University Hospital Llandough

BACKGROUND: Among patients with non-small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary processes in early-stage NSCLC. METHODS: In this prospective cohort study, we performed multiregion whole-exome sequencing on 100 early-stage NSCLC tumors that had been resected before systemic therapy. We sequenced and analyzed 327 tumor regions to define evolutionary histories, obtain a census of clonal and subclonal events, and assess the relationship between intratumor heterogeneity and recurrence-free survival. RESULTS: ), which remained significant in multivariate analysis. CONCLUSIONS: Intratumor heterogeneity mediated through chromosome instability was associated with an increased risk of recurrence or death, a finding that supports the potential value of chromosome instability as a prognostic predictor. (Funded by Cancer Research UK and others; TRACERx ClinicalTrials.gov number, NCT01888601 .).

A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.

PURPOSE: To evaluate signal intensity and border characteristics of lymph nodes at high-spatial-resolution magnetic resonance (MR) imaging in patients with rectal cancer and to compare these findings with size in prediction of nodal status. MATERIALS AND METHODS: Forty-two patients who underwent total mesorectal excision of the rectum to determine if they had rectal carcinoma were studied with preoperative thin-section MR imaging. Lymph nodes were harvested from 42 transversely sectioned surgical specimens. The slice of each lymph node was carefully matched with its location on the corresponding MR images. Nodal size, border contour, and signal intensity on MR images were characterized and related to histologic involvement with metastases. Differences in sensitivity and specificity with border or signal intensity were calculated with CIs by using method 10 of Newcombe. RESULTS: Of the 437 nodes harvested, 102 were too small (<3 mm) to be depicted on MR images, and only two of these contained metastases. In 15 (68%) of 22 patients with nodal metastases, the size of normal or reactive nodes was equal to or greater than that of positive nodes in the same specimen. Fifty-one nodes were above the area imaged, and seven of these contained metastases. The diameter of benign and malignant nodes was similar; therefore, size was a poor predictor of nodal status. If a node was defined as suspicious because of an irregular border or mixed signal intensity, a superior accuracy was obtained and resulted in a sensitivity of 51 (85%) of 60 (95% CI: 74%, 92%) and a specificity of 216 (97%) of 221 (95% CI: 95%, 99%). CONCLUSION: Prediction of nodal involvement in rectal cancer with MR imaging is improved by using the border contour and signal intensity characteristics of lymph nodes instead of size criteria.

BACKGROUND: Ovarian cancer has a high case-fatality ratio, with most women not diagnosed until the disease is in its advanced stages. The United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS) is a randomised controlled trial designed to assess the effect of screening on mortality. This report summarises the outcome of the prevalence (initial) screen in UKCTOCS. METHODS: Between 2001 and 2005, a total of 202 638 post-menopausal women aged 50-74 years were randomly assigned to no treatment (control; n=101 359); annual CA125 screening (interpreted using a risk of ovarian cancer algorithm) with transvaginal ultrasound scan as a second-line test (multimodal screening [MMS]; n=50 640); or annual screening with transvaginal ultrasound (USS; n=50 639) alone in a 2:1:1 ratio using a computer-generated random number algorithm. All women provided a blood sample at recruitment. Women randomised to the MMS group had their blood tested for CA125 and those randomised to the USS group were sent an appointment to attend for a transvaginal scan. Women with abnormal screens had repeat tests. Women with persistent abnormality on repeat screens underwent clinical evaluation and, where appropriate, surgery. This trial is registered as ISRCTN22488978 and with ClinicalTrials.gov, number NCT00058032. FINDINGS: In the prevalence screen, 50 078 (98.9%) women underwent MMS, and 48 230 (95.2%) underwent USS. The main reasons for withdrawal were death (two MMS, 28 USS), non-ovarian cancer or other disease (none MMS, 66 USS), removal of ovaries (five MMS, 29 USS), relocation (none MMS, 39 USS), failure to attend three appointments for the screen (72 MMS, 757 USS), and participant changing their mind (483 MMS, 1490 USS). Overall, 4355 of 50 078 (8.7%) women in the MMS group and 5779 of 48 230 (12.0%) women in the USS group required a repeat test, and 167 (0.3%) women in the MMS group and 1894 (3.9%) women in the USS group required clinical evaluation. 97 of 50 078 (0.2%) women from the MMS group and 845 of 48 230 (1.8%) from the USS group underwent surgery. 42 (MMS) and 45 (USS) primary ovarian and tubal cancers were detected, including 28 borderline tumours (eight MMS, 20 USS). 28 (16 MMS, 12 USS) of 58 (48.3%; 95% CI 35.0-61.8) of the invasive cancers were stage I/II, with no difference (p=0.396) in stage distribution between the groups. A further 13 (five MMS, eight USS) women developed primary ovarian cancer during the year after the screen. The sensitivity, specificity, and positive-predictive values for all primary ovarian and tubal cancers were 89.4%, 99.8%, and 43.3% for MMS, and 84.9%, 98.2%, and 5.3% for USS, respectively. For primary invasive epithelial ovarian and tubal cancers, the sensitivity, specificity, and positive-predictive values were 89.5%, 99.8%, and 35.1% for MMS, and 75.0%, 98.2%, and 2.8% for USS, respectively. There was a significant difference in specificity (p<0.0001) but not sensitivity between the two screening groups for both primary ovarian and tubal cancers as well as primary epithelial invasive ovarian and tubal cancers. INTERPRETATION: The sensitivity of the MMS and USS screening strategies is encouraging. Specificity was higher in the MMS than in the USS group, resulting in lower rates of repeat testing and surgery. This in part reflects the high prevalence of benign adnexal abnormalities and the more frequent detection of borderline tumours in the USS group. The prevalence screen has established that the screening strategies are feasible. The results of ongoing screening are awaited so that the effect of screening on mortality can be determined.

<h3>SUMMARY:</h3> Flow diversion to treat cerebral aneurysms has revolutionized neurointerventional surgery. Because the addition of coils potentially increases the time and complexity of endovascular procedures, we sought to determine whether adjunctive coil use is associated with an increase in complications. Patients in the International Retrospective Study of Pipeline Embolization Device registry were divided into those treated with the Pipeline Embolization Device alone (<i>n</i> = 689 patients; <i>n</i> = 797 aneurysms; mean aneurysm size, 10.3 ± 7.6 mm) versus those treated with the Pipeline Embolization Device and concurrent coil embolization (<i>n</i> = 104 patients; <i>n</i> = 109 aneurysms; mean aneurysm size, 13.6 ± 7.8 mm). Patient demographics and aneurysm characteristics were examined. Rates of neurologic morbidity and mortality were compared between groups. The Pipeline Embolization Device with versus without coiling required a significantly longer procedure time (135.8 ± 63.9 versus 96.7 ± 46.2 min; <i>P</i> &lt; .0001) and resulted in higher neurological morbidity (12.5% versus 7.8%; <i>P</i> = .13). These data suggest that either strategy represents an acceptable risk profile in the treatment of complex cerebral aneurysms and warrants further investigation.

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The International Conference on Harmonization considers older people a 'special population', as they differ from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions (ADRs). Medical practice is often based on single disease guidelines derived from clinical trials that have not included frail older people or those with multiple morbidities. This presents a challenge caring for older people, as drug doses in trials may not be achievable in real world patients and risks of ADRs are underestimated in clinical trial populations. The majority of ADRs in older people are Type A, potentially avoidable and associated with commonly prescribed medications. Several ADRs are particularly associated with major adverse consequences in the elderly and their reduction is therefore a clinical priority. Falls are strongly associated with benzodiazepines, neuroleptics, antidepressants and antihypertensives. There is good evidence for medication review as part of a multifactorial intervention to reduce falls risk in community dwelling elderly. Multiple medications also contribute to delirium, another multifactorial syndrome resulting in excess mortality particularly in frail older people. Clostridium difficile associated with use of broad spectrum antibiotics mainly affects frail older people and results in prolonged hospital stay with substantial morbidity and mortality. Antipsychotics increase the risk of stroke by more than three-fold in patients with dementia. Inappropriate prescribing can be reduced by adherence to prescribing guidelines, suitable monitoring and regular medication review. Given the heterogeneity within the older population, providing individualized care is pivotal to preventing ADRs.

The National Osteoporosis Guideline Group (NOGG) has revised the UK guideline for the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. Accredited by NICE, this guideline is relevant for all healthcare professionals involved in osteoporosis management. INTRODUCTION: The UK National Osteoporosis Guideline Group (NOGG) first produced a guideline on the prevention and treatment of osteoporosis in 2008, with updates in 2013 and 2017. This paper presents a major update of the guideline, the scope of which is to review the assessment and management of osteoporosis and the prevention of fragility fractures in postmenopausal women, and men age 50 years and older. METHODS: Where available, systematic reviews, meta-analyses and randomised controlled trials were used to provide the evidence base. Conclusions and recommendations were systematically graded according to the strength of the available evidence. RESULTS: Review of the evidence and recommendations are provided for the diagnosis of osteoporosis, fracture-risk assessment and intervention thresholds, management of vertebral fractures, non-pharmacological and pharmacological treatments, including duration and monitoring of anti-resorptive therapy, glucocorticoid-induced osteoporosis, and models of care for fracture prevention. Recommendations are made for training; service leads and commissioners of healthcare; and for review criteria for audit and quality improvement. CONCLUSION: The guideline, which has received accreditation from the National Institute of Health and Care Excellence (NICE), provides a comprehensive overview of the assessment and management of osteoporosis for all healthcare professionals involved in its management. This position paper has been endorsed by the International Osteoporosis Foundation and by the European Society for the Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.

NKG2D is an activating receptor for NK, NKT, CD8(+), and gammadelta(+) T cells, whose aberrant loss in cancer is a key mechanism of immune evasion. Soluble NKG2D ligands and growth factors, such as TGFbeta1 emanating from tumors, are mechanisms for down-regulating NKG2D expression. Cancers thereby impair the capacity of lymphocytes to recognize and destroy them. In this study, we show that exosomes derived from cancer cells express ligands for NKG2D and express TGFbeta1, and we investigate the impact of such exosomes on CD8(+) T and NK cell NKG2D expression and on NKG2D-dependent functions. Exosomes produced by various cancer cell lines in vitro, or isolated from pleural effusions of mesothelioma patients triggered down-regulation of surface NKG2D expression by NK cells and CD8(+) T cells. This decrease was rapid, sustained, and resulted from direct interactions between exosomes and NK cells or CD8(+) T cells. Other markers (CD4, CD8, CD56, CD16, CD94, or CD69) remained unchanged, indicating the selectivity and nonactivatory nature of the response. Exosomal NKG2D ligands were partially responsible for this effect, as down-modulation of NKG2D was slightly attenuated in the presence of MICA-specific Ab. In contrast, TGFbeta1-neutralizing Ab strongly abrogated NKG2D down-modulation, suggesting exosomally expressed TGFbeta as the principal mechanism. Lymphocyte effector function was impaired by pretreatment with tumor exosomes, as these cells exhibited poor NKG2D-dependent production of IFN-gamma and poor NKG2D-dependent killing function. This hyporesponsiveness was evident even in the presence of IL-15, a strong inducer of NKG2D. Our data show that NKG2D is a likely physiological target for exosome-mediated immune evasion in cancer.

OBJECTIVE: The aim of the study was to determine whether the loss of fasting and postprandial glycemic control occurs in parallel or sequentially in the evolution of type 2 diabetes. RESEARCH DESIGN AND METHODS: In 130 type 2 diabetic patients, 24-h glucose profiles were obtained using a continuous glucose monitoring system. The individuals with type 2 diabetes were divided into five groups according to A1C levels: 1 (<6.5%, n = 30), 2 (6.5-6.9%, n = 17), 3 (7-7.9%, n = 32), 4 (8-8.9%, n = 25), and 5 (> or =9%, n = 26). The glucose profiles between the groups were compared. The overall glucose concentrations for the diurnal, nocturnal, and morning periods, which represent the postprandial, fasting, and the dawn phenomenon states, respectively, were also compared. RESULTS: Glucose concentrations increased steadily from group 1 to 5 in a stepwise manner. The initial differences in mean glucose concentrations reaching statistical significance occurred 1) between groups 1 and 2 (6.4 vs. 7.7 mmol/l, P = 0.0004) for daytime postprandial periods, followed by differences; 2) between groups 2 and 3 (7.5 vs. 9.3 mmol/l, P = 0.0003) for the morning periods (dawn phenomenon); and finally 3) between groups 3 and 4 (6.3 vs. 8.4 mmol/l, P < 0.0001) for nocturnal fasting periods. CONCLUSIONS: The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment.

OBJECTIVE: To show the increased risk of adverse outcomes in labour and fetomaternal morbidity in obese women (BMI > 30). DESIGN: A population-based observational study. SETTING: University Hospital of Wales. The study sample was drawn from the Cardiff Births Survey, a population-based database comprising of a total of 60,167 deliveries in the South Glamorgan area between 1990 and 1999. Population Primigravid women with a singleton uncomplicated pregnancy with cephalic presentation of 37 or more weeks of gestation with accurate information regarding height and weight recorded at the booking visit (measured by the midwives) were included in the study. METHODS: Comparisons were made between women with a body mass index of 20-30 and those with more than 30. SPSS version 10 was used for statistical analysis. Student's t test, chi(2) and Fisher's exact tests were used wherever appropriate. MAIN OUTCOME MEASURES: Labour outcomes assessed were risk of postdates, induction of labour, mode of delivery, failed instrumental delivery, macrosomia and shoulder dystocia. Maternal adverse outcomes assessed were postpartum haemorrhage, blood transfusion, uterine and wound infection, urinary tract infection, evacuation of uterus, thromboembolism and third- or fourth-degree perineal tears. Fetal wellbeing was assessed using Apgar <7 at 5 minutes, trauma and asphyxia, cord pH < 7.2, babies requiring neonatal ward admissions, tube feeding and incubator. RESULTS: We report an increased risk [quoted as odds ratio (OR) and confidence intervals CI)] of postdates, 1.4 (1.2-1.7); induction of labour, 1.6 (1.3-1.9); caesarean section, 1.6 (1.4-2); macrosomia, 2.1 (1.6-2.6); shoulder dystocia, 2.9 (1.4-5.8); failed instrumental delivery, 1.75 (1.1-2.9); increased maternal complications such as blood loss of more than 500 mL, 1.5 (1.2-1.8); urinary tract infections, 1.9 (1.1-3.4); and increased neonatal admissions with complications such as neonatal trauma, feeding difficulties and incubator requirement. CONCLUSION: Obese women appear to be at risk of intrapartum and postpartum complications. Induction of labour appears to be the starting point in the cascade of events. They should be considered as high risk and counselled accordingly.

CONTEXT: Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. OBJECTIVE: To provide updated practical guidelines for the pathologic diagnosis of MM. DATA SOURCES: Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. CONCLUSIONS: There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

PURPOSE: To evaluate the accuracy of thin-section magnetic resonance (MR) imaging (in-plane resolution, 0.6 x 0.6 mm) in the preoperative assessment of the depth of extramural tumor infiltration, which is a major prognostic indicator in rectal cancer. MATERIALS AND METHODS: In a prospective study of 28 consecutive patients, preoperative MR imaging was performed. The tumor stage according to the TNM classification system and the measured depth of extramural tumor invasion in matched MR images and histopathologic slices were compared. RESULTS: Preoperative MR imaging correctly indicated the histopathologic tumor stage in all 25 patients in whom comparisons were possible. The difference between the depth of extramural tumor measured on preoperative MR images and corresponding measurements on histopathologic slices of the resection specimen ranged from -5.0 mm to +5.5 mm (mean difference, +0.13 mm; 95% CI: -2.72, +2.98 mm), indicating good agreement. The mesorectal fascia, and the relation of the tumor to it, could be visualized in every case. In all five patients with involvement of the circumferential excision margins of resection specimens, extensive extramural invasion was identified on preoperative MR images. CONCLUSION: Preoperative thin-section MR imaging accurately indicates the tumor stage of rectal cancer and depth of extramural tumor infiltration. It provides valuable information for identifying T3 tumors for preoperative adjuvant therapy in patients who are at high risk of failure of complete excision.

Inflammation in patients defined as frail by Fried's phenotypic definition may be related to sarcopenia. This study aimed to investigate inflammation in older patients across different frailty criteria. Frailty status was determined in 110 patients aged over 75 years (mean 83.9 years) according to function (dependent, intermediate, independent); Fried (three or more items of exhaustion, weight loss, slow walking speed, low handgrip strength, low physical activity) and Frailty Index (a measure of accumulated deficits). With increasing patient frailty as defined by function and by Fried phenotype, tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and C-reactive protein (CRP) increased significantly. Albumin was lowest in the frailest subjects by each definition. The greatest differences were seen between intermediate and dependent groups and between the pre-frail and frail. Adjustment for multiple covariates (age, sex, BMI category, smoking status, number of co-morbidities and number of prescribed medications) did not account for any of the observed differences in levels of inflammatory markers. The Frailty Index correlated significantly with log-transformed CRP (r= 0.221, P < 0.05), log-transformed IL-6 (r= 0.369, P < 0.01), TNF-alpha (r= 0.379, P < 0.01) and inversely with albumin (r=- 0.545, P < 0.01). This study provides further evidence linking inflammation and frailty in older people, an association that seems consistent across different frailty measures.

RATIONALE: Chronic obstructive pulmonary disease (COPD) is associated with an increased risk of cardiovascular events and osteoporosis. Increased arterial stiffness is an independent predictor of cardiovascular disease. OBJECTIVES: We tested the hypothesis that patients with COPD would have increased arterial stiffness, which would be associated with osteoporosis and systemic inflammation. METHODS: We studied 75 clinically stable patients with a range of severity of airway obstruction and 42 healthy smoker or ex-smoker control subjects, free of cardiovascular disease. All subjects underwent spirometry, measurement of aortic pulse wave velocity (PWV) and augmentation index, dual-energy X-ray absorptiometry, and blood sampling for inflammatory mediators. MEASUREMENTS AND MAIN RESULTS: Mean (SD) aortic PWV was greater in patients, 11.4 (2.7) m/s, than in control subjects, 8.95 (1.7) m/s, p < 0.0001. Inflammatory mediators and augmentation index were also greater in patients. Patients with osteoporosis at the hip had a greater aortic PWV, 13.1 (1.8) m/s, than those without, 11.2 (2.7) m/s, p < 0.05. In patients, aortic PWV was related to age (r = 0.63, p < 0.0001) and log(10) IL-6 (r = 0.31, p < 0.01), and inversely to FEV(1) (r = -0.34, p < 0.01). The strongest predictors of aortic PWV in all subjects were age (p < 0.0001), percent predicted FEV(1) (p < 0.05), mean arterial pressure (p < 0.05), and log(10) IL-6 (p < 0.05). CONCLUSIONS: Increased arterial stiffness was related to the severity of airflow obstruction and may be a factor in the excess risk for cardiovascular disease in COPD. The increased aortic PWV in patients with osteoporosis and the association with systemic inflammation suggest that age-related bone and vascular changes occur prematurely in COPD.

Weight loss in chronic obstructive airways disease (COPD) is associated with an increased energy cost of breathing. To determine an association between body composition and the inflammatory response we studied 80 clinically stable patients. Body composition was determined anthropometrically and skeletal muscle mass was determined as the creatinine-height index (CHI). Forty patients had their nitrogen balance determined. Circulating concentrations of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and their soluble receptors were determined for 68 patients. Body mass index (BMI) was normal (> 20 kg/m(2)) in 55 patients, of whom 17 (31%) had a low CHI (< 80% predicted). A reduced CHI was associated with increased circulating levels of IL-6 (p = 0.001), TNF-alpha (p = 0.032) and their soluble receptors IL-6sr (p = 0.002), TNF-alpha sr1 (p = 0.03), and TNF-alpha sr2 (p = 0.001). Patients with a normal BMI and low CHI had inflammatory mediator levels similar to patients with a low BMI and CHI; both were significantly greater than in those with a normal BMI and CHI. Nitrogen balance was similar between normal and low CHI groups, although nitrogen excretion was significantly increased in the low CHI group. Skeletal muscle loss in COPD is probably multifactorial in origin, but our data suggest a link with systemic inflammation, even when weight loss is inapparent.

We hypothesized that in patients with chronic obstructive pulmonary disease, loss of fat-free mass (FFM) and loss of bone mineral density (BMD) were related to (1) each other and may be clinically inapparent, (2) urinary markers of cellular and bone collagen protein breakdown, and (3) severity of lung disease. Eight-one patients and 38 healthy subjects underwent dual-energy X-ray absorptiometry to determine body composition and BMD. Urinary protein breakdown markers, inflammatory mediators, and their soluble receptors were determined. Thirty-three patients had a low fat-free mass index (kg/m(2)), 17 of whom had a normal body mass index. Thirty-two percent of patients (13% of healthy subjects) had osteoporosis at the hip or lumbar spine. The marker of cellular protein breakdown was elevated in patients and related to lung disease severity and body composition. The marker of bone collagen breakdown was greater in patients with osteoporosis. Inflammatory mediators were elevated in patients. Loss of FFM and loss of BMD were related, occurred commonly, and could be subclinical in patients with chronic obstructive pulmonary disease. Loss of both was greatest with severe lung disease. Increased excretion of cellular and bone collagen protein breakdown products in those with low FFM and BMD indicates a protein catabolic state in these patients.

BACKGROUND: Pulmonary rehabilitation programmes improve the health of patients disabled by lung disease but their cost effectiveness is unproved. We undertook a cost/utility analysis in conjunction with a randomised controlled clinical trial of pulmonary rehabilitation versus standard care. METHODS: Two hundred patients, mainly with chronic obstructive pulmonary disease, were randomly assigned to either an 18 visit, 6 week rehabilitation programme or standard medical management. The difference between the mean cost of 12 months of care for patients in the rehabilitation and control groups (incremental cost) and the difference between the two groups in quality adjusted life years (QALYs) gained (incremental utility) were determined. The ratio between incremental cost and utility (incremental cost/utility ratio) was calculated. RESULTS: Each rehabilitation programme for up to 20 patients cost pound 12,120. The mean incremental cost of adding rehabilitation to standard care was pound -152 (95% CI -881 to 577) per patient, p=NS. The incremental utility of adding rehabilitation was 0.030 (95% CI 0.002 to 0.058) QALYs per patient, p=0.03. The point estimate of the incremental cost/utility ratio was therefore negative. The bootstrapping technique was used to model the distribution of cost/utility estimates possible from the data. A high likelihood of generating QALYs at negative or relatively low cost was indicated. The probability of the cost per QALY generated being below pound 0 was 0.64. CONCLUSIONS: This outpatient pulmonary rehabilitation programme produces cost per QALY ratios within bounds considered to be cost effective and is likely to result in financial benefits to the health service.

OBJECTIVE: To evaluate the effectiveness and costs of a multifaceted flexible educational programme aimed at reducing antibiotic dispensing at the practice level in primary care. DESIGN: Randomised controlled trial with general practices as the unit of randomisation and analysis. Clinicians and researchers were blinded to group allocation until after randomisation. SETTING: 68 general practices with about 480,000 patients in Wales, United Kingdom. PARTICIPANTS: 34 practices were randomised to receive the educational programme and 34 practices to be controls. 139 clinicians from the intervention practices and 124 from control practices had agreed to participate before randomisation. Practice level data covering all the clinicians in the 68 practices were analysed. INTERVENTIONS: Intervention practices followed the Stemming the Tide of Antibiotic Resistance (STAR) educational programme, which included a practice based seminar reflecting on the practices' own dispensing and resistance data, online educational elements, and practising consulting skills in routine care. Control practices provided usual care. MAIN OUTCOME MEASURES: Total numbers of oral antibiotic items dispensed for all causes per 1000 practice patients in the year after the intervention, adjusted for the previous year's dispensing. Secondary outcomes included reconsultations, admissions to hospital for selected causes, and costs. RESULTS: The rate of oral antibiotic dispensing (items per 1000 registered patients) decreased by 14.1 in the intervention group but increased by 12.1 in the control group, a net difference of 26.1. After adjustment for baseline dispensing rate, this amounted to a 4.2% (95% confidence interval 0.6% to 7.7%) reduction in total oral antibiotic dispensing for the year in the intervention group relative to the control group (P=0.02). Reductions were found for all classes of antibiotics other than penicillinase-resistant penicillins but were largest and significant individually for phenoxymethylpenicillins (penicillin V) (7.3%, 0.4% to 13.7%) and macrolides (7.7%, 1.1% to 13.8%). There were no significant differences between intervention and control practices in the number of admissions to hospital or in reconsultations for a respiratory tract infection within seven days of an index consultation. The mean cost of the programme was £2923 (€3491, $4572) per practice (SD £1187). There was a 5.5% reduction in the cost of dispensed antibiotics in the intervention group compared with the control group (-0.4% to 11.4%), equivalent to a reduction of about £830 a year for an average intervention practice. CONCLUSION: The STAR educational programme led to reductions in all cause oral antibiotic dispensing over the subsequent year with no significant change in admissions to hospital, reconsultations, or costs. Trial registration ISRCT No 63355948.

Revision knee arthroplasty presents a number of challenges, not least of which is obtaining solid primary fixation of implants into host bone. Three anatomical zones exist within both femur and tibia which can be used to support revision implants. These consist of the joint surface or epiphysis, the metaphysis and the diaphysis. The methods by which fixation in each zone can be obtained are discussed. The authors suggest that solid fixation should be obtained in at least two of the three zones and emphasise the importance of pre-operative planning and implant selection.