The reactome pathway knowledgebase 2022.

The Reactome Knowledgebase (https://reactome.org), an Elixir core resource, provides manually curated molecular details across a broad range of physiological and pathological biological processes in humans, including both hereditary and acquired disease processes. The processes are annotated as an ordered network of molecular transformations in a single consistent data model. Reactome thus functions both as a digital archive of manually curated human biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. Recent curation work has expanded our annotations of normal and disease-associated signaling processes and of the drugs that target them, in particular infections caused by the SARS-CoV-1 and SARS-CoV-2 coronaviruses and the host response to infection. New tools support better simultaneous analysis of high-throughput data from multiple sources and the placement of understudied ('dark') proteins from analyzed datasets in the context of Reactome's manually curated pathways.

Deap-seated infection and nonunion following internal fixation for Charcot foot deformity correction. A proportional meta-analysis of level 4 evidence.

BACKGROUND: Given the paucity of literature on the management of infected metalwork and nonunion in neuropathic diabetic patients, a meta-analysis was designed to investigate the two major complications following Charcot reconstruction performed by means of internal fixation methods. METHODS: We searched PubMed, Scopus and CENTRAL until the 17th of May 2022 for completed studies investigating outcomes following midfoot and/or hindfoot and/or ankle diabetic Charcot reconstruction. For a paper to qualify for inclusion, an internal fixation element should have been considered. Random effects meta-analysis of proportion was performed to calculate the rate of post-operative deep-seated infections with the associated amputation rate and nonunions by using Open Meta-analyst software. Sub-analysis linked to anatomical location of reconstruction was performed and the quality of the included studies was appraised using the Moga tool. RESULTS: Thirty studies with 492 eligible reconstructions were considered. Of those, deep-seated infections were diagnosed in 46 cases (Estimated proportion was 6.7%, 95% CI [4.2%-9.2%]). Debridement and antibiotic administration with or without metalwork removal were considered in the majority of the participants with successful clinical outcomes. Amputation was performed in 15 patients due to unmanageable post-operative infection and nonunion was reported in 17 studies (Estimated rates were 36.6%, 95% CI [18.4%-56.3%]; and 11.9%, 95%CI [6.6%-18.1%]; respectively). CONCLUSIONS: Meta-analysis showed that although the overall risk of infection development is less than 10%, just below one third of the infected cases undergo late amputation. Moreover, internal fixation reconstructions carry a nonunion risk of just above 10%.

ReactomeGSA - Efficient Multi-Omics Comparative Pathway Analysis.

Pathway analyses are key methods to analyze 'omics experiments. Nevertheless, integrating data from different 'omics technologies and different species still requires considerable bioinformatics knowledge.Here we present the novel ReactomeGSA resource for comparative pathway analyses of multi-omics datasets. ReactomeGSA can be used through Reactome's existing web interface and the novel ReactomeGSA R Bioconductor package with explicit support for scRNA-seq data. Data from different species is automatically mapped to a common pathway space. Public data from ExpressionAtlas and Single Cell ExpressionAtlas can be directly integrated in the analysis. ReactomeGSA greatly reduces the technical barrier for multi-omics, cross-species, comparative pathway analyses.We used ReactomeGSA to characterize the role of B cells in anti-tumor immunity. We compared B cell rich and poor human cancer samples from five of the Cancer Genome Atlas (TCGA) transcriptomics and two of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) proteomics studies. B cell-rich lung adenocarcinoma samples lacked the otherwise present activation through NFkappaB. This may be linked to the presence of a specific subset of tumor associated IgG+ plasma cells that lack NFkappaB activation in scRNA-seq data from human melanoma. This showcases how ReactomeGSA can derive novel biomedical insights by integrating large multi-omics datasets.

The reactome pathway knowledgebase.

The Reactome Knowledgebase (https://reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations in a single consistent data model, an extended version of a classic metabolic map. Reactome functions both as an archive of biological processes and as a tool for discovering functional relationships in data such as gene expression profiles or somatic mutation catalogs from tumor cells. To extend our ability to annotate human disease processes, we have implemented a new drug class and have used it initially to annotate drugs relevant to cardiovascular disease. Our annotation model depends on external domain experts to identify new areas for annotation and to review new content. New web pages facilitate recruitment of community experts and allow those who have contributed to Reactome to identify their contributions and link them to their ORCID records. To improve visualization of our content, we have implemented a new tool to automatically lay out the components of individual reactions with multiple options for downloading the reaction diagrams and associated data, and a new display of our event hierarchy that will facilitate visual interpretation of pathway analysis results.

Which is the optimal minimally invasive treatment for osteoid osteoma of the hip? A systematic review and proportional meta-analysis.

BACKGROUND: Osteoid osteomata comprise approximately 10% of benign bone tumours, with 20% of them being located in the proximal femur and 1-3% in the pelvis. In this meta-analysis, we sought to investigate positive and negative outcomes relating to minimally invasive surgery (MIS), which has superseded open resection and conservative measures over the last decades. METHODS: We searched the PubMed, CENTRAL and grey literature for completed studies published until 10 August 2020. Articles with a minimum of ten patients diagnosed with osteoid osteomata of the proximal femur and/or acetabulum were included. Primary outcomes were success rates, complications and recurrences following treatment. Delays in diagnosis were also recorded. We conducted random effects meta-analysis of success rates for MIS modalities using MedCalc statistical software. Quality was assessed with a modified Delphi checklist. RESULTS: Sixteen case-series were identified. Success rates for computed-tomography (CT)-guided radiofrequency ablation (RFA), CT-guided percutaneous resection drilling and arthroscopic resection were 98.2% (95% CI 95.8-99.5), p = 0.47; 91.5% (95% CI 81.1-97.9), p = 0.06; and 98% (95% CI 89.3-99.7), p = 0.95, respectively. Both RFA and percutaneous drilling resection were associated with two iatrogenic femoral fractures. Arthroscopic removal was not associated with any complications. Definitive diagnosis was established at least six months after symptom onset in up to 43% of patients. CONCLUSIONS: RFA could be the most effective treatment options for patients suffering from osteoid osteomata of the hip. Arthroscopy could be potentially as effective as RFA as long as further large-scale studies confirm its efficacy and safety. Reported complications stemming from these modalities were sparse in nature. In order to avoid inordinate diagnostic delays, a high index of suspicion and low threshold for CT scan investigation is required.

Is sonication superior to dithiothreitol in diagnosis of periprosthetic joint infections? A meta-analysis.

PURPOSE: Even though effective techniques in diagnosis of periprosthetic joint infections (PJIs) have been developed, the optimal modality has yet to be determined. The present meta-analysis aimed to compare the diagnostic accuracy of dithiothreitol (DTT) and sonication against the Musculoskeletal Infection Society criteria in patients undergoing revision joint surgery. METHODS: We searched the PubMed, Scopus, and Central Cochrane register of controlled trials as well as gray literature until the 9th of November, 2021. We included articles considering the comparative diagnostic accuracy of sonication and DTT in adult patients having revision hip and knee arthroplasty for septic or aseptic reasons. We calculated pooled sensitivity, specificity, and diagnostic accuracy of the above diagnostic techniques against the Musculoskeletal Infection Society (MSIS) criteria and created receiver operating characteristics (ROC) curves to enable comparisons between each other. The quality of included papers was evaluated utilizing QUADAS-2 and QUADAS-C tools. RESULTS: Data from five comparative studies totaling 726 implants were pooled together. The diagnostic accuracy of DTT and sonication were 86.7% (95% CI 82.7 to 90.1) and 83.9% (95% CI 79.7 to 87.5), respectively. Pooled sensitivity and specificity showed no statistically significant differences between DTT and sonication (0.7 [95% CI 0.62 to 0.77] vs 0.72 [95% CI 0.65 to 0.78], p = 0.14; and 0.99 [95% CI 0.97 to 1] vs 0.97 [95% CI 0.93 to 0.99], p = 5.5, respectively). CONCLUSIONS: This meta-analysis did not identify any clinically meaningful difference between the diagnostic potential of sonication and the chemical-based biofilm dislodgment methods. This finding remained robust after adjusting for the administration of antibiotics prophylaxis, implementation of the polymerase chain reaction of sonicated fluid, and study quality.

Is coating of titanium implants effective at preventing Staphylococcus aureus infections? A meta-analysis of animal model studies.

AIM OF THE STUDY: To assess the effects of the available coating methods against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) biofilm development on titanium implants. METHODS: We searched the MEDLINE, Embase, and CENTRAL databases until May 18, 2019, for studies that used animal models of infections to evaluate various titanium implant coating methods to prevent S. aureus infection. Twenty-seven studies were eligible for inclusion in qualitative synthesis. Of those, twenty-three were considered in pair-wise meta-analysis. In addition, subgroup analysis of implant protection strategies relative to uncoated controls was performed, and any adverse events stemming from the coating applications were reported. Quality assessment was performed using SYRCLE's risk of bias tool for animal studies. RESULTS: Meta-analysis showed that active coating with antibiotics was favoured over uncoated controls (standardised mean differences [SMD] for MRSA and MSSA were - 2.71 [95% CI, - 4.24 to - 1.18], p = 0.0005, and - 2.5 [- 3.79 to - 1.22], p = 0.0001, respectively). Likewise, large effect sizes were demonstrated when a combination of active and conventional non-degradable passive coatings was compared with controls (SMDs for MRSA and MSSA were - 0.62 [95% CI, - 1.15 to - 0.08], p = 0.02, and - 1.93 [95% CI, - 2.87 to - 0.98], p < 0.001, respectively). DISCUSSION/CONCLUSION: As a standalone prevention method, active titanium coating with antibiotics yielded promising results against both MSSA and MRSA. Combinations between active and non-degradable passive coatings, potentially allowing for sustained antimicrobial substance release, provided consistent hardware infection protection. Thus, we recommend that future research efforts focus on combined coating modalities against S. aureus biofilm infections in the presence of titanium implants. SYSTEMATIC REVIEW REGISTRATION: CRD42019123462.

The Reactome Pathway Knowledgebase.

The Reactome Knowledgebase (https://reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism, and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression profiles or somatic mutation catalogues from tumor cells. To support the continued brisk growth in the size and complexity of Reactome, we have implemented a graph database, improved performance of data analysis tools, and designed new data structures and strategies to boost diagram viewer performance. To make our website more accessible to human users, we have improved pathway display and navigation by implementing interactive Enhanced High Level Diagrams (EHLDs) with an associated icon library, and subpathway highlighting and zooming, in a simplified and reorganized web site with adaptive design. To encourage re-use of our content, we have enabled export of pathway diagrams as 'PowerPoint' files.

Do External Supports Improve Dynamic Balance in Patients with Chronic Ankle Instability? A Network Meta-analysis.

BACKGROUND: To improve ankle stability in patients who have experienced an ankle sprain with residual symptoms of instability and/or objective joint laxity, external supports (such as taping, bracing, and orthotic insoles) are used sometimes. However, available randomized trials have disagreed on whether restraints improve balance in those individuals. In this situation, a network meta-analysis can help because it allows for comparing multiple treatments simultaneously, taking advantage not only of direct but also indirect evidence synthesis. QUESTIONS/PURPOSES: The aim of this network meta-analysis was to assess (1) the impact of taping and orthotic devices on dynamic postural control in individuals with ankle instability and (2) the presence of a placebo effect in participants treated with sham taping and complications resulting from the administered treatments. METHODS: We searched the PubMed, Scopus, and CENTRAL databases up to February 13, 2019 for completed studies. Randomized trials assessing the results of real and/or sham taping, wait-and-see protocols, ankle bracing, and foot orthotics for ankle instability as determined by one or more ankle sprains followed by ongoing subjective symptoms and/or mechanical laxity were included. We evaluated dynamic postural control in terms of the Star Excursion Balance Test in the posteromedial direction (SEBT-PM), which is considered the most representative of balance deficits in patients with ankle instability. Standardized mean differences were re-expressed to percentage differences in SEBT-PM, with higher scores representing possible improvement. Subsequently, those data were checked against the established minimal detectable change of 14% for this scale to make judgements on clinical importance. We also assessed the presence of a placebo effect by comparing the results of sham taping with no treatment and complications resulting from the administered treatments. Additionally, we judged the quality of trials using the Cochrane risk of bias tool and quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. A total of 22 trials met our inclusion criteria, 18 of which were deemed to be at a low risk of bias. A network of treatments consisting of 13 studies was created, and the level of evidence was judged to be high. As far as participants' allocation to treatment arms, 85 patients followed a wait-and-see protocol, 29 received placebo taping, 99 were treated with taping, 16 were treated with bracing, 27 were administered insoles, and six individuals were offered a combination of insoles with bracing. Of note, with statistical power set at 80%, a minimum of 16 patients per treatment group was required to provide sufficient statistical power and detect a SEBT-PM percentage difference of 14%. RESULTS: A network meta-analysis did not demonstrate a benefit of taping or bracing over no treatment (percentage difference in SEBT-PM between taping and bracing versus control: -2.4 [95% CI -6 to 1.1]; p = 0.18, and -7.5 [95% CI -15.9 to 1]; p = 0.08, respectively). This was also the case for sham taping because the measurement increase failed to exceed the minimal detectable change (percentage difference in SEBT-PM between sham taping and untreated control: -1.1 [95% CI -6.9 to 4.7]; p = 0.72). Importantly, there were no reported adverse events after treatment application. CONCLUSIONS: Evidence of moderate strength indicated that external supports of any type were no more effective than controls in improving dynamic postural control in patients with at least one ankle sprain and residual functional or mechanical deficits. Therefore, implementing those tools as a standalone treatment does not appear to be a viable strategy for the primary management of ankle instability. It is conceivable that combinations of rehabilitation and external supports could be more effective than external supports alone, and future trials should evaluate the potential of such combinations in enhancing not only clinician-reported but also patient-oriented outcomes using long-term follow-up measurements. LEVEL OF EVIDENCE: Level I, therapeutic study.

Reactome diagram viewer: data structures and strategies to boost performance.

Motivation: Reactome is a free, open-source, open-data, curated and peer-reviewed knowledgebase of biomolecular pathways. For web-based pathway visualization, Reactome uses a custom pathway diagram viewer that has been evolved over the past years. Here, we present comprehensive enhancements in usability and performance based on extensive usability testing sessions and technology developments, aiming to optimize the viewer towards the needs of the community. Results: The pathway diagram viewer version 3 achieves consistently better performance, loading and rendering of 97% of the diagrams in Reactome in less than 1 s. Combining the multi-layer html5 canvas strategy with a space partitioning data structure minimizes CPU workload, enabling the introduction of new features that further enhance user experience. Through the use of highly optimized data structures and algorithms, Reactome has boosted the performance and usability of the new pathway diagram viewer, providing a robust, scalable and easy-to-integrate solution to pathway visualization. As graph-based visualization of complex data is a frequent challenge in bioinformatics, many of the individual strategies presented here are applicable to a wide range of web-based bioinformatics resources. Availability and implementation: Reactome is available online at: https://reactome.org. The diagram viewer is part of the Reactome pathway browser (https://reactome.org/PathwayBrowser/) and also available as a stand-alone widget at: https://reactome.org/dev/diagram/. The source code is freely available at: https://github.com/reactome-pwp/diagram. Contact: fabregat@ebi.ac.uk or hhe@ebi.ac.uk. Supplementary information: Supplementary data are available at Bioinformatics online.

Reactome graph database: Efficient access to complex pathway data.

Reactome is a free, open-source, open-data, curated and peer-reviewed knowledgebase of biomolecular pathways. One of its main priorities is to provide easy and efficient access to its high quality curated data. At present, biological pathway databases typically store their contents in relational databases. This limits access efficiency because there are performance issues associated with queries traversing highly interconnected data. The same data in a graph database can be queried more efficiently. Here we present the rationale behind the adoption of a graph database (Neo4j) as well as the new ContentService (REST API) that provides access to these data. The Neo4j graph database and its query language, Cypher, provide efficient access to the complex Reactome data model, facilitating easy traversal and knowledge discovery. The adoption of this technology greatly improved query efficiency, reducing the average query time by 93%. The web service built on top of the graph database provides programmatic access to Reactome data by object oriented queries, but also supports more complex queries that take advantage of the new underlying graph-based data storage. By adopting graph database technology we are providing a high performance pathway data resource to the community. The Reactome graph database use case shows the power of NoSQL database engines for complex biological data types.

Open Targets: a platform for therapeutic target identification and validation.

We have designed and developed a data integration and visualization platform that provides evidence about the association of known and potential drug targets with diseases. The platform is designed to support identification and prioritization of biological targets for follow-up. Each drug target is linked to a disease using integrated genome-wide data from a broad range of data sources. The platform provides either a target-centric workflow to identify diseases that may be associated with a specific target, or a disease-centric workflow to identify targets that may be associated with a specific disease. Users can easily transition between these target- and disease-centric workflows. The Open Targets Validation Platform is accessible at https://www.targetvalidation.org.

Reactome enhanced pathway visualization.

MOTIVATION: Reactome is a free, open-source, open-data, curated and peer-reviewed knowledge base of biomolecular pathways. Pathways are arranged in a hierarchical structure that largely corresponds to the GO biological process hierarchy, allowing the user to navigate from high level concepts like immune system to detailed pathway diagrams showing biomolecular events like membrane transport or phosphorylation. Here, we present new developments in the Reactome visualization system that facilitate navigation through the pathway hierarchy and enable efficient reuse of Reactome visualizations for users' own research presentations and publications. RESULTS: For the higher levels of the hierarchy, Reactome now provides scalable, interactive textbook-style diagrams in SVG format, which are also freely downloadable and editable. Repeated diagram elements like 'mitochondrion' or 'receptor' are available as a library of graphic elements. Detailed lower-level diagrams are now downloadable in editable PPTX format as sets of interconnected objects. AVAILABILITY AND IMPLEMENTATION: http://reactome.org. CONTACT: fabregat@ebi.ac.uk or hhe@ebi.ac.uk.

The Reactome pathway Knowledgebase.

The Reactome Knowledgebase (www.reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression pattern surveys or somatic mutation catalogues from tumour cells. Over the last two years we redeveloped major components of the Reactome web interface to improve usability, responsiveness and data visualization. A new pathway diagram viewer provides a faster, clearer interface and smooth zooming from the entire reaction network to the details of individual reactions. Tool performance for analysis of user datasets has been substantially improved, now generating detailed results for genome-wide expression datasets within seconds. The analysis module can now be accessed through a RESTFul interface, facilitating its inclusion in third party applications. A new overview module allows the visualization of analysis results on a genome-wide Reactome pathway hierarchy using a single screen page. The search interface now provides auto-completion as well as a faceted search to narrow result lists efficiently.

Reactome pathway analysis: a high-performance in-memory approach.

BACKGROUND: Reactome aims to provide bioinformatics tools for visualisation, interpretation and analysis of pathway knowledge to support basic research, genome analysis, modelling, systems biology and education. Pathway analysis methods have a broad range of applications in physiological and biomedical research; one of the main problems, from the analysis methods performance point of view, is the constantly increasing size of the data samples. RESULTS: Here, we present a new high-performance in-memory implementation of the well-established over-representation analysis method. To achieve the target, the over-representation analysis method is divided in four different steps and, for each of them, specific data structures are used to improve performance and minimise the memory footprint. The first step, finding out whether an identifier in the user's sample corresponds to an entity in Reactome, is addressed using a radix tree as a lookup table. The second step, modelling the proteins, chemicals, their orthologous in other species and their composition in complexes and sets, is addressed with a graph. The third and fourth steps, that aggregate the results and calculate the statistics, are solved with a double-linked tree. CONCLUSION: Through the use of highly optimised, in-memory data structures and algorithms, Reactome has achieved a stable, high performance pathway analysis service, enabling the analysis of genome-wide datasets within seconds, allowing interactive exploration and analysis of high throughput data. The proposed pathway analysis approach is available in the Reactome production web site either via the AnalysisService for programmatic access or the user submission interface integrated into the PathwayBrowser. Reactome is an open data and open source project and all of its source code, including the one described here, is available in the AnalysisTools repository in the Reactome GitHub ( https://github.com/reactome/ ).

Microscopy image analysis of p63 immunohistochemically stained laryngeal cancer lesions for predicting patient 5-year survival.

The aim of the present study was to design a microscopy image analysis (MIA) system for predicting the 5-year survival of patients with laryngeal squamous cell carcinoma, employing histopathology images of lesions, which had been immunohistochemically (IHC) stained for p63 expression. Biopsy materials from 42 patients, with verified laryngeal cancer and follow-up, were selected from the archives of the University Hospital of Patras, Greece. Twenty six patients had survived more than 5 years and 16 less than 5 years after the first diagnosis. Histopathology images were IHC stained for p63 expression. Images were first processed by a segmentation method for isolating the p63-expressed nuclei. Seventy-seven features were evaluated regarding texture, shape, and physical topology of nuclei, p63 staining, and patient-specific data. Those features, the probabilistic neural network classifier, the leave-one-out (LOO), and the bootstrap cross-validation methods, were used to design the MIA-system for assessing the 5-year survival of patients with laryngeal cancer. MIA-system accuracy was about 90 % and 85 %, employing the LOO and the Bootstrap methods, respectively. The image texture of p63-expressed nuclei appeared coarser and contained more edges in the 5-year non-survivor group. These differences were at a statistically significant level (p < 0.05). In conclusion, this study has proposed an MIA-system that may be of assistance to physicians, as a second opinion tool in assessing the 5-year survival of patients with laryngeal cancer, and it has revealed useful information regarding differences in nuclei texture between 5-year survivors and non-survivors.

Is there sufficient evidence to support the use of antibiotic holiday just before the second stage of an infected total hip or knee arthroplasty revision surgery?

The practice of implementing an antibiotic holiday before the second stage of hip or knee arthroplasty is currently controversial due to limited evidence for this approach, as per the International Consensus Meeting 2018 on Musculoskeletal Infection. A greater understanding of this issue could augment the quality of Alrayes and Sukeik's mini-review (2023) on diagnosing, managing, and treating periprosthetic knee infections. However, a significant lack of literature exists concerning the optimal duration for the antibiotic holiday, calling for more research before establishing any clinical guidelines.

A Novel Surgical Treatment Management Algorithm for Elbow Posterolateral Rotatory Instability (PLRI) Based on the Common Extensor Origin Integrity.

Background: Here, we introduce a comprehensive treatment algorithm for posterolateral rotatory instability (PLRI) of the elbow, a condition affecting elbow mobility. We outline a diagnostic approach and a novel surgical management plan through the arthroscopic surgeon's point of view. Methods: The central focus of this management approach is the integrity of common extensor origin (CEO). High clinical suspicion must be evident to diagnose PLRI. Special clinical and imaging tests can confirm PLRI but sometimes the final confirmation is established during the arthroscopic treatment. The most appropriate treatment is determined by the degree of CEO integrity. Results: The treatment strategy varies with the CEO's condition: intact or minor tears require arthroscopic lateral collateral ligament imbrication, while extensive tears may need plication reinforced with imbrication or, in cases of retraction, a triceps tendon autograft reconstruction of the lateral ulnar collateral ligament alongside CEO repair. These approaches aim to manage residual instability and are complemented using a tailored rehabilitation protocol to optimize functional outcomes. Conclusion: PLRI is a unique clinical condition and should be treated likewise. This algorithm offers valuable insights for diagnosing and treating PLRI, enhancing therapeutic decision-making.

Septic Tibial Nonunions on Proximal and Distal Metaphysis-A Systematic Narrative Review.

BACKGROUND: Infected nonunion of the tibia represents a challenging complication for orthopedic surgeons and poses a major financial burden to healthcare systems. The situation is even more compounded when the nonunion involves the metaphyseal region of long bones, a rare yet demanding complication due to the poor healing potential of infected cancellous bone; this is in addition to the increased likelihood of contamination of adjacent joints. The purpose of this study was to determine the extent and level of evidence in relation to (1) available treatment options for the management of septic tibial metaphyseal nonunions; (2) success rates and bone healing following treatment application; and (3) functional results after intervention. METHODS: We searched the MEDLINE, Embase, and CENTRAL databases for prospective and retrospective studies through to 25 January 2021. Human-only studies exploring the efficacy of various treatment options and their results in the setting of septic, quiescent, and metaphyseal (distal or proximal) tibia nonunions in the adult population were included. For infection diagnosis, we accepted definitions provided by the authors of source studies. Of note, clinical heterogeneity rendered data pooling inappropriate. RESULTS: In terms of the species implicated in septic tibial nonunions, staphylococcus aureus was found to be the most commonly isolated microorganism. Many authors implemented the Ilizarov external fixation device with a mean duration of treatment greater than one year. Exceptional or good bone and functional results were recorded in over 80% of patients, although the literature is scarce and possible losses of the follow-up were not recorded. CONCLUSION: A demanding orthopedic condition that is scarcely studied is infected metaphyseal tibial nonunion. External fixation seems promising, but further research is needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO No. CRD42020205781.