Patient-reported outcomes in Primary Spinal Intradural Tumours: a systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: Primary Spinal Intradural Tumours (PSITs) are rare pathologies that can significantly impact quality of life. This study aimed to review patient reported outcomes (PROs) in PSITs. METHODS: A systematic search of Pubmed and Embase was performed to identify studies measuring PROs in adults with PSITs. PRO results were categorised as relating to Global, Physical, Social, or Mental health. Outcomes were summarised descriptively. RESULTS: Following review of 2382 records, 11 studies were eligible for inclusion (737 patients). All studies assessed surgically treated patients. Schwannoma was the commonest pathology (n = 190). 7 studies measured PROs before and after surgery, the remainder assessed only post-operatively. For eight studies, PROs were obtained within 12 months of treatment. 21 PRO measurement tools were used across included studies, of which Euro-Qol-5D (n = 8) and the pain visual/numerical analogue scale (n = 5) were utilised most frequently. Although overall QoL is lower than healthy controls in PSITs, improvements following surgery were found in Extramedullary tumours (EMT) in overall physical, social, and mental health. Similar improvements were not significant across studies of Intramedullary tumours (IMT). Overall QoL and symptom burden was higher in IMT patients than in brain tumour patients. No studies evaluated the effect of chemotherapy or radiotherapy. CONCLUSION: Patients with PSITs suffer impaired PROs before and after surgery. This is particularly true for IMTs. PRO reporting in PSITs is hindered by a heterogeneity of reporting and varied measurement tools. This calls for the establishment of a standard set of PROs as well as the use of registries.

Characterisation and development of histopathological lesions in a guinea pig model of Mycobacterium tuberculosis infection.

Tuberculosis (TB) remains a very significant infectious disease worldwide. New vaccines and therapies are needed, even more crucially with the increase of multi-drug resistant Mycobacterium tuberculosis strains. Preclinical animal models are very valuable for the development of these new disease control strategies. Guinea pigs are one of the best models of TB, sharing many features with the pathology observed in human TB. Here we describe the development of TB lesions in a guinea pig model of infection. We characterise the granulomatous lesions in four developmental stages (I-IV), using histopathological analysis and immunohistochemical (IHC) techniques to study macrophages, T cells, B cells and granulocytes. The granulomas in the guinea pigs start as aggregations of macrophages and few heterophils, evolving to larger lesions showing central caseous necrosis with mineralisation and abundant acid-fast bacilli, surrounded by a rim of macrophages and lymphocytes in the outer layers of the granuloma. Multinucleated giant cells are very rare and fibrotic capsules are not formed in this animal model.

Anterior To Psoas lumbar and lumbosacral combined with posterior reconstruction in Adult Spinal Deformity: A bicentric European study.

Introduction: Lateral lumbar fusion via the trans-psoas approach is popular in adult deformity reconstruction. To overcome its limitations (neurological damage to the plexus and lack of applicability to the lumbosacral junction), a modified anterior-to-psoas (ATP) approach has been described and used. Research question: To investigate the results of ATP lumbar and lumbosacral fusion, in a cohort of adult patients treated with combined anteroposterior approaches for adult spinal deformity (ASD). Materials and methods: ASD patients surgically treated at two tertiary spinal centres were followed up. Forty patients were treated with combined ATP and posterior surgery: 11 with open lumbar lateral interbody-fusions (lumbotomy LLIF) and 29 with lesser invasive oblique lateral interbody-fusions (OLIF). Preoperative demographics, aetiology, clinical characteristics, and spinopelvic parameters were comparable between the two cohorts. Results: At a minimum 2-year follow-up, both cohorts showed significant improvements in patient reported outcome measures (PROMs), i.e. Visual Analogue Scale and Core Outcome Measures Index, as well as radiological parameters, with no significant differences based on the type of surgical approach. No significant differences were found in major (P â€‹= â€‹0.457) and minor (P â€‹= â€‹0.071) complications between the two cohorts. Discusson and conclusion: Anterolateral lumbar interbody fusions, whether performed via a direct or oblique approach, proved to be safe and effective adjuvants to posterior surgery in patients with ASD. No significant complication differences were noted between techniques. In addition, the anterior-to-psoas approaches limited the risks of post-operative pseudoarthrosis by providing solid anterior support to lumbar and lumbosacral segments, demonstrating a positive impact on PROMS.

Definition and surgical timing in cauda equina syndrome-An updated systematic review.

STUDY DESIGN: Systematic review. OBJECTIVES: To conduct a systematic review identifying existing definitions of cauda equina syndrome (CES) and time to surgery in the literature for patients with CES. METHODS: A systematic review was conducted in accordance with the PRISMA statement. Ovid Medline, Embase, CINAHL Plus, and trial registries were searched from October 1st, 2016, to 30th December 2022, and combined with articles identified from a previous systematic review by the same authors (studies published 1990-2016). RESULTS: A total of 110 studies (52,008 patients) were included. Of these only 16 (14.5%) used established definitions in defining CES, including Fraser criteria (n = 6), British Association of Spine Surgeons (BASS) (n = 5), Gleave and MacFarlane (n = 2), and other (n = 3). Most reported symptoms were urinary dysfunction (n = 44, 40%%), altered sensation in the perianal region (n = 28, 25.5%) and bowel dysfunction (n = 20, 18.2%). Sixty-eight (61.8%) studies included details on time to surgery. There was an increase in percentage of studies defining CES published in the last 5 years compared to ones from 1990-2016 (58.6% vs 77.5.%, P = .045). CONCLUSIONS: Despite Fraser recommendations, substantial heterogeneity exists in reporting of CES definitions, and a start point for time to surgery, with most authors using self-defined criteria. A consensus is required to define CES and time to surgery, to allow consistency in reporting and study analysis.

Practitioner characteristics, diagnostic accuracy metrics and discovering-individual with respect to 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Knowledge of accuracy for melanoma diagnosis and melanoma discovering-individual in primary care is limited. We describe general practitioner (GP) characteristics and analyse defined diagnostic accuracy metrics for GPs in the current study comparing this with a previous study for GPs common to both, and we analyse the individual first discovering each melanoma as a lesion of concern. METHODS: The characteristics and diagnostic accuracy of 27 Australasian GPs documenting 637 melanomas on the Skin Cancer Audit Research Database (SCARD) in 2013 were described and analysed. The number needed to treat (NNT) and percentage of melanomas that were in situ (percentage in situ) were analysed as surrogates for specificity and sensitivity, respectively. The discovering-individual was analysed according to patient age and sex and lesion Breslow thickness. RESULTS: The average NNT and percentage in situ were 5.73% and 65.07%, respectively. For 21 GPs in both a 2008-2010 study and the current study, the NNT was 10.78 and 5.56, respectively (p = 0.0037). A consistent trend of decreasing NNT and increasing percentage in situ through increasingly subspecialised GP categories did not reach statistical significance. NNT trended high at ages and sites for which melanoma was rare. While the patient or family member was more likely to discover thick melanomas and melanomas in patients under 40 years, GPs discovered 73.9% of the melanomas as lesions of concern. CONCLUSIONS: GPs were the discovering-individuals for the majority of melanomas in the current study and their accuracy metrics compared favourably with published figures for dermatologists and GPs.

Integrated diagnosis of nevi with severely atypical features and impact of second opinions.

BACKGROUND: A subset of melanocytic proliferations is difficult to classify by dermatopathology alone and their management is challenging. OBJECTIVE: To explore the value of correlation with dermatoscopy and to evaluate the utility of second opinions by additional pathologists. METHODS: For this single center retrospective study we collected 122 lesions that were diagnosed as atypical melanocytic proliferations, we reviewed dermatoscopy and asked two experienced pathologists to reassess the slides independently. RESULTS: For the binary decision of nevus versus melanoma the diagnostic consensus among external pathologists was only moderate (kappa 0.43; 95% CI 0.25-0.61). If ground truth were defined such that both pathologists had to agree on the diagnosis of melanoma, 13.1% of cases would have been diagnosed as melanoma. If one pathologist were sufficient to call it melanoma 29.5% of cases would have been diagnosed as melanoma. In either case, the presence of dermatoscopic white lines was associated with the diagnosis of melanoma. In lesions with peripheral dots and clods, melanoma was not jointly diagnosed by the two pathologists if the patient was younger than 45 years. CONCLUSIONS: A considerable number of atypical melanocytic proliferations may be diagnosed as melanoma if revised by other pathologists. The presence of white lines on dermatoscopy increases the likelihood of revision towards melanoma. Peripheral clods indicate growth but are not a melanoma clue if patients are younger than 45 years.

Extra-viral DNA in adeno-associated viral vector preparations induces TLR9-dependent innate immune responses in human plasmacytoid dendritic cells.

Adeno-associated viral (AAV) vector suspensions produced in either human derived HEK cells or in Spodoptera frugiperda (Sf9) insect cells differ in terms of residual host cell components as well as species-specific post-translational modifications displayed on the AAV capsid proteins. Here we analysed the impact of these differences on the immunogenic properties of the vector. We stimulated human plasmacytoid dendritic cells with various lots of HEK cell-produced and Sf9 cell-produced AAV-CMV-eGFP vectors derived from different manufacturers. We found that AAV8-CMV-eGFP as well as AAV2-CMV-eGFP vectors induced lot-specific but not production platform-specific or manufacturer-specific inflammatory cytokine responses. These could be reduced or abolished by blocking toll-like receptor 9 signalling or by enzymatically reducing DNA in the vector lots using DNase. Successful HEK cell transduction by DNase-treated AAV lots and DNA analyses demonstrated that DNase did not affect the integrity of the vector but degraded extra-viral DNA. We conclude that both HEK- and Sf9-cell derived AAV preparations can contain immunogenic extra-viral DNA components which can trigger lot-specific inflammatory immune responses. This suggests that improved strategies to remove extra-viral DNA impurities may be instrumental in reducing the immunogenic properties of AAV vector preparations.

Dermatoscopic finding of white circles in an invasive pigmented melanoma.

Dermatoscopic white circles, seen with both non-polarized and polarized dermatoscopy, are a known clue to actinic keratosis in a flat lesion and invasive squamous cell carcinoma in a raised lesion. We have not discovered a previous published example of this clue in a melanoma. We present a case report of a 70-year-old Australian male with a pigmented superficial spreading melanoma on the face, Breslow thickness 1 mm, with dermatoscopic white circles displayed with both polarized and non-polarized dermatoscopy, and with dermatopathological correlation.

The Hunt for Baby Melanomas: A Prospective Study of the Dermoscopy Features on 100 Small Melanoma Cases with in Vivo Surface Diameters up to a Maximum of 6 mm.

Introduction: Early diagnosis can improve melanoma prognosis. Dermoscopy can enhance early melanoma recognition. Objectives: Examine the dermoscopy features of early melanoma up to a maximum surface diameter of 6 mm. Methods: Consecutive melanoma cases were collected from two medical practices in Sydney, Australia 2019-2021. Dermoscopy features were recorded for melanomas by maximum surface diameter, to the nearest 0.1 mm, to a limit of 6 mm. Results: Total cases numbered 100; with males (N = 48) and females (N = 52), melanoma in situ (MIS, N = 96) and invasive (N = 4). The most frequent anatomic sites on both males and females were back (males N = 20, females N = 16) then knee or leg (males N = 8, females N = 12). Minimum respective MIS diameters for males/females was 1.2/2.0 mm and for invasive cases 2.0/3.4 mm. Highest frequency dermoscopy features were: light brown, dark brown, gray and asymmetric melanoma shape. Brown pigment in hair follicles were more frequent on legs compared to other anatomic sites (odds ratio [OR] 14.6; 95% CI 1.29-165.17, P 0.03). Pseudopods were substantially increased in frequency comparing diameters less than 4 mm with 4 up to 6 mm (OR 8.81; 95% CI 1.05-73.9, P 0.004). Structureless area cases recorded increased gray (OR 7.08; 95% CI 1.61-31.11, P=0.01). Melanomas with edge angulation were noted in 20%-50% of cases across diameters 1-6 mm, less frequent were pigmented circles and polygons. Conclusions: Watch out! MIS presented with a surface diameter of just 1.2 mm and invasive melanoma 2.5 mm. Pseudopods were a strong clue to melanomas with a surface diameter less than 5mm. We found melanomas on leg sites displayed more frequent pigmented hair follicles.

Characteristics, treatment and outcomes of 589 melanoma patients documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: General practitioners manage more melanomas than dermatologists or surgeons in Australia. Previously undescribed, the management and outcomes of melanoma patients treated by multiple Australasian general practitioners are examined. METHODS: The characteristics, management and outcomes of 589 melanoma patients, managed by 27 Australasian general practitioners and documented on the Skin Cancer Audit Research Database (SCARD), were analysed. RESULTS: Most patients (58.9%) were males with mean age at diagnosis of 62.7 years (range 18-96), and most melanomas were in situ or thin-invasive. Patients aged under 40 years had fewer melanomas, but a higher proportion (the majority) were invasive, compared with older patients (P < 0.0001). Most (55.9%) melanomas were diagnosed following elliptical excision biopsy, the rate of unintended involved margins being eightfold higher for shave biopsies. Wide re-excision was performed by the treating general practitioner for most (74.9%) melanomas, with thick melanomas preferentially referred to surgeons. The average Breslow thickness of invasive melanomas re-excised by general practitioners was 0.67 mm compared with 1.99 mm for those referred to other specialists (P < 0.0001). Of 205 patients with invasive melanoma, 14 progressed to metastatic disease, 50% of these being associated with nodular melanoma. Nine patients progressed to melanoma-specific death. The 5-year survival rate for patients with invasive melanoma was 95.2% (95% CI: 91.2-98.5%). CONCLUSIONS: Diagnostic and therapeutic management of a series of melanoma patients by Australasian general practitioners were closely aligned with current guidelines and 5-year survival with respect to invasive melanoma was at least as favourable as national population-based metrics.

Assessment of a Diagnostic Classification System for Management of Lesions to Exclude Melanoma.

Importance: The proposed MOLEM (Management of Lesion to Exclude Melanoma) schema is more clinically relevant than Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MATH-Dx) for the management classification of melanocytic and nonmelanocytic lesions excised to exclude melanoma. A more standardized way of establishing diagnostic criteria will be crucial in the training of artificial intelligence (AI) algorithms. Objective: To examine pathologists' variability, reliability, and confidence in reporting melanocytic and nonmelanocytic lesions excised to exclude melanoma using the MOLEM schema in a population of higher-risk patients. Design, Setting, and Participants: This cohort study enrolled higher-risk patients referred to a primary care skin clinic in New South Wales, Australia, between April 2019 and December 2019. Baseline demographic characteristics including age, sex, and related clinical details (eg, history of melanoma) were collected. Patients with lesions suspicious for melanoma assessed by a primary care physician underwent clinical evaluation, dermoscopy imaging, and subsequent excision biopsy of the suspected lesion(s). A total of 217 lesions removed and prepared by conventional histologic method and stained with hematoxylin-eosin were reviewed by up to 9 independent pathologists for diagnosis using the MOLEM reporting schema. Pathologists evaluating for MOLEM schema were masked to the original histopathologic diagnosis. Main Outcomes and Measures: Characteristics of the lesions were described and the concordance of cases per MOLEM class was assessed. Interrater agreement and the agreement between pathologists' ratings and the majority MOLEM diagnosis were calculated by Gwet AC1 with quadratic weighting applied. The diagnostic confidence of pathologists was then assessed. Results: A total of 197 patients were included in the study (102 [51.8%] male; 95 [48.2%] female); mean (SD) age was 64.2 (15.8) years (range, 24-93 years). Overall, 217 index lesions were assessed with a total of 1516 histological diagnoses. Of 1516 diagnoses, 677 (44.7%) were classified as MOLEM class I; 120 (7.9%) as MOLEM class II; 564 (37.2%) as MOLEM class III; 114 (7.5%) as MOLEM class IV; and 55 (3.6%) as MOLEM class V. Concordance rates per MOLEM class were 88.6% (class I), 50.8% (class II), 76.2% (class III), 77.2% (class IV), and 74.2% (class V). The quadratic weighted interrater agreement was 91.3%, with a Gwet AC1 coefficient of 0.76 (95% CI, 0.72-0.81). The quadratic weighted agreement between pathologists' ratings and majority MOLEM was 94.7%, with a Gwet AC1 coefficient of 0.86 (95% CI, 0.84-0.88). The confidence in diagnosis data showed a relatively high level of confidence (between 1.0 and 1.5) when diagnosing classes I (mean [SD], 1.3 [0.3]), IV (1.3 [0.3]) and V (1.1 [0.1]); while classes II (1.8 [0.2]) and III (1.5 [0.4]) were diagnosed with a lower level of pathologist confidence (≥1.5). The quadratic weighted interrater confidence rating agreement was 95.2%, with a Gwet AC1 coefficient of 0.92 (95% CI, 0.90-0.94) for the 1314 confidence ratings collected. The confidence agreement for each MOLEM class was 95.0% (class I), 93.5% (class II), 95.3% (class III), 96.5% (class IV), and 97.5% (class V). Conclusions and Relevance: The proposed MOLEM schema better reflects clinical practice than the MPATH-Dx schema in lesions excised to exclude melanoma by combining diagnoses with similar prognostic outcomes for melanocytic and nonmelanocytic lesions into standardized classification categories. Pathologists' level of confidence appeared to follow the MOLEM schema diagnostic concordance trend, ie, atypical naevi and melanoma in situ diagnoses were the least agreed upon and the most challenging for pathologists to confidently diagnose.

Anterolateral thoracic approach for thoracic discectomy using pedicle marking and 3D intraoperative imaging system.

Thoracic disc herniation (TDH) is a rare occurrence comprising of only 0.25-0.75% of all herniated discs in any region. Limitations in direct visualization remains a surgical challenge for complete and safe resection of TDH. In this case report, we describe the use of a 3D intraoperative imaging system (O-arm system TM) coupled with percutaneous pedicle markers placed under fluoroscopic guidance to circumvent the current limitations in visualisation for a patient with a giant calcified TDH using an anterolateral approach. There was an improvement in overall visualisation and ease of procedure, leading to a successful surgery. Post-op, there was a significant improvement in the motor power of the patient.

TB and SIV Coinfection; a Model for Evaluating Vaccine Strategies against TB Reactivation in Asian Origin Cynomolgus Macaques: A Pilot Study Using BCG Vaccination.

This pilot study aimed to determine the utility of a cynomolgus macaque model of coinfection with simian immunodeficiency virus (SIV) for the assessment of vaccines designed to prevent reactivation of TB. Following infection caused by aerosol exposure to an ultralow dose of Mycobacterium tuberculosis (M. tb), data trends indicated that subsequent coinfection with SIVmac32H perturbed control of M. tb infection as evidenced by the increased occurrence of progressive disease in this group, higher levels of pathology and increased frequency of progressive tuberculous granulomas in the lung. BCG vaccination led to improved control of TB-induced disease and lower viral load in comparison to unvaccinated coinfected animals. The M. tb-specific IFNγ response after exposure to M. tb, previously shown to be associated with bacterial burden, was lower in the BCG-vaccinated group than in the unvaccinated groups. Levels of CD4+ and CD8+ T cells decreased in coinfected animals, with counts recovering more quickly in the BCG-vaccinated group. This pilot study provides proof of concept to support the use of the model for evaluation of interventions against reactivated/exacerbated TB caused by human immunodeficiency virus (HIV) infection.

Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma.

PURPOSE: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to date. More than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion. However, recent findings led us to investigate the alternative hypothesis that IDO suppresses the anti-GBM immune response independent of its association with Trp metabolism. EXPERIMENTAL DESIGN: IDO-deficient GBM cell lines reconstituted with IDO wild-type or IDO enzyme-null cDNA were created and validated in vitro and in vivo. Microarray analysis was conducted to search for genes that IDO regulates, followed by the analysis of human GBM cell lines, patient GBM and plasma, and The Cancer Genome Atlas (TCGA) database. Ex vivo cell coculture assays, syngeneic and humanized mouse GBM models, were used to test the alternative hypothesis. RESULTS: Nonenzymic tumor cell IDO activity decreased the survival of experimental animals and increased the expression of complement factor H (CFH) and its isoform, factor H like protein 1 (FHL-1) in human GBM. Tumor cell IDO increased CFH and FHL-1 expression independent of Trp metabolism. Increased intratumoral CFH and FHL-1 levels were associated with poorer survival among patients with glioma. Similar to IDO effects, GBM cell FHL-1 expression increased intratumoral regulatory T cells (Treg) and myeloid-derived suppressor cells while it decreased overall survival in mice with GBM. CONCLUSIONS: Our study reveals a nonmetabolic IDO-mediated enhancement of CFH expression and provides a new therapeutic target for patients with GBM.

Characteristics of 637 melanomas documented by 27 general practitioners on the Skin Cancer Audit Research Database.

BACKGROUND AND OBJECTIVE: Most melanomas (including melanomas in situ), in Australasia, are treated by general practitioners (GPs). Previously undescribed, the characteristics of a series of melanomas treated by multiple GPs are examined. PATIENTS AND METHODS: Six hundred and thirty-seven melanomas treated by 27 Australasian GPs during 2013 and documented on the Skin Cancer Audit Research Database (SCARD) were analysed by anatomical site, subtype, Breslow thickness, diameter, associated naevi and linked adverse outcomes. RESULTS: Most melanomas (59.7%) were on males, mean age at diagnosis being 62.7 years (range 18-96). Most (65.0%) were in situ, with a high incidence of lentiginous melanoma (LM) (38.8%) and 32% were naevus associated. Most LM (86.4%) were in situ, compared to 55% of superficial spreading melanoma (SSM) (P < 0.0001). There was male predominance on the head, neck and trunk and female predominance on extremities. There was no significant association between Breslow thickness and diameter, with small melanomas as likely to be thick as large melanomas, and melanomas ≤3 mm diameter, on average, more likely to be invasive than larger melanomas. There was a positive correlation between age and both melanoma diameter and Breslow thickness. Seven cases progressed to melanoma-specific death: Five nodular melanoma (NM) and two SSM, one of which was thin (Breslow thickness 0.5 mm). CONCLUSIONS: A large series of melanomas treated by Australasian GPs were predominantly in situ, with a high proportion of LM subtype. With implications for GP training, NM linked to death was over-represented and there was a novel finding that older patients had larger diameter melanomas.

Surgical microdiscectomy versus transforaminal epidural steroid injection in patients with sciatica secondary to herniated lumbar disc (NERVES): a phase 3, multicentre, open-label, randomised controlled trial and economic evaluation.

BACKGROUND: The optimal invasive treatment for sciatica secondary to herniated lumbar disc remains controversial, with a paucity of evidence for use of non-surgical treatments such as transforaminal epidural steroid injection (TFESI) over surgical microdiscectomy. We aimed to investigate the clinical and cost-effectiveness of these options for management of radicular pain secondary to herniated lumbar disc. METHODS: We did a pragmatic, multicentre, phase 3, open-label, randomised controlled trial at 11 spinal units across the UK. Eligible patients were aged 16-65 years, had MRI-confirmed non-emergency sciatica secondary to herniated lumbar disc with symptom duration between 6 weeks and 12 months, and had leg pain that was not responsive to non-invasive management. Participants were randomly assigned (1:1) to receive either TFESI or surgical microdiscectomy by an online randomisation system that was stratified by centre with random permuted blocks. The primary outcome was Oswestry Disability Questionnaire (ODQ) score at 18 weeks. All randomly assigned participants who completed a valid ODQ at baseline and at 18 weeks were included in the analysis. Safety analysis included all treated participants. Cost-effectiveness was estimated from the EuroQol-5D-5L, Hospital Episode Statistics, medication usage, and self-reported resource-use data. This trial was registered with ISRCTN, number ISRCTN04820368, and EudraCT, number 2014-002751-25. FINDINGS: Between March 6, 2015, and Dec 21, 2017, 163 (15%) of 1055 screened patients were enrolled, with 80 participants (49%) randomly assigned to the TFESI group and 83 participants (51%) to the surgery group. At week 18, ODQ scores were 30·02 (SD 24·38) for 63 assessed patients in the TFESI group and 22·30 (19·83) for 61 assessed patients in the surgery group. Mean improvement was 24·52 points (18·89) for the TFESI group and 26·74 points (21·35) for the surgery group, with an estimated treatment difference of -4·25 (95% CI -11·09 to 2·59; p=0·22). There were four serious adverse events in four participants associated with surgery, and none with TFESI. Compared with TFESI, surgery had an incremental cost-effectiveness ratio of £38 737 per quality-adjusted life-year gained, and a 0·17 probability of being cost-effective at a willingness-to-pay threshold of £20 000 per quality-adjusted life-year. INTERPRETATION: For patients with sciatica secondary to herniated lumbar disc, with symptom duration of up to 12 months, TFESI should be considered as a first invasive treatment option. Surgery is unlikely to be a cost-effective alternative to TFESI. FUNDING: Health Technology Assessment programme of the National Institute for Health Research (NIHR), UK.

Microdiscectomy compared with transforaminal epidural steroid injection for persistent radicular pain caused by prolapsed intervertebral disc: the NERVES RCT.

BACKGROUND: Sciatica is a common condition reported to affect > 3% of the UK population at any time and is most often caused by a prolapsed intervertebral disc. Currently, there is no uniformly adopted treatment strategy. Invasive treatments, such as surgery (i.e. microdiscectomy) and transforaminal epidural steroid injection, are often reserved for failed conservative treatment. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of microdiscectomy with transforaminal epidural steroid injection for the management of radicular pain secondary to lumbar prolapsed intervertebral disc for non-emergency presentation of sciatica of < 12 months' duration. INTERVENTIONS: Patients were randomised to either (1) microdiscectomy or (2) transforaminal epidural steroid injection. DESIGN: A pragmatic, multicentre, randomised prospective trial comparing microdiscectomy with transforaminal epidural steroid injection for sciatica due to prolapsed intervertebral disc with < 1 year symptom duration. SETTING: NHS services providing secondary spinal surgical care within the UK. PARTICIPANTS: A total of 163 participants (aged 16-65 years) were recruited from 11 UK NHS outpatient clinics. MAIN OUTCOME MEASURES: The primary outcome was participant-completed Oswestry Disability Questionnaire score at 18 weeks post randomisation. Secondary outcomes were visual analogue scores for leg pain and back pain; modified Roland-Morris score (for sciatica), Core Outcome Measures Index score and participant satisfaction at 12-weekly intervals. Cost-effectiveness and quality of life were assessed using the EuroQol-5 Dimensions, five-level version; Hospital Episode Statistics data; medication usage; and self-reported cost data at 12-weekly intervals. Adverse event data were collected. The economic outcome was incremental cost per quality-adjusted life-year gained from the perspective of the NHS in England. RESULTS: Eighty-three participants were allocated to transforaminal epidural steroid injection and 80 participants were allocated to microdiscectomy, using an online randomisation system. At week 18, Oswestry Disability Questionnaire scores had decreased, relative to baseline, by 26.7 points in the microdiscectomy group and by 24.5 points in the transforaminal epidural steroid injection. The difference between the treatments was not statistically significant (estimated treatment effect -4.25 points, 95% confidence interval -11.09 to 2.59 points). Nor were there significant differences between treatments in any of the secondary outcomes: Oswestry Disability Questionnaire scores, visual analogue scores for leg pain and back pain, modified Roland-Morris score and Core Outcome Measures Index score up to 54 weeks. There were four (3.8%) serious adverse events in the microdiscectomy group, including one nerve palsy (foot drop), and none in the transforaminal epidural steroid injection group. Compared with transforaminal epidural steroid injection, microdiscectomy had an incremental cost-effectiveness ratio of £38,737 per quality-adjusted life-year gained and a probability of 0.17 of being cost-effective at a willingness to pay threshold of £20,000 per quality-adjusted life-year. LIMITATIONS: Primary outcome data was invalid or incomplete for 24% of participants. Sensitivity analyses demonstrated robustness to assumptions made regarding missing data. Eighteen per cent of participants in the transforaminal epidural steroid injection group subsequently received microdiscectomy prior to their primary outcome assessment. CONCLUSIONS: To the best of our knowledge, the NErve Root Block VErsus Surgery trial is the first trial to evaluate the comparative clinical effectiveness and cost-effectiveness of microdiscectomy and transforaminal epidural steroid injection. No statistically significant difference was found between the two treatments for the primary outcome. It is unlikely that microdiscectomy is cost-effective compared with transforaminal epidural steroid injection at a threshold of £20,000 per quality-adjusted life-year for sciatica secondary to prolapsed intervertebral disc. FUTURE WORK: These results will lead to further studies in the streamlining and earlier management of discogenic sciatica. TRIAL REGISTRATION: Current Controlled Trials ISRCTN04820368 and EudraCT 2014-002751-25. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 24. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Sciatica or pain related to nerve irritation travelling down the leg is common in young working adults and most likely to be caused by a 'slipped' (prolapsed) disc. Although the majority of cases get better on their own and within 4­6 weeks, a significant group of patients struggle with disabling symptoms sometimes beyond 1 year. Consequently, patients struggle to maintain their home and working lives. Many treatments are available for sciatica, but simpler treatments (e.g. pain tablets, physiotherapy and changing one's lifestyle) are often not very effective and patients have often tried all of them by the time they are seen in hospital to have tests, such as scans, done. Surgery to remove part of the disc is recommended in cases where the pain is accompanied by severe weakness in one or both legs, or where doctors think that nerves may be damaged because patients have bladder, bowel and sexual functioning difficulties (i.e. red flag symptoms). Surgery works well in alleviation of referred leg pain and also to relieve pressure on a physically compressed nerve that may be showing clinical sign of injury/weakness. An alternative to surgery is to inject a mixture of anaesthetic and steroid close to the site of the disc injury and nerve, but at the moment we do not know whether or not these injections work in the long term. They are cheaper and less invasive, with fewer risks than surgery, such as from anaesthetic or infection. WHAT DID OUR STUDY INVESTIGATE?: This study compared the usefulness of surgery with injections for patients who have had sciatica for < 1 year and who have tried simple remedies but are still in pain. Patients were allocated to have either surgery or the injection. Symptoms (e.g. pain) were assessed after 18 weeks. WHAT DID WE FIND?: We found that there was no significant difference between surgery and injection at the primary end point. Surgery was not significantly different from injection in terms of clinical outcome and was not cost-effective compared with injection. OUR CONCLUSION AND RECOMMENDATION: Given the cost of surgery and the risks to patients, we suggest that further studies should be carried out to explore whether or not all patients with sciatica due to a slipped disc should be considered suitable for an injection, unless there is a good reason not to.

The complement system in age-related macular degeneration.

Age-related macular degeneration (AMD) is a chronic and progressive degenerative disease of the retina, which culminates in blindness and affects mainly the elderly population. AMD pathogenesis and pathophysiology are incredibly complex due to the structural and cellular complexity of the retina, and the variety of risk factors and molecular mechanisms that contribute to disease onset and progression. AMD is driven by a combination of genetic predisposition, natural ageing changes and lifestyle factors, such as smoking or nutritional intake. The mechanism by which these risk factors interact and converge towards AMD are not fully understood and therefore drug discovery is challenging, where no therapeutic attempt has been fully effective thus far. Genetic and molecular studies have identified the complement system as an important player in AMD. Indeed, many of the genetic risk variants cluster in genes of the alternative pathway of the complement system and complement activation products are elevated in AMD patients. Nevertheless, attempts in treating AMD via complement regulators have not yet been successful, suggesting a level of complexity that could not be predicted only from a genetic point of view. In this review, we will explore the role of complement system in AMD development and in the main molecular and cellular features of AMD, including complement activation itself, inflammation, ECM stability, energy metabolism and oxidative stress.

MTBVAC vaccination protects rhesus macaques against aerosol challenge with M. tuberculosis and induces immune signatures analogous to those observed in clinical studies.

A single intradermal vaccination with MTBVAC given to adult rhesus macaques was well tolerated and conferred a significant improvement in outcome following aerosol exposure to M. tuberculosis compared to that provided by a single BCG vaccination. Vaccination with MTBVAC resulted in a significant reduction in M. tuberculosis infection-induced disease pathology measured using in vivo medical imaging, in gross pathology lesion counts and pathology scores recorded at necropsy, the frequency and severity of pulmonary granulomas and the frequency of recovery of viable M. tuberculosis from extrapulmonary tissues following challenge. The immune profiles induced following immunisation with MTBVAC reflect those identified in human clinical trials of MTBVAC. Evaluation of MTBVAC- and TB peptide-pool-specific T-cell cytokine production revealed a predominantly Th1 response from poly- (IFN-γ+TNF-α+IL2+) and multi-(IFN-γ+TNF-α+) functional CD4 T cells, while only low levels of Th22, Th17 and cytokine-producing CD8 T-cell populations were detected together with low-level, but significant, increases in CFP10-specific IFN-γ secreting cells. In this report, we describe concordance between immune profiles measured in clinical trials and a macaque pre-clinical study demonstrating significantly improved outcome after M. tuberculosis challenge as evidence to support the continued development of MTBVAC as an effective prophylactic vaccine for TB vaccination campaigns.