Budesonide/Glycopyrrolate/Formoterol for the Management of COPD in a UK Primary Care Population: Real-World Use and Early Medication Success.

Purpose: Real-life research is needed to evaluate the effectiveness of budesonide/glycopyrrolate/formoterol (BGF) in routine COPD primary care management. We assessed the frequency of medication success among patients with COPD who initiated BGF using real-world data. Patients and Methods: Patients with a recorded diagnostic COPD code who started BGF with ≥2 prescriptions within 90-days were identified in the UK Optimum Patient Care Research Database and followed from first prescription until censoring at the end of follow-up (180-days), death, leaving database or end of data at 24/10/2022. The primary outcome was medication success at 90-days post-BGF initiation, defined as no major cardiac or respiratory event (ie no complicated COPD exacerbation, hospitalization for any respiratory event, myocardial infarction, new/hospitalized heart failure, and death) and no incidence of pneumonia. Medication success was also assessed at 180-days post-BGF initiation. Overall real-life medication success was claimed if the lower 95% confidence interval (CI) for the proportion of patients meeting the primary outcome was ≥70% (defined a priori). Results: Two hundred eighty-five patients were included. Prior to BGF initiation, these patients often had severe airflow obstruction (mean ppFEV1: 54.5%), were highly symptomatic (mMRC ≥2: 77.9% (n = 205/263); mean CAT score: 21.7 (SD 7.8)), with evidence of short-acting ß2-agonist (SABA) over-use (≥3 inhalers/year: 62.1%, n=179/285), repeat OCS prescriptions (≥2 courses/year: 33.0%, n = 95/285) and multiple primary care consultations (≥2 visits/year: 61.1%, n = 174/285). Overall, 39.6% of patients (n = 113/285) switched from previous triple therapies. Real-life medication success was achieved by 96.5% of patients (n = 275/285 [95% CI: 93.6, 98.3]) during 90-days treatment with BGF and by 91.8% (n = 169/184 [95% CI: 86.9, 95.4]) of patients at 180-days. The prescribed daily dose of SABA remained stable over the study period. Conclusion: The majority of patients initiating BGF experienced real-life medication success reflecting the absence of severe cardiopulmonary events. These benefits were apparent after 90-days of treatment and sustained over 180-days.

Association between pre-biologic T2-biomarker combinations and response to biologics in patients with severe asthma.

Background: To date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials. Aim: To elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life. Methods: This was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers. Results: Overall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and <0.001, respectively); however, this prediction was not improved by the addition of IgE. Conclusions: The ability of higher baseline BEC, FeNO and their combination to predict biologic-associated lung function improvement may encourage earlier intervention in patients with impaired lung function or at risk of accelerated lung function decline.

Ten-year survival of neoadjuvant dual HER2 blockade in patients with HER2-positive breast cancer.

BACKGROUND: Dual anti-HER2-targeted therapy in breast cancer (BC) significantly increased the rate of pathological complete response (pCR) compared to single blockade when added to chemotherapy. However, limited data exist on the long-term impact on survival of the additional increase in pCR. METHODS: Neoadjuvant lapatinib and/or trastuzumab treatment optimisation (NCT00553358) is an international, randomised, open-label, phase III study investigating the addition of lapatinib to chemotherapy plus trastuzumab in HER2-positive early BC. Ten-year event-free survival (EFS), overall survival (OS) and safety were assessed on intention-to-treat population. The association between pCR and EFS or OS was investigated in landmark population. RESULTS: A total of 455 patients were randomised to receive lapatinib (154), trastuzumab (149) or the combination (152). Ten-year EFS estimates were 63% (95% confidence interval [CI], 54%-71%) in the lapatinib group, 64% (95% CI, 55%-72%) in the trastuzumab group and 67% (95% CI, 58%-74%) in the combination group. Ten-year OS rates were 76% (95% CI, 67%-83%), 75% (95% CI, 66%-82%) and 80% (95% CI, 73%-86%) in the lapatinib, trastuzumab and combination groups, respectively. Women who achieved a pCR had improved EFS (hazard ratio 0.48, 95% CI, 0.31-0.73) and OS (hazard ratio 0.37, 95% CI, 0.20-0.63) compared with those who did not. The numerical difference in survival according to pCR status was greater in women treated with the combination and those with hormone-receptor-negative tumours. There were no new or long-term safety concerns. CONCLUSIONS: Patients with HER2-positive BC showed a durable survival benefit of neoadjuvant anti-HER2, irrespective of treatment arm. Patients who achieve pCR have significantly better outcomes than patients without pCR.

Planned delivery for pre-eclampsia between 34 and 37 weeks of gestation: the PHOENIX RCT.

BACKGROUND: In women with late preterm pre-eclampsia (i.e. at 34+0 to 36+6 weeks' gestation), the optimal delivery time is unclear because limitation of maternal-fetal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether or not planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of perinatal or infant outcomes, compared with expectant management, in women with late preterm pre-eclampsia. METHODS: We undertook an individually randomised, triple non-masked controlled trial in 46 maternity units across England and Wales, with an embedded health economic evaluation, comparing planned delivery and expectant management (usual care) in women with late preterm pre-eclampsia. The co-primary maternal outcome was a maternal morbidity composite or recorded systolic blood pressure of ≥ 160 mmHg (superiority hypothesis). The co-primary short-term perinatal outcome was a composite of perinatal deaths or neonatal unit admission (non-inferiority hypothesis). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The primary 2-year infant neurodevelopmental outcome was measured using the PARCA-R (Parent Report of Children's Abilities-Revised) composite score. The planned sample size of the trial was 900 women; the trial is now completed. We undertook two linked substudies. RESULTS: Between 29 September 2014 and 10 December 2018, 901 women were recruited; 450 women [448 women (two withdrew consent) and 471 infants] were allocated to planned delivery and 451 women (451 women and 475 infants) were allocated to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group [289 (65%) women] than in the expectant management group [338 (75%) women] (adjusted relative risk 0.86, 95% confidence interval 0.79 to 0.94; p = 0.0005). The incidence of the co-primary perinatal outcome was significantly higher in the planned delivery group [196 (42%) infants] than in the expectant management group [159 (34%) infants] (adjusted relative risk 1.26, 95% confidence interval 1.08 to 1.47; p = 0.0034), but indicators of neonatal morbidity were similar in both groups. At 2-year follow-up, the mean PARCA-R scores were 89.5 points (standard deviation 18.2 points) for the planned delivery group (290 infants) and 91.9 points (standard deviation 18.4 points) for the expectant management group (256 infants), both within the normal developmental range (adjusted mean difference -2.4 points, 95% confidence interval -5.4 to 0.5 points; non-inferiority p = 0.147). Planned delivery was significantly cost-saving (-£2711, 95% confidence interval -£4840 to -£637) compared with expectant management. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. CONCLUSION: In women with late preterm pre-eclampsia, planned delivery reduces short-term maternal morbidity compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater short-term neonatal morbidity (such as need for respiratory support). At 2-year follow-up, around 60% of parents reported follow-up scores. Average infant development was within the normal range for both groups; the small between-group mean difference in PARCA-R scores is unlikely to be clinically important. Planned delivery was significantly cost-saving to the health service. These findings should be discussed with women with late preterm pre-eclampsia to allow shared decision-making on timing of delivery. LIMITATIONS: Limitations of the trial include the challenges of finding a perinatal outcome that adequately represented the potential risks of both groups and a maternal outcome that reflects the multiorgan manifestations of pre-eclampsia. The incidences of maternal and perinatal primary outcomes were higher than anticipated on the basis of previous studies, but this did not limit interpretation of the analysis. The trial was limited by a higher loss to follow-up rate than expected, meaning that the extent and direction of bias in outcomes (between responders and non-responders) is uncertain. A longer follow-up period (e.g. up to 5 years) would have enabled us to provide further evidence on long-term infant outcomes, but this runs the risk of greater attrition and increased expense. FUTURE WORK: We identified a number of further questions that could be prioritised through a formal scoping process, including uncertainties around disease-modifying interventions, prognostic factors, longer-term follow-up, the perspectives of women and their families, meta-analysis with other studies, effect of a similar intervention in other health-care settings, and clinical effectiveness and cost-effectiveness of other related policies around neonatal unit admission in late preterm birth. TRIAL REGISTRATION: The trial was prospectively registered as ISRCTN01879376. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Clinical Characteristics and Outcomes From Percutaneous Coronary Intervention of Last Remaining Coronary Artery: An Analysis From the British Cardiovascular Intervention Society Database.

BACKGROUND: Patients with complex high-risk coronary anatomy, such as those with a last remaining patent vessel (LRPV), are increasingly revascularized with percutaneous coronary intervention (PCI) in contemporary practice. There are limited data on the outcomes of these high-risk procedures. METHODS: We analyzed a large longitudinal PCI cohort (2007-2014, n=501 841) from the British Cardiovascular Intervention Society database. Clinical, demographic, procedural, and outcome data were analyzed by dividing patients into 2 groups; LRPV group (n=2432) and all other PCI groups (n=506 691). RESULTS: Patients in the LRPV PCI group were older, had more comorbidities, and higher prevalence of moderate-severe left ventricular systolic dysfunction. Mortality was higher in the LRPV PCI group during hospital admission (12 % versus 1.5 %, P<0.001), at 30 days (15% versus 2%, P<0.001), and at one-year (24% versus 5%, P<0.001). In a propensity score matching analysis the adjusted risk of mortality during index admission (odds ratio, 2.05 [95% CI, 1.65-2.44], P<0.001), at 30 days (odds ratio, 2.13 [95% CI, 1.78-2.5], P<0.001), at 1 year (odds ratio, 1.81 [95% CI, 1.59-2.03], P<0.001), and in-hospital major adverse cardiovascular events (odds ratio, 1.8 [95% CI, 1.42-2.19], P<0.001) were higher in LRPV PCI group as compared to control group. In sensitivity analyses, similar clinical outcomes were observed irrespective of which major epicardial coronary artery was treated. CONCLUSIONS: In this contemporary cohort, patients who had PCI to their LRPV had a higher-risk profile and more adverse clinical outcomes, irrespective of the vessel treated.

Two speeds of increasing milk feeds for very preterm or very low-birthweight infants: the SIFT RCT.

BACKGROUND: Observational data suggest that slowly advancing enteral feeds in preterm infants may reduce necrotising enterocolitis but increase late-onset sepsis. The Speed of Increasing milk Feeds Trial (SIFT) compared two rates of feed advancement. OBJECTIVE: To determine if faster (30 ml/kg/day) or slower (18 ml/kg/day) daily feed increments improve survival without moderate or severe disability and other morbidities in very preterm or very low-birthweight infants. DESIGN: This was a multicentre, two-arm, parallel-group, randomised controlled trial. Randomisation was via a web-hosted minimisation algorithm. It was not possible to safely and completely blind caregivers and parents. SETTING: The setting was 55 UK neonatal units, from May 2013 to June 2015. PARTICIPANTS: The participants were infants born at < 32 weeks' gestation or a weight of < 1500 g, who were receiving < 30 ml/kg/day of milk at trial enrolment. INTERVENTIONS: When clinicians were ready to start advancing feed volumes, the infant was randomised to receive daily feed increments of either 30 ml/kg/day or 18 ml/kg/day. In total, 1400 infants were allocated to fast feeds and 1404 infants were allocated to slow feeds. MAIN OUTCOME MEASURES: The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months of age, corrected for gestational age. The secondary outcomes were mortality; moderate or severe neurodevelopmental disability at 24 months corrected for gestational age; death before discharge home; microbiologically confirmed or clinically suspected late-onset sepsis; necrotising enterocolitis (Bell's stage 2 or 3); time taken to reach full milk feeds (tolerating 150 ml/kg/day for 3 consecutive days); growth from birth to discharge; duration of parenteral feeding; time in intensive care; duration of hospital stay; diagnosis of cerebral palsy by a doctor or other health professional; and individual components of the definition of moderate or severe neurodevelopmental disability. RESULTS: The results showed that survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 out of 1224 (65.5%) infants allocated to faster increments and 848 out of 1246 (68.1%) infants allocated to slower increments (adjusted risk ratio 0.96, 95% confidence interval 0.92 to 1.01). There was no significant difference between groups in the risk of the individual components of the primary outcome or in the important hospital outcomes: late-onset sepsis (adjusted risk ratio 0.96, 95% confidence interval 0.86 to 1.07) or necrotising enterocolitis (adjusted risk ratio 0.88, 95% confidence interval 0.68 to 1.16). Cost-consequence analysis showed that the faster feed increment rate was less costly but also less effective than the slower rate in terms of achieving the primary outcome, so was therefore found to not be cost-effective. Four unexpected serious adverse events were reported, two in each group. None was assessed as being causally related to the intervention. LIMITATIONS: The study could not be blinded, so care may have been affected by knowledge of allocation. Although well powered for comparisons of all infants, subgroup comparisons were underpowered. CONCLUSIONS: No clear advantage was identified for the important outcomes in very preterm or very low-birthweight infants when milk feeds were advanced in daily volume increments of 30 ml/kg/day or 18 ml/kg/day. In terms of future work, the interaction of different milk types with increments merits further examination, as may different increments in infants at the extremes of gestation or birthweight. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76463425. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 18. See the NIHR Journals Library website for further project information.

Some infants who are born early need to be fed through a tube into their stomach. A small volume of milk is given to begin with, which is gradually increased. To determine whether infants do better if they are fed faster or slower, this study compared increasing the milk feeds by 30 ml/kg/day with increasing the milk feeds by 18 ml/kg/day, aiming to get to full feeds (when other fluids are not needed) in 5 or 9 days. We compared results from the two groups at discharge from hospital and at 24 months of age, after correcting for prematurity. We also assessed the economic impact of the two daily feed increments, interviewed parents about taking part in multiple studies and tested methods for improving questionnaire returns. The faster-fed group reached full milk feeds sooner and needed less intravenous nutrition, and the proportion of infants developing bowel inflammation or bloodstream infection were similar. At 24 months of age, we found an unexpected increase in the risk of moderate or severe motor impairment in the faster-fed group, which is difficult to explain. We also saw that other types of disability were more frequent in the faster group, although this was not significantly different mathematically. This means that no clear advantage of increasing feeds at faster or slower rates was identified and health professionals will need to carefully consider how to increase feeds. After accepting the increased risk of disability, an economic evaluation showed that increasing milk feed volumes at a faster rate was not a cost-effective strategy. Interviews with parents showed that they valued opportunities for their infant to take part in studies, but this interaction is complex and difficult to remember at a stressful and confusing time and made worse by considering multiple studies. More questionnaires were returned when vouchers were given before rather than after receiving them.

In-hospital gastrointestinal bleeding following percutaneous coronary intervention.

OBJECTIVES: This study aims to examine in-hospital gastrointestinal (GI) bleeding, its predictors and clinical outcomes, including long-term outcomes, in a national cohort of patients undergoing percutaneous coronary intervention (PCI) in England and Wales. BACKGROUND: GI bleeding remains associated with significant morbidity, mortality, and socioeconomic burden. METHODS: We examined the temporal changes in in-hospital GI bleeding in a national cohort of patients undergoing PCI between 2007 and 2014 in England and Wales, its predictors and prognostic consequences. Multivariate analysis was performed to identify independent risk factors between GI bleeding and 30-day mortality. Survival analysis was performed comparing patients with, and without, GI bleeding. RESULTS: There were 480 in-hospital GI bleeds in 549,298 patients (0.09%). Overall, rates of GI bleeding remained stable over time but a significant decline was observed for patients with ST segment elevation myocardial infarction (STEMI). The strongest predictors of bleeding events were STEMI-odds ratio (OR) 7.28 (95% confidence interval [95% CI] 4.82-11.00), glycoprotein IIb/IIIa inhibitor use OR 3.42 (95% CI 2.76-4.24) and use of circulatory support OR 2.65 (95% CI 1.90-3.71). Antiplatelets/coagulants (clopidogrel, prasugrel, and warfarin) were not independently associated with GI bleeding. GI bleeding was independently associated with a significant increase in all-cause 30-day mortality (OR 2.08 [1.52-2.83]). Patients with in-hospital GI bleed who survived to 30-days had increased all-cause mortality risk at 1 year compared to non-bleeders (HR 1.49 [1.07-2.09]). CONCLUSIONS: In-hospital GI bleeding following PCI is rare but is a clinically important event associated with increased 30-day and long-term mortality.

Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants.

BACKGROUND: Observational data have shown that slow advancement of enteral feeding volumes in preterm infants is associated with a reduced risk of necrotizing enterocolitis but an increased risk of late-onset sepsis. However, data from randomized trials are limited. METHODS: We randomly assigned very preterm or very-low-birth-weight infants to daily milk increments of 30 ml per kilogram of body weight (faster increment) or 18 ml per kilogram (slower increment) until reaching full feeding volumes. The primary outcome was survival without moderate or severe neurodevelopmental disability at 24 months. Secondary outcomes included components of the primary outcome, confirmed or suspected late-onset sepsis, necrotizing enterocolitis, and cerebral palsy. RESULTS: Among 2804 infants who underwent randomization, the primary outcome could be assessed in 1224 (87.4%) assigned to the faster increment and 1246 (88.7%) assigned to the slower increment. Survival without moderate or severe neurodevelopmental disability at 24 months occurred in 802 of 1224 infants (65.5%) assigned to the faster increment and 848 of 1246 (68.1%) assigned to the slower increment (adjusted risk ratio, 0.96; 95% confidence interval [CI], 0.92 to 1.01; P = 0.16). Late-onset sepsis occurred in 414 of 1389 infants (29.8%) in the faster-increment group and 434 of 1397 (31.1%) in the slower-increment group (adjusted risk ratio, 0.96; 95% CI, 0.86 to 1.07). Necrotizing enterocolitis occurred in 70 of 1394 infants (5.0%) in the faster-increment group and 78 of 1399 (5.6%) in the slower-increment group (adjusted risk ratio, 0.88; 95% CI, 0.68 to 1.16). CONCLUSIONS: There was no significant difference in survival without moderate or severe neurodevelopmental disability at 24 months in very preterm or very-low-birth-weight infants with a strategy of advancing milk feeding volumes in daily increments of 30 ml per kilogram as compared with 18 ml per kilogram. (Funded by the Health Technology Assessment Programme of the National Institute for Health Research; SIFT Current Controlled Trials number, ISRCTN76463425.).

Planned early delivery or expectant management for late preterm pre-eclampsia (PHOENIX): a randomised controlled trial.

BACKGROUND: In women with late preterm pre-eclampsia, the optimal time to initiate delivery is unclear because limitation of maternal disease progression needs to be balanced against infant complications. The aim of this trial was to determine whether planned earlier initiation of delivery reduces maternal adverse outcomes without substantial worsening of neonatal or infant outcomes, compared with expectant management (usual care) in women with late preterm pre-eclampsia. METHODS: In this parallel-group, non-masked, multicentre, randomised controlled trial done in 46 maternity units across England and Wales, we compared planned delivery versus expectant management (usual care) with individual randomisation in women with late preterm pre-eclampsia from 34 to less than 37 weeks' gestation and a singleton or dichorionic diamniotic twin pregnancy. The co-primary maternal outcome was a composite of maternal morbidity or recorded systolic blood pressure of at least 160 mm Hg with a superiority hypothesis. The co-primary perinatal outcome was a composite of perinatal deaths or neonatal unit admission up to infant hospital discharge with a non-inferiority hypothesis (non-inferiority margin of 10% difference in incidence). Analyses were by intention to treat, together with a per-protocol analysis for the perinatal outcome. The trial was prospectively registered with the ISRCTN registry, ISRCTN01879376. The trial is closed to recruitment but follow-up is ongoing. FINDINGS: Between Sept 29, 2014, and Dec 10, 2018, 901 women were recruited. 450 women (448 women and 471 infants analysed) were allocated to planned delivery and 451 women (451 women and 475 infants analysed) to expectant management. The incidence of the co-primary maternal outcome was significantly lower in the planned delivery group (289 [65%] women) compared with the expectant management group (338 [75%] women; adjusted relative risk 0·86, 95% CI 0·79-0·94; p=0·0005). The incidence of the co-primary perinatal outcome by intention to treat was significantly higher in the planned delivery group (196 [42%] infants) compared with the expectant management group (159 [34%] infants; 1·26, 1·08-1·47; p=0·0034). The results from the per-protocol analysis were similar. There were nine serious adverse events in the planned delivery group and 12 in the expectant management group. INTERPRETATION: There is strong evidence to suggest that planned delivery reduces maternal morbidity and severe hypertension compared with expectant management, with more neonatal unit admissions related to prematurity but no indicators of greater neonatal morbidity. This trade-off should be discussed with women with late preterm pre-eclampsia to allow shared decision making on timing of delivery. FUNDING: National Institute for Health Research Health Technology Assessment Programme.

Do frailty measures improve prediction of mortality and morbidity following transcatheter aortic valve implantation? An analysis of the UK TAVI registry.

OBJECTIVES: Previous studies indicate frailty to be associated with poor outcomes following transcatheter aortic valve implantation (TAVI), but there is limited evidence from multicentre registries. The aim was to investigate the independent association of frailty with TAVI outcomes, and the prognostic utility of adding frailty into existing clinical prediction models (CPMs). DESIGN: The UK TAVI registry incorporated three frailty measures since 2013: Canadian Study of Health and Ageing, KATZ and poor mobility. We investigated the associations between these frailty measures with short-term and long-term outcomes, using logistic regression to estimate multivariable adjusted ORs, and Cox proportional hazards models to explore long-term survival. We compared the predictive performance of existing TAVI CPMs before and after updating them to include each frailty measure. SETTING: All patients who underwent a TAVI procedure in England or Wales between 2013 and 2014. PARTICIPANTS: 2624 TAVI procedures were analysed in this study. PRIMARY AND SECONDARY OUTCOMES: The primary endpoints in this study were 30-day mortality and long-term survival. The Valve Academic Research Consortium (VARC)-2 composite early safety endpoint was considered as a secondary outcome. RESULTS: KATZ <6 (OR 2.10, 95% CI 1.39 to 3.15) and poor mobility (OR 2.15, 95% CI 1.41 to 3.28) predicted 30-day mortality after multivariable adjustment. All frailty measures were associated with increased odds of the VARC-2 composite early safety endpoint. We observed a significant increase in the area under the receiver operating characteristic curves by approximately 5% after adding KATZ <6 or poor mobility into the TAVI CPMs. Risk stratification agreement was significantly improved by the addition of each frailty measure, with an increase in intraclass correlation coefficient of between 0.15 and 0.31. CONCLUSION: Frailty was associated with worse outcomes following TAVI, and incorporating frailty metrics significantly improved the predictive performance of existing CPMs. Physician-estimated frailty measures could aid TAVI risk stratification, until more objective scales are routinely collected.

The association between chronic airflow obstruction and poverty in 12 sites of the multinational BOLD study.

Poverty is strongly associated with mortality from COPD, but little is known of its relation to airflow obstruction.In a cross-sectional study of adults aged ≥40 years from 12 sites (N=9255), participating in the Burden of Obstructive Lung Disease (BOLD) study, poverty was evaluated using a wealth score (0-10) based on household assets. Obstruction, measured as forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) (%) after administration of 200 µg salbutamol, and prevalence of FEV1/FVC

Extreme hydrothermal conditions at an active plate-bounding fault.

Temperature and fluid pressure conditions control rock deformation and mineralization on geological faults, and hence the distribution of earthquakes. Typical intraplate continental crust has hydrostatic fluid pressure and a near-surface thermal gradient of 31 ± 15 degrees Celsius per kilometre. At temperatures above 300-450 degrees Celsius, usually found at depths greater than 10-15 kilometres, the intra-crystalline plasticity of quartz and feldspar relieves stress by aseismic creep and earthquakes are infrequent. Hydrothermal conditions control the stability of mineral phases and hence frictional-mechanical processes associated with earthquake rupture cycles, but there are few temperature and fluid pressure data from active plate-bounding faults. Here we report results from a borehole drilled into the upper part of the Alpine Fault, which is late in its cycle of stress accumulation and expected to rupture in a magnitude 8 earthquake in the coming decades. The borehole (depth 893 metres) revealed a pore fluid pressure gradient exceeding 9 ± 1 per cent above hydrostatic levels and an average geothermal gradient of 125 ± 55 degrees Celsius per kilometre within the hanging wall of the fault. These extreme hydrothermal conditions result from rapid fault movement, which transports rock and heat from depth, and topographically driven fluid movement that concentrates heat into valleys. Shear heating may occur within the fault but is not required to explain our observations. Our data and models show that highly anomalous fluid pressure and temperature gradients in the upper part of the seismogenic zone can be created by positive feedbacks between processes of fault slip, rock fracturing and alteration, and landscape development at plate-bounding faults.

Development of an international scale of socio-economic position based on household assets.

BACKGROUND: The importance of studying associations between socio-economic position and health has often been highlighted. Previous studies have linked the prevalence and severity of lung disease with national wealth and with socio-economic position within some countries but there has been no systematic evaluation of the association between lung function and poverty at the individual level on a global scale. The BOLD study has collected data on lung function for individuals in a wide range of countries, however a barrier to relating this to personal socio-economic position is the need for a suitable measure to compare individuals within and between countries. In this paper we test a method for assessing socio-economic position based on the scalability of a set of durable assets (Mokken scaling), and compare its usefulness across countries of varying gross national income per capita. RESULTS: Ten out of 15 candidate asset questions included in the questionnaire were found to form a Mokken type scale closely associated with GNI per capita (Spearman's rank rs = 0.91, p = 0.002). The same set of assets conformed to a scale in 7 out of the 8 countries, the remaining country being Saudi Arabia where most respondents owned most of the assets. There was good consistency in the rank ordering of ownership of the assets in the different countries (Cronbach's alpha = 0.96). Scores on the Mokken scale were highly correlated with scores developed using principal component analysis (rs = 0.977). CONCLUSIONS: Mokken scaling is a potentially valuable tool for uncovering links between disease and socio-economic position within and between countries. It provides an alternative to currently used methods such as principal component analysis for combining personal asset data to give an indication of individuals' relative wealth. Relative strengths of the Mokken scale method were considered to be ease of interpretation, adaptability for comparison with other datasets, and reliability of imputation for even quite large proportions of missing values.

Successful treatment of a radial artery pseudoaneurysm in an octogenarian.

The transradial approach for coronary catheterisation has gained rising popularity owing to its fewer access site complications compared with the transfemoral approach. A rare but recognisable complication of the procedure is radial artery pseudoaneurysm (PSA). We report a case of radial PSA occurring 2 h following percutaneous coronary intervention in an 85-year-old woman, which was successfully treated by ultrasound-guided thrombin injection. This non-surgical technique has recently gained rising popularity as a relatively novel modality of managing radial PSA.

Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values.

AIMS: Myocardial deformation is a key to clinical decision-making. Feature-tracking cardiovascular magnetic resonance (FT-CMR) provides quantification of motion and strain using standard steady-state in free-precession (SSFP) imaging, which is part of a routine CMR left ventricular (LV) study protocol. An accepted definition of a normal range is essential if this technique is to enter the clinical arena. METHODS AND RESULTS: One hundred healthy individuals, with 10 men and women in each of 5 age deciles from 20 to 70 years, without a history of cardiovascular disease, diabetes, renal impairment, or family history of cardiovascular disease, and with a normal stress echocardiogram, underwent FT-CMR assessment of LV myocardial strain and strain rate using SSFP cines.Peak systolic longitudinal strain (Ell) was -21.3 ± 4.8%, peak systolic circumferential strain (Ecc) was -26.1 ± 3.8%, and peak systolic radial strain (Err) was 39.8 ± 8.3%. On Bland-Altman analyses, peak systolic Ecc had the best inter-observer agreement (bias 0.63 ± 1.29% and 95% CI -1.90 to 3.16) and peak systolic Err the least inter-observer agreement (bias 0.13 ± 6.41 and 95% CI -12.44 to 12.71). There was an increase in the magnitude of peak systolic Ecc with advancing age, which was greatest in subjects over the age of 50 years (R(2) = 0.11, P = 0.003). There were significant gender differences (P < 0.001) in peak systolic Ell, with a greater magnitude of deformation in females (-22.7%) than in males (-19.3%). CONCLUSION: Normal values for myocardial strain measurements using FT-CMR are provided. All circumferential and longitudinal based variables had excellent intra- and inter-observer variability.

Etiology of severe childhood pneumonia in the Gambia, West Africa, determined by conventional and molecular microbiological analyses of lung and pleural aspirate samples.

Molecular analyses of lung aspirates from Gambian children with severe pneumonia detected pathogens more frequently than did culture and showed a predominance of bacteria, principally Streptococcus pneumoniae, >75% being of serotypes covered by current pneumococcal conjugate vaccines. Multiple pathogens were detected frequently, notably Haemophilus influenzae (mostly nontypeable) together with S. pneumoniae.

Service configuration, unit characteristics and variation in intervention rates in a national sample of obstetric units in England: an exploratory analysis.

OBJECTIVES: To explore whether service configuration and obstetric unit (OU) characteristics explain variation in OU intervention rates in 'low-risk' women. DESIGN: Ecological study using funnel plots to explore unit-level variations in adjusted intervention rates and simple linear regression, stratified by parity, to investigate possible associations between unit characteristics/configuration and adjusted intervention rates in planned OU births. Characteristics considered: OU size, presence of an alongside midwifery unit (AMU), proportion of births in the National Health Service (NHS) trust planned in midwifery units or at home and midwifery 'under' staffing. SETTING: 36 OUs in England. PARTICIPANTS: 'Low-risk' women with a 'term' pregnancy planning vaginal birth in a stratified, random sample of 36 OUs. MAIN OUTCOME MEASURES: Adjusted rates of intrapartum caesarean section, instrumental delivery and two composite measures capturing birth without intervention ('straightforward' and 'normal' birth). RESULTS: Funnel plots showed unexplained variation in adjusted intervention rates. In NHS trusts where proportionately more non-OU births were planned, adjusted intrapartum caesarean section rates in the planned OU births were significantly higher (nulliparous: R(2)=31.8%, coefficient=0.31, p=0.02; multiparous: R(2)=43.2%, coefficient=0.23, p=0.01), and for multiparous women, rates of 'straightforward' (R(2)=26.3%, coefficient=-0.22, p=0.01) and 'normal' birth (R(2)=17.5%, coefficient=0.24, p=0.01) were lower. The size of the OU (number of births), midwifery 'under' staffing levels (the proportion of shifts where there were more women than midwives) and the presence of an AMU were associated with significant variation in some interventions. CONCLUSIONS: Trusts with greater provision of non-OU intrapartum care may have higher intervention rates in planned 'low-risk' OU births, but at a trust level this is likely to be more than offset by lower intervention rates in planned non-OU births. Further research using high quality data on unit characteristics and outcomes in a larger sample of OUs and trusts is required.

Feature-tracking cardiovascular magnetic resonance as a novel technique for the assessment of mechanical dyssynchrony.

BACKGROUND: Myocardial tagging using cardiovascular magnetic resonance (CMR) is the gold-standard for the assessment of myocardial mechanics. Feature-tracking cardiovascular magnetic resonance (FT-CMR) has been validated against myocardial tagging. We explore the potential of FT-CMR in the assessment of mechanical dyssynchrony, with reference to patients with cardiomyopathy and healthy controls. METHODS: Healthy controls (n=55, age: 42.9 ± 13 yrs, LVEF: 70 ± 5%, QRS: 88 ± 9 ms) and patients with cardiomyopathy (n=108, age: 64.7 ± 12 yrs, LVEF: 29 ± 6%, QRS: 147 ± 29 ms) underwent FT-CMR for the assessment of the circumferential (CURE) and radial (RURE) uniformity ratio estimate based on myocardial strain (both CURE and RURE: 0 to 1; 1=perfect synchrony) RESULTS: CURE (0.79 ± 0.14 vs. 0.97 ± 0.02) and RURE (0.71 ± 0.14 vs. 0.91 ± 0.04) were lower in patients with cardiomyopathy than in healthy controls (both p<0.0001). CURE (area under the receiver-operator characteristic curve [AUC]: 0.96), RURE (AUC: 0.96) and an average of these (CURE:RUREAVG, AUC: 0.98) had an excellent ability to discriminate between patients with cardiomyopathy and controls (sensitivity 90%; specificity 98% at a cut-off of 0.89). The time taken for semi-automatically tracking myocardial borders was 5.9 ± 1.4 min. CONCLUSION: Dyssynchrony measures derived from FT-CMR, such as CURE and RURE, provide almost absolute discrimination between patients with cardiomyopathy and healthy controls. The rapid acquisition of these measures, which does not require specialized CMR sequences, has potential for the assessment of mechanical dyssynchrony in clinical practice.

Mortality in South Asians and Caucasians after percutaneous coronary intervention in the United Kingdom: an observational cohort study of 279,256 patients from the BCIS (British Cardiovascular Intervention Society) National Database.

OBJECTIVES: The purpose of this study was to compare baseline characteristics and medium-term prognosis in South Asian and Caucasian patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: It is unclear whether South Asians undergoing PCI have worse outcomes than Caucasians. METHODS: We performed a retrospective analysis of 279,256 patients undergoing PCI from 2004 to 2011 from the British Cardiovascular Intervention Society national database, of whom 259,318 (92.9%) were Caucasian and 19,938 (7.1%) were South Asian (South Asian includes patients of Pakistani, Indian, Bangladeshi, or Sri Lankan ethnic origin). The main outcome measures were in-hospital major adverse cardiac and cerebrovascular events and all-cause mortality during a median follow-up of 2.8 years (interquartile range: 1.5 to 4.5 years). RESULTS: South Asians were younger (59.69 ± 0.27 years vs. 64.69 ± 0.13 years, p > 0.0001); more burdened by cardiovascular risk factors, particularly diabetes mellitus (42.1 ± 1.2% vs. 15.4 ± 0.4%, p > 0.0001); and more likely to have multivessel coronary disease than Caucasians. In-hospital rates of major adverse cardiac and cerebrovascular events were similar for South Asians and Caucasians (3.5% vs. 2.8%, p = 0.40). Unadjusted Kaplan-Meier estimates of all-cause mortality showed better survival for South Asians compared with Caucasians, after PCI for either acute myocardial infarction or angina. Age-adjusted analysis revealed increased mortality (hazard ratio: 1.24; 95% confidence interval: 1.18 to 1.30), but after adjustment for the substantial variation in baseline risk factors including diabetes, there was no significant difference between South Asians and Caucasians (hazard ratio: 0.99; 95% confidence interval: 0.94 to 1.05). CONCLUSIONS: In this large, contemporary cohort of patients treated by PCI, South Asians were younger but had more extensive disease and major risk factors, particularly diabetes. However, after correcting for these differences, in-hospital and medium-term mortality of South Asians was no worse than that of Caucasians. This suggests that in South Asians, the high prevalence of diabetes exerts an adverse influence on mortality, but ethnicity itself is not an independent predictor of outcome.