ABSTRACT:Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). Immunofluorescent staining revealed demyelination and chronic infiltration of immune cells in Morton's neuroma. RNA bulk sequencing identified 3349 differentially expressed genes between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed higher densities of macrophages and B cells in Morton's neuroma than control samples. Modules associated with defence response, neurogenesis, and muscle system development as well as macrophage cell populations identified by deconvolution correlated with patients' paroxysmal or evoked pain. Of note, we identified a consistently differentially expressed gene signature ( MARCO, CD163, STAB1 ) , indicating the presence of a specific M(GC) subset of macrophages. MARCO gene expression correlated with paroxysmal pain. Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163 + MARCO + macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO + subset implicated.

Peripheral neuropathic pain remains challenging to treat, partly due to our limited understanding of the molecular mechanisms at play in humans. In this multicentre cohort study, we describe the local molecular signature of neuropathic pain at the lesion site, using peripheral nerves of patients with Morton’s neuroma as a human model system of neuropathic pain. Plantar tibial nerves were collected from 22 patients with Morton’s neuroma (18 female, median age 60.0 [IQR 16.0] years) and control nerves from 11 participants (4 females, 58.0 [21.0] years) without a nerve injury. Pre-surgery, we collected data on pain severity, duration and nature (e.g., neuropathic pain inventory, NPSI). RNA bulk sequencing of peripheral nerves identified 3349 genes to be differentially expressed between Morton’s neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses (WGCNA) revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed that the densities of macrophages as well as B-cells were higher in Morton’s neuroma than control samples. The findings for T-cells were inconclusive. Modules associated with defence response, neurogenesis and muscle system development correlated with paroxysmal and evoked pain in people with Morton’s neuroma. Macrophage cell populations identified by deconvolution analysis as well as single differentially expressed genes ( MARCO, CD163, STAB1; indicating the presence of a specific M(GC) subset of macrophages) correlated with paroxysmal pain. Immunofluorescent analyses confirmed the presence of demyelination, higher densities of intraneural T-cells and CD163+MARCO+ macrophage subsets in Morton’s neuroma compared to control nerves. Histological CD68+ macrophage density correlated with burning pain. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+ subset implicated. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement ABS is supported by a Wellcome Trust Clinical Career Development Fellowship (222101/Z/20/Z). IDS and PSS were funded by the Clinical Research Priority Program (CRPP) Pain from the University of Zurich, Switzerland. PSS is supported by postdoctoral fellowships from the International Foundation for Research in Paraplegia (P198F), the Swiss National Science Foundation (P500PB_214416), and Michael Smith Health Research BC (RT-2023-3173). This research was funded in whole, or in part, by the Wellcome Trust [222101/Z/20/Z]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. We also received funding from from ONO pharamceuticals Ltd. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics Committee South Central - Oxford C Research Ethics Committee gave ethical approval for this research (REF 18/SC/0410). Ethics Committee London - Camden & Kings Cross Research Ethics Committee gave ethical approval for this research (REC16/LO/1920) Ethics committee of Canton of Zurich gave ethical approval for this work (2018-02198). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes

Over the last two decades, there has been a growing emphasis on the publication quality in Foot & Ankle research. A level-of-evidence rating system for clinical scientific papers has been proposed by the Centre for Evidence-based medicine in Oxford, United Kingdom. As opposed to other subspecialities, foot & ankle surgery deals with a wide variety of clinical problems and surgical solutions, which in turn leads to a generally low number of patients available for study groups. However, level III and IV studies still have a valuable place in orthopaedic research, given the challenges in running high-level studies.The measurement of outcomes in medicine from the patients' perspective (PROMS:(patient reported outcome measures) has grown almost exponentially in all surgical specialties including foot & ankle surgery. There are many PROMs available to foot & ankle surgeons, but there is little consensus on which assessment is most appropriate for a given procedure or diagnosis. Their use in research and clinical practice offers many advantages in clinical practice and research, however, besides the advantages there are also some downsides.

Achilles tendinopathy can be a debilitating condition affecting 2–3 in 1000 of the population, rising to 1 in 20 in runners. A variety of non-operative and operative treatments are available for both insertional and non-insertional tendinopathy. This review summarises the current management options of these different pathologies.

BackgroundVarious procedures exist to augment or reconstruct the Achilles tendon (AT) in patients suffering from chronic pathologies. The aim of this study is to assess patient reported outcomes and satisfaction following single incision FHL augmentation using a short tendon harvest with interference screw fixation.MethodsThis is a multicentre case series where postoperative patient reported outcome and satisfaction scores were collected on 30 patients. Outcome measures included EQ-5D, EQ-VAS, Achilles Tendon Rupture Scores (ATRS), and satisfaction scores. Scores were also collected on the unaffected limbs for comparison.ResultsMean patient age was 61 years (range 40–79, SD 11). Mean EQ-5D index value was 0.750 (0.100–1.00, SD 0.238), and mean EQ-VAS score was 74 (36–99, SD 15), at a mean follow-up of 57 months (4–118, SD 32). For patients with ≥24 months’ follow-up, a mean deficit of 16 ATRS points was found between the operated and unaffected limb. Overall satisfaction was over 86%. In cases of chronic AT rupture, younger age and increasing time from initial injury to surgery were predictors of greater residual deficit. No serious complications or failures occurred.ConclusionsFHL augmentation using short tendon harvest and interference screw fixation is a safe treatment option. It appears to take at least 24 months to functionally recover following this procedure, and despite a residual function deficit, there is a high level of patient satisfaction. Further studies are required to determine optimal patient selection and timing of surgery.

AIMS:Functional rehabilitation has become an increasingly popular treatment for Achilles tendon rupture (ATR), providing comparably low re-rupture rates to surgery, while avoiding risks of surgical complications. Limited evidence exists on whether gap size should affect patient selection for this treatment option. The aim of this study was to assess if size of gap between ruptured tendon ends affects patient-reported outcome following ATR treated with functional rehabilitation.METHODS:Analysis of prospectively collected data on all 131 patients diagnosed with ATR at Royal Berkshire Hospital, UK, from August 2016 to January 2019 and managed non-operatively was performed. Diagnosis was confirmed on all patients by dynamic ultrasound scanning and gap size measured with ankle in full plantarflexion. Functional rehabilitation using an established protocol was the preferred treatment. All non-operatively treated patients with completed Achilles Tendon Rupture Scores (ATRS) at a minimum of 12 months following injury were included.RESULTS:In all, 82 patients with completed ATRS were included in the analysis. Their mean age was 51 years (standard deviation (SD) 14). The mean ATRS was 76 (SD 19) at a mean follow-up of 20 months (SD 11) following injury. Gap inversely affected ATRS with a Pearson's correlation of -0.30 (p = 0.008). Mean ATRS was lower with gaps > 5 mm compared with ≤ 5 mm (73 (SD 21) vs 82 (SD 16); p = 0.031). Mean ATRS was lowest (70 (SD 23)) with gaps > 10 mm, with significant differences in perceived strength and pain. The overall re-rupture rate was two out of 131 (1.5%).CONCLUSION:Increasing gap size predicts lower patient-reported outcome, as measured by ATRS. Tendon gap > 5 mm may be a useful predictor in physically demanding individuals, and tendon gap > 10 mm for those with low physical demand. Further studies that control for gap size when comparing non-operative and operative treatment are required to assess if these patients may benefit from surgery, particularly when balanced against the surgical risks. Cite this article: Bone Joint J 2020;102-B(11):1535-1541.

Background: The aim of this systematic review was to perform a qualitative synthesis of the current literature to determine the union frequencies for first metatarsophalangeal joint arthrodesis as well as the influence of pathology, joint preparation and fixation methods on union.Methods: MEDLINE and EMBASE were searched to identify relevant studies reporting on first metatarsophalangeal joint union frequencies.Results: 26 studies with 2059 feet met our inclusion criteria. The mean age was 60 years (range 18-84) and themean follow-up was 32.6 months (range 1.5-156). The union frequency was 93.5% (1923/2059). The union frequencies were significantly higher when low velocity joint preparation methods were used (P < 0.0001, Chi Square 22.5) and the pathology was hallux rigidus (P = 0.002, Chi square 9.3). There were similarly high union frequencies with crossed screws, locking plate and non-locking plates.Conclusions: High union frequency can be expected following first metatarsophalangeal arthrodesis, especially when low velocity joint preparation methods are used in patients with hallux rigidus. (C) 2016 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

Background: The purpose of this RCT was to compare the extended plantar limb (modified) chevron osteotomy with the scarf osteotomy in correcting hallux valgus deformity and improving functional scores and patient satisfaction.Methods: Patients were randomly assigned and kept blind to surgical allocation. Cases requiring additional procedures including the Akin osteotomy were excluded. Outcomes were measured at 1 year following surgery.Results: 84 patients (109 feet) were analysed (60 modified chevron; 49 Scarf). The mean age was 50.7 years (75F: 9M). Post-operative intermetatarsal angle (IMA) was significantly lower in the modified chevron group (5.8 degrees versus 6.9 degrees, p = 0.045). Hallux valgus angle and distal metatarsal articular angle were similar. The magnitude of IMA correction with the modified chevron was also significantly greater (9.1 degrees versus 7.1 degrees, p = 0.007). Both osteotomies produced comparable MOxFQ scores and satisfaction ratings.Conclusion: The modified chevron was superior to the scarf osteotomy in correcting IMA in hallux valgus deformity. (C) 2015 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

AIMS The objective of this double-blind randomised controlled trial was to assess whether ultrasound guidance improved the efficacy of corticosteroid injections for Morton's neuroma (MN). PATIENTS AND METHODS In all, 50 feet (40 patients) were recruited for this study but five feet were excluded due to the patients declining further participation. The mean age of the remaining 36 patients (45 feet) was 57.8 years (standard deviation (sd) 12.9) with a female preponderance (33F:12M). All patients were followed-up for 12 months. Treatment was randomised to an ultrasound guided (Group A) or non-ultrasound guided (Group B) injection of 40 mg triamcinolone acetonide and 2 ml 1% lignocaine, following ultrasound confirmation of the diagnosis. RESULTS The mean visual analogue score for pain improved significantly in both groups (Group A - from 64 mm, sd 25 mm to 29 mm, sd 27; Group B - from 69 mm, sd 23 mm to 37 mm, sd 25) with no statistical difference between them at all time-points. The failure rate within 12 months of treatment was 11/23 (48%) and 12/22 (55%) in Groups A and B, respectively (p = 0.458). The improvement in Manchester Oxford Foot Questionnaire Index and patient satisfaction favoured Group A in the short-term (three months) that almost reached statistical significance (p = 0.059 and 0.066 respectively). However, this difference was not observed beyond three months. CONCLUSION This study has shown that ultrasound guidance did not demonstrably improve the efficacy of corticosteroid injections in patients with MN. TAKE HOME MESSAGE In the presence of a clear diagnosis of MN, a trained clinician who understands the forefoot anatomy may perform an injection without ultrasound guidance with good and safe results.

Background: This study investigated factors that may predict the need for Morton's neuroma (MN) to undergo further treatment within 2 years of a single ultrasound-guided corticosteroid injection.Methods: A retrospective study was undertaken over a three-year period. The data was stratified into two groups: Group A - did not receive further intervention and Group B - received further treatment. We investigated age, gender, neuroma size and presence of other forefoot pathology or ipsilateral neuromas.Results: 54 patients (57 feet) were reviewed. 29 feet (51%) required further treatment within 2 years (11 repeat injections, 18 surgical excisions). Binary logistic regression showed that larger neuromas (p = 0.011) and younger patients (p = 0.007) predicted the need for further intervention but not gender (p = 0.272). The distribution of concomitant forefoot pathology and ipsilateral neuromas were similar between the two groups.Conclusion: Size and age appear to be predictors for further treatment of MN within 2 years of corticosteroid injection. (C) 2015 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

The aim of the present study was to assess the diagnostic accuracy of 7 clinical tests for Morton's neuroma (MN) compared with ultrasonography (US). Forty patients (54 feet) were diagnosed with MN using predetermined clinical criteria. These patients were subsequently referred for US, which was performed by a single, experienced musculoskeletal radiologist. The clinical test results were compared against the US findings. MN was confirmed on US at the site of clinical diagnosis in 53 feet (98%). The operational characteristics of the clinical tests performed were as follows: thumb index finger squeeze (96% sensitivity, 96% accuracy), Mulder's click (61% sensitivity, 62% accuracy), foot squeeze (41% sensitivity, 41% accuracy), plantar percussion (37% sensitivity, 36% accuracy), dorsal percussion (33% sensitivity, 26% accuracy), and light touch and pin prick (26% sensitivity, 25% accuracy). No correlation was found between the size of MN on US and the positive clinical tests, except for Mulder's click. The size of MN was significantly larger in patients with a positive Mulder's click (10.9 versus 8.5 mm, p = .016). The clinical assessment was comparable to US in diagnosing MN. The thumb index finger squeeze test was the most sensitive screening test for the clinical diagnosis of MN.

Background: The purpose of this study was to investigate the influence of joint configuration and preparation on first metatarsophalangeal (MTPJ) union rates.Methods: We performed a retrospective analysis of first MTPJ arthrodeses undertaken in our institution. Clinical notes, radiographs and postal questionnaires were used to determine outcome.Results: Two hundred first MTPJ arthrodeses (172 patients) were included in the analysis (34 male: 138 female; mean age 62 yr). The overall union rate was 93.5%. Union was achieved in 109/118 MTPJs (92.4%) prepared in the flat-on-flat configuration and in 78/82 (95%) prepared in the ball-and-socket configuration (p = 0.438). Higher union rates favoured low-velocity joint preparation [using rongeur only 21/21 (100%), rongeur and burr 26/27 (96.3%) and conical reamer 31/34 (91.2%)] but this did not reach statistical significance (p = 0.317). There was a 95% satisfaction rate with surgery but male patients were less satisfied (p = 0.031).Conclusion: Union rates were not influenced by joint configuration or preparation techniques. (C) 2014 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.

The purpose of this review was to appraise the use of computer-assisted navigation in total knee arthroplasty and to assess whether this technology has improved clinical outcomes. Studies were identified through searches in MEDLINE, Embase, and PubMed. Numerous studies have shown improved leg and component alignment using navigation systems. However, the better alignment achieved in navigated knee arthroplasty has not been shown to lead to better clinical outcomes. Navigated knee arthroplasty had lower calculated blood loss and lower incidence of fat embolism compared with conventional knee arthroplasty using intramedullary jigs. It may be most valued when dealing with complex knee deformities, revision surgery, or minimally invasive surgery. Navigated knee arthroplasty, however, is only cost-effective in centers with a high volume of joint replacements. Overall, computer-assisted navigated knee arthroplasty provides some advantages over conventional surgery, but its clinical benefits to date are unclear and remain to be defined on a larger scale.

This study tests the null hypothesis that there is no difference between sciatic nerve block (SNB) and periarticular anesthetic infiltration (PI) as adjuncts to femoral nerve blockade (FNB) in total knee arthroplasty in terms of postoperative opioid requirements. Fifty-two patients undergoing total knee arthroplasty were randomized to receive either (a) combined FNB-SNB or (b) combined FNB-PI. Average morphine consumption in the first 24 (20 vs 23 mg) and 48 hours (26 vs 33 mg) showed no significant difference. Visual Analogue Scale scores, knee flexion (60° vs 67.5°) and extension lag (0° vs 5°) were comparable. Anesthetic time, surgical time, and length of hospital stay (5.5 vs 6 days) were similar. This study showed no significant difference between the 2 groups. The PI offers a practical and potentially safer alternative to SNB.

Effective utilisation of blood products is fundamental. The introduction of maximum surgical blood ordering schedules (MSBOS) for operations has been shown to improve transfusion services. A retrospective analysis was undertaken to establish an evidence-based MSBOS for revision total hip replacement (THR) and total knee revision (TKR). The impact of this schedule on blood conservation was analysed.

BACKGROUND:Revision total hip replacement (THR) is associated with increased blood loss and extended hospitalization.MATERIALS AND METHODS:We reviewed 146 patients who underwent revision THR to identify predictors of blood loss, transfusion requirements, and length of hospitalization.RESULTS:Blood loss was greater with increasing age and in men. Femoral and dual-component revision and revision of cemented hip components were also associated with greater blood loss. Transfusion requirements were greater in patients who had lower preoperative hemoglobin concentration and in patients undergoing dual-component revision. Length of hospitalization was significantly increased in patients who received transfusion but less in patients who underwent isolated acetabular-component hip revision.CONCLUSIONS:This study shows significantly greater blood loss in men, older patients, revision surgery of cemented implants, and dual-component revisions. More complex revision surgery and preoperative anemia are clearly associated with increased transfusion requirements and length of hospitalization. Identification and treatment of patients at higher risk of transfusion may guide likely transfusion requirements, shorten the length of hospitalization, and reduce the overall cost of treatment.

Cement extrusion during total hip arthroplasty is a common finding and is usually harmless. A rare case of obturator nerve impingement causing pain and atrophy of the adductor muscles of the hip is described. The computed tomographic images revealed an atrophied thigh adductor compartment. Injection of local anesthetic/steroid around the cement mass under computed tomographic guidance relieved the symptoms briefly. The cement mass was excised, and complete recovery was achieved. Persistent pain and muscle weakness after total hip arthroplasty with evidence of extruded cement may indicate this complication. Injection of local anesthetic/steroid under image guidance can help elucidate this diagnosis and provide a pain-relieving effect.