Aims. Patients undergoing limb reconstruction surgery often face a challenging and lengthy process to complete their treatment journey. The majority of existing outcome measures do not adequately capture the patient-reported outcomes relevant to this patient group in a single measure. Following a previous systematic review, the Stanmore Limb Reconstruction Score (SLRS) was designed with the intent to address this need for an effective instrument to measure patient-reported outcomes in limb reconstruction patients. We aim to assess the face validity of this score in a pilot study. Methods. The SLRS was designed following structured interviews with several groups including patients who have undergone limb reconstruction surgery, limb reconstruction surgeons, specialist nurses, and physiotherapists. This has subsequently undergone further adjustment for language and clarity. The score was then trialled on ten patients who had undergone limb reconstruction surgery, with subsequent structured questioning to understand the perceived suitability of the score. Results. Ten patients completed the score and the subsequent structured interview. Considering the tool as a whole, 100% of respondents felt the score to be comprehensible, relevant, and comprehensive regarding the areas that were important to a patient undergoing limb reconstruction surgery. For individual questions, on a five-point Likert scale, importance/relevance was reported as a mean of 4.78 (4.3 to 5.0), with ability to understand rated as 4.92 (4.7 to 5.0) suggesting high levels of relevance and comprehension. Flesch-Kincaid reading grade level was calculated as 5.2 (10 to 11 years old). Conclusion. The current SLRS has been shown to have acceptable scores from a patient sample regarding relevance, comprehensibility, and comprehensiveness. This suggests face validity, however further testing required and is ongoing in a larger cohort of patients to determine the reliability, responsiveness, precision, and criterion validity of the score in this patient group. Cite this article: Bone Jt Open 2021;2(9):705–709

Aims. Patient-reported outcome measures have become an important part of routine care. The aim of this study was to determine if Patient-Reported Outcomes Measurement Information System (PROMIS) measures can be used to create patient subgroups for individuals seeking orthopaedic care. Methods. This was a cross-sectional study of patients from Duke University Department of Orthopaedic Surgery clinics (14 ambulatory and four hospital-based). There were two separate cohorts recruited by convenience sampling (i.e. patients were included in the analysis only if they completed PROMIS measures during a new patient visit). Cohort #1 (n = 12,141; December 2017 to December 2018,) included PROMIS short forms for eight domains (Physical Function, Pain Interference, Pain Intensity, Depression, Anxiety, Sleep Quality, Participation in Social Roles, and Fatigue) and Cohort #2 (n = 4,638; January 2019 to August 2019) included PROMIS Computer Adaptive Testing instruments for four domains (Physical Function, Pain Interference, Depression, and Sleep Quality). Cluster analysis (K-means method) empirically derived subgroups and subgroup differences in clinical and sociodemographic factors were identified with one-way analysis of variance. Results. Cluster analysis yielded four subgroups with similar clinical characteristics in Cohort #1 and #2. The subgroups were: 1) Normal Function: within normal limits in Physical Function, Pain Interference, Depression, and Sleep Quality; 2) Mild Impairment: mild deficits in Physical Function, Pain Interference, and Sleep Quality but with Depression within normal limits; 3) Impaired Function, Not Distressed: moderate deficits in Physical Function and Pain Interference, but within normal limits for Depression and Sleep Quality; and 4) Impaired Function, Distressed: moderate (Physical Function, Pain Interference, and Sleep Quality) and mild (Depression) deficits. Conclusion. These findings suggest orthopaedic patient subgroups differing in physical function, pain, and psychosocial distress can be created from as few as four different PROMIS measures. Longitudinal research is necessary to determine whether these subgroups have prognostic validity. Cite this article: Bone Jt Open 2021;2(7):493–502

Aim. The coronavirus disease 2019 (COVID-19) pandemic presents significant challenges to healthcare systems globally. Orthopaedic surgeons are at risk of contracting COVID-19 due to their close contact with patients in both outpatient and theatre environments. The aim of this review was to perform a literature review, including articles of other coronaviruses, to formulate guidelines for orthopaedic healthcare staff. Methods. A search of Medline, EMBASE, the Cochrane Library, World Health Organization (WHO), and Centers for Disease Control and Prevention (CDC) databases was performed encompassing a variety of terms including ‘coronavirus’, ‘covid-19’, ‘orthopaedic’, ‘personal protective environment’ and ‘PPE’. Online database searches identified 354 articles. Articles were included if they studied any of the other coronaviruses or if the basic science could potentially applied to COVID-19 (i.e. use of an inactivated virus with a similar diameter to COVID-19). Two reviewers independently identified and screened articles based on the titles and abstracts. 274 were subsequently excluded, with 80 full-text articles retrieved and assessed for eligibility. Of these, 66 were excluded as they compared personal protection equipment to no personal protection equipment or referred to prevention measures in the context of bacterial infections. Results. There is a paucity of high quality evidence surrounding COVID-19. This review collates evidence from previous coronavirus outbreaks to put forward recommendations for orthopaedic surgeons during the COVID-19 pandemic. The key findings have been summarized and interpreted for application to the orthopaedic operative setting. Conclusion. For COVID-19 positive patients, minimum suggested PPE includes N95 respirator, goggles, face shield, gown, double gloves, and surgical balaclava. Space suits not advised. Be trained in the correct technique of donning and doffing PPE. Use negative pressure theatres if available. Minimize aerosolization and its effects (smoke evacuation and no pulse lavage). Minimize further unnecessary patient-staff contact (dissolvable sutures, clear dressings, split casts)

We evaluated the top 13 journals in trauma and orthopaedics by impact factor and looked at the longer-term effect regarding citations of their papers.

All 4951 papers published in these journals during 2007 and 2008 were reviewed and categorised by their type, subspecialty and super-specialty. All citations indexed through Google Scholar were reviewed to establish the rate of citation per paper at two, four and five years post-publication. The top five journals published a total of 1986 papers. Only three (0.15%) were on operative orthopaedic surgery and none were on trauma. Most (n = 1084, 54.5%) were about experimental basic science. Surgical papers had a lower rate of citation (2.18) at two years than basic science or clinical medical papers (4.68). However, by four years the rates were similar (26.57 for surgery, 30.35 for basic science/medical), which suggests that there is a considerable time lag before clinical surgical research has an impact.

We conclude that high impact journals do not address clinical research in surgery and when they do, there is a delay before such papers are cited. We suggest that a rate of citation at five years post-publication might be a more appropriate indicator of importance for papers in our specialty.

Cite this article: Bone Joint J 2014;96-B:414–19.

Aims. Chronic osteomyelitis (COM) of the lower limb in adults can be surgically managed by either limb reconstruction or amputation. This scoping review aims to map the outcomes used in studies surgically managing COM in order to aid future development of a core outcome set. Methods. A total of 11 databases were searched. A subset of studies published between 1 October 2020 and 1 January 2011 from a larger review mapping research on limb reconstruction and limb amputation for the management of lower limb COM were eligible. All outcomes were extracted and recorded verbatim. Outcomes were grouped and categorized as per the revised Williamson and Clarke taxonomy. Results. A total of 3,303 records were screened, of which 99 studies were included. Most studies were case series (77/99; 78%) and assessed one method of reconstruction (68/99; 69%). A total of 511 outcomes were reported, which were grouped into 58 distinct outcomes. Overall, 143/511 of all outcomes (28%) were provided with a clear, in-text definition, and 231 outcomes (45%) had details reported of how and when they were measured. The most commonly reported outcome was ‘recurrence of osteomyelitis’ (62; 12%). The single-most patient-reported outcome measure was ‘pain’. Conclusion. This study has highlighted significant inconsistencies in the defining, reporting, and measuring of outcomes across studies investigating surgical management for chronic osteomyelitis of the lower limb in adults. Future studies should clearly report complete details of how outcomes are defined and measured, including timing. The development of a standardized core outcome set would be of significant benefit in order to allow evidence synthesis and comparison across studies. Cite this article: Bone Jt Open 2023;4(3):146–157

Aims. Bacterial infection activates neutrophils to release neutrophil extracellular traps (NETs) in bacterial biofilms of periprosthetic joint infections (PJIs). The aim of this study was to evaluate the increase in NET activation and release (NETosis) and haemostasis markers in the plasma of patients with PJI, to evaluate whether such plasma induces the activation of neutrophils, to ascertain whether increased NETosis is also mediated by reduced DNaseI activity, to explore novel therapeutic interventions for NETosis in PJI in vitro, and to evaluate the potential diagnostic use of these markers. Methods. We prospectively recruited 107 patients in the preoperative period of prosthetic surgery, 71 with a suspicion of PJI and 36 who underwent arthroplasty for non-septic indications as controls, and obtained citrated plasma. PJI was confirmed in 50 patients. We measured NET markers, inflammation markers, DNaseI activity, haemostatic markers, and the thrombin generation test (TGT). We analyzed the ability of plasma from confirmed PJI and controls to induce NETosis and to degrade in vitro-generated NETs, and explored the therapeutic restoration of the impairment to degrade NETs of PJI plasma with recombinant human DNaseI. Finally, we assessed the contribution of these markers to the diagnosis of PJI. Results. Patients with confirmed PJI had significantly increased levels of NET markers (cfDNA (p < 0.001), calprotectin (p < 0.001), and neutrophil elastase (p = 0.022)) and inflammation markers (IL-6; p < 0.001) in plasma. Moreover, the plasma of patients with PJI induced significantly more neutrophil activation than the plasma of the controls (p < 0.001) independently of tumour necrosis factor alpha. Patients with PJI also had a reduced DNaseI activity in plasma (p < 0.001), leading to a significantly impaired degradation of NETs (p < 0.001). This could be therapeutically restored with recombinant human DNaseI to the level in the controls. We developed a model to improve the diagnosis of PJI with cfDNA, calprotectin, and the start tail of TGT as predictors, though cfDNA alone achieved a good prediction and is simpler to measure. Conclusion. We confirmed that patients with PJI have an increased level of NETosis in plasma. Their plasma both induced NET release and had an impaired ability to degrade NETs mediated by a reduced DNaseI activity. This can be therapeutically restored in vitro with the approved Dornase alfa, Pulmozyme, which may allow novel methods of treatment. A combination of NETs and haemostatic biomarkers could improve the diagnosis of PJI, especially those patients in whom this diagnosis is uncertain. Cite this article: Bone Joint J 2024;106-B(9):1021–1030

Aims. The aims of this study were to describe the demographic, socioeconomic, and educational factors associated with core surgical trainees (CSTs) who apply to and receive offers for higher surgical training (ST3) posts in Trauma & Orthopaedics (T&O). Methods. Data collected by the UK Medical Education Database (UKMED) between 1 January 2014 and 31 December 2019 were used in this retrospective longitudinal cohort study comprising 1,960 CSTs eligible for ST3. The primary outcome measures were whether CSTs applied for a T&O ST3 post and if they were subsequently offered a post. A directed acyclic graph was used for detecting confounders and adjusting logistic regression models to calculate odds ratios (ORs), which assessed the association between the primary outcomes and relevant exposures of interest, including: age, sex, ethnicity, parental socioeconomic status (SES), domiciliary status, category of medical school, Situational Judgement Test (SJT) scores at medical school, and success in postgraduate examinations. This study followed STROBE guidelines. Results. Compared to the overall cohort of CSTs, females were significantly less likely to apply to T&O (OR 0.37, 95% CI 0.30 to 0.46; n = 155/720 female vs n = 535/1,240 male; p < 0.001). CSTs who were not UK-domiciled prior to university were nearly twice as likely to apply to T&O (OR 1.99, 95% CI 1.39 to 2.85; n = 50/205 vs not UK-domiciled vs n = 585/1,580 UK-domiciled; p < 0.001). Age, ethnicity, SES, and medical school category were not associated with applying to T&O. Applicants who identified as ‘black and minority ethnic’ (BME) were significantly less likely to be offered a T&O ST3 post (OR 0.70, 95% CI 0.51 to 0.97; n = 165/265 BME vs n = 265/385 white; p = 0.034). Differences in age, sex, SES, medical school category, and SJT scores were not significantly associated with being offered a T&O ST3 post. Conclusion. There is an evident disparity in sex between T&O applicants and an ethnic disparity between those who receive offers on their first attempt. Further high-quality, prospective research in the post-COVID-19 pandemic period is needed to improve equality, diversity, and inclusion in T&O training. Cite this article: Bone Jt Open 2024;5(8):697–707

Aims. COVID-19 has compounded a growing waiting list problem, with over 4.5 million patients now waiting for planned elective care in the UK. Views of patients on waiting lists are rarely considered in prioritization. Our primary aim was to understand how to support patients on waiting lists by hearing their experiences, concerns, and expectations. The secondary aim was to capture objective change in disability and coping mechanisms. Methods. A minimum representative sample of 824 patients was required for quantitative analysis to provide a 3% margin of error. Sampling was stratified by body region (upper/lower limb, spine) and duration on the waiting list. Questionnaires were sent to a random sample of elective orthopaedic waiting list patients with their planned intervention paused due to COVID-19. Analyzed parameters included baseline health, change in physical/mental health status, challenges and coping strategies, preferences/concerns regarding treatment, and objective quality of life (EuroQol five-dimension questionnaire (EQ-5D), Generalized Anxiety Disorder 2-item scale (GAD-2)). Qualitative analysis was performed via the Normalization Process Theory. Results. A total of 888 patients responded. Better health, pain, and mood scores were reported by upper limb patients. The longest waiters reported better health but poorer mood and anxiety scores. Overall, 82% had tried self-help measures to ease symptoms; 94% wished to proceed with their intervention; and 21% were prepared to tolerate deferral. Qualitative analysis highlighted the overall patient mood to be represented by the terms ‘understandable’, ‘frustrated’, ‘pain’, ‘disappointed’, and ‘not happy/depressed’. COVID-19-mandated health and safety measures and technology solutions were felt to be implemented well. However, patients struggled with access to doctors and pain management, quality of life (physical and psychosocial) deterioration, and delay updates. Conclusion. This is the largest study to hear the views of this ‘hidden’ cohort. Our findings are widely relevant to ensure provision of better ongoing support and communication, mostly within the constraints of current resources. In response, we developed a reproducible local action plan to address highlighted issues. Cite this article: Bone Jt Open 2021;2(8):583–593

Aims. The primary aim was to assess the rate of patient deferral of elective orthopaedic surgery and whether this changed with time during the coronavirus disease 2019 (COVID-19) pandemic. The secondary aim was to explore the reasons why patients wanted to defer surgery and what measures/circumstances would enable them to go forward with surgery. Methods. Patients were randomly selected from elective orthopaedic waiting lists at three centres in the UK in April, June, August, and September 2020 and were contacted by telephone. Patients were asked whether they wanted to proceed or defer surgery. Patients who wished to defer were asked seven questions relating to potential barriers to proceeding with surgery and were asked whether there were measures/circumstances that would allow them to go forward with surgery. Results. There was a significant decline in the rate of deferral for surgery from April (n = 38/50, 76%), June (n = 68/233, 29%), to August (n = 6/50, 12%) and September (n = 5/100, 5%) (p < 0.001). Patients wishing to defer were older (68 years (SD 10.1) vs 65 (SD 11.9)), more likely to be female (65% (44/68) vs 53% (88/165)) and waiting for a knee arthroplasty (65% (44/68) vs 41% (67/165); p < 0.001). By September 2020, all patients that deferred in June at one centre had proceeded or wanted to proceed with surgery due to a perceived lower risk of acquiring COVID-19 perioperatively (68%, n = 15) or because their symptoms had progressed (32%, n = 7). The most common reason (n = 14/17, 82%) for patients deferring surgery in September was the perceived risk of acquiring COVID-19 while as an inpatient. When asked what measures or circumstances would enable them to proceed with surgery, the most common (n = 7, 41%) response was reassurance of a COVID-19 free hospital. Conclusion. The rate of deferral fell to 5% by September, which was due to a lower perceived risk of contracting COVID-19 perioperatively or worsening of symptoms while waiting. The potential of a COVID-19-free hospital and communication of mortality risk may improve a patient’s willingness to go forward with surgery. Cite this article: Bone Joint Open 2020;1-10:663–668

Aims. During the COVID-19 pandemic, drilling has been classified as an aerosol-generating procedure. However, there is limited evidence on the effects of bone drilling on splatter generation. Our aim was to quantify the effect of drilling on splatter generation within the orthopaedic operative setting. Methods. This study was performed using a Stryker System 7 dual rotating drill at full speed. Two fluid mediums (Videne (Solution 1) and Fluorescein (Solution 2)) were used to simulate drill splatter conditions. Drilling occurred at saw bone level (0 cm) and at different heights (20 cm, 50 cm, and 100 cm) above the target to simulate the surgeon ‘working arm length’, with and without using a drill guide. The furthest droplets were marked and the droplet displacement was measured in cm. A surgical microscope was used to detect microscopic droplets. Results. Bone drilling produced 5 cm and 7 cm droplet displacement using Solutions 1 and 2, respectively. Drilling at 100 cm above the target produced the greatest splatter generation with a 95 cm macroscopic droplet displacement using Solution 2. Microscopic droplet generation was noticed at further distances than what can be macroscopically seen using Solution 1 (98 cm). Using the drill guide, there was negligible drill splatter generation. Conclusion. Our study has shown lower than anticipated drill splatter generation. The use of a drill guide acted as a protective measure and significantly reduced drill splatter. We therefore recommend using a drill guide at all times to reduce the risk of viral transmission in the operative setting. Cite this article: Bone Jt Open 2021;2(9):752–756

Aims. The COVID-19 pandemic presents an unprecedented burden on global healthcare systems, and existing infrastructures must adapt and evolve to meet the challenge. With health systems reliant on the health of their workforce, the importance of protection against disease transmission in healthcare workers (HCWs) is clear. This study collated responses from several countries, provided by clinicians familiar with practice in each location, to identify areas of best practice and policy so as to build consensus of those measures that might reduce the risk of transmission of COVID-19 to HCWs at work. Methods. A cross-sectional descriptive survey was designed with ten open and closed questions and sent to a representative sample. The sample was selected on a convenience basis of 27 senior surgeons, members of an international surgical society, who were all frontline workers in the COVID-19 pandemic. This study was reported according to the Standards for Reporting Qualitative Research (SRQR) checklist. Results. Responses were received by all 27 surgeons from 22 countries across six continents. A number of the study respondents reported COVID-19-related infection and mortality in HCWs in their countries. Differing areas of practice and policy were identified and organized into themes including the specification of units receiving COVID-19 patients, availability and usage of personal protective equipment (PPE), other measures to reduce staff exposure, and communicating with and supporting HCWs. Areas more specific to surgery also identified some variation in practice and policy in relation to visitors to the hospital, the outpatient department, and in the operating room for both non-urgent and emergency care. Conclusion. COVID-19 presents a disproportionate risk to HCWs, potentially resulting in a diminished health system capacity, and consequently an impairment to population health. Implementation of these recommendations at an international level could provide a framework to reduce this burden

Aims. The adequate provision of personal protective equipment (PPE) for healthcare workers has come under considerable scrutiny during the COVID-19 pandemic. This study aimed to evaluate staff awareness of PPE guidance, perceptions of PPE measures, and concerns regarding PPE use while caring for COVID-19 patients. In addition, responses of doctors, nurses, and other healthcare professionals (OHCPs) were compared. Methods. The inclusion criteria were all staff working in clinical areas of the hospital. Staff were invited to take part using a link to an online questionnaire advertised by email, posters displayed in clinical areas, and social media. Questions grouped into the three key themes - staff awareness, perceptions, and concerns - were answered using a five-point Likert scale. The Kruskal-Wallis test was used to compare results across all three groups of staff. Results. Overall, 315 staff took part in our study. There was a high awareness of PPE guidance at 84.4%, but only 52.4% of staff reported adequate PPE provision. 67.9% were still keen to come to work, despite very high levels of anxiety relating to contracting COVID-19 despite wearing PPE. Doctors had significantly higher ratings for questions relating to PPE awareness compared to other staff groups, while nursing staff and OHCPs had significantly higher levels of anxiety compared to doctors in relation to PPE and contracting COVID-19 (p < 0.05 using a Kruskal-Wallis test). Conclusion. We believe four recommendations are key to improve PPE measures and decrease anxiety: 1) nominated ward/department PPE champions; 2) anonymized reporting for PPE concerns; 3) formal PPE education sessions; and 4) drop-in counselling sessions for staff. We hope the insight and recommendations from this study can improve the PPE situation and maintain the health and wellbeing of the clinical work force, in order to care for COVID-19 patients safely and effectively

Aims

It is well described that patients with bone and joint infections (BJIs) commonly experience significant functional impairment and disability. Published literature is lacking on the impact of BJIs on mental health. Therefore, the aim of this study was to assess health-related quality of life (HRQoL) and the impact on mental health in patients with BJIs.

Aims

The use of fluoroscopy in orthopaedic surgery creates risk of radiation exposure to surgeons. Appropriate personal protective equipment (PPE) can help mitigate this. The primary aim of this study was to assess if current radiation protection in orthopaedic trauma is safe. The secondary aims were to describe normative data of radiation exposure during common orthopaedic procedures, evaluate ways to improve any deficits in protection, and validate the use of electronic personal dosimeters (EPDs) in assessing radiation dose in orthopaedic surgery.

Aims

The evidence base within trauma and orthopaedics has traditionally favoured quantitative research methodologies. Qualitative research can provide unique insights which illuminate patient experiences and perceptions of care. Qualitative methods reveal the subjective narratives of patients that are not captured by quantitative data, providing a more comprehensive understanding of patient-centred care. The aim of this study is to quantify the level of qualitative research within the orthopaedic literature.

Aims

As an alternative to external fixators, intramedullary lengthening nails (ILNs) can be employed for distraction osteogenesis. While previous studies have demonstrated that typical complications of external devices, such as soft-tissue tethering, and pin site infection can be avoided with ILNs, there is a lack of studies that exclusively investigated tibial distraction osteogenesis with motorized ILNs inserted via an antegrade approach.

Aims

Global literature suggests that female surgical trainees have lower rates of independent operating (operative autonomy) than their male counterparts. The objective of this study was to identify any association between gender and lead/independent operating in speciality orthopaedic trainees within the UK national training programme.

Aims. The increase in prescription opioid misuse and dependence is now a public health crisis in the UK. It is recognized as a whole-person problem that involves both the medical and the psychosocial needs of patients. Analyzing aspects of pathophysiology, emotional health, and social wellbeing associated with persistent opioid use after injury may inform safe and effective alleviation of pain while minimizing risk of misuse or dependence. Our objectives were to investigate patient factors associated with opioid use two to four weeks and six to nine months after an upper limb fracture. Methods. A total of 734 patients recovering from an isolated upper limb fracture were recruited in this study. Opioid prescription was documented retrospectively for the period preceding the injury, and prospectively at the two- to four-week post-injury visit and six- to nine-month post-injury visit. Bivariate and multivariate analysis sought factors associated with opioid prescription from demographics, injury-specific data, Patient Reported Outcome Measurement Instrumentation System (PROMIS), Depression computer adaptive test (CAT), PROMIS Anxiety CAT, PROMIS Instrumental Support CAT, the Pain Catastrophizing Scale (PCS), the Pain Self-efficacy Questionnaire (PSEQ-2), Tampa Scale for Kinesiophobia (TSK-11), and measures that investigate levels of social support. Results. A new prescription of opioids two to four weeks after injury was independently associated with less social support (odds ratio (OR) 0.26, p < 0.001), less instrumental support (OR 0.91, p < 0.001), and greater symptoms of anxiety (OR 1.1, p < 0.001). A new prescription of opioids six to nine months after injury was independently associated with less instrumental support (OR 0.9, p < 0.001) and greater symptoms of anxiety (OR 1.1, p < 0.001). Conclusion. This study demonstrates that potentially modifiable psychosocial factors are associated with increased acute and chronic opioid prescriptions following upper limb fracture. Surgeons prescribing opioids for upper limb fractures should be made aware of the screening and management of emotional and social health. Cite this article: Bone Jt Open 2021;2(2):119–124

Aims

The aim of this study was to develop and evaluate machine-learning-based computerized adaptive tests (CATs) for the Oxford Hip Score (OHS), Oxford Knee Score (OKS), Oxford Shoulder Score (OSS), and the Oxford Elbow Score (OES) and its subscales.

Despite the vast quantities of published artificial intelligence (AI) algorithms that target trauma and orthopaedic applications, very few progress to inform clinical practice. One key reason for this is the lack of a clear pathway from development to deployment. In order to assist with this process, we have developed the Clinical Practice Integration of Artificial Intelligence (CPI-AI) framework – a five-stage approach to the clinical practice adoption of AI in the setting of trauma and orthopaedics, based on the IDEAL principles (https://www.ideal-collaboration.net/). Adherence to the framework would provide a robust evidence-based mechanism for developing trust in AI applications, where the underlying algorithms are unlikely to be fully understood by clinical teams.

Cite this article: Bone Joint Res 2024;13(9):507–512.