Detection of asymptomatic carotid stenosis in patients with lower-extremity arterial disease: development and external validations of a risk score.

BACKGROUND: Recommendations for screening patients with lower-extremity arterial disease (LEAD) to detect asymptomatic carotid stenosis (ACS) are conflicting. Prediction models might identify patients at high risk of ACS, possibly allowing targeted screening to improve preventive therapy and compliance. METHODS: A systematic search for prediction models for at least 50 per cent ACS in patients with LEAD was conducted. A prediction model in screened patients from the USA with an ankle : brachial pressure index of 0.9 or less was subsequently developed, and assessed for discrimination and calibration. External validation was performed in two independent cohorts, from the UK and the Netherlands. RESULTS: After screening 4907 studies, no previously published prediction models were found. For development of a new model, data for 112 117 patients were used, of whom 6354 (5.7 per cent) had at least 50 per cent ACS and 2801 (2.5 per cent) had at least 70 per cent ACS. Age, sex, smoking status, history of hypercholesterolaemia, stroke/transient ischaemic attack, coronary heart disease and measured systolic BP were predictors of ACS. The model discrimination had an area under the receiver operating characteristic (AUROC) curve of 0.71 (95 per cent c.i. 0.71 to 0.72) for at least 50 per cent ACS and 0.73 (0.72 to 0.73) for at least 70 per cent ACS. Screening the 20 per cent of patients at greatest risk detected 12.4 per cent with at least 50 per cent ACS (number needed to screen (NNS) 8] and 5.8 per cent with at least 70 per cent ACS (NNS 17). This yielded 44.2 and 46.9 per cent of patients with at least 50 and 70 per cent ACS respectively. External validation showed reliable discrimination and adequate calibration. CONCLUSION: The present risk score can predict significant ACS in patients with LEAD. This approach may inform targeted screening of high-risk individuals to enhance the detection of ACS.

Twelve-week secukinumab treatment is consistently efficacious for moderate-to-severe psoriasis regardless of prior biologic and non-biologic systemic treatment: Post hoc analysis of six randomised trials.

BACKGROUND: The efficacy of biologic therapies is greater among biologic-naïve vs. biologic-experienced psoriasis patients. However, little is known as to whether prior use of other systemic therapies impacts secukinumab efficacy in patients with moderate-to-severe psoriasis. OBJECTIVE: To investigate the impact of prior exposure to systemic therapies upon the efficacy and safety of secukinumab 300 mg for moderate-to-severe psoriasis. METHODS: Post hoc analysis of six randomised controlled trials (RCTs) comparing secukinumab with placebo, ustekinumab or etanercept at 12 weeks of treatment. Data comparing secukinumab with placebo and ustekinumab were meta-analysed, while comparisons between secukinumab and etanercept were from a single RCT. Four subgroups of patients were assessed: (i) naïve to non-biologic systemics (NBS) and biologics; (ii) exposed to NBS but naïve to biologics; (iii) naïve to NBS but exposed to biologics; and (iv) exposed to NBS and biologics. Outcomes of interest included the following: investigator's global assessment (IGA) score, absolute psoriasis area and severity index (PASI) response, PASI 75, PASI 90 and PASI 100 responses, and dermatology life quality index (DLQI). Safety was also assessed. RESULTS: One thousand three hundred and eighty-three patients were included in the secukinumab vs. placebo meta-analysis: 1776 in the secukinumab vs. ustekinumab meta-analysis and 653 in the within-trial analyses of secukinumab vs. etanercept. For all subgroups, secukinumab was significantly more efficacious than placebo for all outcomes measured. Secukinumab generated greater responses in biologic-naïve patients, while prior NBS had a negligible impact on treatment response. Furthermore, secukinumab was more efficacious than both ustekinumab and etanercept on many outcomes, with an even greater difference for biologic-naïve than biologic-exposed patients. Safety results were consistent with individual clinical trial results. CONCLUSIONS: Twelve-week treatment with secukinumab 300 mg is consistently more efficacious than placebo, etanercept and ustekinumab in patients with moderate-to-severe psoriasis, regardless of prior exposure to biologics or NBS. Secukinumab had a comparable safety profile to both etanercept and ustekinumab.

Timing of procedural stroke and death in asymptomatic patients undergoing carotid endarterectomy: individual patient analysis from four RCTs.

BACKGROUND: The effectiveness of carotid endarterectomy (CEA) for stroke prevention depends on low procedural risks. The aim of this study was to assess the frequency and timing of procedural complications after CEA, which may clarify underlying mechanisms and help inform safe discharge policies. METHODS: Individual-patient data were obtained from four large carotid intervention trials (VACS, ACAS, ACST-1 and GALA; 1983-2007). Patients undergoing CEA for asymptomatic carotid artery stenosis directly after randomization were used for the present analysis. Timing of procedural death and stroke was divided into intraoperative day 0, postoperative day 0, days 1-3 and days 4-30. RESULTS: Some 3694 patients were included in the analysis. A total of 103 patients (2·8 per cent) had serious procedural complications (18 fatal strokes, 68 non-fatal strokes, 11 fatal myocardial infarctions and 6 deaths from other causes) [Correction added on 20 April, after first online publication: the percentage value has been corrected to 2·8]. Of the 86 strokes, 67 (78 per cent) were ipsilateral, 17 (20 per cent) were contralateral and two (2 per cent) were vertebrobasilar. Forty-five strokes (52 per cent) were ischaemic, nine (10 per cent) haemorrhagic, and stroke subtype was not determined in 32 patients (37 per cent). Half of the strokes happened on the day of CEA. Of all serious complications recorded, 44 (42·7 per cent) occurred on day 0 (20 intraoperative, 17 postoperative, 7 with unclear timing), 23 (22·3 per cent) on days 1-3 and 36 (35·0 per cent) on days 4-30. CONCLUSION: At least half of the procedural strokes in this study were ischaemic and ipsilateral to the treated artery. Half of all procedural complications occurred on the day of surgery, but one-third after day 3 when many patients had been discharged.

ANTECEDENTES: La efectividad de la endarterectomía carotídea (carotid endarterectomy, CEA) en la prevención de un accidente cerebrovascular depende de que este procedimiento tenga pocos riesgos. El objetivo de este estudio fue evaluar la frecuencia y el momento de aparición de las complicaciones tras una CEA, lo que podría clarificar los mecanismos subyacentes y ayudar a establecer una política de altas hospitalarias segura. MÉTODOS: Se utilizaron los datos de los pacientes incluidos en cuatro grandes ensayos de intervención carotídea (VACS, ACAS, ACST-1 y GALA; 1983-2007). Para el presente análisis se utilizaron los datos de pacientes sometidos a CEA por estenosis de la arteria carótida asintomática recogidos inmediatamente tras la aleatorización. Se consideraron diferentes intervalos entre el procedimiento, la muerte o el accidente cerebrovascular: intraoperatorio día 0, postoperatorio día 0, postoperatorio días 1-3 y postoperatorio días 4-30. RESULTADOS: En el análisis se incluyeron 3.694 pacientes. Se detectaron complicaciones graves relacionadas con el procedimiento en 103 (2,8%) pacientes (18 accidentes cerebrovasculares fatales, 68 accidentes cerebrovasculares no fatales, 11 infartos de miocardio fatales y 6 muertes por otras causas). De los 86 accidentes cerebrovasculares, 67 (78%) fueron ipsilaterales, 17 (20%) contralaterales y dos (2%) vertebrobasilares. Los accidentes cerebrovasculares fueron isquémicos en 45 (52%) casos, hemorrágicos en 9 (10%) y no se pudo determinar el subtipo de ictus en 32 (37%). La mitad de los accidentes cerebrovasculares ocurrieron el día de la CEA. De todas las complicaciones graves registradas, 44 (43%) ocurrieron en el día 0 (20 intraoperatorias, 17 postoperatorias y 7 en períodos poco definidos), 23 (22%) entre los días 1-3 y 36 (35%) entre los días 4-30. CONCLUSIÓN: En este estudio, al menos la mitad de los accidentes cerebrovasculares relacionados con la CEA fueron isquémicos e ipsilaterales respecto a la arteria tratada. La mitad de todas las complicaciones de la CEA ocurrieron el día de la cirugía, pero un tercio de los casos se presentaron después del día 3, cuando muchos pacientes ya habían sido dados de alta.

Patellar tendon enthesis abnormalities and their association with knee pain and structural abnormalities in older adults.

OBJECTIVE: To describe associations between presence of patellar tendon enthesis (PTE) abnormalities and symptoms, structural abnormalities, and total knee replacement (TKR) in older adult cohort. METHODS: PTE abnormalities (presence of abnormal bone signal and/or bone erosion), were measured on T2-weighted magnetic resonance (MR) images at baseline in 961 community-dwelling older adults. Knee pain and function limitation were assessed using Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Bone marrow lesions (BMLs), cartilage volume and defects score, and infrapatellar fat pad (IPFP) area were measured using validated methods. Incidence of TKR was determined by data linkage. RESULTS: Participants with abnormal PTE bone signal and/or erosion was 20%. Cross-sectionally, presence of PTE abnormalities was associated with greater pain intensity while going up and down stairs (ß = 0.22 (95% confidence interval (CI); 0.03, 0.41)), greater risk of femoral BMLs (RR = 1.46 (1.12, 1.90)) and worse tibial cartilage defects score (RR = 1.70 (1.16, 2.47), and smaller IPFP area (ß = -0.27 (-0.47, -0.06) cm2), after adjustment of confounders. Longitudinally, presence of baseline PTE abnormalities was associated with a deleterious increase in tibial BML size (RR = 1.52 (1.12, 2.05)) over 10.7 years but not symptoms, other structural changes, or TKR. CONCLUSION: PTE abnormalities are common in older adults. Presence of cross-sectional but not longitudinal associations suggests they are commonly co-exist with other knee structural abnormalities but may not play a major role in symptom development or structural change, excepting tibial BMLs.

Association of childhood adiposity measures with adulthood knee cartilage defects and bone marrow lesions: a 25-year cohort study.

OBJECTIVE: To describe the associations between childhood adiposity measures and adulthood knee cartilage defects and bone marrow lesions (BMLs) measured 25 years later. METHODS: 327 participants from the Australian Schools Health and Fitness Survey (ASHFS) of 1985 (aged 7-15 years) were followed up 25 years later (aged 31-41 years). Childhood measures (weight, height and skinfolds) were collected in 1985. Body mass index (BMI), overweight status and fat mass were calculated. Participants underwent 1.5 T knee magnetic resonance imaging (MRI) during 2008-2010, and cartilage defects and BMLs were scored from knee MRI scans. Log binomial regressions were used to examine the associations. RESULTS: Among 327 participants (47.1% females), 21 (6.4%) were overweight in childhood. Childhood adiposity measures were associated with the increased risk of adulthood patellar cartilage defects (Weight relative risk (RR) 1.05/kg, 95% confidence interval (CI) 1.01-1.09; BMI 1.10/kg/m2, 1.01-1.19; Overweight 2.22/yes, 1.21-4.08; fat mass 1.11/kg, 1.01-1.22), but not tibiofemoral cartilage defects. Childhood adiposity measures were not significantly associated with adulthood knee BMLs except for the association between childhood overweight status and adulthood patellar BMLs (RR 2.87/yes, 95% CI 1.10-7.53). These significant associations persisted after adjustment for corresponding adulthood adiposity measure. CONCLUSION: Childhood adiposity measures were associated with the increased risk of adulthood patellar cartilage defects and, to a lesser extent, BMLs, independent of adulthood adiposity measures. These results suggest that adiposity in childhood has long-term effects on patellar structural abnormalities in young adults.

Meta-analysis of the procedural risks of carotid endarterectomy and carotid artery stenting over time.

BACKGROUND: Stroke/death rates within 30 days of carotid endarterectomy (CEA) and carotid artery stenting (CAS) in RCTs inform current clinical guidelines. However, the risks may have changed in recent years with wider use of effective stroke prevention therapies, especially statins, improved patient selection and growing operator expertise. The aim of this study was to investigate whether the procedural stroke/death risks from CEA and CAS have changed over time. METHODS: MEDLINE and Embase were searched systematically from inception to May 2016 for observational cohort studies of CEA and CAS. Studies included reported on more than 1000 patients, with 30-day outcomes after the procedure according to patients' symptom status (recent stroke or transient ischaemic attack). Restricted maximum likelihood random-effects and meta-regressions methods were used to synthesize procedural stroke/death rates of CEA and CAS according to year of study recruitment completion. RESULTS: Fifty-one studies, including 223 313 patients undergoing CEA and 72 961 undergoing CAS, were reviewed. Procedural stroke/death risks of CEA decreased over time in symptomatic and asymptomatic patients. Risks were substantially lower in studies completing recruitment in 2005 or later, both in symptomatic (5·11 per cent before 2005 versus 2·68 per cent from 2005 onwards; P = 0·002) and asymptomatic (3·17 versus 1·50 per cent; P < 0·001) patients. Procedural stroke/death rates of CAS did not change significantly over time (4·77 per cent among symptomatic and 2·59 per cent among asymptomatic patients). There was substantial heterogeneity in event rates and recruitment periods were long. CONCLUSIONS: Risks of procedural stroke/death following CEA appear to have decreased substantially. There was no evidence of a change in stroke/death rates following CAS.

Secukinumab significantly reduces psoriasis-related work impairment and indirect costs compared with ustekinumab and etanercept in the United Kingdom.

BACKGROUND: Psoriasis causes work productivity impairment that increases with disease severity. Whether differential treatment efficacy translates into differential indirect cost savings is unknown. OBJECTIVE: To assess work hours lost and indirect costs associated with secukinumab versus ustekinumab and etanercept in the United Kingdom (UK). METHODS: This was a post hoc analysis of work impairment data collected in the CLEAR study (secukinumab vs. ustekinumab) and applied to the FIXTURE study (secukinumab vs. etanercept). Weighted weekly and annual average indirect costs per patient per treatment were calculated from (i) overall work impairment derived from Work Productivity and Activity Impairment data collected in CLEAR at 16 and 52 weeks by Psoriasis Area and Severity Index (PASI) response level; (ii) weekly/annual work productivity loss by PASI response level; (iii) weekly and annual indirect costs by PASI response level, based on hours of work productivity loss; and (iv) weighted average indirect costs for each treatment. In the primary analysis, work impairment data for employed patients in CLEAR at Week 16 were used to compare secukinumab and ustekinumab. Secondary analyses were conducted at different time points and with patient cohorts, including FIXTURE. RESULTS: In CLEAR, 452 patients (67%) were employed at baseline. At Week 16, percentages of weekly work impairment/mean hours lost decreased with higher PASI: PASI < 50: 22.8%/7.60 h; PASI 50-74: 13.3%/4.45 h; PASI 75-89: 6.4%/2.14 h; PASI ≥ 90: 4.9%/1.65 h. Weighted mean weekly/annual work hours lost were significantly lower for secukinumab than ustekinumab (1.96/102.51 vs. 2.40/125.12; P = 0.0006). Results were consistent for secukinumab versus etanercept (2.29/119.67 vs. 3.59/187.17; Ρ<0.0001). Average annual indirect cost savings with secukinumab were £355 vs. ustekinumab and £1061 versus etanercept. Results at 52 weeks were similar. CONCLUSIONS: Secukinumab significantly reduced work impairment and associated indirect costs of psoriasis compared with ustekinumab and etanercept at Week 16 through 52 in the United Kingdom.

Pre-operative Carotid Plaque Echolucency Assessment has no Predictive Value for Long-Term Risk of Stroke or Cardiovascular Death in Patients Undergoing Carotid Endarterectomy.

INTRODUCTION: In patients with carotid stenosis receiving medical treatment, carotid plaque echolucency has been thought to predict risk of future stroke and of other cardiovascular events. This study evaluated the prognostic value of pre-operative plaque echolucency for future stroke and cardiovascular death in patients undergoing carotid endarterectomy in the first Asymptomatic Carotid Surgery Trial (ACST-1). METHODS: In ACST-1, 1832/3120 patients underwent carotid endarterectomy (CEA), of whom 894 had visual echolucency assessment according to the Gray-Weale classification. During follow-up patients were monitored both for peri-procedural (i.e. within 30 days) death, stroke, or MI, and for long-term risk of stroke or cardiovascular death. Unconditional maximum likelihood estimation was used to calculate odds ratios of peri-procedural risk and Kaplan-Meier statistics with log-rank test were used to compare cumulative long-term risks. RESULTS: Of 894 operated patients in whom echolucency was assessed, 458 plaques (51%) were rated as echolucent and peri-procedural risk of death/stroke/MI in these patients was non-significantly higher when compared with patients with non-echolucent plaques (OR 1.48 [95% CI 0.76-2.88], p = .241). No differences were found in the 10 year risk of any stroke (30/447 [11.6%] vs. 29/433 [11.0%], p = .900) or cardiovascular (non-stroke) death (85/447 [27.9%] vs. 93/433 [32.1%], p = .301). CONCLUSION: In ACST-1, carotid plaque echolucency assessment in patients undergoing CEA offered no predictive value with regard to peri-operative or long-term stroke risk or of cardiovascular (non-stroke) death.

Diastolic Blood Pressure is a Risk Factor for Peri-procedural Stroke Following Carotid Endarterectomy in Asymptomatic Patients.

OBJECTIVE/BACKGROUND: Carotid endarterectomy (CEA) prevents future stroke, but this benefit depends on detection and control of high peri-operative risk factors. In symptomatic patients, diastolic hypertension has been causally related to procedural stroke following CEA. The aim was to identify risk factors causing peri-procedural stroke in asymptomatic patients and to relate these to timing of surgery and mechanism of stroke. METHODS: In the first Asymptomatic Carotid Surgery Trial (ACST-1), 3,120 patients with severe asymptomatic carotid stenosis were randomly assigned to CEA plus medical therapy or to medical therapy alone. In 1,425 patients having their allocated surgery, baseline patient characteristics were analysed to identify factors associated with peri-procedural (< 30 days) stroke or death. Multivariate analysis was performed on risk factors with a p value < .3 from univariate analysis. Event timing and mechanism of stroke were analysed using chi-square tests. RESULTS: A total of 36 strokes (27 ischaemic, four haemorrhagic, five unknown type) and six other deaths occurred during the peri-procedural period, resulting in a stroke/death rate of 2.9% (42/1,425). Diastolic blood pressure at randomisation was the only significant risk factor in univariate analysis (odds ratio [OR] 1.34 per 10 mmHg, 95% confidence interval [CI] 1.04-1.72; p = .02) and this remained so in multivariate analysis when corrected for sex, age, lipid lowering therapy, and prior infarcts or symptoms (OR 1.34, 95% CI 1.05-1.72; p = .02). In patients with diastolic hypertension (> 90 mmHg) most strokes occurred during the procedure (67% vs. 20%; p = .02). CONCLUSION: In ACST-1, diastolic blood pressure was the only independent risk factor associated with peri-procedural stroke or death. While the underlying mechanisms of the association between lower diastolic blood pressure and peri-procedural risk remain unclear, good pre-operative control of blood pressure may improve procedural outcome of carotid surgery in asymptomatic patients.

Choices of Stent and Cerebral Protection in the Ongoing ACST-2 Trial: A Descriptive Study.

OBJECTIVE/BACKGROUND: Several plaque and lesion characteristics have been associated with an increased risk for procedural stroke during or shortly after carotid artery stenting (CAS). While technical advancements in stent design and cerebral protection devices (CPD) may help reduce the procedural stroke risk, and anatomy remains important, tailoring stenting procedures according to plaque and lesion characteristics might be a useful strategy in reducing stroke associated with CAS. In this descriptive report of the ongoing Asymptomatic Carotid Surgery Trial-2 (ACST-2), it was assessed whether choice for stent and use or type of CPD was influenced by plaque and lesion characteristics. METHODS: Trial patients who underwent CAS between 2008 and 2015 were included in this study. Chi-square statistics were used to study the effects of plaque echolucency, ipsilateral preocclusive disease (90-99%), and contralateral high-grade stenosis (>50%) or occlusion of the carotid artery on interventionalists' choice for stent and CPD. Differences in treatment preference between specialties were also analysed. RESULTS: In this study, 831 patients from 88 ACST-2 centres were included. Almost all procedures were performed by either interventional radiologists (50%) or vascular surgeons (45%). Plaque echolucency, ipsilateral preocclusive disease (90-99%), and significant contralateral stenosis (>50%) or occlusion did not affect the choice of stent or either the use of cerebral protection and type of CPD employed (i.e., filter/flow reversal). Vascular surgeons used a CPD significantly more often than interventional radiologists (98.6% vs. 76.3%; p < .001), but this choice did not appear to be dependent on patient characteristics. CONCLUSION: In ACST-2, plaque characteristics and severity of stenosis did not primarily determine interventionalists' choice of stent or use or type of CPD, suggesting that other factors, such as vascular anatomy or personal and centre preference, may be more important. Stent and CPD use was highly heterogeneous among participating European centres.

Antiplatelet Therapy in Carotid Artery Stenting and Carotid Endarterectomy in the Asymptomatic Carotid Surgery Trial-2.

OBJECTIVE: Strokes are infrequent but potentially serious complications following carotid intervention, but antiplatelet therapy can reduce these risks. There are currently no specific guidelines on dose or duration of peri-procedural antiplatelet treatment for patients undergoing carotid intervention. Within the ongoing Asymptomatic Carotid Surgery Trial-2 (ACST-2), this study aimed at assessing the current use of antiplatelet therapy before, during, and after CEA and CAS in patients with asymptomatic carotid stenosis. METHODS: Questionnaires were sent to ACST-2 collaborators seeking information about the use of antiplatelet therapy during the pre-, peri-, and post-operative periods in patients undergoing carotid intervention at 77 participating sites and also whether sites tested for antiplatelet therapy resistance. RESULTS: The response rate was 68/77 (88%). For CAS, 82% of sites used dual antiplatelet therapy (DAPT) pre-operatively and 86% post-operatively with a mean post-procedural duration of 3 months (range 1-12), while 9% continued DAPT life-long. For CEA only 31% used DAPT pre-operatively, 24% post-operatively with a mean post-procedural duration of 3 months (range 1-5), while 10% continued DAPT life-long. For those prescribing post-procedural mono antiplatelet (MAPT) therapy (76%), aspirin was more commonly prescribed (59%) than clopidogrel (6%) and 11% of centres did not show a preference for either aspirin or clopidogrel. Eleven centres (16%) tested for antiplatelet therapy resistance. CONCLUSION: There appears to be broad agreement on the use of antiplatelet therapy in ACST-2 patients undergoing carotid artery stenting and surgery. Although evidence to help guide the duration of peri-procedural antiplatelet therapy is limited, long-term treatment with DAPT appears similar between both treatment arms.

Plaque Echolucency and the Risk of Ischaemic Stroke in Patients with Asymptomatic Carotid Stenosis Within the First Asymptomatic Carotid Surgery Trial (ACST-1).

OBJECTIVE/BACKGROUND: On ultrasound, potentially "high risk" carotid plaques may appear echolucent. In this study, whether a confident classification of echolucent plaque was a predictor of future ipsilateral ischaemic stroke in asymptomatic patients randomized to medical therapy in the Asymptomatic Carotid Surgery Trial-1 (ACST-1) was assessed. METHODS: We performed a post-hoc analysis of 814 ACST-1 patients randomized to medical therapy alone with baseline plaque assessment classified as definitely echolucent (> 25% soft plaque) or nonecholucent (< 25% soft plaque). Kaplan-Meier survival curves were used to compare cumulative rates of ipsilateral ischaemic stroke in both groups. RESULTS: In the first 5 years after randomization, a significantly higher risk of ipsilateral stroke was observed in patients with definitely echolucent plaques (8.0%; 95% confidence interval [CI] 6.4-9.6) when compared with patients with definitely nonecholucent plaques (3.1%; 95% CI 2.1-4.1; p = .009). After adjustments for other risk factors, plaque echolucency was associated with a 2.5-times increased risk of ipsilateral ischaemic stroke (hazard ratio 2.52; 95% CI 1.20-5.25; p = .014). Use of lipid-lowering therapy was low in both groups during the first 5 years after randomization but rose sharply during years 5-10 of follow-up, and was significantly more likely to be prescribed for patients with echolucent plaques (p = .001). The risk of ipsilateral ischaemic stroke at 10 years was similar for both groups of patients (p = .233). CONCLUSION: Although the numbers of events in this study was low, definite plaque echolucency (> 25% soft plaque) was associated with a higher 5-year ipsilateral stroke risk in ACST-1 and may therefore help to identify patients at increased risk of stroke for whom carotid intervention may be particularly beneficial.

Volatile accretion history of the Earth.

It has long been thought that the Earth had a protracted and complex history of volatile accretion and loss. Albarède paints a different picture, proposing that the Earth first formed as a dry planet which, like the Moon, was devoid of volatile constituents. He suggests that the Earth's complement of volatile elements was only established later, by the addition of a small veneer of volatile-rich material at ∼100 Myr (here and elsewhere, ages are relative to the origin of the Solar System). Here we argue that the Earth's mass balance of moderately volatile elements is inconsistent with Albarède's hypothesis but is well explained by the standard model of accretion from partially volatile-depleted material, accompanied by core formation.

Mass effect and signal intensity alteration in the suprapatellar fat pad: associations with knee symptoms and structure.

OBJECTIVE: To describe cross-sectional associations between mass effect or signal intensity alteration of the suprapatellar fat pad (SPFP) with knee symptoms and structure in older adults. METHODS: A cross-sectional sample of 904 randomly selected subjects (mean 62.4 years, 49.9% female) was studied. T1- or T2-weighted fat suppressed magnetic resonance imaging (MRI) was used to assess mass effect or signal intensity alteration of SPFP, cartilage volume, cartilage defects, and bone marrow lesions (BMLs). Knee pain was assessed by self-administered Western Ontario McMaster Osteoarthritis Index (WOMAC) questionnaire. The Osteoarthritis Research Society International (OARSI) atlas was used to assess knee osteophyte, joint space narrowing (JSN) and radiographic osteoarthritis (ROA). Univariable and multivariable linear or logistic regression analyses were used to examine the associations. RESULTS: After adjustment for confounders including age, sex, body mass index (BMI), disease status, tibial bone area and/or ROA, the presence of SPFP mass effect was significantly associated with any knee pain (OR: 2.39; 95% confidence interval (CI): 1.54, 3.70) and ROA (OR: 2.10; 95% CI: 1.33, 3.31) but not with cartilage volume, cartilage defects or BMLs. The presence of SPFP signal intensity alteration was significantly associated with any knee pain (OR: 1.90; 95% CI: 1.43, 2.53), ROA (OR: 1.83; 95% CI: 1.37, 2.45), any BMLs (OR: 1.55; 95% CI: 1.17, 2.06) but not with cartilage volume and cartilage defects. Significant associations with knee pain and BMLs were more evident in subjects with ROA. Presence of SPFP mass effect and/or signal intensity alteration combined was associated with any tibial cartilage defects (OR: 1.45; 95% CI: 1.04, 2.04). CONCLUSIONS: SPFP mass effect and/or signal intensity alterations are deleteriously associated with knee pain, radiographic OA and BMLs in this cross-sectional study, suggesting that SPFP abnormalities may contribute to pain and structural abnormalities in the knee.

Current practice of carotid endarterectomy in the UK.

BACKGROUND: Carotid endarterectomy (CEA) reduces the risk of stroke in patients with internal carotid stenosis of 50-99 per cent. This study assessed national surgical practice through audit of CEA procedures and outcomes. METHODS: This was a prospective cohort study of UK surgeons performing CEA, using clinical audit data collected continuously and reported in two rounds, covering operations from December 2005 to December 2007, and January 2008 to September 2009. RESULTS: Some 352 (92·6 per cent) of 380 eligible surgeons contributed data. Of 19,935 CEAs recorded by Hospital Episode Statistics, 12,496 (62·7 per cent) were submitted to the audit. A total of 10,452 operations (83·6 per cent) were performed for symptomatic carotid stenosis; among these patients, the presenting symptoms were transient ischaemic attack in 4507 (43·1 per cent), stroke in 3572 (34·2 per cent) and amaurosis fugax in 1965 (18·8 per cent). The 30-day mortality rate was 1·0 per cent (48 of 4944) in round 1 and 0·8 per cent (50 of 6151) in round 2; the most common cause of death was stroke, followed by myocardial infarction. The rate of death or stroke within 30 days of surgery was 2·5 per cent (124 of 4918) in round 1 and 1·8 per cent (112 of 6135) in round 2. CONCLUSION: CEA is performed less commonly in the UK than in other European countries and probably remains underutilized in the prevention of stroke. Increasing the number of CEAs done in the UK, together with reducing surgical waiting times, could prevent more strokes.

Attempts to immunize sheep against Teladorsagia circumcincta using fourth-stage larval extracts.

A ConcanavilinA (ConA)-binding fraction of a detergent-soluble membrane extract from Teladorsagia circumcincta (formerly Ostertagia circumcincta) fourth-stage larvae was isolated, and two vaccine trials were conducted with this preparation in groups of 7 worm-free sheep. All groups were challenged with a total of 5000 T. circumcincta larvae from 1 week after the final immunization and protection assessed by comparing the egg and worm counts, and length of developing worms, of the immunized groups with their respective controls. Immunization with the ConA-binding antigen induced high-titre serum antibody responses in both trials. However, no significant reduction in either egg count or worm burdens was observed in the vaccinated groups in either trial. It was concluded that detergent-soluble, ConA-binding extracts prepared from T. circumcincta fourth-stage larvae did not contain significantly protective antigens, despite the fact that an extract prepared in a similar manner from Ostertagia ostertagi had previously significantly protected calves against homologous challenge.

Protective immunization of calves against Ostertagia ostertagi using fourth stage larval extracts.

ConA lectin was used to isolate glycoproteins from detergent extracts of fourth stage Ostertagia ostertagi larvae. This preparation contained proteins additional to those observed in a similar fraction prepared from adult O. ostertagi. Two vaccine trials were conducted with this preparation, and sub-fractions thereof, in groups of 6-8 worm-free calves. All groups were challenged with 50,000 O. ostertagi larvae 1 week after the final immunization, and protection was assessed by comparing the egg and worm counts of the immunized groups with their respective controls. Immunization with the ConA-binding antigen or its sub-fractions induced high titre serum antibody responses. In the first trial, the cumulative egg count of the group immunized with unfractionated antigen was 60% lower than the corresponding control value, and worm counts were 47% lower. In the second trial, the cumulative egg counts of the vaccinated groups ranged from 70% to 85% lower than the corresponding controls, with worm counts up to 64% lower. It was concluded that detergent-soluble, ConA-binding extracts prepared from O. ostertagi fourth stage larvae contained protective immunogens that were as effective as the best antigens published for O. ostertagi to date.