.68 mm, p = 0.031). The HHS at 2 years postoperatively were 89.38 ± 6.81 vs 85.33 ± 8.81 p = 0.019. After propensity score matching, we generated cohorts of 75 patients in manual DAA and PA groups. And there were significant differences in postoperative LLD between the DAA and PA cohorts. (4.03 ± 3.93 mm vs 5.39 ± 3.83 mm, p = 0.031) The HHS at 2 years postoperatively were 89.71 ± 6.18 vs 86.91 ± 7.20 p = 0.012. CONCLUSION: This study found no significant difference in postoperative LLD between RPA and DAA, but we found a significant difference between RPA and manual PA, DAA and manual PA in ONFH patients. We found a significant advantage in leg length restoration in primary total hip arthroplasty with robot-assisted surgery.

Single-domain antibody-based noninvasive in vivo imaging of α-synuclein or tau pathology.

Intracellular deposition of α-synuclein and tau are hallmarks of synucleinopathies and tauopathies, respectively. Recently, several dye-based imaging probes with selectivity for tau aggregates have been developed, but suitable imaging biomarkers for synucleinopathies are still unavailable. Detection of both of these aggregates early in the disease process may allow for prophylactic therapies before functional impairments have manifested, highlighting the importance of developing specific imaging probes for these lesions. In contrast to the ß sheet dyes, single-domain antibodies, found in camelids and a few other species, are highly specific, and their small size allows better brain entry and distribution than whole antibodies. Here, we have developed such imaging ligands via phage display libraries derived from llamas immunized with α-synuclein and tau preparations, respectively. These probes allow noninvasive and specific in vivo imaging of α-synuclein versus tau pathology in mice, with the brain signal correlating strongly with lesion burden. These small antibody derivatives have great potential for in vivo diagnosis of these diseases.

Undetected Intraoperative Periprosthetic Femoral Fractures in Patients Undergoing Primary Total Hip Arthroplasty: A Retrospective Case Series and Literature Review.

OBJECTIVE: Periprosthetic fracture in total hip arthroplasty (THA) can be catastrophic, and early detection and appropriate management are vital to the overall prognosis. This study aimed to describe and summarize the features of undetected intraoperative periprosthetic femoral fractures (IPFFs) in primary THA patients and treatment measures and to review the relevant literature. METHODS: We reviewed a total of 6350 primary THAs performed at our institution between January 2013 and December 2020 and screened all IPFFs. Of 138 IPFFs, 24 were undetected and met the inclusion criteria. We recorded and compared basic patient and operative information and measured some parameters to evaluate canal morphologies based on preoperative radiographs. We also compared fracture line characteristics using postoperative radiographs to summarize the features of intraoperative fractures and propose treatment strategies. The Kolmogorov-Smirnov test was used to test the normality of the variable distributions. Measured parameters in all groups were analyzed using one-way analysis of variance and compared using Dunnett's test. The χ2 and Fisher exact tests were used to compare reoperation rates across the groups. Interrater and intrarater reliability were evaluated by intraclass correlation coefficients. RESULTS: Among the 24 hips, there was no significant difference in patient demographics, basic operative information or morphology. The incidence of IPFFs in primary THA patients was 2.17%, and up to 17.4% of IPFFs were undetected until postoperative fluoroscopy. The incidence of undetected IPFFs among all primary THA patients was 0.38% and varied by stem type, with the highest incidence in femurs with either anatomical (1.04%, 4/385) or modular stems (0.90%, 9/1003). Femurs with anatomical stems had a higher reoperation rate. The distal periprosthetic (Gruen zone 4) fracture line of femurs with tapered stems was more prone to involve the medial or lateral bone cortex, which could cause instability. CONCLUSION: An undetected IPFF is most likely in femurs fitted with a prosthesis of an inappropriate size or type. Anatomical stems will most likely cause unstable fractures; thus, it is recommended to use them with caution and note the possibility of medial distal femoral fracture. Improper modular stem type or size selection results in longitudinal fractures of the distal femur, and prophylactic cerclage wire binding is recommended in dysplastic hips. Incorrect use of tapered stems in well-ossified femurs may cause distal femoral fractures involving the medial or lateral bone cortex. Intraoperative fluoroscopy after implantation may help detect hidden fractures.