Validating a Novel 2D to 3D Knee Reconstruction Method on Preoperative Total Knee Arthroplasty Patient Anatomies.

BACKGROUND: As advanced technology continues to evolve, incorporating robotics into surgical procedures has become imperative for precision and accuracy in preoperative planning. Nevertheless, the integration of three-dimensional (3D) imaging into these processes presents both financial considerations and potential patient safety concerns. This study aims to assess the accuracy of a novel 2D-to-3D knee reconstruction solution, RSIP XPlan.ai™ (RSIP Vision, Jerusalem, Israel), on preoperative total knee arthroplasty (TKA) patient anatomies. METHODS: Accuracy was calculated by measuring the Root Mean Square Error (RMSE) between X-ray-based 3D bone models generated by the algorithm and corresponding CT bone segmentations (distances of each mesh vertex to the closest vertex in the second mesh). The RMSE was computed globally for each bone, locally for eight clinically relevant bony landmark regions, and along simulated bone cut contours. In addition, the accuracies of three anatomical axes were assessed by comparing angular deviations to inter- and intra-observer baseline values. RESULTS: The global RMSE was 0.93 ± 0.25 mm for the femur and 0.88 ± 0.14 mm for the tibia. Local RMSE values for bony landmark regions were 0.51 ± 0.33 mm for the five femoral landmarks and 0.47 ± 0.17 mm for the three tibial landmarks. The RMSE along simulated cut contours was 0.75 ± 0.35 mm for the distal femur cut and 0.63 ± 0.27 mm for the proximal tibial cut. Anatomical axial average angular deviations were 1.89° for the trans epicondylar axis (with an inter- and intra-observer baseline of 1.43°), 1.78° for the posterior condylar axis (with a baseline of 1.71°), and 2.82° (with a baseline of 2.56°) for the medial-lateral transverse axis. CONCLUSIONS: The study findings demonstrate promising results regarding the accuracy of XPlan.ai™ in reconstructing 3D bone models from plain-film X-rays. The observed accuracy on real-world TKA patient anatomies in anatomically relevant regions, including bony landmarks, cut contours, and axes, suggests the potential utility of this method in various clinical scenarios. Further validation studies on larger cohorts are warranted to fully assess the reliability and generalizability of our results. Nonetheless, our findings lay the groundwork for potential advancements in future robotic arthroplasty technologies, with XPlan.ai™ offering a promising alternative to conventional CT scans in certain clinical contexts.

Engineered tRNAs suppress nonsense mutations in cells and in vivo.

Nonsense mutations are the underlying cause of approximately 11% of all inherited genetic diseases1. Nonsense mutations convert a sense codon that is decoded by tRNA into a premature termination codon (PTC), resulting in an abrupt termination of translation. One strategy to suppress nonsense mutations is to use natural tRNAs with altered anticodons to base-pair to the newly emerged PTC and promote translation2-7. However, tRNA-based gene therapy has not yielded an optimal combination of clinical efficacy and safety and there is presently no treatment for individuals with nonsense mutations. Here we introduce a strategy based on altering native tRNAs into  efficient suppressor tRNAs (sup-tRNAs) by individually fine-tuning their sequence to the physico-chemical properties of the amino acid that they carry. Intravenous and intratracheal lipid nanoparticle (LNP) administration of sup-tRNA in mice restored the production of functional proteins with nonsense mutations. LNP-sup-tRNA formulations caused no discernible readthrough at endogenous native stop codons, as determined by ribosome profiling. At clinically important PTCs in the cystic fibrosis transmembrane conductance regulator gene (CFTR), the sup-tRNAs re-established expression and function in cell systems and patient-derived nasal epithelia and restored airway volume homeostasis. These results provide a framework for the development of tRNA-based therapies with a high molecular safety profile and high efficacy in targeted PTC suppression.

Efficacy increase of lipid nanoparticles in vivo by inclusion of bis(monoacylglycerol)phosphate.

Aim: To investigate the effect of incorporating bis(monoacylglycerol)phosphate (BMP) lipid into a lipid nanoparticle and the functional transport of mRNA by the formulated nanoparticles in vivo. Materials & methods: The nanoparticles were prepared from ionizable lipid, 1,2-distearoyl-sn-glycerol-3-phosphocholine, cholesterol, 1,2-dimyristoyl-sn-glycerol PEG 2000, BMP and formulated mRNA encoding human erythropoietin. We measured the effect of BMP on physicochemical properties and impact on functional efficacy to transport mRNA to its target cells/tissue as measured by protein expression both in vitro and in vivo. Results: Lipid nanoparticles composed of BMP displayed increased endosomal membrane fusion and improved mRNA delivery to the cytosol. Conclusion: The results establish the foundation for future development of these nanoparticulated entities by designing new BMP derivatives and correlating structures to enhanced pharmacokinetic profiles.

Artificial intelligence for image analysis in total hip and total knee arthroplasty : a scoping review.

AIMS: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are common orthopaedic procedures requiring postoperative radiographs to confirm implant positioning and identify complications. Artificial intelligence (AI)-based image analysis has the potential to automate this postoperative surveillance. The aim of this study was to prepare a scoping review to investigate how AI is being used in the analysis of radiographs following THA and TKA, and how accurate these tools are. METHODS: The Embase, MEDLINE, and PubMed libraries were systematically searched to identify relevant articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews and Arksey and O'Malley framework were followed. Study quality was assessed using a modified Methodological Index for Non-Randomized Studies tool. AI performance was reported using either the area under the curve (AUC) or accuracy. RESULTS: Of the 455 studies identified, only 12 were suitable for inclusion. Nine reported implant identification and three described predicting risk of implant failure. Of the 12, three studies compared AI performance with orthopaedic surgeons. AI-based implant identification achieved AUC 0.992 to 1, and most algorithms reported an accuracy > 90%, using 550 to 320,000 training radiographs. AI prediction of dislocation risk post-THA, determined after five-year follow-up, was satisfactory (AUC 76.67; 8,500 training radiographs). Diagnosis of hip implant loosening was good (accuracy 88.3%; 420 training radiographs) and measurement of postoperative acetabular angles was comparable to humans (mean absolute difference 1.35° to 1.39°). However, 11 of the 12 studies had several methodological limitations introducing a high risk of bias. None of the studies were externally validated. CONCLUSION: These studies show that AI is promising. While it already has the ability to analyze images with significant precision, there is currently insufficient high-level evidence to support its widespread clinical use. Further research to design robust studies that follow standard reporting guidelines should be encouraged to develop AI models that could be easily translated into real-world conditions. Cite this article: Bone Joint J 2022;104-B(8):929-937.

The safe resumption of elective orthopaedic services following the first wave of the COVID-19 pandemic : a review of 2,316 consecutive cases and implications for recovery following further waves.

AIMS: There is little published on the outcomes after restarting elective orthopaedic procedures following cessation of surgery due to the COVID-19 pandemic. During the pandemic, the reported perioperative mortality in patients who acquired SARS-CoV-2 infection while undergoing elective orthopaedic surgery was 18% to 20%. The aim of this study is to report the surgical outcomes, complications, and risk of developing COVID-19 in 2,316 consecutive patients who underwent elective orthopaedic surgery in the latter part of 2020 and comparing it to the same, pre-pandemic, period in 2019. METHODS: A retrospective service evaluation of patients who underwent elective surgical procedures between 16 June 2020 and 12 December 2020 was undertaken. The number and type of cases, demographic details, American society of Anesthesiologists (ASA) grade, BMI, 30-day readmission rates, mortality, and complications at one- and six-week intervals were obtained and compared with patients who underwent surgery during the same six-month period in 2019. RESULTS: A total of 2,316 patients underwent surgery in 2020 compared to 2,552 in the same period in 2019. There were no statistical differences in sex distribution, BMI, or ASA grade. The 30-day readmission rate and six-week validated complication rates were significantly lower for the 2020 patients compared to those in 2019 (p < 0.05). No deaths were reported at 30 days in the 2020 group as opposed to three in the 2019 group (p < 0.05). In 2020 one patient developed COVID-19 symptoms five days following foot and ankle surgery. This was possibly due to a family contact immediately following discharge from hospital, and the patient subsequently made a full recovery. CONCLUSION: Elective surgery was safely resumed following the cessation of operating during the COVID-19 pandemic in 2020. Strict adherence to protocols resulted in 2,316 elective surgical procedures being performed with lower complications, readmissions, and mortality compared to 2019. Furthermore, only one patient developed COVID-19 with no evidence that this was a direct result of undergoing surgery. Level of evidence: III Cite this article: Bone Jt Open 2022;3(1):42-53.

Nickel hypersensitivity and skin patch testing in total hip replacement surgery: a systematic review.

Approximately 60,000 cemented femoral stems are implanted in the UK each year with the majority being manufactured from stainless steel containing 10-15% nickel. Nickel hypersensitivity has been reported in up to 13% of the general population and there is a concern that nickel hypersensitivity might adversely affect the outcome of total hip replacement (THR). We reviewed the current literature on the potential link between nickel hypersensitivity and THR complications, and the usefulness of patch testing.We conducted a literature search in PubMed, MEDLINE and EMBASE databases. The level of evidence and the quality of the selected studies were assessed using the Oxford Centre for Evidence-Based Medicine Criteria and the Methodological Index for Non-Randomised Studies tool, respectively.Twenty-six studies met the inclusion criteria, reporting on 1852 patients who underwent primary or revision THR. All studies detailed skin patch testing and recorded prevalence of nickel hypersensitivity from 1.5% to 33.3%. Five studies reported a rise in Nickel hypersensitivity following THR, while four reported a decreased prevalence post-operatively. Eight studies concluded that metal hypersensitivity could have developed following THR, while seven studies did not support a link between metal hypersensitivity and THR complications. Four of the studies recommended routine patch testing pre-operatively, but three others concluded that routine patch testing was not indicated.We have not identified a link between nickel hypersensitivity and THR complications, and the role of patch testing remains unclear. Further large-scale studies would be required to investigate this relationship and to clarify the role of patch testing in facilitating implant selection. Cite this article: EFORT Open Rev 2021;6:825-838. DOI: 10.1302/2058-5241.6.210051.

Property-Driven Design and Development of Lipids for Efficient Delivery of siRNA.

Ionizable cationic lipids are critical components involved in nanoparticle formulations, which are utilized in delivery platforms for RNA therapeutics. While general criteria regarding lipophilicity and measured pKa in formulation are understood to have impacts on utility in vivo, greater granularity with respect to the impacts of the structure on calculated and measured physicochemical parameters and the subsequent performance of those ionizable cationic lipids in in vivo studies would be beneficial. Herein, we describe structural alterations made within a lipid class exemplified by 4, which allow us to tune calculated and measured physicochemical parameters for improved performance, resulting in substantial improvements versus the state of the art at the outset of these studies, resulting in good in vivo activity within a range of measured basicity (pKa = 6.0-6.6) and lipophilicity (cLogD = 10-14).

Self-immolative polymers.

Smart polymers are special kinds of polymeric molecules that respond to external stimuli. We have developed a novel smart polymer designed to sequentially disassemble into its building blocks upon initiation by a triggering event at the polymer head. The polymer structure is based on a polyurethane backbone that disassembles through a domino-like, 1,6-elimination and decarboxylation reactions. We synthesized a self-immolative polymer that amplifies a single cleavage reaction into multiple release of fluorogenic molecules and confirmed the head-to-tail disassembly concept. These polymers can be used to prepare highly sensitive molecular sensors with large signal-to-noise ratios. The sensors should be useful for the detection of a wide range of biological and chemical activities through use of the appropriate trigger at the polymer head.

Remarkable drug-release enhancement with an elimination-based AB3 self-immolative dendritic amplifier.

Self-immolative dendritic prodrugs, activated through a single catalytic reaction by a specific enzyme, could offer significant advantages in inhibition of tumor growth relative to monomeric prodrug, especially if the targeted or secreted enzyme exists at relatively low levels in the malignant tissue. We have designed and synthesized new AB(3) self-immolative dendritic prodrug system that releases three active drugs by a single cleavage of the enzyme penicillin-G-amidase. The cleavage signal is transferred from the dendron focal point to its periphery through fast elimination reactions and the design leads to three-fold signal amplification. In cell-growth inhibition assays, the elimination-based AB(3) self-immolative dendritic prodrug was significantly more effective than a cyclization-based AB(3) dendritic prodrug.

Amperometric assay for aldolase activity: antibody-catalyzed ferrocenylamine formation.

Screening of new catalysts for aldolase activity is a major task in bioorganic chemistry. For this purpose, fast and convenient methods are required for the detection of the catalysts. We have developed the first amperometric assay for aldol or retro-aldol catalytic activity. A new ferrocene-aldol derivative was synthesized with redox activity significantly different from that of ferrocenylamine. It was shown that the reaction between aldolase antibody 38C2 and a ferrocene-aldol substrate generated free ferrocenylamine, which could be detected and quantified by simple electrochemical measurement. The amperometric assay was applied to perform a Michaelis-Menten analysis of catalytic antibody 38C2 in order to determine the enzymatic kinetic parameters.