Research utilising artificial intelligence (AI) and cardiovascular magnetic resonance (CMR) is rapidly evolving with various objectives, however AI model development, generalisation and performance may be hindered by availability of robust training datasets including contrast enhanced images.NotIs CMR is a large UK, prospective, multicentre, observational cohort study to guide the development of a biventricular AI scar model. Patients with ischaemic heart disease undergoing clinically indicated contrast-enhanced cardiac magnetic resonance imaging will be recruited at Nottingham University Hospitals NHS Trust and Mid-Yorkshire Hospital NHS Trust. Baseline assessment will include cardiac magnetic resonance imaging, demographic data, medical history, electrocardiographic and serum biomarkers. Participants will undergo monitoring for a minimum of 5 years to document any major cardiovascular adverse events. The main objectives include (1) AI training, validation and testing to improve the performance, applicability and adaptability of an AI biventricular scar segmentation model being developed by the authors and (2) develop a curated, disease-specific imaging database to support future research and collaborations and, (3) to explore associations in clinical outcome for future risk prediction modelling studies.NotIs CMR will collect and curate disease-specific, paired imaging and clinical datasets to develop an AI biventricular scar model whilst providing a database to support future research and collaboration in Artificial Intelligence and ischaemic heart disease.The online version contains supplementary material available at 10.1186/s12968-023-00978-1. Digital technologies, particularly artificial intelligence (AI), are advancing at a significant rate with growing interest and an increase in their application and deployment in clinical medicine. Within radiology, oncology and cardiology use of AI has gained significant momentum due to the data-rich nature of medical imaging.Cardiovascular magnetic resonance (CMR) has a significant, and established, role in international guidelines , 2. In pSeveral AI models have utilised LGE-CMR datasets for clinical challenges, including diagnostics, myocardial/scar segmentation and prediction modelling, with promising results . HoweverSeveral open access datasets already exist. However, low numbers and limited sequences restrict their utilisation for AI training . ProjectFurther benefit may be gained by the inclusion of a variety of scar visualisation sequences utilised in clinical practice as well as scanner variations such as manufacturers and field strength with supplementary participant demographics. This is particularly true for patients with implantable cardioverter defibrillators who are often excluded from research studies due to significant device artefact affecting image quality.Insight obtained from our initial experience of developing an AI segmentation model using 500 2D LGE-CMR scans from two UK sites has highlighted the limitations posed by retrospective data collection including limited access to detailed clinical outcomes and acquisition sequences. Nonetheless, this retrospective, disease-specific, multi-vendor, multi-sequence LGE-CMR database has been critical for the preliminary AI development utilising the most commonly available clinical LGE-CMR manufacturers and acquisition sequences.Prospectively we aim to develop a robust, paired, clinical and curated LGE-CMR imaging database including multiple manufacturers and a variety of acquisition sequences to broaden AI model training exposure, model refinement, validation and testing. The subsequent disease-specific curated data aims to support future collaborative research projects and clinical outcome prediction modelling.To broaden and improve the performance, applicability and adaptability of our AI segmentation model using varied CMR sequences available in routine clinical practice.Develop a curated database, available via application, to support broader research opportunities and collaboration.Allow examination of associations between clinical data, imaging data and clinical outcomes.A prospective disease-specific (ischaemic heart disease), paired, multi-vendor, LGE-CMR imaging and clinical database, “NotIs CMR”, will be created with the following objectives:A non-randomised, observational, multicentre resource for the recruitment of routinely acquired LGE-CMR scans in patients with ischaemic scar, including those with implanted cardiac devices e.g. implantable cardioverter defibrillators Fig. .Fig. 1PrProspective recruitment will include all adults above 18 yrs of age with no contraindication to LGE-CMR, attending for clinically indicated scans with presumed or confirmed ischaemic aetiology. “All comers” will be approached for full inclusivity, to reflect the local demographics of the disease condition and to support broad recruitment.Image segmentation is a key component of this study. As little guidance exists on sample-size calculations in AI model development we aim to collect a large dataset of disease specific scans for this purpose .Having developed our preliminary AI scar model utilising 500 retrospective LGE-CMR scans, the NotIs CMR study will recruit a further 500 participants prospectively based primarily on the feasibility of the two recruiting sites. We will use cross validation and sub-sampling methods to investigate the effects of sample size on our AI model.Patients, with confirmed or presumed ischaemic heart disease, will be identified either at the time of referral for CMR, at the time of CMR attendance or shortly after CMR acquisition.Exclusion criteria include clinical contraindication to CMR or inability to provide informed consent. Subsequent absence of ischaemic scar on CMR in those recruited will not result in exclusion from the data resource but will not count towards the ischaemic target required for the study.Recruitment will complete once 500 scans with ischaemic scar have been collected.Consent will be obtained from individuals explicitly acknowledging the use of their de-identified data in prospective AI and computational modelling projects. All participants have the right to withdraw from the study at any point.Data including baseline demographics, risk factors, medical history, routinely reported clinical CMR parameters, standard clinical blood tests, electrocardiograms and clinical outcomes will be stored on the research electronic data capture (REDCap) database.Imaging data will be obtained from the clinical CMR reports. Follow-up data will be collected from primary and secondary care medical case notes at predefined times up to 5 years post enrolment. This will include major adverse cardiac events (MACE), ventricular arrhythmias, cardiac procedures and death Tables , 2. DefiWe acknowledge the limitations of robust capture of ventricular arrhythmias in a study where only a proportion of participants will have implanted cardiac devices for monitoring however to maximise data capture, participants will provide consent allowing direct contact with them should further data clarification become necessary.The primary diagnosis will be confirmed only after acquisition of CMR sequences and clinical reporting. Ischaemic heart disease will be defined as either (a) presence of ischaemic-pattern LGE in the absence of any other significant cardiac findings OR (b) alternative imaging confirming the presence of atherosclerotic disease or a history of previous coronary artery bypass grafting/coronary artery intervention, in the absence of ischaemic LGE pattern on CMR.Whilst all patients recruited will have their data collected and stored, only those with confirmation of ischaemic heart disease on the subsequent CMR results will be included in the specific ischaemic database. The subsequent “normal and non-ischaemic” scans will still be utilised as the “control group” for ultimate AI performance testing.®, Bayer Pharma, Berlin, Germany). Examples of LGE protocol parameters can be found in Table Local clinical protocols will be utilised to acquire CMR imaging data. LGE images will be typically acquired 10–20 min after a single bolus of 0.1mmol/kg gadobutrol .Clinical outcomes will include death (including aetiology), ventricular arrhythmic events, ischaemic events, heart failure admissions and cardiac device implantation . Second operator labelling will be present. The labelling operator will utilise all available images  to inform the labelling process. The minimum-labelled series will include short-axis CINE and LGE. Labels for CINE images will include the left and right ventricular endo- and epicardium contoured with trabeculations excluded. Papillary muscles and aortic root/ascending aorta will be separately labelled. Scar will be delineated on LGE utilising several methods including manual, full-width half-maximum and n-standard deviations  As a quality control measure, each full study as well as the individual image slices will receive an image quality score based on a combination of the clinical CMR report and visual assessment by the labelling operator. The quality of the CINE and LGE sequences will be scored using the technical quality comments from the clinical scan report. Additional quality scores will be allocated by the labelling operators according to technical image quality and confidence in the segmentation. This will be used to facilitate clinical interpretability of AI outputs for future clinical use.At least 100 scans containing ischaemic scar will be utilised for the purpose of testing and retraining of a deep learning LGE segmentation model  developed by our group. For current model retraining, we will extract and reserve a test set (20% of the whole dataset) representing the diversity of data  to validate the final trained AI method. The remaining 80% data will be used for AI model training and development using k-fold cross validation. Evaluation of the retrained model will be undertaken utilising multi-modality assessments including, but not limited to, overlap, distance and volume metrics .This study has been supported with regular input from a dedicated Patient and Public Involvement (PPI) group since the inception of the project idea in 2018. The group consists of individuals who have lived with the consequences of ischaemic heart disease and ventricular arrhythmias. The PPI Patient Lead for this taskforce group holds a position on the data access committee for the curated database.Artificial intelligence research in CMR is being increasingly undertaken with various objectives but model development, generalisation and performance may be hindered by the lack of availability of robust, and representative, training datasets including contrast-enhanced images, multivendor sequences and ICD patients.The NotIs CMR study aims to collect and curate data from clinically indicated investigations including contrast enhanced CMR imaging with a minimum of 5 years clinical follow up for major adverse cardiovascular events including ventricular arrhythmic events. To our knowledge this will produce the largest disease-specific curated paired LGE-CMR imaging and clinical database with the potential of advancing the field of research utilising AI.The prospectively collected database allows the potential to integrate patient outcomes (e.g. arrhythmic events) with clinical, imaging and scar characteristics to develop risk prediction models whilst supporting the development of a robust and more broadly clinically applicable AI biventricular scar model to guide future clinical therapies including ventricular tachycardia ablation.Additional file 1. Study and clinical definitions.


What are the treatment outcomes for distal radius fractures in older adults in the short-term (≤3 months) and intermediate-term (>3 months to 1 year) postoperative periods?In this systematic review and network meta-analysis of 23 randomized clinical trials including 3054 participants, distal radius fracture treatment with open reduction and internal fixation with volar locking plate was associated with clinically and statistically significant improvements in short-term patient-reported outcomes assessed with the Disabilities of the Hand and Shoulder Questionnaire and Patient-Rated Wrist Evaluation.The findings of this study suggest that open reduction and internal fixation with volar locking plate may achieve greater patient-reported quality of life in the early postoperative recovery period compared with casting alone. Randomized clinical trials (RCTs) and meta-analyses have reported inconsistent conclusions regarding optimal distal radius fracture (DRF) treatment in older adults and are limited due to the inclusion of cohort studies with small sample sizes. A network meta-analysis (NMA) addresses these limitations by only synthesizing direct and indirect evidence from RCTs and may clarify optimal DRF treatment in older adults.To examine DRF treatment results in optimal short-term and intermediate-term patient-reported outcomes.Searches of MEDLINE, Embase, Scopus, and Cochrane Central Register of Controlled Trials were conducted for RCTs that investigated DRF treatment outcomes in older adults between January 1, 2000, and January 1, 2022.Randomized clinical trials including patients with a mean age of 50 years or older that compared the following DRF treatments were eligible for inclusion: casting, open reduction and internal fixation with volar lock plating (ORIF), external fixation, percutaneous pinning, and nail fixation.Two reviewers independently completed all data extraction. An NMA aggregated all direct and indirect evidence among DRF treatments. Treatments were ranked by surface under the cumulative ranking curve score. Data are reported as standard mean differences (SMDs) and 95% CIs.The primary outcome was short-term (≤3 months) and intermediate-term (>3 months to 1 year) Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire scores. Secondary outcomes included Patient-Rated Wrist Evaluation (PRWE) scores and 1-year complication rates.In this NMA, 23 RCTs consisting of 3054 participants (2495 women [81.7%]) with a mean (SD) age of 66 (7.8) years were included. At 3 months, DASH scores were significantly lower for nail fixation  and ORIF  compared with casting. The PRWE scores were also significantly lower for ORIF  at 3 months. In the intermediate term, ORIF was associated with lowered DASH  and PRWE  scores. One-year complication rates were comparable among all treatments.The findings of this NMA suggest that ORIF may be associated with clinically significant improvements in short-term recovery compared with casting for multiple patient-reported outcomes measures with no increase in 1-year complication rates. Shared decision-making with patients may be useful to identify patient preferences regarding recovery to determine optimal treatment. This meta-analysis examines short- and intermediate-term outcomes among older adults with optimal distal radius fracture treated with casting, open reduction and internal fixation with volar lock plating, external fixation, percutaneous pinning, and nail fixation. Moreover, these studies typically evaluate long-term outcomes (≥1 year) and group all surgical treatments into 1 category rather than separating by treatment type. There are substantial differences in DRF outcomes among various surgical treatments, and grouping all of them into 1 category does not provide sufficient evidence to identify the optimal DRF treatment in older adults.15 The limitations of traditional meta-analyses can be overcome by performing a network meta-analysis (NMA). An NMA uses direct comparisons from multiple RCTs to make indirect comparisons between other treatment options. For example, if one study compares ORIF with casting and another study compares casting with external fixation, an NMA can make an indirect comparison between external fixation and ORIF by using casting as a constant. Therefore, NMAs can include combinations of RCTs that were not previously used in traditional meta-analyses, thereby capturing the full breadth of DRF outcomes studies in the literature and producing level 1A evidence  to estimate which treatment modality achieves superior patient-reported outcomes (PROs) in the early recovery period.Several meta-analyses have been performed to compare operative vs nonoperative treatment of DRFs.18 These NMAs were not designed to detect differences in outcomes across treatment types in older adults during the short and intermediate time frames, when differences in recovery are most relevant to patients. Therefore, we conducted an NMA to investigate the short-term (≤3 months) and intermediate-term (>3 months to 1 year) outcomes of RCTs across multiple surgical options and casting. The purpose of this NMA was to collate data from all DRF RCTs published between January 1, 2000, and January 1, 2022, in older adults to compare the particular treatment modalities in the early recovery period. We hypothesized that patients undergoing surgery who receive ORIF may have the largest improvements in PRO scores in the short-term and intermediate-term recovery periods compared with other treatment modalities in older adults.Previous NMAs on DRF outcomes have evaluated long-term outcomes (≥1-year follow-up), whereas others did not present PROs and focused on patients younger than 50 years.PRISMA) reporting guideline.20In this network meta-analysis, we searched MEDLINE (PubMed), Embase (Elsevier), Scopus (Elsevier), and Cochrane Central Register of Controlled Trials for peer-reviewed RCTs evaluating surgical and casting treatments for DRFs in older adults from January 1, 2000, to January 31, 2022. A research librarian assisted in the development of the search strategy and algorithm provided in eTable 1 in 21 Article characteristics, patient demographic characteristics, follow-up periods, and outcomes data were collected. Discrepancies were discussed by the 2 reviewers until a consensus was reached. If a disagreement persisted, a third reviewer (R.L.K.) was available. Each article underwent a risk-of-bias assessment according to the Cochrane Collaboration guidelines  trained in systematic reviews and meta-analyses. The same 2 reviewers independently examined the title and abstract for articles obtained from the initial search. After review of the titles and abstracts, full-text articles were obtained and uploaded to the web-based systematic review software Rayyan for an in-depth evaluation.9 Secondary outcomes included Patient-Rated Wrist Evaluation (PRWE) scores and 1-year complication rates.Outcome measurements for the analysis were determined after data collection. Disabilities of the Arm, Shoulder and Hand (DASH) and Patient-Rated Wrist Evaluation (PRWE) questionnaires were the most frequently reported outcome measurements in the literature. Studies that did not include DASH and PRWE scores were not included in the analysis. Patients use DASH and PRWE questionnaires, scaled from 0 (no disability) to 100 (fully impaired), to rate their functionality. The data were split into short-term outcomes (≤3 months) and intermediate-term outcomes (>3 months to 1 year), consistent with a previous meta-analysis.22 Because SUCRA analysis identifies the probability that a certain DRF treatment is the optimal treatment, it is a helpful supplement for interpreting pairwise comparisons between treatments by minimizing the effect of small sample sizes on treatment ranking.For the analysis, a series of pairwise meta-analyses were conducted to measure the direct comparison between treatments. A nodal map was created to establish the geometry among the treatments. Next, an NMA was used to examine outcomes by combining direct and indirect evidence across all treatments. A random-effects model was used for the analysis to account for any heterogeneity that may be present among the study methods. For all analyses, we calculated and report the standard mean differences (SMDs) with the corresponding 95% CIs. A surface under the cumulative ranking curve (SUCRA) value was used to determine the ranking of treatments. SUCRA is measured on a scale of 0 to 1. The closer the SUCRA value is to 1, the higher the likelihood that it is the best or one of the best treatment options, whereas a lower SUCRA score indicates a higher likelihood that the treatment is ranked lower than other treatments.45 Thirteen studies assessed short-term patient-reported outcomes with DASH and PRWE; intermediate-term outcomes were assessed in 18 studies with DASH and 15 studies with PRWE. Of the included studies, 20 evaluated ORIF, 11 evaluated casting, 6 evaluated external fixation, 5 evaluated percutaneous pinning, and 4 studies evaluated nail fixation. A total of 3054 study participants  were included in the analysis. The mean sample size was 68  participants per study. Participants’ age ranged from 19 to 90 years  with a mean (SD) age of 66 (7.8) years. Fifty-seven percent of the studies used the AO (Arbeitsgemeinschaft für Osteosynthesefragen) Classification system46 to report fracture type. Of the studies that reported fracture classification, type A fractures were the most common (930), followed by type C (819) and type B (20). The search strategy yielded 1140 studies; 188 articles were eligible for full-text review. Fifty-six articles originally met all inclusion criteria for the analysis, but only 41% of these articles shared an outcome measure. Therefore, 23 articles were included in the final analysis .23,24,25A risk of bias assessment was performed, and a moderate level of bias was present  and ORIF  compared with casting A. After The SUCRA values for each treatment were calculated for the DASH and PRWE questionnaires . For DASThe results of our NMA and systematic review show level 1A evidence that ORIF is associated with better short-term PROs in older adults compared with other DRF treatment modalities with no increase in 1-year complication rates. To our knowledge, this is the first NMA conducted of studies of older adults (age ≥50 years) that compared DASH and PRWE scores among various DRF treatments in the early and intermediate recovery periods. Patient-reported outcomes such as DASH and PRWE provide comprehensive insights into recovery after treatment by including both functional elements and psychosocial components related to recovery. By using PROs as our primary outcome, we identified that casting in all patients with DRFs does not align with optimal patient-perceived recovery compared with other treatment modalities. Therefore, we would recommend offering surgical treatment of DRFs to older adults with excellent physiologic health, regardless of chronologic age, while engaging in a shared decision-making process with each patient to tailor optimal management.48 However, by the intermediate term, the improvements were limited to 3.55 in DASH and 2.90 in PRWE scores after ORIF. Although these values were statistically significant, they did not meet the minimal clinically important difference threshold and were not clinically significant. These findings are consistent with the current literature that suggests long-term recovery is similar regardless of treatment choice. Another notable finding is that nail fixation noted an approximate 18-point improvement in DASH scores in the early recovery period. However, only 1 study included in this analysis investigated nail fixation in the short-term recovery period compared with the 7 ORIF studies included for this time point. Further studies are needed to examine whether nail fixation can provide better outcomes than ORIF in older adults in the short term.After consolidating all direct and indirect comparisons among DRF treatments from 23 RCTs, we observed that older adults receiving ORIF performed 9.28 points better on DASH outcomes and 9.55 points better on the PRWE outcomes by the 3-month recovery period. These values fall within the range of the minimal clinically important difference for DRFs, which is estimated to be between 6.8 and 10.8 for DASH and 8.5 and 11.5 for PRWE outcomes.52 We advise clinicians to prioritize identifying patient preferences for treatment recovery to assist them in making an informed decision about their treatment plan. Moreover, the consolidation of data from these RCTs suggests that ORIF is the optimal surgical fixation strategy in older adults compared with other methods, such as external fixation and percutaneous pinning. Therefore, older adults who desire surgical fixation and are amenable to volar lock plating should be informed that ORIF is associated with the best short-term outcomes after DRF after consolidating data from multiple RCTs.Based on these findings, using chronologic age as a proxy for functional demand and recommending casting for all older adults does not apply equally to all patients. Patients who desire earlier recovery could substantially benefit from ORIF treatment and should be counseled on the advantages of surgical treatment during their clinical visits. Moreover, future DRF studies should focus on identifying which older adults would most greatly benefit from ORIF treatment compared with casting. Stratifying older adults by activity status, level of frailty, or number of comorbidities could be one method to estimate functional demand and integrate physiologic health into treatment decisions.5 which was one of the largest multisite RCTs performed in older adults with DRFs. Despite not being able to include all RCTs, the results of this NMA are consistent with findings from WRIST demonstrating higher short-term PRO scores for individuals receiving ORIF compared with casting. Several of the common PROs reported in the literature included instruments such as the DASH, PRWE, Michigan Hand Outcomes Questionnaire, Short Form-36, and visual analog scale. Additionally, functional metrics, such as grip strength, also greatly varied in the literature, sometimes reported in kilograms or other times as a percentage of the uninjured hand. Given the various outcome measurements, a standardized reporting measure for DRF outcome studies would be necessary so that these data can be synthesized appropriately. This could be one opportunity to minimize variation among outcome measures in the literature and provide more comprehensive treatment recommendations for this population.An incidental finding from this study was the profound heterogeneity in outcome instruments used and variables reported in the literature. After full-text review, 56 articles had met all inclusion criteria; however, only 41% of those original studies were eligible for inclusion after limiting the included articles to shared outcome measures. Consequently, numerous RCTs could not be studied in this analysis, including the Wrist and Radius Injury Surgical Trial (WRIST),51 Additionally, a major assumption for the property of transitivity is that the distribution of effect modifiers across treatments does not vary significantly across studies. We attempted to ensure the study populations were similar by imposing strict criteria (mean age ≥50 years and examining specific treatments for DRFs), but there could be other differences between the study populations and study designs investigated that were not homogeneous. Additionally, PRO metrics were standardized to improve the homogeneity of the study population. Moreover, the differences between direct and indirect pairwise comparisons were minimal among studies with overlap across the 95% CI. Next, our study did not discriminate based on type of DRF, primary or secondary displacement, or high-energy vs low-energy fracture. Some high-energy fractures from a motor vehicle collision could not safely be treated with casting and would require operative management. Therefore, results could have been different depending on fracture type. A random-effects model was used to minimize potential heterogeneity from these variables. In addition, because casting and ORIF are considered the predominant DRF treatments in older adults, there were few studies that directly compared these treatments with other modalities. As a result, the nodal maps did not close completely and there were fewer pairwise comparisons at certain follow-up points.This study has several limitations. To perform an NMA, we must assume the property of transitivity, which assumes study populations from RCTs are homogeneous enough to make indirect comparisons among different treatment modalities.In this NMA, level 1A evidence suggests that ORIF is associated with earlier recovery after DRF treatment in older adults. It may be useful for clinicians to work with patients to determine their preferences for DRF treatment and consider offering ORIF to patients who desire more rapid recovery rather than waiting 1 year for optimal treatment outcomes. Future studies should investigate alternative methods for identifying which patients would benefit most from ORIF treatment in the short term and intermediate term.


Disruptions to the gut microbiota have been associated with adverse outcomes including graft-versus-host disease, infections, and mortality after hematopoietic cell transplantation and cellular therapy. Evidence for causal links is accumulating, thus supporting therapeutic interventions targeting the microbiota with the goal of preventing and treating adverse outcomes. One such intervention is fecal microbiota transplantation (FMT) by which an entire community of gut microbiota is transferred to the patient with dysbiosis. As this approach in transplant and cellular therapy recipients is still in its infancy, no best approach has been defined and many open questions need to be addressed before FMT becomes a standard treatment. In this review, we highlight microbiota-outcome associations with the highest level of evidence, provide an overview of the main FMT trials, and suggest some paths forward. To name a few, the gut microbiota is critical in (i) synthesis of essential amino acids and vitamins, and metabolism of indigestible dietary polysaccharides,2 (ii) colonization resistance, the process by which the gut microbiota resists invasion by other microorganisms, thus protecting the host from infections,3 (iv) maintenance of a robust intestinal barrier and its repair after injury,5 (v) regulation of intestinal and systemic immunity,7 and (vi) production of many metabolites that circulate in the bloodstream, with distant and organism-level physiological effects.8 Not surprisingly, disruptions to the gut microbiota have been implicated in common diseases such as obesity,9 depression,10 and type 2 diabetes.11 Recent evidence for the presence of axes such as the gut-brain axis,12 gut-lung axis,13 and even brain-gut-kidney axis14 attest to the broad involvement of the gut microbiota in tissue and organismal homeostasis.Harboring 10Hematopoietic cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cells are potentially curative treatments for patients with hematologic malignancies. The HCT process starts with administration of a conditioning regimen consisting of chemotherapy with or without total body irradiation, followed by infusion of hematopoietic cells. Hematopoietic cells may be derived from the same patient (autologous) or another individual . Following the infusion of the graft, there is a period of profound immunosuppression lasting weeks to months, during which patients receive antibiotics to prevent and treat infections. Enteral nutrition is often compromised due to the toxicity of conditioning regimens to the upper and lower intestinal tract. Infections and graft-versus-host disease  are common complications of HCT.15 Detailed reviews of the classic pathophysiology of acute GVHD have been published16 and more recent translational aspects of this process have been highlighted.17 A critical pathway in acute GVHD pathogenesis involves the effects of the conditioning regimen  used before HCT on the intestinal microenvironment. Conditioning regimens damage the intestinal barrier separating the intestinal microbiota from subepithelial immune cells. Intestinal tissue injury leads to the recruitment and activation of neutrophils, triggering acute GVHD. Tissue damage may occur directly by activated neutrophils.18 In addition, activated neutrophils can migrate to mesenteric lymph nodes, a process dependent on the intestinal microbiota. Once in the mesenteric lymph nodes, these neutrophils present antigens to T cells via MHC class II and lead to their activation.19 Conditioning also augments expression of microbiota-derived Toll-like receptor ligands and MHC class II on intestinal epithelial cells, triggering downstream pro-inflammatory pathways via macrophages, innate lymphoid type 1 cells, and conventional T cells.20 The intestinal microbiota regulates intestinal tissue sensitivity to chemotherapy and radiation.5Acute GVHD is the clinical outcome of an early alloimmune attack by donor T cells against host tissues. In intestinal acute GVHD, intestinal stem cells seem to be the main target in this attack.21 CARs are synthetic receptors expressed by an immune effector cell, typically T cells, which recognize cognate antigens on target cancer cells. Before CAR T-cell infusion, low-dose lymphodepletion chemotherapy is administered. The consequent immunosuppression triggers the use of prophylactic and therapeutic antibiotics. Infection, cytokine release syndrome (CRS), and immune effector cell – associated neurotoxicity syndrome (ICANS) are common complications of CAR-T cell therapy.CAR-T cells are a more recent immunotherapeutic treatment modality for patients with specific lymphoid malignancies.In this review, we first discuss gut microbiota disruptions in HCT and CAR-T recipients and the potential clinical impact of these disruptions. Next, we focus on one of the strategies – fecal microbiota transplantation (FMT) – to repair microbiota injuries and improve clinical outcomes in these patients. We synthesize the strongest pieces of evidence from the rapidly expanding literature.22 As HCT recipients frequently have a history of treatment for their underlying blood disorder, the process of dysbiosis may have already started by the time they are referred for HCT. As a result, when they arrive for HCT, the gut microbiota may show a “scar” of prior injuries.23–25 In addition, after allo-HCT, the gut microbiota diversity further declines.26–28 Diversity loss is commonly associated with decreased abundance of obligate anaerobic commensals30 and domination by a few species. Intestinal domination has been most consistently demonstrated for Enterococcus.31–34The two most consistent features of dysbiosis repeatedly observed in HCT recipients are loss of alpha diversity and pathobiont overgrowth. Alpha diversity is measured by various indices of microbial richness (number of different taxa) and evenness (taxa relative abundances).35 However, published data on long-term trajectory of microbiota after HCT are limited. In the longest follow-up (median >6 years) thus far of the gut microbiota in allogeneic HCT recipients (59 patients), gut microbial diversity and the abundance of butyrate-producing bacteria continued to be lower than the age- and sex-matched healthy control,36 supporting the microbiota scar theory.After the removal of various causes of gut microbiota injury, partial though slow resolution of damage seems to occur.37–43 Potent activity against obligate anaerobic bacteria is a shared feature of these antibiotics. In murine studies, carbapenem use led to the expansion of mucus-degrading species Akkermansia muciniphila38 and Bacteroides thetaiotaomicron.37 The use of anti-anaerobic antibiotics is also associated with Enterococcus expansion.33Antibiotic exposure is arguably the leading cause of dysbiosis in HCT recipients. Piperacillin-tazobactam and carbapenems are the antibiotics most consistently associated with microbiota injury in HCT patients.44 and nutrition 45–47 may influence the gut microbiota in HCT patients. Enteral nutrition is possibly beneficial for clinical outcomes and may improve microbiota indices but the evidence is weak and more rigorous trials are needed.48 In a large study of allogeneic HCT patients combined with mechanistic murine studies, lactose drove Enterococcus expansion in the gut which was associated with lower overall survival and higher acute GVHD-related mortality.32Conditioning regimens49 large population-based studies have found relations between the gut microbiota and variables including anthropometric measures , stool consistency, common diseases , non-antibiotic drugs , and smoking history (direct or indirect exposure).50–53 Some of these variables are frequently present or relevant to HCT and cellular therapy recipients.The gut microbiota is modulated by several other intrinsic and extrinsic factors. Although evidence in the setting of HCT and CAR-T therapy is limited,Associations have been reported between dysbiosis and various outcomes of HCT and CAR-T therapy. However, the most consistent associations have been for acute GVHD and transplant-related mortality .54–58 Microbiota changes associated with acute GVHD or its mortality include loss of alpha diversity,28 loss of butyrogenic bacteria,58 loss of Clostridia,58 loss of Blautia,59 loss of Lachnospiraceae,55 lower ratios of strict-to-facultative anaerobic bacteria,58 colonization with oral Actinobacteria and Firmicutes,55 expansion of picobirnaviruses,56Enterococcus domination,32 and large fluctuations in microbial community composition  in the early phase after HCT.57 Certain microbiome-associated systemic metabolomic alterations can be detected at the onset of acute GVHD. In one analysis, the concentration of several microbiota-derived metabolites  at the onset of acute GVHD was significantly different from healthy donors.60Dysbiosis has been associated with more GVHD in several studies.61 A total of 94 variables including 17 antibacterial antibiotic classes used between 7 days before and 30 days after transplant  along with relevant clinical and demographic variables were analyzed. We applied three orthogonal statistical methods: conventional Cox proportional hazard regression, marginal structural models, and machine learning. Marginal structural models consider antibiotic exposures on a given day as a function of antibiotic exposures on the previous day and the baseline covariates. By machine learning, we attempted to reveal non-linear, more complex associations between antibiotic use and acute GVHD. Exposure to carbapenems during weeks 1 and 2 after HCT and exposure to combinations of penicillins with a β-lactamase inhibitor (e.g. piperacillin-tazobactam) during week 1 after HCT were most consistently associated with increased risk for acute GVHD. These two classes of antibiotics have been associated with acute GVHD in other studies as well.37–43 Intriguingly, the use of metronidazole, another strong anti-anaerobic antibiotic, led to less acute GVHD in a seminal randomized trial.62We recently analyzed a large single-center database of allogeneic HCT recipients .Enterococcus domination was less frequent among patients receiving tocilizumab than historical controls.63 In the therapeutic setting, a phase 2 trial of a novel recombinant human interleukin-22 dimer used in combination with systemic corticosteroids for frontline treatment of lower gastrointestinal acute GVHD showed expansion of commensal anaerobes and greater microbiota diversity in responders.64Preservation of the gut microbiota may be involved or even required in the success of novel therapeutics in prevention of acute GVHD. In a phase 2 trial of tocilizumab (an interleukin-6 inhibitor) used for GVHD prophylaxis, the expected loss of microbiota diversity after HCT was less than in a historical control cohort. Similarly, 56The gut virome has also been associated with the risk of acute GVHD. A viral ‘bloom’ seems to occur after HCT, accompanied with an expansion of vertebrate viral sequences following transplantation. Patients developing gastrointestinal acute GVHD had increased presence and abundance of specific DNA viruses  over time and lower phage richness. Picobirnaviruses were predictive of subsequent intestinal acute GVHD.65 Acute GVHD and infection are the leading causes of TRM in HCT recipients. A specific timeframe when dysbiosis may impact mortality is weeks 2 and 3 after HCT, coinciding with hematopoietic engraftment.30 Loss of Blautia and expansion of Enterococcus have been associated with acute GVHD-related mortality.59 Loss of urinary 3-indoxyl sulfate and butyrogenic bacteria, associated with reduction of Lachnospiraceae and Ruminococcaceae and expansion of Bacilli, in the first 10 days after allogeneic HCT was predictive of increased TRM.54There is a repeatedly observed association between low gut microbiota diversity and TRM after allogeneic HCT.67 immune reconstitution,69 respiratory tract infections,71 CDI,72 chronic GVHD,73 and disease relapse74 after HCT.Some data suggest associations between the gut microbiota and bloodstream infection (BSI),Ruminococcus, Bacteroides, and Faecalibacterium were associated with complete response to therapy in patients with B-cell malignancies.75 These associations were independent of several other variables potentially reflecting more aggressive disease and disease-related complications. Whether exposure to oral vancomycin may have the same association could not be evaluated because exposure to this antibiotic in the absence of piperacillin/tazobactam and carbapenems was infrequent. In another study of B-cell lymphoma patients, piperacillin-tazobactam, meropenem, cefepime or ceftazidime use within 3 weeks before CAR-T infusion was associated with lower response to treatment. Focusing on patients not exposed to these antibiotics, the analysis revealed several bacteria associated with CAR-T response. These bacteria included Bifidobacterium longum, Bacteroides eggerthii, Ruminococcus lactaris, Eubacterium spp. CAG 180, Akkermansia muciniphila, Erysipelatoclostridium ramosum, and Bacteroides stercoris.76Microbiota results from CAR-T studies are more recent. In one study, exposure to piperacillin/tazobactam and carbapenems within 4 weeks before CAR-T infusion was associated with worse survival and increased neurotoxicity. Baseline alpha diversity, as well the abundance of 77 could intestinal damage be the underlying cause for both microbiota injury and acute GVHD without the latter two being causally linked? Mechanistic evidence for causality is accumulating in murine models. However, whether results from controlled murine experiments can be generalized to the human setting is unclear. Germ-free mice, a common and useful model for microbiota studies, do not represent antibiotic-treated patients undergoing HCT as the gut microbiota of patients often contains a large microbial community even after heavy antibiotic exposure. Through coprophagy, specific pathogen-free (SPF) mice may replenish their gut microbiota from their own stool and the stool of their co-housed mice. Finally, a fundamental unanswered question is whether microbiota effects are primarily mediated by individual taxa  or community-level properties of the microbiota (e.g. diversity). Complicating the matters is the fact that community-level properties such as alpha diversity are frequently associated with the relative abundance of specific taxa. For example, enterococcal domination is very common in low-diversity communities depleted of obligate anaerobic commensals after HCT.33The possible causal link between microbiota and subsequent clinical outcomes is unclear. In the human setting, it is difficult to eliminate confounding with certainty. Conditioning-induced intestinal barrier damage, peak antibiotic exposure, altered nutrition, and maximum microbiota damage tend to occur about the same time after HCT, making it difficult to determine the effect of each one in isolation. As an example, and given the importance of intestinal damage in the pathogenesis of acute intestinal GVHD,78–80 and gut barrier enhancing effects79–84 and may protect against acute (indole)79 and chronic (butyrate/propionate)73 GVHD. Although most results thus far have been in murine studies, cumulative evidence suggests involvement of these metabolites in the outcomes of HCT in patients. In a pilot pharmacomicrobiomics study with 20 adults undergoing allogeneic HCT using mycophenolate mofetil (MMF) and tacrolimus for GVHD prophylaxis, the association between the gut microbiota and enterohepatic recirculation (EHR) of mycophenolic acid was evaluated. Several Bacteroides species  were more abundant in the high vs. low EHR group,85 introducing the possibility that the gut microbiota may modulate acute GVHD risk via differential metabolism of prophylactic medications. As MMF is a key drug in GVHD prophylaxis in the increasingly more common HLA-haploidentical HCT, more pharmacomicrobiomics studies are warranted.Loss of short-chain fatty acids  and indole (a tryptophan degradation product) are two metabolic changes that have been repeatedly observed in the setting of dysbiosis in HCT recipients. These microbiota-derived metabolites have immunosuppressiveB. thetaiotaomicron and aggravation of acute colonic GVHD.37 Through its mucolytic activity, B. thetaiotaomicron caused thinning of the colonic mucus layer and decreased xylose levels within the lumen, a process which was prevented by oral supplementation of xylose. Another study attempted to block the successful entry of live bacteria through the intestinal wall by immunizing mice against the conserved microbial surface poly-N-acetylglucosamine. By depleting bacteria penetrating the gut barrier without altering microbiota diversity, this approach reduced bacterial-induced neutrophil activation and acute GVHD.86Meropenem treatment of mice undergoing allogeneic HCT led to the expansion of Enterococcus expansion, a predictor of higher acute GVHD risk in patients, was dependent on lactose. Oral lactose depletion attenuated Enterococcus outgrowth and reduced the severity of GVHD, supporting a causal link.32 In the opposite direction, the process of immune attack during acute GVHD can cause damage to the gut microbiota by increasing oxygen tension in the normally hypoxic intestinal lumen, leading to a loss of obligate anaerobic commensals. This in turn worsens intestinal pathology. Importantly, oral iron chelation in murine models mitigated dysbiosis and reduced the GVHD severity, supporting a causal link.87In another murine study, A. muciniphila may increase the translocation of bacteria, their components , and metabolites to the bloodstream.89 Decreased oral intake potentiates expansion of mucolytic bacteria because they can use mucin as a nutrient.90Enterococcus expansion in the gut has been repeatedly associated with the risk of enterococcal BSI91 and Gram-negative bacteria domination of the gut microbiota with Gram-negative bacteremia.67 The mechanism seems to be a concentration effect, by which dominant bacteria have a higher chance of passing through the intestinal barrier.By thinning the intestinal barrier, expanded 92 In a murine CD19+ lymphoma model, microbiota conditioning with vancomycin combined with CD19 CAR-T therapy enhanced cross-presentation of tumor-associated antigens and improved tumor control compared to CAR-T alone.92 In another study, peptidoglycan biosynthesis was the metabolic pathway most strongly associated with disease progression after CAR-T, independently of demographic or clinical variables.76Findings from a small retrospective study in patients with B-cell acute lymphoblastic leukemia treated with CAR-T suggested better CAR-T expansion in patients exposed to oral vancomycin before infusion.93 with implications for clinical outcomes such as mortality,65 acute GVHD,79 poor immune reconstitution,95 and disease relapse.74 Similar to HCT recipients, specific antibiotic exposures and gut microbiota changes in CAR-T recipients have been associated with treatment response, mortality, and ICANS.76 Inspired by these associations, strategies to mitigate dysbiosis to improve clinical outcomes after HCT and CAR-T therapy have been a subject of recent interest.96 Fecal microbiota transplantation (FMT) is one such strategy by which gut microbial communities are transferred as a whole to the patient to prevent or ameliorate dysbiosis. FMT is currently approved only for the treatment of multiply recurrent or refractory Clostridioides difficile infection (CDI).97HCT recipients experience significant disruptions to their gut microbiota,98–101 and steroid-refractory acute GVHD (see below). There has been a large variability in approach, as we will discuss in the following sections. A summary of the key features of the previous FMT trials in the field with at least 10 patients treated with FMT is shown in 102–108Restoring the commensal microbiota and eradicating pathogens including multi-drug resistant organisms (MDROs) is the main idea in the prophylactic use of FMT after HCT. Clinical outcomes that might improve with this approach include infection rate, acute (and perhaps chronic) GVHD, and TRM. In the therapeutic setting after HCT, FMT has been used for the treatment of refractory CDI109 11 patients received third-party FMT at least 2 weeks before their planned HCT. Eight of these patients proceeded to allogeneic HCT. A non-randomized comparator group was used. Compared to the 6-month period before FMT, patients receiving FMT had a shorter hospitalization and fewer days on carbapenems during HCT. This change did not occur in the comparator group. In another retrospective study,110 8 MDRO-colonized patients received third-party FMT before HCT. When compared to their pair-matched controls without MDRO colonization, 1-year survival was not different. In contrast, MDRO-colonized patients who did not receive FMT had a significantly lower 1-year survival compared to their matched controls without MDRO organization. These findings suggested that the mortality increment due to MDRO colonization may be ameliorated by FMT. Based on limited available data, successful decolonization seems to occur in 50–70% of MDRO-colonized HCT recipients.104The efficacy of FMT in eradicating highly refractory cases of CDI has inspired its use in HCT recipients (both before and after HCT) with MDRO colonization. The ultimate goal of such attempts would be to prevent clinical infections with these organisms. In the largest report thus far with clinical outcomes,Clinical outcomes after MDRO decolonization may improve, but the evidence is weak. Most studies have been small, retrospective or non-randomized, and without a primary clinical endpoint. With improved supportive care and antibiotics, a randomized trial to demonstrate better survival after FMT vs. placebo in MDRO-colonized patients will require a large sample size which may not be feasible. BSI as a clinical endpoint may be easier to study, and it is an important endpoint because BSIs are associated with re-hospitalization, increased healthcare costs, and more dysbiosis due to antibiotic exposure which could in turn increase the risk of GVHD.111 A unique aspect of this study was that only patients with a low fecal abundance of Bacteroidetes were treated. FMT improved microbiota alpha diversity and compositional recovery toward baseline including Lachnospiraceae, Ruminococcaceae, and Bacteroidetes which contain many commensal bacteria. Shotgun metagenomic sequencing suggested enrichment in the control group in antimicrobial-peptide resistance and pathways associated with microbial virulence, biofilm formation, and bacterial flagella assembly. In the second trial,108 we randomized 74 patients to receive FMT or placebo (2:1 ratio) after neutrophil engraftment. FMT enhanced recovery of alpha diversity and Collinsella and reduced the abundance of expanded genera Enterococcus and Dialister. Notably, Blautia recovered to the same extent in both arms, arguing against an essential FMT impact. More details about the design of this trial and clinical outcomes are provided in the next section.Two randomized trials thus far have evaluated the effect of FMT on the microbiota after allogeneic HCT. In the first trial, 25 allogeneic HCT recipients were randomized after neutrophil engraftment to receive autologous FMT vs. no intervention.108 The trial also had an independent cohort of patients with acute myeloid leukemia receiving induction chemotherapy, which is not of primary interest for this review. Five standardized third-party oral capsules were administered per dose. Strict donor and product screening were implemented to minimize the risk of pathogen transmission. The first treatment was given at the time of neutrophil recovery and at least 2 days after discontinuation of antibacterial antibiotics. Patients re-exposed to antibacterial antibiotics after dose 1 received up to 2 more doses. Although infection rate was numerically lower after FMT than placebo, the difference did not reach statistical significance (P = 0.49). Acute toxicities were limited to mild gastrointestinal symptoms. The incidence of acute GVHD (secondary endpoint) was higher in the FMT arm, but the small number of events and imbalance in GVHD prophylaxis regimens between the two arms prohibited a firm conclusion. A randomized placebo-controlled study powered to evaluate the effect of FMT on preventing acute GVHD rate is needed.We recently reported the results of our randomized placebo-controlled FMT trial in allogeneic HCT recipients with 4-month all-cause infection rate as the primary endpoint.Refractory acute GVHD is a life-threatening complication of HCT in need of novel therapeutics. Current treatment is only partially effective and most patients who are refractory to two lines of treatment die. Standard treatment is based on the use of immunosuppressive medications with a wide range of toxicities and does not address other aspects of GVHD pathogenesis such as tissue repair and tolerance.112 three patients with steroid-refractory and one with steroid-dependent acute intestinal GVHD received 1–2 sessions of third-party FMT via a nasoduodenal tube (34–307 grams). Three patients achieved a complete response and 1 achieved a partial response, with no major treatment-related toxicity. The 3 complete responders were not exposed to antibacterial antibiotics during the two weeks after FMT, except trimethoprim-sulfamethoxazole in one patient and a brief course of levofloxacin in another. In contrast, the patient with a partial response was heavily exposed to anti-anaerobic antibiotics after FMT. It is tempting to hypothesize that such exposure decreased the efficacy of FMT, but it is also possible that the use of these antibiotics reflected a worse case of GVHD, with less response to FMT even without antibiotic exposure. Effector regulatory T cells increased in the circulation after FMT, suggestive of a systemic anti-inflammatory response. Taxa that increased after FMT in complete responders included Bacteroides, Faecalibacterium, Lactobacillus, and Bifidobacterium. Escherichia was the dominant taxon after FMT in the partial responder. FMT did not normalize microbiota diversity, suggesting that full restoration of the microbiota may not be necessary for clinical response.In the first use of FMT to treat steroid-refractory acute GVHD,113 In the largest prospective study thus far,107 41 patients with steroid-refractory acute gut GVHD received third-party FMT (23 patients). A control group of 18 patients who received other treatments was included in this non-randomized study. In addition to FMT, the FMT cohort received next-line immunosuppressive treatment, thus FMT was an adjunct treatment rather than a replacement for standard immunosuppression. The FMT cohort received 1–6 FMT treatments via a nasojejunal or gastric tube. Response and survival were higher in the FMT cohort, without increased toxicity. The relative abundance of Firmicutes and Bacteroidetes seemed to increase after FMT while the relative abundance of Proteobacteria seemed to decrease, although a robust analysis was not possible due to the small number of stool samples. In another prospective single-arm study,105 15 patients with steroid-refractory or -dependent acute intestinal GVHD safely received one third-party FMT via nasoduodenal infusion 2 hours after a bowel lavage. Prior immunosuppressive therapy was not changed. Ten patients achieved a complete response within a month, associated with signals for improved alpha diversity, partial donor microbiota engraftment, and increased abundance of Clostridiales, Blautia, and predicted butyrate-producing taxa. However, confidence intervals were large, likely contributing to non-significant differences between responders and non-responders.Several reports were subsequently published on the use of FMT in patients with refractory acute GVHD.114 Such factors do not oppose the attacking agents (e.g. T cells) directly, but rather help with tissue resistance and repair. Whether and how the microbiota may contribute to this process is unclear, but ideas such as butyrate serving as a growth factor for injured colonocytes could be entertained.116Although a randomized trial of FMT for the treatment of refractory acute GVHD has not been published, the available evidence suggests efficacy. An important question to be addressed is the mechanism by which microbiota restoration may improve acute GVHD outcomes. Factors other than a poorly controlled alloimmune attack seem to be involved in steroid-refractory acute GVHD. Tissue tolerance, a concept adopted from non-transplant settings and recently introduced in the HCT setting, posits that tissue-intrinsic factors may have a key role in both progression and resolution of acute GVHD.117 The risk is not limited to bacteria. As an example, eosinophilic gastroenteritis due to Norovirus transmitted via FMT in an allogeneic HCT patient has been reported.118 Major regulatory organizations have established strict rules for screening FMT donors and their stool. It is noteworthy that a BSI after FMT does not necessarily point to the FMT product as the origin of infection. Strain-level analysis of 13 BSI events after FMT in patients with steroid-refractory or -dependent acute GVHD did not find the BSI-associated strains in the FMT product.119 Several bacteria isolated from blood cultures  were present in stools sample before BSI, suggesting that the patients’ own microbiota was likely the source of infection. In our randomized trial, we found no bloodstream infections attributable to FMT.108Besides occasional and typically transient gastrointestinal side effects  that tend to happen in the first 1–2 days after FMT, the main risk associated with FMT is pathogen transmission. The introduction of millions of additional bacteria to the gut, particularly in the setting of profound immunosuppression and intestinal barrier damage after HCT can potentially result in microbial translocation to the bloodstream infection and life-threatening sepsis.An arbitrary interval after neutrophil engraftment has been commonly used to administer FMT after HCT, an approach based on the perceived increased risk of infection in a neutropenic patient. However, no compelling evidence indicates the pre-engraftment period as an especially high-risk period for FMT. As pre-engraftment HCT patients are severely immunosuppressed and at high risk for infection even without FMT, it is important to perform FMT in such patients only in the context of clinical trials, and ideally in a randomized setting to permit distinguishing FMT-related safety signals from baseline risks.Enterococcus and mucolytic species may potentiate complications and lead to poor outcomes. The multitude of factors mediating both clinical outcomes and gut microbiota in these settings makes causal links difficult to establish in humans. Controlled murine experiments have suggested mechanistic connections, but generalization to the human setting is not trivial. In particular, procedures to access the mucosal-adherent microbiota in this patient population are risky and stool samples represent luminal microbiota, which is different from the likely more relevant mucosal-adherent microbiota. One approach to demonstrate a causal link in humans is by randomized trials. Randomization reduces the imbalance between the arms in measured and unmeasured variables. Different outcomes between the arms in such a design would strongly suggest causality. The only completed randomized controlled FMT trial after allogeneic HCT with primary (infections) and secondary (acute GVHD) clinical endpoints did not improve outcomes despite substantial amelioration of dysbiosis.108Several associations have been reported between intestinal dysbiosis and poor clinical outcomes after HCT and cellular therapy. The evidence is currently stronger in the HCT setting, but recent studies have found similar associations after CAR-T therapy. In particular, early loss of obligate anaerobic commensal bacteria and expansion of 120 Sterile fecal filtrates contain bacterial debris, proteins, antimicrobial compounds, metabolic products, oligonucleotides/DNA, and viruses, but not intact bacteria. Such filtrates  have been tested with success for the treatment of recurrent CDI in small series121 and may have a role in HCT recipients too. Currently, there are no published FMT trials in CAR-T recipients, and to our knowledge, no such trial is ongoing in this setting. Given recent findings about microbiota associations with CAR-T efficacy and toxicity, FMT should be tested in clinical trials in this setting. The interval between CAR-T referral and lymphodepletion chemotherapy is often several weeks long, providing sufficient opportunity for FMT to modulate the microbiota in patients deemed high-risk based on the available associational data. If the association between microbiota injury and disease progression after CAR-T therapy is confirmed in more cohorts, pre- or post-CAR FMT may be a testable strategy to boost treatment effect and improve cure rates.Novel aspects of microbiota and its role in tissue homeostasis need to be translated to clinical trials. Although most attention has been paid to the bacteria in the setting of FMT, the possible role of other microorganisms such as viruses (e.g. phages) is becoming more clear. Removing the bacterial component of donor stool by sterile filtration maintains FMT efficacy on gut microbiota composition and host metabolome.122From a mechanistic standpoint, the determinants of donor microbiota engraftment in the HCT setting are unknown. In addition, the effect of FMT on non-bacterial compartments of the microbiome  is rather unexplored.113 FMT has been administered by enema,123 via nasogastric/nasoduodenal tube,124 or by upper127 or lower endoscopy.102 Another open question concerns the FMT source. Both third-party125 and autologous111 products have been used. While an autologous product may be simpler and less expensive to manufacture, most HCT recipients have had microbiota insults before referral for transplant and the efficacy of a product manufactured from a “scarred” microbiota needs further investigation. Similarly, whether a single “super donor”,126 several donors (one used for each patient), or pooled donors provide better outcomes is unknown. Pooling stool from multiple donors may generate a more diverse microbiota in the product, but the value of an extra-high diversity beyond what an average healthy individual has is unknown. Whether concurrent use of antibiotics may be detrimental to FMT efficacy and safety is also unclear. Related to this point, the optimal washout after the last antibiotic use has not been established. Finally, the efficacy of “microbiota conditioning” by antibiotic gut decontamination before FMT to increase donor microbiota engraftment has not been determined.The optimal timing and schedule of administration and minimum required dose of FMT are unknown. With rigorous screening of donors and stools to minimize the risk of pathogen transmission, the existence of a specific neutrophil count threshold for FMT is questionable. Careful examination of FMT safety during severe neutropenia in a properly designed clinical trial with safety as the primary endpoint would be informative as the pre-engraftment period when antibiotic pressure tends to be maximal may offer a new window of opportunity for intervention on the microbiota. Most studies have administered FMT on a single day or on 2 consecutive days. Whether a more sustained schedule extending for several days and potentially delivering a larger dose of microbiota is beneficial is unknown. The route of administration is another unknown factor potentially influencing efficacy. Besides the oral encapsulated form,


Acquisition and pre-processing pipelines for diffusion-weighted imaging (DWI) volumes are resource- and time-consuming. Generating synthetic DWI scalar maps from commonly acquired brain MRI sequences such as fluid-attenuated inversion recovery (FLAIR) could be useful for supplementing datasets. In this work we design and compare GAN-based image translation models for generating DWI scalar maps from FLAIR MRI for the first time.We evaluate a pix2pix model, two modified CycleGANs using paired and unpaired data, and a convolutional autoencoder in synthesizing DWI fractional anisotropy (FA) and mean diffusivity (MD) from whole FLAIR volumes. In total, 420 FLAIR and DWI volumes  from multi-center dementia and vascular disease cohorts were used for training/testing. Generated images were evaluated using two groups of metrics: (1) human perception metrics including peak signal-to-noise ratio (PSNR) and structural similarity (SSIM), (2) structural metrics including a newly proposed histogram similarity (Hist-KL) metric and mean squared error (MSE).p < 0.001) correlations between real and synthetic FA values in both tissue types .Pix2pix demonstrated the best performance both quantitatively and qualitatively with mean PSNR, SSIM, and MSE metrics of 23.41 dB, 0.8, 0.004, respectively for MD generation, and 24.05 dB, 0.78, 0.004, respectively for FA generation. The new histogram similarity metric demonstrated sensitivity to differences in fine details between generated and real images with mean pix2pix MD and FA Hist-KL metrics of 11.73 and 3.74, respectively. Detailed analysis of clinically relevant regions of white matter (WM) and gray matter (GM) in the pix2pix images also showed strong significant (Our results show that pix2pix’s FA and MD models had significantly better structural similarity of tissue structures and fine details than other models, including WM tracts and CSF spaces, between real and generated images. Regional analysis of synthetic volumes showed that synthetic DWI images can not only be used to supplement clinical datasets, but demonstrates potential utility in bypassing or correcting registration in data pre-processing. Scalar maps such as mean diffusivity (MD) and fractional anisotropy (FA) are typically derived from diffusion weighted MRI (DWI), and used as proxies of water diffusion and diffusion directionality in brain tissue, respectively. Increased water diffusion and decreased directionality are related to microstructural tissue integrity loss related to neurodegenerative diseases such as dementia. However, acquiring scalar maps from DWI relies on processing pipelines such as Tractoflow , which aRecent studies successfully used generative models for translation between brain MRI modalities to synthesize mainly between T1 and T2-weighted images . Only feWe make several contributions. First, we design and develop the first image translation tools for synthesizing DWI scalar maps from FLAIR MRI. Second, while previous works used only several slices from each volume for training and generating synthetic data, we demonstrate anatomical diversity in our GAN models with the use of full volumes. Third, we integrate the Frechet Inception Distance (FID) into training to reduce resource consumption and the FID is computed using a state-of-the-art medical imaging pre-trained architecture. Lastly, we propose a new performance metric based on histogram KL divergence to evaluate the quality of structural information in the generated images. Commonly used GAN evaluation metrics including PSNR and SSIM are criticized for instability and insensitivity shortcomings in medical imaging . We hypoTwo datasets of brain FLAIR and DWI MRI are used in this work. The first is from the Canadian Consortium on Neurodegeneration in Aging (CCNA)  which coAll FLAIR volumes were brain extracted  and inteTo generate synthetic DWI scalar maps using GAN-based translation models, we implement an optimized (paired) CycleGAN model, an unpaired CycleGAN, a paired pix2pix and a standard autoencoder for comparison purposes. Paired indicates images from the two domains are matching, in this case, the registered FLAIR and DWI. CycleGAN was chosen as the base model due to its success in image translation between modalities . It emplPreliminary tests on paired CycleGAN showed the baseline model had partial mode collapse in early epochs of training as generators failed to map the diverse anatomical features and instead generated the same anatomy on every slice . Mode coAn unpaired CycleGAN was trained for comparison purposes, as well as a baseline pix2pix architecture developed by CycleGAN uses adversarial loss and cycle consistency loss , where tThe pix2pix model was trained using binary cross entropy (BCE) for both generator and discriminator losses . The totWhere λ = 100 as defined in Two groups of evaluation metrics, based on human perception and structural information, are used to evaluate the generated test images. The human perception metrics include peak signal-to-noise ratio (PSNR)  and strul, c, and s are the three components of luminance, contrast, and structure and ∝, β, γ are parameters for adjusting the weight of each component:Where x and y are two images being compared, R is the size of luminance change relative to background luminance, μ is the mean intensity of an image, σ is the standard deviation of an image, and C1,2,3 are constants.where The structural metrics include mean squared error (MSE) and a proposed metric measuring the KL divergence of histograms (Hist-KL) between real and generated images. The histogram of an image reflects the probability distribution of the pixels within the image. Histogram analysis is particularly important when evaluating modalities such as DWI in which different tissue types appear at different intensities, thus corresponding to specific histogram peaks. Additionally, previous studies have found that increased kurtosis of FLAIR histogram distributions is related to worsening cognition and decreased tissue integrity , demonstP and Q are the distributions of the two images, and x is the histogram bins.Where The FID score is commonly used for evaluating GAN performance . It emplQualitative results for all models are shown in t-tests between models is shown in the p < 0.05). Quantitative performance for MD and FA models is shown in Structural similarity index and PSNR may not be adequately quantifying the subtle differences between generated and real images, such as overestimating CSF in the sulci and gyri (subarachnoid spaces) and underestimation of small structures such as WM tracts. The fine-details and structural similarity between generated and real images may be better measured by Hist-KL. See The best-performing pix2pix method was further evaluated in its ability to synthesize accurate structural information by regional analysis. All further experiments use only pix2pix generated test volumes.The gray and white matter tissue regions of the MD and FA test volumes were analyzed. From the test set, a total of 32 patients from both datasets had corresponding registered GM and WM masks. The masks were used to segment GM and WM from both real and synthetic volumes, and evaluation metrics were computed in the sub-regions. p < 0.001) R correlations of 0.71 and 0.88 were found between real and synthetic FA of the GM and WM, respectively, while no significant correlations were found for MD volumes  with paired data. For ablation purposes, a convolutional autoencoder was also compared, which is essentially pix2pix without the discriminator. FID scores, computed using Rad-InceptionV3 , were used to determine the optimal epoch on the fly rather than after training. Through qualitative and quantitative performance, pix2pix offered the highest quality image generations for MD and FA images. This was followed by the optimized paired CycleGAN, unpaired CycleGAN and lastly, the autoencoder, which failed to generate anything meaningful for the task.The pix2pix model outperformed all other models. Comparing to the autoencoder, our findings demonstrate the utility of a discriminator network to force outputs to be more realistic. The autoencoder used MSE loss and was unable to reconstruct the complex mappings between FLAIR and DWI. We expected the paired CycleGAN to yield similar results to pix2pix. However, pix2pix was qualitatively and quantitative superior, which may be attributed to pix2pix’s objective function that leverages paired data to learn pixel-wise mappings between modalities. On the other hand, CycleGAN matches FLAIR and DWI domain distributions, but does not directly map each input pixel to the output. The paired CycleGAN performed better than the unpaired model, demonstrating the modifications we proposed to mainly remove mode collapse improved performance.Perceptual metrics (PSNR and SSIM) from our pix2pix models are comparable to those in existing literature , which uGreater errors between real and synthetic images were mainly attributed to registration warping in the real volumes as seen in This work proposes generation methods for supplementing datasets with synthetic FA and MD measures. Such methods may also be used for generating other microstructure measures related to diffusion-weighted imaging. A previous study investigated the use of GANs for generating synthetic DWI volumes , from whTo improve the paired CycleGAN model, future work could leverage the strengths of pix2pix (pixel-wise objective function) and our modified CycleGAN models (cycle consistency). The unpaired model may be improved with additional datasets or 3D CycleGAN models. A limitation of the work includes lower performance in cerebellar slices, which may be due to the small amount of tissue (low sample sizes) and varying anatomy which hinders performance. A 3D model may help, or it may be possible to train separate 2D models for each region. Another limitation of the work is the lower performance of the MD models compared to FA. Future work may include optimization methods to optimize models specifically for MD volume generation. To determine clinical utility, future work could include domain-adaptation, dataset-specific models, and using the generated data in classification/segmentation tasks. Further, model performance should be evaluated on out-of-distribution cohorts to evaluate mapping on entirely different datasets. Future investigation into the generation of other DWI measures would also be clinically useful.We design and evaluate GAN-based image translation tools for generating MD and FA scalar maps from FLAIR MRI. Pix2pix is the top performer that can best generate fine details such as WM tracts, due to the objective function that leverages paired data to learn pixelwise mappings between modalities. Ablation with an autoencoder (pix2pix without the discriminator) produces insensible results, which highlights that a discriminator is needed to force realism in the generations. The CycleGAN with paired data was successfully optimized to prevent mode collapse, but because CycleGAN aims to match FLAIR and DWI domain distributions, rather than directly mapping each input pixel to the output, the performance is suboptimal. CycleGAN with unpaired data performs the worst and is likely due to the problem space being too large to resolve fine details in the images. We have also shown that Hist-KL is an effective metric in evaluating the accuracy of tissue structures in synthetic images and may be used alongside existing visual quality metrics. Additionally, regional analysis of volumes generated using the pix2pix model demonstrated that synthetic DWI FA volumes may be useful in supplementing clinical datasets and correcting registration errors.https://ccna.loris.ca/ and AK, akhademi@torontomu.ca.The data analyzed in this study is subject to the following licenses/restrictions: The datasets presented in this article are not readily available because of patient privacy and confidentiality. Requests to access these datasets should be directed to KC and AK contributed to the conception and design of the study, performed statistical analysis, and wrote the first draft of the manuscript. All authors contributed to manuscript revision.


Face perception in humans and nonhuman primates is accomplished by a patchwork of specialized cortical regions. How these regions develop has remained controversial. In sighted individuals, facial information is primarily conveyed via the visual modality. Early blind individuals, on the other hand, can recognize shapes using auditory and tactile cues. Here we demonstrate that such individuals can learn to distinguish faces from houses and other shapes by using a sensory substitution device (SSD) presenting schematic faces as sound-encoded stimuli in the auditory modality. Using functional MRI, we then asked whether a face-selective brain region like the fusiform face area (FFA) shows selectivity for faces in the same subjects, and indeed, we found evidence for preferential activation of the left FFA by sound-encoded faces. These results imply that FFA development does not depend on experience with visual faces per se but may instead depend on exposure to the geometry of facial configurations. Face perception is one of the most studied human skills because of its evolutionary relevance for survival –4. CompaOn the other hand, selectivity for face stimuli within the FFA develops gradually and becomes more finely tuned over the first decade of human development –36, suggAs facial information is predominantly conveyed through the visual modality in sighted humans, conveying facial information through another modality, such as hearing or touch in early blind (EB) individuals, could help to clarify the role experience plays in the specialization of the FFA. Visually deprived individuals thus offer a unique window into assessing how the morphological and functional architecture of the human brain develops and what role sensory experience plays in shaping the functional organization of the human brain.). Previous functional neuroimaging studies have shown activation in various extrastriate areas of the visual cortex with similar devices in blind and sighted individuals  for details).Six early blind (EB) and ten sighted controls (SC) were trained to identify sound-encoded schematic images of faces, houses, and geometrical shapes using a visual-to-auditory sensory substitution device (SSD) referred to as the PSVA . The visIn a further fMRI session , right, Six EB and ten SC participants completed the one-back PSVA task which comprised sound-encoded images of the schematic stimuli that were also used as one type of visual stimuli in the SC . Given oTen sighted controls took part in the visual one-back comparison task. The visual task incorporated photographs of real faces, houses or geometrical shapes as well as the visual version of the sound-encoded schematic stimuli (drawings) used in the PSVA task. These conditions were used as localizers for identifying the FFA region .right-sided activation of the fusiform gyrus (see upper part of left fusiform gyrus (see lower part of Whole-brain random effects (RFX) analyses using a corrected threshold of q-FDR < 0.05 (with p < 0.01 cluster-forming threshold) were performed in SC subjects. The contrast [Schematic Faces minus Rest] showed predominantly A 5-mm radius sphere  was created around the main voxel peak  located within the FFA, as identified by a functional  localizer in the SC, using the contrast [Schematic Faces minus Schematic Houses]  in the spherical FFA-ROI as a function of group  and condition/stimulus . Beta values for the schematic visual conditions in SC are provided as a reference on the left. In EB subjects, the Face condition was significantly above the baseline  and above the House condition . See , penultimate line, in bold). In SC, the same contrast, [Schematic Faces minus Schematic Houses], did not show a significant activation focus in the fusiform gyrus at the selected threshold.To visualize activation patterns and their specificity, whole-brain analyses were also performed. The contrast [Schematic Faces minus Schematic Houses] in the six EB subjects showed an activation focus in the left FFA  activates the fusiform gyrus (BA 37) in EB subjects, in a region identified as the left fusiform face area (FFA) in sighted subjects. The fact that the FFA is activated in the blind by sound-encoded patterns of faces suggests that the computational algorithms for the detection of faces can develop without experience in the visual domain. Training and testing with the SSD and subsequent brain imaging reveals the presence of face-specific modules that seem to resonate with the underlying geometry of the recipient structure.Our results are the first to document that a specific, prominent region of the ventral pathway, the FFA of the left cerebral hemisphere, shows a preference for the perception of sound-encoded schematic faces in EB subjects. Activation of the FFA observed in sighted individuals when they perceived the same schematic faces visually, corresponded to the same location that had previously been found to identify that cortical region .In the current study, only the left FFA in the EB group showed a preference for sound-encoded images of schematic faces. This is in line with previous evidence of left-hemispheric involvement in analytic processing of local facial parts or features, as opposed to configural or ‘holistic’ face perception, which engages mostly the right FFA, –64. InteAlthough there is strong evidence for the analytical processing of schematic faces, there is also evidence in favor of schematic faces that show holistic processing , demonstAnother study  focused What is obvious is that the left FFA makes a substantial contribution to face processing, so the assumption is warranted that, being able to process relational information about faces, blind participants using an SSD should be able to gain some semblance of face recognition as in haptic face processing . Whetherhttps://osf.io/ta8xw/), although this was not systematically tested. EB individuals spontaneously produce facial expressions of basic emotions that are very similar to those produced by sighted individuals in the same situations . These activation maps were used as inclusive masks in further analyses of the FFA. The maps were obtained using a corrected threshold of qFDR < 0.05 in combination with a cluster size threshold correction of p < 0.01. An activation focus was found in the left fusiform gyrus Click here for additional data file.S1 Filehttps://osf.io/ta8xw/).Recognition of schematic visual patterns by a blind volunteer using a sensory substitution device (SSD). The SSD converts two-dimensional visual images viewed through a head-mounted camera into audible signals modulated by scanning motions of the head. (Video can be downloaded from (MP4)Click here for additional data file.S1 TableParaHippo G: parahippocampal gyrus, Post CG: posterior cingulate gyrus, Med FG: median frontal gyrus, Mid FG: middle frontal gyrus, SFG, superior frontal gyrus, Prec G: precentral gyrus, IPL: inferior parietal lobule, FFA: fusiform face area, IFG: inferior frontal gyrus.(DOCX)Click here for additional data file.S2 TableSTG: superior temporal gyrus, Mid TG: middle temporal gyrus, SFG: superior frontal gyrus, Cing G: cingulate gyrus, ITG: inferior temporal gyrus, FFA: fusiform face area.(DOCX)Click here for additional data file.


The Ligament Advanced Reinforcement System (LARS) is a common choice for ligament reconstruction in the lower limb due to its good functional and quality of life (QoL)-related outcomes. It is commonly used for Achilles tendon repair following a rupture. While it facilitates tissue ingrowth and boasts good biocompatibility, we report on multiple cases whereby foreign body reactions have led to the growth of granulomas requiring surgical excision and Flexor Hallucis Longus (FHL) transfer. Following these cases, patients have been shown to have excellent functional and QoL-related outcomes using the Manchester Oxford Foot Questionnaire (MOX-FQ) and Foot and Ankle Ability Measure (FAAM). Surgeons should consider FHL transfer as an alternative in patients undergoing Achilles tendon repair and be aware of the risk of foreign body reactions and the impact on ankle function and QoL post-operatively. The Achilles tendon is the largest tendon in the human body, with the highest strength. It is also, however, the most commonly ruptured tendon in the lower extremity, commonly occurring in the young to middle-aged population. Most frequently, this is due to sporting injuries caused by excessive loading . AchilleThe Ligament Advanced Reinforcement System (LARS) is a synthetic, non-absorbable ligament comprising polyethylene terephthalate fibres (PET) composed of two parts: an intraosseous segment composed of longitudinal fibres bound together by a transverse knitted structure and an intra-articular segment composed of parallel longitudinal free fibres twisted at 90° . LARS haCase 1A 59-year-old male sustained a traumatic rupture of the Achilles tendon while playing soccer. Initially, they were treated in an Equinus cast for a period of six weeks. Following the removal of the cast and his return to work, he sustained a further injury while walking on uneven ground two weeks later. They underwent surgical repair using the LARS system. Following a period of physiotherapy, the patient reported no functional limitations relating to his foot or ankle and returned to work. Thirteen years post-operatively, they report that swelling began to occur at the surgical site, which continued to grow over a period of seven years Figure -1B. TherCase 2This 68-year-old male sustained a forced ankle dorsiflexion injury while diving into a swimming pool. The diagnosis of Achilles tendon rupture was delayed, and at the time of diagnosis, there was significant tendon retraction. They were initially treated surgically using the LARS system. Post-operatively, there were no functional limitations, and the patient returned to their functional baseline, recommending an active lifestyle. Two years post-operatively, they reported swelling at the surgical site without any functional limitations. This swelling expanded over a period of 18 months prior to the orthopaedic referral. The large cystic swelling did not demonstrate evidence of infection. MRI demonstrated a 10 cm × 3.3 cm × 3cm collection within the Achilles tendon, reported to demonstrate an evolving haematoma.Case 3A 69-year-old male who sustained a traumatic rupture of the Achilles tendon during a paraglider landing was presented. This traumatic Achilles tendon rupture was treated in an Equinus cast for six weeks, followed by full mobilisation. He sustained a re-rupture one year later while walking and underwent repair using the LARS system. This patient reported a full return to functionality, including his ability to run long distances. Again, there was a delay in the swelling. This was first noticed ten years after Achilles tendon repair. Over the course of five years, this increased in size while not impacting the function of his foot or ankle. He sought an orthopaedic opinion again as a result of difficulties with footwear, in which he described having to remove the heel counter from shoes in order to fit his foot inside. Again, there were no issues relating to either a deep or superficial infection. An MRI scan revealed a 16 cm × 6 cm × 3 cm heterogenous collection within the Achilles tendon.Differential diagnoses in cases of such a swelling overlying Achilles tendon include chronic tendon ruptures, mid-substance tendinopathy, and benign lesions, including lipoma or ganglion cysts. In the case of those having undergone previous Achilles tendon repair using the LARS system, foreign body granuloma, abscess, and infection were considered to be more likely. In each case, surgical excision and analysis of excised material were required for histological diagnosis.Surgical techniqueAll three patients underwent excision of the Achilles tendon pseudotumour and FHL transfer. All were approached via a posterior midline incision using the site of the previous scar. Skin flaps were raised, allowing visualisation of the pseudotumour, alongside visualisation and protection of the short saphenous vein and sural nerve. Tendoachilles/pseudotumour was excised proximally at the transverse intermuscular septum and distally at the calcaneum. The excised tendons were sent for histological analysis. FHL tendon harvest was performed in each case, with attachment to the calcaneum via the G-Force tenodesis system and JuggerKnot all-suture anchors. An Equinus cast and PICO dressing were applied in each case, with instructions for a period of non-weight bearing post-operatively.ResultsInitial assessment of excised material demonstrated clearly visible synthetic fibrous strands with surrounding granulomatous tissue, consistent with foreign body granuloma Figure -3B. MacrOutcomesPatient-reported outcomes were measured via the Foot and Ankle Ability Measure (FAAM) Activities of Daily Living (ADL) subscale and the Manchester Oxford Foot Questionnaire (MOX-FQ), both independently validated scoring systems for health-related quality of life (QoL) and ankle functionality. MOF-FQ has been validated for the impact of intervention following operative intervention . FAAM prA higher score in MOX-FQ correlates to a worse function of the joint (scored out of 64 points), while a higher score in FAAM (scored out of 84) reflects a higher level of physical function. The average score in the study cohort was 75.5 (range 69-82) in the FAAM questionnaire, with an average score of five (range 2-10) in MOX-FQ scoring with evidence of strong surgical outcomes across the pain, walking/standing, and social interaction domains. Overall, these indicate excellent physical function post-operatively. One patient reported no limitation in the pain and social interaction subscales on the MOX-FQ PROMS questionnaire, while their only consideration was being conscious of causing discomfort when walking on rough surfaces. Another patient described occasional mild pain in his ankle in the evenings. Neither had any functional limitations following their surgery.Analysis of the PROMS scoring of the FAAM Activities of Daily Living subscale demonstrated excellent outcomes following pseudotumour excision and FHL transfer, with one patient reporting no limitation of difficulties, including heavy work; the other patient scored 63/84 points, with his limitations described as an inability to stand on his toes and squat following the FHL transfer replacement of the Achilles tendon following pseudotumour excision. Other limitations included ‘slight’ limitations to heavy work such as climbing or pushing/pulling items and ‘slight’ difficulty traversing stairs. On further discussion, these caused no functional limitations to his day-to-day living. At the time of writing, the third patient included in the series was still in a protective cast, so the above scales were not applicable.The surgical approach to the repair of ruptured tendons provides a reconstructive conundrum. Autografts have limitations, for example, the variation of properties and limited dimensions of the donor tendon, alongside the initial loss of strength during the necrotic stage . SynthetThere are limited reports of the development of complications relating to foreign body reactions with the LARS system for Achilles tendon repair. Studies of ligament reconstruction using LARS have primarily focused on ACL repair. A recent prospective study from Smolle et al. into long-term clinical and QoL-related outcomes in LARS treatment of ACL tears showed good functional and QoL-related results but a high complication rate . These included graft failure in 24% (n=10) of patients and reactive synovitis in 20% (n=8) .There are limited resources detailing the outcomes of Achilles tendon repair using LARS, with two case reports of foreign body reactions leading to a granuloma that required resection ,17. ThisWhile the synthetic option is easily accessible, research shows that it lacks real biocompatibility; hence, FHL transfer should be taken into consideration over the use of LARS ligament in patients deemed suitable for surgical intervention in the repair of severe Achilles tendon rupture. No high-quality prospective trials evaluating outcomes or complication rates after Achilles tendon replacement utilizing the LARS ligament repair technique were found in the literature review. Foreign body reactions must be taken into consideration in cases where oedema surrounds the site of previous ligament reconstruction utilizing the LARS technique, with FHL transfer being a suitable option for reconstruction.