Designing a synthetic simulator to teach open surgical skills for limb exploration in trauma: a qualitative study exploring the experiences and perspectives of educators and surgical trainees.

BACKGROUND: Simulation is an important adjunct to aid in the acquisition of surgical skills of surgical trainees. The simulators used to adequately enable trainees to learn, practice and be assessed in surgical skills need to be of the highest standards. This study investigates the perceived requirements of simulation and simulators used to acquire skills in limb exploratory procedures in trauma. METHODS: Semi-structured interviews were conducted with an international group of 11 surgical educators and 11 surgical trainees who had experience with surgical simulation. The interviews focused on the perceptions of simulation, the integration of simulators within a curriculum and the features of a simulator itself. Interviews were recorded, transcribed and underwent thematic analysis. RESULTS: Analysis of the perspectives of surgical educators and surgical trainees on simulated training in limb trauma surgery yielded three main themes: (1) Attitudes to simulation. (2) Implementing simulation. (3) Features of an open skills simulator. The majority felt simulation was relevant, intuitive and a good way for procedure warmup and the supplementation of surgical logbooks. They felt simulation could be improved with increased accessibility and variety of simulator options tailored to the learner. Suggested simulator features included greater fidelity, haptic feedback and more complex inbuilt scenarios. On a practical level, there was a desire for cost effectiveness, easy set up and storage. The responses of the educators and the trainees were similar and reflected similar concerns and suggestions for improvement. CONCLUSION: There is a clear positive appetite for the incorporation of simulation into limb trauma training. The findings of this will inform the optimal requirements for high quality implementation of simulation into a surgical trauma curriculum and a reference to optimal features desired in simulator or task trainer design.

The utility of preoperative radiological evaluation of early rectal neoplasia: a systematic review and meta-analysis.

AIM: The diagnostic role for preoperative imaging of clinically benign rectal adenomas is unclear. The objective of this systematic review and meta-analysis was to examine the diagnostic accuracy of preoperative imaging in distinguishing benign adenomas from rectal cancer. METHOD: A systematic search was performed for all studies published that correlated staging of clinically benign rectal adenomas with endorectal ultrasound (ERUS) or MRI and histology. Imaging was compared with postoperative histology and data on the numbers of true positives, false positives, true negatives and false negatives were extracted. Summary estimates of sensitivity and specificity with 95% CIs were calculated using a bivariate random effects model. The QUADAS2 tool was used to determine the methodological quality of included studies. RESULTS: Eleven studies describing 1511 patients were retrieved. A total of 1134 patients underwent local excision and 377 had a formal proctectomy. A benign rectal adenoma was diagnosed in 840 and 214 had a T1 rectal cancer. For confirming benign adenomas, the pooled sensitivity of ERUS was 0.81 (95% CI 0.69-0.89) and specificity was 0.85 (95% CI 0.68-0.93). For detecting occult T1 tumours, the pooled sensitivity of ERUS was 0.50 (95% CI 0.33-0.66) and specificity was 0.89 (95% CI 0.82-0.94). Quantitative analysis of MRI could not be performed due to insufficient studies. CONCLUSION: This study demonstrates the limited accuracy of preoperative ERUS in distinguishing benign adenomas from T1 rectal cancer. Preoperative imaging must be interpreted with caution to prevent over-staging and unnecessary proctectomy. We propose that clinically benign lesions may undergo local excision, with subsequent management based on final histology.

Objective physical activity levels in people with multiple sclerosis: Meta-analysis.

To quantify physical activity (PA) levels in people with multiple sclerosis (pwMS) using objective measurement and to establish using a meta-analytical approach if pwMS are less active than the general population. A systematic search of eight databases was conducted. Cohort and intervention studies which included an objective measure of PA were included. Objective PA outputs of steps per day and minutes of moderate-vigorous activity (MVPA) per day were extracted from the MS studies and the published NHANES dataset. Meta-analysis was used to compare the differences between the groups for these parametric outcomes. A general population sample from the National Health and Nutritional Examination Survey (NHANES) in the United States of America was used as a comparative group. The systematic search resulted in 32 papers (n = 2 randomized control trials, n = 30 cohort studies). A total of 3 762 pwMS were included. The sample was largely female (n = 3 118, 82.8%) and ambulatory with/without use of an aid (n = 31 studies). There were significant differences between the MS and the published NHANES comparative group with respect to 1) steps per day [mean difference: -3845 (-4120.17, -3569.83), P < .0001, n = 10 studies] and 2) minutes of MVPA per day [mean difference: 9.00 (-12.5, -5.4), P < .0001, n = 3 studies], indicating pwMS are less physically active than the NHANES sample. Results suggest that pwMS are less physically active than a general population across PA outputs of steps per day and minutes of MVPA per day. There is a need to increase PA levels among pwMS.

Musculoskeletal services in primary care in the Republic of Ireland: an insight into the perspective of physiotherapists.

OBJECTIVES: With a shift in musculoskeletal physiotherapy from secondary to primary care in Ireland, this study aimed to explore physiotherapists' experiences of providing musculoskeletal physiotherapy in primary care to gain an insight into their changing roles, challenges in service delivery and continuing professional development (CPD) needs. DESIGN: Qualitative design using focus group interviews. SETTING: Primary care physiotherapy services in the Republic of Ireland. PARTICIPANTS: Four focus groups with four junior and 15 senior physiotherapists working in a musculoskeletal public primary care setting took place nationally, representing an urban and rural case mix. RESULTS: Physiotherapists identified significant differences in the provision of musculoskeletal physiotherapy services across primary care sites. A number of environmental barriers were identified that impacted on service delivery, including physical infrastructure, equipment, interaction with acute sites, administration support and engagement in CPD. The role of the physiotherapist in the context of the broader multidisciplinary team also emerged as a theme, as well as the balance between the generalist versus specialist role of the physiotherapist in the primary care setting. CONCLUSIONS: Considerable variation exists in the provision of physiotherapy, and CPD opportunities and support across primary care sites. Future research should focus on pragmatic methods to optimise service delivery and patient care in this setting.

Prevalence and burden of osteoarthritis amongst older people in Ireland: findings from The Irish LongituDinal Study on Ageing (TILDA).

OBJECTIVE: To investigate the prevalence of osteoarthritis (OA) in a population aged ≥50 years in Ireland, and to determine its relationship with demographic and health-related variables. METHODS: Cross-sectional data from Wave 1 of The Irish Longitudinal Study on Ageing (TILDA), a population-based study of 8175 people aged ≥50 years were analyzed. Logistic regression was used to determine associations between the presence of OA and a range of demographic and health-related variables. RESULTS: A total of 8175 people ≥50 years in Ireland were identified from the TILDA database of whom 45.7% (n = 2941) were male and 54.3% (n = 4431) were female. The overall prevalence of OA was 12.9% (women-17.3%; men-9.4%). Prevalence increased with age, with prevalence in those aged ≥ 80 years twice that [17.7%; 95% confidence interval (CI) 13.97, 21.54] of those aged 50-60 years (8.23, 95% CI 7.32, 9.13). On multivariable analysis, OA was significantly associated (P < 0.02) with female gender, older age, pain severity, higher body mass index (BMI), fear of falling, greater number of physical limitations and medication use. In particular, there was a strong association between the use of NSAIDS and the presence of OA [adj odd ratio (OR) = 5.88, 95% CI 4.16, 8.31]. A significant association was also found between OA and increasing number of chronic diseases (adj OR = 2.75 9, 95% CI = 2.44, 3.09). CONCLUSIONS: OA is a common and multifaceted condition, with comparable prevalence of self-reported OA in Ireland with similar populations. Assessment and management should focus on potentially modifiable factors such as BMI, pain, physical limitations, polypharmacy and fear of falling. More research is required to understand the complex inter-relationships between these and other risk-associated variables.

Health, perceived quality of life and health services use among homeless illicit drug users.

INTRODUCTION: Drug misuse has been identified as a significant problem in homeless populations. This study examines aspects of physical and mental health, perceived quality of life and health service use among homeless illicit drug users and compares these to non-drug users. METHODS: Participants were recruited through health clinics across Dublin. A questionnaire assessed participants' drug use, health and well-being, health behaviours and use of health services. Descriptive statistics are presented for the entire cohort and drug users separately. Logistic regression analysis was used to examine the relationship between drug use and (i) multimorbidity, (ii) anxiety and/or depression, (iii) perceived quality of life and (iv) use of health services. RESULTS: Of 105 participants recruited, 35 (33%) were current drug users. Current and previous drug users were significantly more likely to have multimorbidity than those who had never taken drugs (OR 4.86, 95% CI 1.00-23.66). There was no significant difference between drug users and non-drug users in the prevalence of anxiety and/or depression. Drug users were five times more likely than non-drug users to have a low perceived quality of life (OR 5.2, 95% CI 1.7-16.0). Health service utilization was high, although some services were used less by drug users (e.g., dentist and psychiatric outpatient services) while others were used more often (e.g., phoneline services and day care centres). CONCLUSION: This study highlights the high levels of drug use in this population and the negative impact of drug use on health and perceived quality of life of a homeless population in Dublin.

Addition of motivational interventions to exercise and traditional physiotherapy: a review and meta-analysis.

BACKGROUND: Incontestable epidemiological trends indicate that, for the foreseeable future, mortality and morbidity will be dominated by an escalation in chronic lifestyle-related diseases. International guidelines recommend the implementation of evidence-based approaches to bring about health behaviour changes. Motivational interventions to increase adherence and physical activity are not part of traditional physiotherapy for any condition. OBJECTIVE: To evaluate the evidence for the effectiveness of adding motivational interventions to traditional physiotherapy to increase physical activity and short- and long-term adherence to exercise prescriptions. DATA SOURCES: A literature search of PubMed, EMBASE, Scopus, CINAHL, PsychINFO, AMED and Allied Health Evidence database using keywords and subject headings. STUDY SELECTION: Only randomised controlled trials comparing two or more arms, with one arm focused on motivational interventions influencing exercise and one control arm, were included. The search identified 493 titles, of which 14 studies (comprising 1504 participants) were included. DATA EXTRACTION: The principal investigator extracted data that were reviewed independently by another author. Methodological quality was assessed independently by two authors using the Cochrane Risk of Bias tool and the PEDro scale. Outcomes were measured at the level of impairment, activity limitation and participation restriction. The standardised mean difference between the control and intervention groups at follow-up time points was used as the mode of analysis. I2≤50% was used as the cut-off point for acceptable heterogeneity, above which a random effects model was applied. RESULTS: Exercise attendance was measured in six studies (n=378), and the results indicate that there was no significant difference in exercise attendance between the groups (Random effects model, standardised mean difference 0.33, 95% confidence interval -0.03 to 0.68, I2 62%). Perceived self-efficacy results were pooled from six studies (n=722), and a significant difference was found between the groups in favour of the interventions (Fixed effects model, standardised mean difference 0.71, 95% confidence interval 0.55 to 0.87, I2 41%). The results for levels of activity limitation were pooled (n=550), and a significant difference was found between the groups in favour of the interventions (REM, standardised mean difference -0.37, 95% confidence interval -0.65 to -0.08, I(2) 61%). LIMITATIONS: The majority of the included studies were of medium quality, and four studies were of low quality. Data were pooled from a wide variety of different populations and settings, increasing the assortment of study characteristics. CONCLUSIONS: Motivational interventions can help adherence to exercise, have a positive effect on long-term exercise behaviour, improve self-efficacy and reduce levels of activity limitation. The optimal theory choice and the most beneficial length and type of intervention have not been defined, although all interventions showed benefits. There is a need to determine how practising physiotherapists currently optimise adherence, and their current levels of knowledge about motivational interventions. IMPLICATIONS OF KEY FINDINGS: The results indicate that motivational interventions are successful for increasing healthy physical activity behaviour. Physiotherapists are ideally placed to take on this role, and motivational interventions must become part of physiotherapy practice.

Withholding clopidogrel for 3 to 6 versus 7 days or more before surgery in hip fracture patients.

PURPOSE. To compare morbidity and mortality after hip fracture surgery in patients withholding clopidogrel for 3 to 6 days versus ≥7 days or more. METHODS. Records of 16 men and 31 women aged 49 to 92 (mean, 80.2) years who underwent hip fracture surgery after withholding clopidogrel for 3 to 6 days (n=24) versus ≥7 days or more (n=23) were compared. The patients were taking clopidogrel owing to ischaemic heart disease (n=37), cerebrovascular disease (n=7), and intolerance to aspirin (n=3). Patient demographics, American Society of Anesthesiologists status, preoperative delay, length of hospital stay, perioperative haemoglobin reduction, receipt of blood and platelet transfusions, morbidity, and mortality were recorded. RESULTS. Respectively in the early-surgery and delayed-surgery groups, the mean surgical delay was 4.2 and 8.0 days, the mean length of hospital stay was 21.1 and 28.7 days, the mean peri-operative haemoglobin reduction was 1.5 and 1.1 g/dl, the mean units of blood transfusion per patient was 0.8 and 0.7. No severe intra-operative bleeding or wound haematoma was encountered in either group. Two patients in each group died within one month, and 2 more in the delayed-surgery group died within 3 months. The main cause of death was cardiovascular. CONCLUSION. Withholding clopidogrel for <7 days before surgery conferred no increased risk in hip fracture patients.

EFNS guidelines for diagnosis, therapy and prevention of Wernicke encephalopathy.

BACKGROUND: Although Wernicke encephalopathy (WE) is a preventable and treatable disease it still often remains undiagnosed during life. OBJECTIVES: To create practical guidelines for diagnosis, management and prevention of the disease. METHODS: We searched MEDLINE, EMBASE, LILACS, Cochrane Library. CONCLUSIONS AND RECOMMENDATIONS: 1 The clinical diagnosis of WE should take into account the different presentations of clinical signs between alcoholics and non alcoholics (Recommendation Level C); although prevalence is higher in alcoholics, WE should be suspected in all clinical conditions which could lead to thiamine deficiency (good practice point - GPP). 2 The clinical diagnosis of WE in alcoholics requires two of the following four signs; (i) dietary deficiencies (ii) eye signs, (iii) cerebellar dysfunction, and (iv) either an altered mental state or mild memory impairment (Level B). 3 Total thiamine in blood sample should be measured immediately before its administration (GPP). 4 MRI should be used to support the diagnosis of acute WE both in alcoholics and non alcoholics (Level B). 5 Thiamine is indicated for the treatment of suspected or manifest WE. It should be given, before any carbohydrate, 200 mg thrice daily, preferably intravenously (Level C). 6 The overall safety of thiamine is very good (Level B). 7 After bariatric surgery we recommend follow-up of thiamine status for at least 6 months (Level B) and parenteral thiamine supplementation (GPP). 8 Parenteral thiamine should be given to all at-risk subjects admitted to the Emergency Room (GPP). 9 Patients dying from symptoms suggesting WE should have an autopsy (GPP).

Suppression of Wnt signaling by Dkk1 attenuates PTH-mediated stromal cell response and new bone formation.

Parathyroid hormone (PTH) suppresses Dickkopf 1 (Dkk1) expression in osteoblasts. To determine whether this suppression is essential for PTH-mediated Wnt signaling and bone formation, we examined mice that overexpress Dkk1 in osteoblasts (Dkk1 mice). Dkk1 mice were osteopenic due to abnormal osteoblast and osteoclast activity. When fed a low-calcium diet, and in two other models of hyperparathyroidism, these mice failed to develop the peritrabecular stromal cell response ("osteitis fibrosis") and new bone formation seen in wild-type mice. Despite these effects of Dkk1 overexpression, PTH still activated Wnt signaling in Dkk1 mice and in osteoblastic cells cultured from these mice. In cultured MC3T3E1 preosteoblastic cells, PTH dramatically suppressed Dkk1 expression, induced PKA-mediated phosphorylation of beta-catenin, and significantly enhanced Lef1 expression. Our findings indicate that the full actions of PTH require intact Wnt signaling but that PTH can activate the Wnt pathway despite overexpression of Dkk1.

Aetiology and prognosis of encephalopathic patterns on electroencephalogram in a general hospital.

The purpose of this study was to investigate the frequency and clinical outcome of patients with encephalopathic electroencephalograms (EEGs) in a neurophysiology department based in a general hospital. We performed a retrospective review of all EEGs obtained during an 18-month period in a large tertiary referral hospital. The referral reasons for EEG, the diagnoses reached, and patient outcomes were reviewed according to EEG severity. One hundred and twenty-three patients with encephalopathic EEGs were reviewed. The most common referral reason found was for an assessment of a possible first-onset seizure. The most common diagnosis found was one of dementia or learning disability. Of patients who were followed-up for a median of 19 months, 20.7% had died. The mortality rate generally increased according to the severity of the encephalopathy on EEG. However, 21.4% of those patients with excessive theta activity only on EEG had died. This study highlights an increased mortality even in the apparently 'milder' degrees of EEG abnormalities.

Non-traumatic brachial plexopathies, clinical, radiological and neurophysiological findings from a tertiary centre.

OBJECTIVE: To establish the clinical characteristics, aetiology, neuro-physiological characteristics, imaging findings and other investigations in a cohort of patients with non-traumatic brachial plexopathy (BP). METHODS: A 3-year retrospective study of patients with non-traumatic BP identified by electromyography (EMG) and nerve conduction studies (NCS). Clinical information was retrieved from patients' medical charts. RESULTS: Twenty-five patients were identified. Causes of BP included neuralgic amyotrophy (NA) (48%), neoplastic (16%), radiation (8%), post infectious (12%), obstetric (4%), rucksack injury (4%), thoracic outlet syndrome (4%) and iatrogenic (4%). Patients with NA presented acutely in 50%. The onset was subacute in all others. Outcome was better for patients with NA. All patients with neoplastic disease had a previous history of cancer. MRI was abnormal in 3/16 patients (18.8%). PET scanning diagnosed metastatic plexopathy in two cases. CONCLUSIONS: NA was the most common cause of BP in our cohort and was associated with a more favourable outcome. The authors note potentially discriminating clinical characteristics in our population that aid in the assessment of patients with brachial plexopathies. We advise NCS and EMG be performed in all patients with suspected plexopathy. Imaging studies are useful in selected patients.

One Europe, one neurologist?

In recent years, there has been a major shift in emphasis within neurology from being a largely diagnostic discipline to one much more actively involved in treating disease. There have been major scientific advances leading to new and effective treatments. There is also a much greater awareness of the burden of neurological disease (Olesen J, Leonardi M. European Journal of Neurology 2003; 10: 471) and informed sufferers are requesting specific intervention. There is wide variation in the delivery of neurological services throughout Europe. This is reflected in manpower levels, the place of neurology related to other medical specialties and different mixes of hospital and private office practice. These differences have been thrown into sharper focus by the recent expansion of the European Union (EU). Initial training in neurology is given to undergraduate/pre-graduate students. Post-graduate education is delivered within a residency program leading to specialist qualification and certification. We now recognize that this is only the beginning of a life long program of continuous education and development (CME/CPD). National and international exchange programs facilitate the growth of knowledge and promote professional harmony and cooperation. The free migration of medical specialists has been an aspiration but remains limited by cultural, linguistic, personal, professional, political and economic factors. Two bodies, the European Board of Neurology (EBN-UEMS) http://www.uems-neuroboard.org (Union Européenne des Médecins Spécialistes) and the European Federation of Neurological Societies (EFNS) http://www.efns.org are actively involved in harmonising and developing neurology at the European level.

A study of idiopathic generalised epilepsy in an Irish population.

UNLABELLED: Idiopathic generalised epilepsy (IGE) is subdivided into syndromes based on clinical and EEG features. PURPOSE: The aim of this study was to characterise all cases of IGE with supportive EEG abnormalities in terms of gender differences, seizure types reported, IGE syndromes, family history of epilepsy and EEG findings. We also calculated the limited duration prevalence of IGE in our cohort. METHODS: Data on abnormal EEGs were collected retrospectively from two EEG databases at two tertiary referral centres for neurology. Clinical information was obtained from EEG request forms, standardised EEG questionnaires and medical notes of patients. RESULTS: two hundred twenty-three patients met our inclusion criteria, 89 (39.9%) male and 134 (60.1%) females. Tonic clonic seizures were the most common seizure type reported, 162 (72.65%) having a generalised tonic clonic seizure (GTCS) at some time. IGE with GTCS only (EGTCSA) was the most common syndrome in our cohort being present in 94 patients (34 male, 60 female), with 42 (15 male, 27 female) patients diagnosed with Juvenile myoclonic epilepsy (JME), 23 (9 male, 14 female) with Juvenile absence epilepsy (JAE) and 20 (9 male, 11 female) with childhood absence epilepsy (CAE). EEG studies in all patients showed generalised epileptiform activity. CONCLUSIONS: More women than men were diagnosed with generalised epilepsy. Tonic clonic seizures were the most common seizure type reported. EGTCSA was the most frequent syndrome seen. Gender differences were evident for JAE and JME as previously reported and for EGTCSA, which was not reported to date, and reached statistical significance for EGTCA and JME.

PINP: a serum biomarker of bone formation in the rat.

Serum PINP has emerged as a reliable marker of bone turnover in humans and is routinely used to monitor bone formation. However, the effects of PTH (1-34) on bone turnover have not been evaluated following short-term treatment. We present data demonstrating that PINP is an early serum biomarker in the rat for assessing bone anabolic activity in response to treatment with PTH (1-38). Rat serum PINP levels were found to increase following as few as 6 days of treatment with PTH (1-38) and these increases paralleled expression of genes associated with bone formation, as well as, later increases in BMD. Additionally, PINP levels were unaffected by treatment with an antiresorptive bisphosphonate. PINP may be used to detect PTH-induced early bone formation in the rat and may be more generally applicable for preclinical testing of potential bone anabolic drugs.

EFNS guideline on the diagnosis and management of alcohol-related seizures: report of an EFNS task force.

Despite being a considerable problem in neurological practice and responsible for one-third of seizure-related admissions, there is little consensus as to the optimal investigation and management of alcohol-related seizures. The final literature search was undertaken in September 2004. Consensus recommendations are given graded according to the EFNS guidance regulations. To support the history taking, use of a structured questionnaire is recommended. When the drinking history is inconclusive, elevated values of carbohydrate-deficient transferrin and/or gammaglutamyl transferase can support a clinical suspicion. A first epileptic seizure should prompt neuroimaging (CT or MRI). Before starting any carbohydrate containing fluids or food, patients presenting with suspected alcohol overuse should be given prophylactic thiamine parenterally. After an alcohol withdrawal seizure (AWS), the patient should be observed in hospital for at least 24 h and the severity of withdrawal symptoms needs to be followed. For patients with no history of withdrawal seizures and mild to moderate withdrawal symptoms, routine seizure preventive treatment is not necessary. Generally, benzodiazepines are efficacious and safe for primary and secondary seizure prevention; diazepam or, if available, lorazepam, is recommended. The efficacy of other drugs is insufficiently documented. Concerning long-term recommendations for non-alcohol dependent patients with partial epilepsy and controlled seizures, small amounts of alcohol may be safe. Alcohol-related seizures require particular attention both in the diagnostic work-up and treatment. Benzodiazepines should be chosen for the treatment and prevention of recurrent AWS.

Effects of parathyroid hormone on Wnt signaling pathway in bone.

The Wnt signaling pathway has recently been demonstrated to play an important role in bone cell function. In previous studies using DNA microarray analyses, we observed a change in some of the molecular components of the canonical Wnt pathway namely, frizzled-1 (FZD-1) and axil, in response to continuous parathyroid hormone (PTH) treatment in rats. In the present study, we further explored other components of the Wnt signaling pathway in rat distal metaphyseal bone in vivo, and rat osteoblastic osteosarcoma cells (UMR 106) in culture. Several Wnt pathway components, including low-density lipoprotein-receptor-related protein 5 (LRP5), LRP6, FZD-1, Dickkopf-1 (Dkk-1), and Kremen-1 (KRM-1), were expressed in bone in vivo and in osteoblasts in vitro. Continuous exposure to PTH (1-38) both in vivo and in vitro upregulated the mRNA expression of LRP6 and FZD-1 and decreased LRP5 and Dkk-1. These effects in UMR 106 cells were associated with an increase in beta-catenin as measured by Western blots and resulted in functional activation (three to six-fold) of a downstream Wnt responsive TBE6-luciferase (TCF/LEF-binding element) reporter gene. Activation of the TBE6-luciferase reporter gene by PTH (1-38) in UMR 106 cells was inhibited by the protein kinase A (PKA) inhibitor, H89. Activation was mimicked by PTH (1-31), PTH-related protein (1-34), and forskolin, but both PTH (3-34) and (7-34) had no effect. These findings suggest that the effect of PTH on the canonical Wnt signaling pathway occurs at least in part via the cAMP-PKA pathway through the differential regulation of the receptor complex proteins (FZD-1/LRP5 or LRP6) and the antagonist (Dkk-1). Taken together, these results reveal a possible role for the Wnt signaling pathway in PTH actions in bone.