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1.
Mol Ther ; 32(2): 457-468, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38053333

RESUMO

CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumor control. Antibodies targeting CTLA-4 have been promising treatments for numerous cancers, but the mechanistic basis of their anti-tumoral immune-boosting effects is poorly understood. Although the ctla4 gene also encodes an alternatively spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in a murine cancer model. We show that expression of sCTLA-4 by tumor cells suppresses CD8+ T cells in vitro and accelerates growth and experimental metastasis of murine tumors in vivo. These effects were accompanied by modification of the immune infiltrate, notably restraining CD8+ T cells in a non-cytotoxic state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoral CD8+ T cell activation and cytolytic potential, correlating with therapeutic efficacy and tumor control. This previously unappreciated role of sCTLA-4 suggests that the biology and function of multi-gene products of immune checkpoint receptors need to be fully elucidated for improved mechanistic understanding of cancer immunotherapies.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Animais , Camundongos , Anticorpos , Linfócitos T CD8-Positivos/metabolismo , Antígeno CTLA-4/genética , Neoplasias/genética , Neoplasias/terapia , Isoformas de Proteínas/genética
2.
Osteoporos Int ; 35(5): 903-909, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38448782

RESUMO

Patients who sustain a contralateral hip fracture experience significantly inferior outcomes; however, the incidence and predictors of contralateral hip fracture remain poorly understood. In the present study, 2.5% of patients sustained a contralateral hip fracture within 12 months, and socioeconomic deprivation was associated with reduced risk of contralateral hip fracture. INTRODUCTION: Hip fractures are associated with high morbidity and mortality, and patients that sustain a subsequent contralateral fracture experience inferior outcomes. The risk of contralateral fracture is highest within the first year; however, the incidence and associated factors remain poorly understood. The aims were to investigate (i) the incidence of a subsequent contralateral hip fracture within the first year, (ii) identify factors associated with an increased risk of contralateral fracture and (iii) compare early mortality risk after index versus contralateral hip fracture. METHODS: This study included all patients aged over 50 years admitted to NHS hospitals in Scotland between 1st March 2020 and 31st December 2020 (n = 5566) as routine activity of the Scottish Hip Fracture Audit (SHFA). Multivariate logistic regression was used to examine factors associated with 30-day mortality, and cox regression was used to identify factors associated with a contralateral fracture. RESULTS: During the study period 2.5% (138/5566) of patients sustained a contralateral hip fracture within 12 months of the index hip fracture. Socioeconomic deprivation was inversely associated with increased risk of contralateral fracture (odds ratio 2.64, p < 0.001), whilst advancing age (p = 0.427) and sex (p = 0.265) were not. After adjusting for significant cofounders, there was no significant difference in 30-day mortality following contralateral fracture compared to index fracture (OR 1.22, p = 0.433). CONCLUSION: One in 40 (2.5%) hip fracture patients sustained a contralateral fracture within 12 months of their index fracture, and deprivation was associated with a reduced risk of contralateral fracture. No difference in 30-day mortality was found.


Assuntos
Fraturas do Quadril , Humanos , Pessoa de Meia-Idade , Incidência , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/etiologia , Hospitalização , Escócia , Hospitais , Fatores de Risco , Estudos Retrospectivos
3.
Eur J Orthop Surg Traumatol ; 34(2): 909-918, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37773419

RESUMO

PURPOSE: To determine the feasibility and reliability of ultrasound in the assessment of humeral shaft fracture healing and estimate the accuracy of 6wk ultrasound in predicting nonunion. METHODS: Twelve adults with a non-operatively managed humeral shaft fracture were prospectively recruited and underwent ultrasound scanning at 6wks and 12wks post-injury. Seven blinded observers evaluated sonographic callus appearance to determine intra- and inter-observer reliability. Nonunion prediction accuracy was estimated by comparing images for patients that united (n = 10/12) with those that developed a nonunion (n = 2/12). RESULTS: The mean scan duration was 8 min (5-12) and all patients tolerated the procedure. At 6wks and 12wks, sonographic callus (SC) was present in 11 patients (10 united, one nonunion) and sonographic bridging callus (SBC) in seven (all united). Ultrasound had substantial intra- (weighted kappa: 6wk 0.75; 12wk 0.75) and inter-observer reliability (intraclass correlation coefficient: 6wk 0.60; 12wk 0.76). At 6wks, the absence of SC demonstrated sensitivity 50%, specificity 100%, positive predictive value (PPV) 100% and negative predictive value (NPV) 91% in nonunion prediction (overall accuracy 92%). The absence of SBC demonstrated sensitivity 100%, specificity 70%, PPV 40% and NPV 100% in nonunion prediction (overall accuracy 75%). Of three patients at risk of nonunion (Radiographic Union Score for HUmeral fractures < 8), one had SBC on 6wk ultrasound (that subsequently united) and the others had non-bridging/absent SC (both developed nonunion). CONCLUSIONS: Ultrasound assessment of humeral shaft fracture healing was feasible, reliable and may predict nonunion. Ultrasound could be useful in defining nonunion risk among patients with reduced radiographic callus formation.


Assuntos
Fraturas não Consolidadas , Fraturas do Úmero , Adulto , Humanos , Consolidação da Fratura , Fraturas não Consolidadas/diagnóstico por imagem , Fraturas não Consolidadas/etiologia , Fraturas não Consolidadas/cirurgia , Estudo de Prova de Conceito , Reprodutibilidade dos Testes , Estudos de Viabilidade , Fraturas do Úmero/diagnóstico por imagem , Fraturas do Úmero/cirurgia , Úmero , Estudos Retrospectivos , Resultado do Tratamento
4.
World J Surg ; 47(4): 912-921, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36725742

RESUMO

AIMS: This study aims to determine whether intraoperative intravenous (IV) tranexamic acid (TXA) affects blood loss following the surgical management of femoral fragility fractures (FFF). METHODS: This was a single centre (university teaching hospital) non-randomised case-control study. There were 361 consecutive patients with FFF admitted over a 4-month period were included (mean age 81.4yrs; mean BMI 23.5; 73.7% female). Patient demographics, comorbidities, preoperative anticoagulation use, surgical management, intravenous TXA use, perioperative haemoglobin (Hb) and haematocrit, and requirement for blood transfusion were recorded. The primary outcome was postoperative blood transfusion requirement. Secondary outcomes included postoperative day one calculated blood loss (CBL) (using the Nadler and Gross formulae) and fall in Hb (percentage) from preoperative levels; and the incidence of thrombotic events and mortality up to 30 days. RESULTS: Groups were well matched in terms of patient demographics, comorbidities, preoperative anticoagulation use, injury types and surgical management. Intravenous TXA 1 g given at the beginning of surgery at the discretion of the operating team: 178 (49%) received TXA and 183 (51%) did not. The requirement for postoperative blood transfusion was significantly less in the TXA group: 15/178 (8.4%) compared to 58/183 (31.7%) (p < 0.001; Chi square). TXA significantly reduced both the percentage fall in Hb (mean difference 4.3%, p < 0.001) and the CBL (mean difference -222 ml, p < 0.001). There was no difference in VTE (2 vs 1, p = 0.620) or other thrombotic events (2 vs 0, p = 0.244) between groups. CONCLUSION: 1 g of intraoperative intravenous TXA during the surgical management of FFF was associated with reduced rate of transfusion, CBL and the percentage drop in HB. The use of TXA in this study was not randomised, so there could be un-quantifiable bias in the patient selection.


Assuntos
Fraturas do Fêmur , Ácido Tranexâmico , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Administração Intravenosa , Anticoagulantes , Perda Sanguínea Cirúrgica/prevenção & controle , Transfusão de Sangue , Estudos de Casos e Controles , Hospitais de Ensino
5.
J Sports Sci ; 41(17): 1596-1604, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37983261

RESUMO

This study assessed the lead and trail arm peak and average extensor carpi ulnaris (ECU) muscle activity in association with tri-planar angular velocities of the lead and trail wrists during the golf swing. Fifteen sub-elite, male right-handed golfers (Mage = 34.7 years ±13.3, Mhandicap = 1.5 ± 2.2) were recruited to execute five shots each with their pitching wedge, 7-iron and driver clubs in an indoor golf simulator. Surface electromyography (EMG) sensors were placed over the ECU muscle belly and inertial measurement unit sensors were placed bi-laterally on the distal forearm and dorsum of the hand. There was a statistically greater recruitment of the trail ECU muscle during the downswing (p < 0.001) for all clubs. The lead ECU muscle was recruited more during the backswing (p < 0.001) and follow through (p < 0.024) phases. There were statistically different tri-planar movement patterns between the lead and trail wrist throughout all three phases of the golf swing. No significant relationships were found between downswing EMG data and clubhead kinematics at impact. In conclusion, differing wrist kinematics and associated muscle activity may contribute to the asymmetrical injury pattern seen clinically.


Assuntos
Golfe , Punho , Humanos , Masculino , Adulto , Antebraço , Golfe/fisiologia , Fenômenos Biomecânicos , Músculo Esquelético/fisiologia , Articulação do Punho , Movimento
6.
Emerg Med J ; 40(8): 576-582, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37169546

RESUMO

BACKGROUND: Plain radiographs cannot identify all scaphoid fractures; thus ED patients with a clinical suspicion of scaphoid injury often undergo immobilisation despite normal imaging. This study determined (1) the prevalence of scaphoid fracture among patients with a clinical suspicion of scaphoid injury with normal radiographs and (2) whether clinical features can identify patients that do not require immobilisation and further imaging. METHODS: This systematic review of diagnostic test accuracy studies included all study designs that evaluated predictors of scaphoid fracture among patients with normal initial radiographs. Quality assessment was undertaken using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. Meta-analyses included all studies. RESULTS: Eight studies reported data on 1685 wrist injuries. The prevalence of scaphoid fracture despite normal radiographs was 9.0%. Most studies were at overall low risk of bias but two were at unclear risk; all eight were at low risk for applicability concerns. The most accurate clinical predictors of occult scaphoid fracture were pain when the examiner moved the wrist from a pronated to a supinated position against resistance (sensitivity 100%, specificity 97.9%, LR+ 45.0, 95% CI 6.5 to 312.5), supination strength <10% of contralateral side (sensitivity 84.6%, specificity 76.9%, LR+ 3.7, 95% CI 2.2 to 6.1), pain on ulnar deviation (sensitivity 55.2%, specificity 76.4%, LR+ 2.3, 95% CI 1.8 to 3.0) and pronation strength <10% of contralateral side (sensitivity 69.2%, specificity 64.6%, LR+ 2.0, 95% CI 1.2 to 3.2). Absence of anatomical snuffbox tenderness significantly reduced the likelihood of an occult scaphoid fracture (sensitivity 92.1%, specificity 48.4%, LR- 0.2, 95% CI 0.0 to 0.7). CONCLUSION: No single feature satisfactorily excludes an occult scaphoid fracture. Further work should explore whether a combination of clinical features, possibly in conjunction with injury characteristics (such as mechanism) and a normal initial radiograph might exclude fracture. Pain on supination against resistance would benefit from external validation. TRIAL REGISTRATION NUMBER: CRD42021290224.


Assuntos
Fraturas Ósseas , Traumatismos da Mão , Osso Escafoide , Diagnóstico Diferencial , Fraturas Ósseas/complicações , Fraturas Ósseas/diagnóstico , Testes Diagnósticos de Rotina , Humanos , Dor/etiologia , Traumatismos da Mão/complicações , Traumatismos da Mão/diagnóstico
7.
Eur J Orthop Surg Traumatol ; 33(5): 1635-1640, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35794424

RESUMO

PURPOSE: Positive ulnar variance following a distal radius malunion can lead to ulnar-sided wrist pain, loss of grip strength, and distal radioulnar joint impingement. The primary aim of this study is to describe upper limb-specific functional outcomes following ulnar shortening osteotomy (USO) for ulnar-sided wrist pain associated with malunion of the distal radius. METHODS: We retrospectively identified 40 adult patients from a single centre over a 9-year period that had undergone an USO for symptomatic malunion of the distal radius. The primary outcome was the patient-rated wrist evaluation (PRWE). Secondary outcomes were the QuickDASH, EQ-5D-5L, complications, and net promoter score (NPS). RESULTS: Outcomes were available for 37 patients (93%). The mean age was 56 years and 25 patients were female (68%). At a mean follow-up of 6 years (range 1-10 years) the median PRWE was 11 (IQR 0-29.5), the median QuickDASH 6.8 (IQR 0-29.5), and the median EQ-5D-5L index was 0.88 (IQR 0.71-1). The NPS was 73. Complications occurred in nine patients (24%) and included non-union (n = 4), early loss of fixation requiring revision surgery (n = 1), superficial wound infection (n = 2), neurological injury (n = 1), and further surgery for symptomatic hardware removal (n = 1). CONCLUSIONS: For patients with a symptomatic distal radius malunion where the predominant deformity is ulnar positive variance, this study has demonstrated that despite 1 in 4 patients experiencing a complication, USO can result in excellent patient reported outcomes with high levels of satisfaction. LEVEL OF EVIDENCE: III (Cohort Study).


Assuntos
Fraturas Mal-Unidas , Fraturas do Rádio , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Rádio (Anatomia)/diagnóstico por imagem , Rádio (Anatomia)/cirurgia , Estudos de Coortes , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/cirurgia , Estudos Retrospectivos , Fraturas Mal-Unidas/cirurgia , Amplitude de Movimento Articular , Ulna/cirurgia , Articulação do Punho/diagnóstico por imagem , Articulação do Punho/cirurgia , Osteotomia/efeitos adversos , Artralgia , Resultado do Tratamento
8.
Eur J Orthop Surg Traumatol ; 33(7): 3167-3173, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37071221

RESUMO

AIMS: To develop a reliable and effective radiological score to assess the healing of isolated ulnar shaft fractures (IUSF), the Radiographic Union Score for Ulna fractures (RUSU). METHODS: Initially, 20 patients with radiographs six weeks following a non-operatively managed ulnar shaft fracture were selected and scored by three blinded observers. After intraclass correlation (ICC) analysis, a second group of 54 patients with radiographs six weeks after injury (18 who developed a nonunion and 36 who united) were scored by the same observers. RESULTS: In the initial study, interobserver and intraobserver ICC were 0.89 and 0.93, respectively. In the validation study, the interobserver ICC was 0.85. The median score for patients who united was significantly higher than those who developed a nonunion (11 vs. 7, p < 0.001). A ROC curve demonstrated that a RUSU ≤ 8 had a sensitivity of 88.9% and specificity of 86.1% in identifying patients at risk of nonunion. Patients with a RUSU ≤ 8 (n = 21) were more likely to develop a nonunion (n = 16/21) than those with a RUSU ≥ 9 (n = 2/33; OR 49.6, 95% CI 8.6-284.7). Based on a PPV of 76%, if all patients with a RUSU ≤ 8 underwent fixation at 6 weeks, the number of procedures needed to avoid one nonunion would be 1.3. CONCLUSION: The RUSU shows good interobserver and intraobserver reliability and is effective in identifying patients at risk of nonunion six weeks after fracture. This tool requires external validation but may enhance the management of patients with isolated ulnar shaft fractures.


Assuntos
Fraturas não Consolidadas , Fraturas da Ulna , Humanos , Reprodutibilidade dos Testes , Consolidação da Fratura , Fraturas não Consolidadas/diagnóstico por imagem , Fraturas não Consolidadas/cirurgia , Fraturas da Ulna/diagnóstico por imagem , Fraturas da Ulna/cirurgia , Radiografia , Estudos Retrospectivos , Resultado do Tratamento
9.
Surgeon ; 20(6): e429-e446, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35430111

RESUMO

AIMS: This international study aimed to assess: 1) the prevalence of preoperative and postoperative COVID-19 among patients with hip fracture, 2) the effect on 30-day mortality, and 3) clinical factors associated with the infection and with mortality in COVID-19-positive patients. METHODS: A multicentre collaboration among 112 centres in 14 countries collected data on all patients presenting with a hip fracture between 1st March-31st May 2020. Demographics, residence, place of injury, presentation blood tests, Nottingham Hip Fracture Score, time to surgery, management, ASA grade, length of stay, COVID-19 and 30-day mortality status were recorded. RESULTS: A total of 7090 patients were included, with a mean age of 82.2 (range 50-104) years and 4959 (69.9%) being female. Of 651 (9.2%) patients diagnosed with COVID-19, 225 (34.6%) were positive at presentation and 426 (65.4%) were positive postoperatively. Positive COVID-19 status was independently associated with male sex (odds ratio (OR) 1.38, p = 0.001), residential care (OR 2.15, p < 0.001), inpatient fall (OR 2.23, p = 0.003), cancer (OR 0.63, p = 0.009), ASA grades 4 (OR 1.59, p = 0.008) or 5 (OR 8.28, p < 0.001), and longer admission (OR 1.06 for each increasing day, p < 0.001). Patients with COVID-19 at any time had a significantly lower chance of 30-day survival versus those without COVID-19 (72.7% versus 92.6%, p < 0.001). COVID-19 was independently associated with an increased 30-day mortality risk (hazard ratio (HR) 2.83, p < 0.001). Increasing age (HR 1.03, p = 0.028), male sex (HR 2.35, p < 0.001), renal disease (HR 1.53, p = 0.017), and pulmonary disease (HR 1.45, p = 0.039) were independently associated with a higher 30-day mortality risk in patients with COVID-19 when adjusting for confounders. CONCLUSION: The prevalence of COVID-19 in hip fracture patients during the first wave of the pandemic was 9%, and was independently associated with a three-fold increased 30-day mortality risk. Among COVID-19-positive patients, those who were older, male, with renal or pulmonary disease had a significantly higher 30-day mortality risk.


Assuntos
COVID-19 , Infecção Hospitalar , Fraturas do Quadril , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , Pandemias , Infecção Hospitalar/complicações , Infecção Hospitalar/epidemiologia , Mortalidade Hospitalar , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/cirurgia , Estudos Retrospectivos
10.
Surgeon ; 20(4): 237-240, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34103268

RESUMO

INTRODUCTION: The Coronavirus Disease 2019 (COVID-19) pandemic resulted in major disruption to hip fracture services. This frail patient group requires specialist care, and disruption to services is likely to result in increases in morbidity, mortality and long-term healthcare costs. AIMS: To assess disruption to hip fracture services during the COVID-19 pandemic. METHODS: A questionnaire was designed for completion by a senior clinician or service manager in each participating unit between April-September 2020. The survey was incorporated into existing national-level audits in Germany (n = 71), Scotland (n = 16), and Ireland (n = 16). Responses from a further 82 units in 11 nations were obtained via an online survey. RESULTS: There were 185 units from 14 countries that returned the survey. 102/160 (63.7%) units reported a worsening of overall service quality, which was attributed predominantly to staff redistribution, reallocation of inpatient areas, and reduced access to surgical facilities. There was a high rate of redeployment of staff to other services: two thirds lost specialist orthopaedic nurses, a third lost orthogeriatrics services, and a quarter lost physiotherapists. Reallocation of inpatient areas resulted in patients being managed by non-specialised teams in generic wards, which increased transit of patients and staff between clinical areas. There was reduced operating department access, with 74/160 (46.2%) centres reporting a >50% reduction. Reduced theatre efficiency was reported by 135/160 (84.4%) and was attributed to staff and resource redistribution, longer anaesthetic and transfer times, and delays for preoperative COVID-19 testing and using personal protective equipment (PPE). CONCLUSION: Hip fracture services were disrupted during the COVID-19 pandemic and this may have a sustained impact on health and social care. Protection of hip fracture services is essential to ensure satisfactory outcomes for this vulnerable patient group.


Assuntos
COVID-19 , Fraturas do Quadril , Ortopedia , COVID-19/epidemiologia , Teste para COVID-19 , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/cirurgia , Humanos , Pandemias , Inquéritos e Questionários
11.
Eur J Orthop Surg Traumatol ; 32(1): 27-36, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33675406

RESUMO

PURPOSE: The aim of this study was to report outcomes following mini-open lower limb fasciotomy (MLLF) in active adults with chronic exertional compartment syndrome (CECS). METHODS: From 2013-2018, 38 consecutive patients (mean age 31 years [16-60], 71% [n = 27/38] male) underwent MLLF. There were 21 unilateral procedures, 10 simultaneous bilateral and 7 staged bilateral. There were 22 anterior fasciotomies, five posterior and 11 four-compartment. Early complications were determined from medical records of 37/38 patients (97%) at a mean of four months (1-19). Patient-reported outcomes (including EuroQol scores [EQ-5D/EQ-VAS], return to sport and satisfaction) were obtained via postal survey from 27/38 respondents (71%) at a mean of 3.7 years (0.3-6.4). RESULTS: Complications occurred in 16% (n = 6/37): superficial infection (11%, n = 4/37), deep infection (3%, n = 1/37) and wound dehiscence (3%, n = 1/37). Eight per cent (n = 3/37) required revision fasciotomy for recurrent leg pain. At longer-term follow-up, 30% (n = 8/27) were asymptomatic and another 56% (n = 15/27) reported improved symptoms. The mean pain score improved from 6.1 to 2.5 during normal activity and 9.1 to 4.7 during sport (both p < 0.001). The mean EQ-5D was 0.781 (0.130-1) and EQ-VAS 77 (33-95). Of 25 patients playing sport preoperatively, 64% (n = 16/25) returned, 75% (n = 12/16) reporting improved exercise tolerance. Seventy-four per cent (n = 20/27) were satisfied and 81% (n = 22/27) would recommend the procedure. CONCLUSION: MLLF is safe and effective for active adults with CECS. The revision rate is low, and although recurrent symptoms are common most achieve symptomatic improvement, with reduced activity-related leg pain and good health-related quality of life. The majority return to sport and are satisfied with their outcome.


Assuntos
Síndromes Compartimentais , Fasciotomia , Adulto , Doença Crônica , Síndrome Compartimental Crônica do Esforço , Síndromes Compartimentais/etiologia , Síndromes Compartimentais/cirurgia , Humanos , Perna (Membro) , Extremidade Inferior/cirurgia , Masculino , Qualidade de Vida , Estudos Retrospectivos , Resultado do Tratamento
12.
J Pathol ; 250(4): 420-439, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31960425

RESUMO

Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour-infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour-associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1, and ß-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 - mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Melanoma/metabolismo , Mutação/genética , Microambiente Tumoral , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Neoplasias Uveais/metabolismo , Biomarcadores Tumorais/genética , Humanos , Fatores Imunológicos , Imunossupressores , Imunoterapia/métodos , Linfócitos do Interstício Tumoral/metabolismo , Melanoma/genética , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Neoplasias Uveais/genética
13.
J Hand Surg Am ; 46(5): 403-408, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33744014

RESUMO

PURPOSE: To describe patients' self-reported hand normality before and after surgery for Dupuytren contracture and to determine whether this metric could be used as an adjunct to determine the success of surgery. METHODS: Preoperative and 1-year postoperative Quick-Disabilities of the Arm, Shoulder, and Hand and EuroQol 5-Dimensions 5-level scores were collected prospectively over 5 years. Patients were asked "How normal is your hand?" Scores were recorded on a 100-point visual analog scale. Outcomes were available for 296 patients (77%). RESULTS: Median hand normality score improved significantly from 50 to 86 after surgery. Effect size of the change in normality was 1.2 SDs. The change in normality score correlated significantly with the Quick-Disabilities of the Arm, Shoulder, and Hand score. No significant floor or ceiling effects were observed. CONCLUSIONS: This study introduced the concept of self-perceived hand normality in Dupuytren disease. Hand normality improved after surgery for Dupuytren disease, and this score performed favorably compared with preexisting outcome measures, which suggests it may be a useful adjunct to gauge the success of surgery. CLINICAL RELEVANCE: This study introduces the concept of self-perceived hand normality in patients undergoing surgery for Dupuytren disease and quantifies improvement observed after surgery.


Assuntos
Contratura de Dupuytren , Contratura de Dupuytren/cirurgia , Mãos/cirurgia , Humanos , Medição da Dor , Ombro , Resultado do Tratamento
14.
J Shoulder Elbow Surg ; 30(10): 2283-2295, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33636324

RESUMO

BACKGROUND: The primary aim was to identify patient and injury factors independently associated with humeral diaphyseal fracture nonunion after nonoperative management. The secondary aim was to determine the effect of management (operative/nonoperative) on nonunion. METHODS: From 2008-2017, a total of 734 humeral shaft fractures (732 consecutive skeletally mature patients) were retrospectively identified from a trauma database. Follow-up was available for 663 fractures (662 patients, 90%) that formed the study cohort. Patient and injury characteristics were recorded. There were 523 patients (79%) managed nonoperatively and 139 (21%) managed operatively. Outcome (union/nonunion) was determined from medical records and radiographs. RESULTS: The median age at injury was 57 (range 16-96) years and 54% (n = 359/662) were female. Median follow-up was 5 (1.2-74) months. Nonunion occurred in 22.7% (n = 119/524) of nonoperatively managed injuries. Multivariate analysis demonstrated preinjury nonsteroidal anti-inflammatory drugs (NSAIDs; odds ratio [OR] 20.58, 95% confidence interval [CI] 2.12-199.48; P = .009) and glenohumeral arthritis (OR 2.44, 95% CI 1.03-5.77; P = .043) were independently associated with an increased risk of nonunion. Operative fixation was independently associated with a lower risk of nonunion (2.9%, n = 4/139) compared with nonoperative management (OR for nonoperative/operative management 9.91, 95% CI 3.25-30.23; P < .001). Based on these findings, 5 patients would need to undergo primary operative fixation in order to avoid 1 nonunion. CONCLUSIONS: Preinjury NSAIDs and glenohumeral arthritis were independently associated with nonunion following nonoperative management of a humeral diaphyseal fracture. Operative fixation was the independent factor most strongly associated with a lower risk of nonunion. Targeting early operative fixation to at-risk patients may reduce the rate of nonunion and the morbidity associated with delayed definitive management.


Assuntos
Fraturas não Consolidadas , Fraturas do Úmero , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Consolidação da Fratura , Humanos , Fraturas do Úmero/diagnóstico por imagem , Fraturas do Úmero/cirurgia , Úmero , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto Jovem
15.
Eur J Orthop Surg Traumatol ; 31(5): 981-987, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33891155

RESUMO

BACKGROUND: Acute carpal tunnel syndrome (ACTS) is a known complication of distal radius fractures. This study aimed to document the demographics, range of presenting symptoms and risk factors of patients who develop ACTS following a fracture of the distal radius. METHODS: A retrospective review of 1189 patients with an acute distal radius fracture treated in the study centre over a one-year period were identified. Demographic and clinical variables were collected and compared between controls (did not develop ACTS) and those patients who did develop ACTS to identify factors associated with developing ACS. RESULTS: There were 51 (4.3%) distal radius fractures complicated by ACTS. The mean age of patients who developed ACTS was 56 years (range, 16-89) and 73% were female. The median time of onset post-injury was one week (range, 1-12). There was no association between patient background and comorbidities with the development of ACTS. AO-OTA Type C fractures had significantly increased rates of developing ACTS. CONCLUSION: Four percent of distal radius fractures were complicated by ACTS. There was no association between patient background and comorbidities with the development of ACTS. AO-OTA type C complete articular fractures had a significantly higher rate of ACTS. A suggested treatment algorithm for patients presenting with ACTS has been presented. LEVEL OF EVIDENCE: III.


Assuntos
Síndrome do Túnel Carpal , Fraturas do Rádio , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome do Túnel Carpal/epidemiologia , Síndrome do Túnel Carpal/etiologia , Feminino , Fixação Interna de Fraturas , Humanos , Masculino , Pessoa de Meia-Idade , Rádio (Anatomia) , Fraturas do Rádio/complicações , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
16.
J Hand Surg Am ; 45(11): 1029-1036, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33153530

RESUMO

PURPOSE: This study describes the impact of self-reported hand-arm vibration (HAV) exposure on patient-reported outcomes, health-related quality of life, and satisfaction after carpal tunnel release. METHODS: We prospectively collected data from Quick-Disabilities of the Arm, Shoulder, and Hand (QuickDASH), patient satisfaction, and 5-level EuroQol-5D questionnaires before and after surgery. Patient-reported outcomes were available for 475 patients (78% follow-up at a mean of 14 months). Fifteen patients were excluded, giving a final cohort of 460 patients. RESULTS: A total of 119 patients reported HAV exposure (26%). Median postoperative QuickDASH and QuickDASH improvement were significantly worse in the HAV-exposed group, although both groups improved after surgery. Multivariable linear regression revealed a significantly worse postoperative score and change in QuickDASH in HAV-exposed patients. There was no difference in satisfaction, but after surgery, the 5-level EuroQol-5D score was significantly worse in HAV-exposed patients. CONCLUSIONS: Carpal tunnel release in HAV-exposed patients results in a significantly lower improvement in self-reported disability compared with patients without HAV exposure. This study provides important prognostic information for patients with previous HAV exposure undergoing carpal tunnel release. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III.


Assuntos
Síndrome do Túnel Carpal , Qualidade de Vida , Síndrome do Túnel Carpal/cirurgia , Humanos , Estudos Prospectivos , Autorrelato , Inquéritos e Questionários , Vibração
17.
Med Princ Pract ; 29(1): 6-17, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31158841

RESUMO

OBJECTIVE: This study aims to present the diagnostic characteristics of multimodal intraoperative monitoring (IOM) in spinal deformity surgery and to define and categorise the neuromonitoring events, as well as propose an algorithm of action. MATERIALS AND METHODS: We reviewed 1,155 consecutive patients (807 female, 348 male) who underwent deformity correction using standardised perioperative care, cortical/cervical somatosensory evoked potentials (SSEPs), and upper/lower limb transcranial electrical motor evoked potential (MEPs) by a single surgeon. The mean age at surgery was 13.8 years (range 10-23.3). We categorised IOM events as true, transient true, and false positive or negative. Diagnostic performance criteria were calculated. RESULTS: The most common diagnosis was adolescent idiopathic scoliosis in 717 (62%) patients. We identified 3 true positive monitoring events occurring in 2 patients (0.17%), 8 transient true positive (0.69%), and 8 transient false positive events (0.69%). There were no false negative events and no patient had postoperative neurological complications. The multimodal IOM technique had a sensitivity of 100%, specificity of 99.3%, positive predictive value of 55.6%, and negative predictive value of 100%. Sensitivity was 100% for MEPs and multimodal monitoring compared to 20% for cortical or cervical SSEPs. The frequency of true or transient true positive events was higher (p = 0.07) in Scheuermann's kyphosis (3/91 patients, 3.3%) compared to adolescent idiopathic scoliosis (6/717 patients, 0.84%). CONCLUSION: Multimodal IOM is highly sensitive and specific for spinal cord injury. This technique is reliable for the assessment of the condition of the spinal cord during major deformity surgery. We propose an algorithm of intraoperative action to allow close cooperation between the surgical, anaesthetic, and neurophysiology teams and to prevent neurological deficits.


Assuntos
Monitorização Intraoperatória/métodos , Monitorização Intraoperatória/estatística & dados numéricos , Procedimentos Neurocirúrgicos/métodos , Doenças da Coluna Vertebral/cirurgia , Adolescente , Algoritmos , Criança , Potenciais Somatossensoriais Evocados , Feminino , Humanos , Masculino , Monitorização Intraoperatória/efeitos adversos , Escoliose , Medula Espinal , Doenças da Coluna Vertebral/congênito , Resultado do Tratamento , Reino Unido , Adulto Jovem
18.
Clin Orthop Relat Res ; 477(11): 2531-2540, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31389899

RESUMO

BACKGROUND: The evidence for treating acute, unreconstructable radial head fractures in unstable elbows with radial head replacement predominantly consists of short- to mid-term follow-up studies with a heterogenous mix of implants and operative techniques. Data on longer-term patient-reported outcomes after radial head replacement is lacking. QUESTIONS/PURPOSES: (1) What proportion of patients undergo revision or implant removal after radial head replacement? (2) At a minimum of 8 years follow-up, what are the patient-reported outcomes (QuickDASH, Oxford Elbow Score, and EuroQol-5D)? (3) What factors are associated with a superior long-term patient-reported outcome, according to the QuickDASH? METHODS: Between September 1994 and September 2010, we surgically treated 157 patients for acute radial head fractures. We excluded patients where the radial head was excised (n = 21), internally fixed (n = 15), or replaced as a secondary procedure after failed internal fixation (n = 2). A total of 119 patients who underwent radial head replacement surgery for an acute unreconstructable fracture were included, with a mean age of 50 years (range 15 to 93 ± 19 years), and 53% of patients (63) were women. All but two implants were uncemented, loose-fitting, monopolar prostheses, of which 86% (102) were metallic and 14% (17) were silastic. Implants were only cemented if they appeared unstable within the proximal radius. Silastic implants were used in the earlier series and replaced by metallic implants starting in 2000. We reviewed electronic records to document postoperative complications and prosthesis revision and removal. A member of the local research team (THC, CDC) who was not previously involved in patient care contacted patients to confirm complications, reoperations and to obtain long-term patient-reported outcomes scores. Nineteen patients had died at the point of outcome score collection. Of the remaining 100 patients, 80 were contacted (67% of total cohort), at a median of 11 years (range 8 to 24 years) after injury. The primary outcome measure was the QuickDASH score. RESULTS: Of 119 patients, 25% (30) underwent reoperation, with three patients undergoing revision and 27 patients undergoing prosthesis removal at a median of 7 months (range 0 to 125 months). Twenty-one of 30 procedures (70%) occurred within 1 year after implantation. Kaplan-Meier survivorship analysis demonstrated a cumulative implant survival rate of 71%. In the 80 patients contacted, the mean QuickDASH score was 13 ± 14, the mean Oxford Elbow Score was 43 ± 6, and the median EuroQol-5D score was 0.8 (-0.3 to 1.0). After controlling for covariates, we found that prothesis revision or removal (p = 0.466) and prosthesis type (p = 0.553) were not associated with patient-reported outcome, according to the QuickDASH. CONCLUSIONS: The management of acute unreconstructable fractures of the radial head in unstable elbow injuries with radial head replacement has a high risk of reoperation. Patients must be counselled regarding this risk of secondary intervention, of which the peak risk appears to be within 1 year after implantation. Despite this, patients report low disability according to the QuickDASH at a minimum follow-up of 8 years. LEVEL OF EVIDENCE: Level IV, therapeutic study.


Assuntos
Artroplastia de Substituição do Cotovelo/efeitos adversos , Articulação do Cotovelo , Instabilidade Articular/cirurgia , Complicações Pós-Operatórias/epidemiologia , Fraturas do Rádio/cirurgia , Reoperação/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Remoção de Dispositivo , Prótese de Cotovelo , Feminino , Seguimentos , Fixação Interna de Fraturas/efeitos adversos , Humanos , Instabilidade Articular/etiologia , Masculino , Pessoa de Meia-Idade , Amplitude de Movimento Articular , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
Br J Sports Med ; 53(1): 13-18, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30366967

RESUMO

OBJECTIVE: The distribution of injuries affecting professional golfers is yet to be fully understood. We performed a systematic review of the clinical literature to establish the epidemiology of musculoskeletal injuries affecting professional golfers. DESIGN: Systematic review. DATA SOURCES: Searched databases in July 2018 were PubMed, SPORTDiscus and Embase. ELIGIBILITY CRITERIA: Published observational research articles relating to the incidence or prevalence of musculoskeletal injuries in professional golfers, which were written in the English language and not restricted by age or gender. RESULTS: Of the 1863 studies identified on the initial search, 5 studies were found to satisfy the inclusion criteria for analysis. The mean age of the golfers in these studies was 34.8 (±3.6) years. The gender of patients in included studies compromised 72% males and 28% females. Four studies reported that lumbar spine injuries were the most common (range 22%-34%). Excluding injuries to the spine (lumbar, thoracic and cervical), the hand/wrist was the next most common region of injury (range 6%-37%). The quality of the studies was relatively poor with no study satisfying >50% of the quality assessment tool questions and only one study giving a clear definition of how they defined injury. CONCLUSION: There is a paucity of well-designed epidemiological studies evaluating musculoskeletal injuries affecting professional golfers. Injuries to the spine are the most frequently affected region, followed by the hand/wrist. This study has identified targeted areas of future research that aims to improve the management of injuries among professional golfers.


Assuntos
Traumatismos em Atletas/epidemiologia , Golfe/lesões , Doenças Musculoesqueléticas/epidemiologia , Atletas , Humanos , Estudos Observacionais como Assunto
20.
Br J Neurosurg ; 31(6): 688-694, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28691531

RESUMO

OBJECT: The Wallis fixed interspinous spacer may augment traditional decompression in the treatment of lumbar spinal stenosis. The aim of this study was to determine factors influencing survival of the Wallis interspinous spacer and to identify specific modes and predictors of failure. METHODS: We performed a retrospective cohort study of 244 Wallis interspinous spacers implanted in 195 consecutive patients with a mean age of 56 years (range 21-87) to augment single or multi-level decompression. We examined patient demographics, indications for surgery, surgical techniques and pathology on magnetic resonance imaging (MRI). A Kaplan-Meier survival analysis was performed. RESULTS: Median follow-up was 4.5 years (range 2-8). Sixteen patients were lost to follow-up. Repeat MRI was performed in 98 patients (50%). A recurrent stenosis was found in 21% of patients (41/195) and occurred at a similar incidence at the level of the spacer and at adjacent spinal levels. Revision decompression was performed in 19 patients (10%) at 2.8 ± 1.8 years (range 6 months-6 years) with implant removal in 15 and conversion to fusion in 4 patients. No specific patient factors or pre-operative MRI findings predicted failure. Five-year survival was 91% (95% CI: 79-96%). CONCLUSIONS: The Wallis implant is generally implanted without complication when used as an adjunct to decompression with a good medium term survival. Though disc heights were maintained, the Wallis spacer did not however appear to reduce the incidence of recurrent spinal or foraminal stenosis from that expected from decompression alone.


Assuntos
Descompressão Cirúrgica/instrumentação , Fixadores Internos , Vértebras Lombares/cirurgia , Coluna Vertebral/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Descompressão Cirúrgica/efeitos adversos , Descompressão Cirúrgica/métodos , Feminino , Humanos , Fixadores Internos/efeitos adversos , Estimativa de Kaplan-Meier , Vértebras Lombares/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Próteses e Implantes , Reoperação/estatística & dados numéricos , Estudos Retrospectivos , Estenose Espinal/diagnóstico por imagem , Estenose Espinal/cirurgia , Coluna Vertebral/diagnóstico por imagem , Resultado do Tratamento , Adulto Jovem
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