Patterns of allergic sensitization and factors associated with emergence of sensitization in the rural tropics early in the life course: findings of an Ecuadorian birth cohort.

INTRODUCTION: There are limited data on emergence of allergic sensitization (or atopy) during childhood in tropical regions. METHODS: We followed a birth cohort of 2404 newborns to 8 years in tropical Ecuador and collected: risk factor data by maternal questionnaires periodically from birth; atopy was measured by skin prick test reactivity (SPT) to aeroallergens in parents, and aeroallergens and food allergens in children at 2, 3, 5, and 8 years; and stool samples for soil-transmitted helminths (STH) from children periodically to 8 years and from parents and household members at the time of recruitment of cohort children. Data on risk factors were measured either at birth or repeatedly (time-varying) from birth to 8 years. Longitudinal repeated-measures analyses were done using generalized estimating equations to estimate an the age-dependent risk of positive SPT (SPT+) to any allergen or mite during early childhood to school age. RESULTS: SPT+ to any allergen was present in 29.0% of fathers and 24.8% of mothers, and in cohort children increased with age, initially to mite but later to cockroach, reaching 14.8% to any allergen (10.7% mite and 5.3% cockroach) at 8 years. Maternal SPT+, particularly presence of polysensitization (OR 2.04, 95% CI 1.49-2.77) significantly increased the risk of SPT+ during childhood, while household overcrowding at birth decreased the risk (OR 0.84, 95% CI 0.72-0.98). For mite sensitization, maternal polysensitization increased (OR 2.14, 95% CI 1.40-3.27) but rural residence (OR 0.69, 95% CI 0.50-0.94) and birth order (3rd -4th vs. 1st - 2nd: OR 0.71, 95% CI 0.52-0.98) decreased the risk. Time-varying exposures to agricultural activities (OR 0.77, 95% CI 0.60-0.98) and STH parasites (OR 0.70, 95% CI 0.64-0.91) during childhood decreased while anthelmintics increased the childhood risk (OR 1.47, 95% CI 1.05-2.05) of mite sensitization. CONCLUSION: Our data showed the emergence of allergic sensitization, primarily to mite and cockroach allergens, during childhood in tropical Ecuador. A role for both antenatal and postnatal factors acting as potential determinants of SPT+ emergence was observed.

Biventricular Myocardial Fibrosis and Sudden Death in Patients With Brugada Syndrome.

BACKGROUND: Electrophysiological, imaging, and pathological studies have reported the presence of subtle structural abnormalities in hearts from patients with Brugada syndrome (BrS). However, data concerning disease involvement outside of the right ventricular outflow tract are limited. OBJECTIVES: This study sought to characterize the presence and distribution of ventricular myocardial fibrosis in a cohort of decedents experiencing sudden cardiac death caused by BrS. METHODS: The authors evaluated 28 whole hearts from consecutive sudden cardiac death cases attributed to BrS and 29 hearts from a comparator group comprised of noncardiac deaths (control subjects). Cardiac tissue from 6 regions across the right and left ventricle were stained with Picrosirius red for collagen and tissue composition was determined using image analysis software. Postmortem genetic testing was performed in cases with DNA retained for analysis. RESULTS: Of 28 BrS decedents (75% men; median age of death 25 years), death occurred in sleep or at rest in 24 of 28 (86%). The highest proportion of collagen was observed in the epicardial right ventricular outflow tract of the BrS group (23.7%; 95% CI: 20.8%-26.9%). Ventricular myocardium from BrS decedents demonstrated a higher proportion of collagen compared with control subjects (ratio 1.45; 95% CI: 1.22-1.71; P < 0.001), with no significant interactions with respect to sampling location or tissue layer. There was insufficient evidence to support differences in collagen proportion in SCN5A-positive cases (n = 5) when compared with control subjects (ratio 1.23; 95% CI: 0.75-1.43; P = 0.27). CONCLUSIONS: Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer.

Changing knowledge, attitudes and behaviours towards cytomegalovirus in pregnancy through film-based antenatal education: a feasibility randomised controlled trial of a digital educational intervention.

BACKGROUND: Congenital cytomegalovirus (CMV) is the most common congenital infection globally, however information about CMV is not routinely included in antenatal education in the United Kingdom. This feasibility study aimed to gather the essential data needed to design and power a large randomised controlled trial (RCT) to investigate the efficacy of a digital intervention in reducing the risk of CMV acquisition in pregnancy. In order to do this, we carried out a single-centre RCT, which explored the knowledge, attitudes and risk reduction behaviours in women in the intervention and treatment as usual groups, pre- and post-intervention. METHODS: CMV seronegative women living with a child less than four years old, receiving antenatal care at a single UK tertiary centre, were randomised to the digital intervention or 'treatment as usual' groups. Participants completed questionnaires before the digital intervention and after and at 34 gestational weeks, and responses within groups and between groups were compared using tailored randomisation tests. CMV serology was tested in the first trimester and at the end of pregnancy. RESULTS: Of the 878 women screened, 865 samples were analysed with 43% (n = 372) being CMV seronegative and therefore eligible to take part in the RCT; of these, 103 (27.7%) women were enrolled and 87 (84%) of these completed the study. Most participants (n = 66; 64%) were unfamiliar with CMV at enrolment, however at 34 gestational weeks, women in the intervention group (n = 51) were more knowledgeable about CMV compared to the treatment as usual group (n = 52) and reported engaging in activities that may increase the risk of CMV transmission less frequently. The digital intervention was highly acceptable to pregnant women. Overall, four participants seroconverted over the course of the study: two from each study group. CONCLUSIONS: A large multi-centre RCT investigating the efficacy of a CMV digital intervention is feasible in the United Kingdom; this study has generated essential data upon which to power such a study. This single-centre feasibility RCT demonstrates that a digital educational intervention is associated with increase in knowledge about CMV and can result in behaviour change which may reduce the risk of CMV acquisition in pregnancy. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03511274 , Registered 27.04.18, http://www.Clinicaltrials.gov.

The LIFT trial: study protocol for a double-blind, randomised, placebo-controlled trial of K+-binder Lokelma for maximisation of RAAS inhibition in CKD patients with heart failure.

BACKGROUND: CKD is common in heart failure (HF) and associated with morbidity and mortality, yet life-prolonging medications such as renin-angiotensin-aldosterone inhibitors (RAASi) are underused due to risk of hyperkalaemia. Sodium zirconium cyclosilicate (SZC) is a potassium-binding medication that has been shown to reduce incidence of hyperkalaemia in CKD, non-CKD, and HF populations, which we propose will support maximisation of RAASi therapy. METHODS: We propose a 1:1 randomised, double-blind, placebo-controlled trial in which participants will receive either SZC or placebo. We will up-titrate participants' RAASi therapy while monitoring their serum potassium levels and adjusting their SZC dose if necessary. Participants with CKD and HF will be recruited from CKD and HF clinics at St George's Hospital. The total study period will be 18 months; 130 participants will be enrolled for approximately two months each following screening. Our primary outcome will be the proportion of participants who achieve maximum RAASi dose while maintaining normokalaemia. Secondary outcomes include participants reaching maximum RAASi dose without severe hyperkalaemia; time from randomisation to hyperkalaemia; time from randomisation to severe hyperkalaemia; number of RAASi dose escalations per participant; final doses of RAASi therapy; changes in quality of life score, eGFR, ACR, serum sodium, troponin T; number and duration of hospital admissions; and within-participant change in serum potassium compared to baseline. DISCUSSION: This trial will be the first to examine the use of SZC for the maximisation of RAASi dosing in patients with advanced CKD and HF. We will assess the impact of achieving target RAASi dosing on hospital admission rates and duration of stay, with the hope that optimum RAASi treatment will translate into reduced morbidity and improved QoL. If clinical benefit is demonstrated, we hope that the joint multidisciplinary CKD-HF approach will be expanded. TRIAL REGISTRATION: EudraCT number 2020-002946-18. Registered on 08 June 2020. Online record pending.

Impact of vitamin D on cardiac structure and function in chronic kidney disease patients with hypovitaminosis D: a randomized controlled trial and meta-analysis.

AIMS: Vitamin D deficiency is associated with cardiovascular events in chronic kidney disease (CKD) yet the impact of supplementation is controversial. Previous active vitamin D supplementation studies did not show improvement in cardiac structure or function but the effect of native vitamin D supplementation in CKD patients with low vitamin D levels is unknown. We have addressed this question via both a randomized double-blind prospective study and a meta-analysis of three randomized placebo-controlled studies. METHODS AND RESULTS: We conducted a randomized double-blind, placebo-controlled trial of vitamin D supplementation in stable, non-diabetic, CKD three to four patients with circulating vitamin D <75nmol/L, who were receiving treatment with ACEi or ARB and had high-normal left ventricular (LV) mass. Patients were randomized to receive six directly observed doses of 100 000 IU cholecalciferol (n = 25) or matched placebo (n = 23). The primary endpoint was changed in LV mass index (LVMI) over 52 weeks, as assessed by cardiac magnetic resonance imaging. Secondary endpoints included changes in LV ejection fraction (LVEF); LV and right ventricular volumes and left and right atrial area. Vitamin D concentration increased with the administration of cholecalciferol. The change in LVMI with cholecalciferol [median (inter-quartile range), -0.25 g (-7.20 to 5.30)] was no different from placebo [-4.30 g (9.70 to 2.60)]. There was no difference in changes of LVEF; LV and right ventricular volumes and left and right atrial area. The meta-analysis of three 52-week, randomized placebo-controlled studies using active/native vitamin D supplementation showed no differences in LVMI measurements. CONCLUSION: Vitamin D supplementation does not have beneficial effects on LV mass in CKD patients.

Systematic Review and Meta-analysis of COVID-19 and Kidney Transplant Recipients, the South West London Kidney Transplant Network Experience.

INTRODUCTION: There is paucity of literature comparing outcomes of kidney transplant patients with COVID-19 to that of dialysis and waitlisted patients. This report describes our data, provides comparative analysis, together with a meta-analysis of published studies, and describes our protocols to restart the transplant program. METHODS: Data were analyzed on kidney transplant, dialysis, and waitlisted patients tested positive for SARS-CoV-2 (nasopharyngeal swab polymerase chain reaction [PCR] test) between March 1, 2020, and June 30, 2020, together with a meta-analysis of 16 studies. RESULTS: Twenty-three of 1494 kidney transplant patients tested positive for SARS-CoV-2 compared with 123 of 1278 hemodialysis patients (1.5% vs. 9.6%, P < 0.001) and 12 of 253 waitlisted patients (1.5% vs. 4.7%, P = 0.002). Nineteen patients required hospital admission, of whom 6 died and 13 developed AKI. The overall case fatality ratio was 26.1% compared with patients on hemodialysis (27.6%, P = 0.99) and waitlisted patients (8.3%, P = 0.38). Within our entire cohort, 0.4% of transplant patients died compared with 0.4% of waitlisted patients and 2.7% of hemodialysis patients. Patients who died were older (alive [median age 71 years] vs. dead [median age 59 years], P = 0.01).In a meta-analysis of 16 studies, including ours, the pooled case fatality ratio was 24% (95% confidence interval [CI] 19%, 28%); AKI proportion in 10 studies was 50% (95% CI 45%, 56%), with some evidence against no heterogeneity between studies (P = 0.02). CONCLUSIONS: From our cohort of transplant patients, a significantly lower proportion of patients contracted COVID-19 compared with waitlisted and dialysis patients. The case fatality ratio was comparable to that of the dialysis cohort and to a pooled case fatality ratio from a meta-analysis of 16 studies. The pooled AKI ratio in the meta-analysis was similar to our results.

Derepression of glomerular filtration, renal blood flow and antioxidant defence in patients with type 2 diabetes at high-risk of cardiorenal disease.

BACKGROUND: The role of antioxidant status on microvascular blood flow and glomerular filtration (eGFR) in patients with type 2 diabetes and hypertension whose risk of progressive renal disease varies by ethnicity is unknown. METHODS: Adult, non-Caucasian (n = 101) and Caucasian (n = 69) patients with type 2 diabetes, hypertension and/or microalbuminuria and an eGFR > 45 mL/min/1.73 m2 were randomised to receive 400 IU vitamin E and/or 20 µg selenium daily or matching placebo. eGFR (CKD-EPI) was measured at baseline, 3,6 and 12 months and renal blood flow by contrast-enhanced ultrasonography in a sub-group (n = 9) at baseline and 3 months by assessing the area under the time intensity curve (TIC). Circulating glutathione peroxidase 3 (GPx-3) activity was measured as a biomarker of oxidative defence status. RESULTS: The time to change in eGFR was shortest with combined vitamin E and selenium than usual care (5.6 [4.0-7.0] vs 8.9 [6.8-10.9 months]; p = 0.006). Area under the TIC was reduced compared to baseline (38.52 [22.41-90.49] vs 123 [86.98-367.03]dB.s; P ≤ 0.05 and 347 [175.88-654.92] vs 928.03 [448.45-1683]dB.s; P ≤ 0.05, respectively] at 3 months suggesting an increase in rate of perfusion. The proportional change in eGFR at 12 months was greater in the group whose GPx-3 activity was above, compared with those below the cohort median (360 U/L) in the non-Caucasian and the Caucasian groups (19.1(12.5-25.7] % vs 6.5[-3.5 to 16.5] % and 12.8 [0.7 to 24] % vs 0.2 [-6.1 to 6.5] %). CONCLUSION: In these patients with type 2 diabetes and early CKD, antioxidant treatment derepresses renal blood flow and a rise in eGFR correlated directly with GPx-3 activity. SIGNIFICANCE: Diabetes mellitus is the world's leading cause of end-stage renal disease which has a predilection for black and minor ethnic groups compared with Caucasians. The differences in risk despite the benefits of conventional care may be related to oxidative stress. We found that glomerular filtration and renal blood flow is suppressed when renal function is preserved in high-risk patients with type 2 diabetes. Conventional care supplemented with selenium - the co-factor for glutathione peroxidase-3 (GPx-3) - improves renal perfusion and increase glomerular filtration according to host antioxidant defence determined by GPx-3 activity. Circulating GPx-3 activity warrants further investigation as a novel biomarker of reversible haemodynamic changes in early diabetic kidney disease to better enable targeting of renoprotective strategies.

Management and outcomes of heart failure patients with CKD: experience from an inter-disciplinary clinic.

AIMS: CKD-HF patients suffer excess hospitalization and mortality, often under-treated with life-prolonging medications due to fear of worsening renal function and hyperkalaemia. Yet, role of inter-disciplinary working in improving therapy is unknown, which this study aims to investigate. METHODS AND RESULTS: Clinical, biochemical data, and medications at first and last clinic visit were obtained from patient records for 124 patients seen in kidney failure-heart failure clinic (23 March 2017 to 11 April 2019). Medication dose groups (none, low, and high dose), number of RAASi agents, and blood test results were compared between first and last visit in patients with at least two clinic visits (n = 97). Patient characteristics were age 78.5 years (IQR 68.1-84.4 years), male 67.7%, diabetes 51.6%, moderate (45.2%) vs. severe (39.5%) CKD, HF with reduced ejection fraction (HFrEF) (49.2%), follow-up 234 days (IQR 121-441 days). HFrEF was associated with increased risk of death (adjusted OR 4.49, 95% CI 1.43-14.05; P = 0.01). Distributions of patients according to number of RAASi agents they were on differed between first and last visit (P = 0.03). Dosage was increased in 25.9% for beta-blockers, 33.0% for ACEi/ARBs, and 17.5% for MRAs. Distributions of patients across MRA dosage groups was different (P = 0.03), with higher proportions on higher dosages at last visit, without significant changes in serum potassium or creatinine. Serum ferritin improved (131.0 vs. 267.5 µg/L; P < 0.001), and fewer patients had iron deficiency (56.7% vs. 26.8%; P = 0.002) at last visit compared to the first. CONCLUSIONS: This inter-disciplinary clinic improved guideline-recommended medication prescription, MRA dosages in CKD-HF patients without significant biochemical abnormality, and iron status. A prospectively designed study with medication titration protocol and defined patient-centred outcomes is needed to further assess effectiveness of such clinic.

Morphometric characterization of collagen and fat in normal ventricular myocardium.

OBJECTIVE: We used automated image analysis software to determine the proportion of collagen, fat, and myocytes across six histological regions of normal ventricular myocardium. METHODS: Twenty-nine non-cardiac death cases referred to our national cardiac pathology center were included in this study. Whole hearts were macroscopically and microscopically normal following expert histopathological evaluation. Tissue sections from the right ventricular outflow tract, right ventricle (RV), anterior interventricular septum (IVS), posterior IVS, anterior left ventricle (LV), and posterior LV were stained with Picrosirius red for collagen and scanned using a high-resolution slide scanner. Quantification of collagen, fat, and myocyte proportions was performed using Visiopharm software after automated exclusion of perivascular collagen. RESULTS: The majority of decedents were male (25/29; 86%) with a mean age at death of 32.1 ± 9.9 (range 18-54) and mean BMI 28.7 ± 7.3. We report predicted values (collagen %, fat %, myocytes %) for cardiac tissue composition within the RV, IVS, and LV (including epicardial and endocardial layers). The proportion of collagen and fat were higher in the RV compared with the LV (ratios 1.61 [1.45-1.78]; 2.63 [1.99-3.48], respectively) and RV compared with the IVS (ratios 1.77 [1.60-1.97]; 8.41[6.35-11.13], respectively). The ratio of epicardial versus endocardial fat was increased in both ventricles (RV: ratio 4.49 [3.67-5.49]; LV: ratio 3.46 [2.49-4.81]). In multivariable analysis, there was no significant association between collagen or fat proportion and sex (p=0.12; p=0.08, respectively), age at death (p=0.36; p=0.23, respectively), or BMI (p=0.45; p=0.43, respectively). CONCLUSIONS: Our findings provide location and sex-specific proportions of myocardial histological tissue composition that may aid quantitative evaluation of pathology in future studies.

COVID-19 infection in kidney transplant recipients.

By 21 March 2020 infections related to the novel coronavirus SARS-CoV-2 had affected people from 177 countries and caused 11,252 reported deaths worldwide. Little is known about risk, presentation and outcomes of SARS-CoV-2 (COVID-19) infection in kidney transplantation recipients, who may be at high-risk due to long-term immunosuppression, comorbidity and residual chronic kidney disease. Whilst COVID-19 is predominantly a respiratory disease, in severe cases it can cause kidney and multi-organ failure. It is unknown if immunocompromised hosts are at higher risk of more severe systemic disease. Therefore, we report on seven cases of COVID-19 in kidney transplant recipients (median age 54 (range 45-69), three females, from a cohort of 2082 managed transplant follow-up patients) over a six-week period in three south London hospitals. Two of seven patients presented within three months of transplantation. Overall, two were managed on an out-patient basis, but the remaining five required hospital admission, four in intensive care units. All patients displayed respiratory symptoms and fever. Other common clinical features included hypoxia, chest crepitation, lymphopenia and high C-reactive protein. Very high D dimer, ferritin and troponin levels occurred in severe cases and likely prognostic. Immunosuppression was modified in six of seven patients. Three patients with severe disease were diabetic. During a three week follow up one patient recovered, and one patient died. Thus, our findings suggest COVID-19 infection in kidney transplant patients may be severe, requiring intensive care admission. The symptoms are predominantly respiratory and associated with fever. Most patients had their immunosuppression reduced and were treated with supportive therapy.

Recreational marathon running does not cause exercise-induced left ventricular hypertrabeculation.

BACKGROUND: Marathon running in novices represents a natural experiment of short-term cardiovascular remodeling in response to running training. We examine whether this stimulus can produce exercise-induced left ventricular (LV) trabeculation. METHODS: Sixty-eight novice marathon runners aged 29.5 ± 3.2 years had indices of LV trabeculation measured by echocardiography and cardiac magnetic resonance imaging 6 months before and 2 weeks after the 2016 London Marathon race, in a prospective longitudinal study. RESULTS: After 17 weeks unsupervised marathon training, indices of LV trabeculation were essentially unchanged. Despite satisfactory inter-observer agreement in most methods of trabeculation measurement, criteria defining abnormally hypertrabeculated cases were discordant with each other. LV hypertrabeculation was a frequent finding in young, healthy individuals with no subject demonstrating clear evidence of a cardiomyopathy. CONCLUSION: Training for a first marathon does not induce LV trabeculation. It remains unclear whether prolonged, high-dose exercise can create de novo trabeculation or expose concealed trabeculation. Applying cut off values from published LV noncompaction cardiomyopathy criteria to young, healthy individuals risks over-diagnosis.

High on-clopidogrel platelet reactivity in ischaemic stroke or transient ischaemic attack: Systematic review and meta-analysis.

OBJECTIVES: To assess the prevalence of high on-clopidogrel platelet reactivity (HCPR) in patients with ischaemic stroke or transient ischaemic attack (IS/TIA), their outcome and genetic basis of on-treatment response variability in IS/TIA patients. METHODS: We conducted a comprehensive search of PubMed and EMBASE from their inceptions to March 9, 2019. Studies that reported absolute numbers/percentages of HCRP at any time point after IS/TIA onset evaluated with any type of platelet function tests, clinical outcomes and genotyping data were included. RESULTS: Among 21 studies of 4312 IS/TIA patients treated with clopidogrel, the pooled prevalence of HCPR was 28% (95%CI: 24-32%; high heterogeneity: I2 = 88.2%, p < 0.001). Heterogeneity degree diminished across groups defined by the HCPR testing method. Clopidogrel non-responder IS/TIA patients had poorer outcome compared to responders (RR = 2.09, 95%CI: 1.61-2.70; p = 0.036; low heterogeneity across studies: I2 = 27.4%, p = 0.210). IS/TIA carriers of CYP2C19*2 or CYP2C19*3 loss of function alleles had a higher risk of HCPR compared to wild type (RR = 1.69, 95%CI: 1.47-1.95; p < 0.001; I2 = 0.01%, p = 0.475). CONCLUSIONS: This systematic review shows a high prevalence of clopidogrel resistance in IS/TIA and poor outcome in these patients. CYP2C19 polymorphisms may potentially influence clopidogrel resistance.

Sudden Death and Left Ventricular Involvement in Arrhythmogenic Cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is an inherited heart muscle disorder characterized by myocardial fibrofatty replacement and an increased risk of sudden cardiac death (SCD). Originally described as a right ventricular disease, ACM is increasingly recognized as a biventricular entity. We evaluated pathological, genetic, and clinical associations in a large SCD cohort. METHODS: We investigated 5205 consecutive cases of SCD referred to a national cardiac pathology center between 1994 and 2018. Hearts and tissue blocks were examined by expert cardiac pathologists. After comprehensive histological evaluation, 202 cases (4%) were diagnosed with ACM. Of these, 15 (7%) were diagnosed antemortem with dilated cardiomyopathy (n=8) or ACM (n=7). Previous symptoms, medical history, circumstances of death, and participation in competitive sport were recorded. Postmortem genetic testing was undertaken in 24 of 202 (12%). Rare genetic variants were classified according to American College of Medical Genetics and Genomics criteria. RESULTS: Of 202 ACM decedents (35.4±13.2 years; 82% male), no previous cardiac symptoms were reported in 157 (78%). Forty-one decedents (41/202; 20%) had been participants in competitive sport. The adjusted odds of dying during physical exertion were higher in men than in women (odds ratio, 4.58; 95% CI, 1.54-13.68; P=0.006) and in competitive athletes in comparison with nonathletes (odds ratio, 16.62; 95% CI, 5.39-51.24; P<0.001). None of the decedents with an antemortem diagnosis of dilated cardiomyopathy fulfilled definite 2010 Task Force criteria. The macroscopic appearance of the heart was normal in 40 of 202 (20%) cases. There was left ventricular histopathologic involvement in 176 of 202 (87%). Isolated right ventricular disease was seen in 13%, isolated left ventricular disease in 17%, and biventricular involvement in 70%. Among whole hearts, the most common areas of fibrofatty infiltration were the left ventricular posterobasal (68%) and anterolateral walls (58%). Postmortem genetic testing yielded pathogenic variants in ACM-related genes in 6 of 24 (25%) decedents. CONCLUSIONS: SCD attributable to ACM affects men predominantly, most commonly occurring during exertion in athletic individuals in the absence of previous reported cardiac symptoms. Left ventricular involvement is observed in the vast majority of SCD cases diagnosed with ACM at autopsy. Current Task Force criteria may fail to diagnose biventricular ACM before death.

Inter-Rater Reliability and Downstream Financial Implications of Electrocardiography Screening in Young Athletes.

BACKGROUND: Preparticipation screening for cardiovascular disease in young athletes with electrocardiography is endorsed by the European Society of Cardiology and several major sporting organizations. One of the concerns of the ECG as a screening test in young athletes relates to the potential for variation in interpretation. We investigated the degree of variation in ECG interpretation in athletes and its financial impact among cardiologists of differing experience. METHODS AND RESULTS: Eight cardiologists (4 with experience in screening athletes) each reported 400 ECGs of consecutively screened young athletes according to the 2010 European Society of Cardiology recommendations, Seattle criteria, and refined criteria. Cohen κ coefficient was used to calculate interobserver reliability. Cardiologists proposed secondary investigations after ECG interpretation, the costs of which were based on the UK National Health Service tariffs. Inexperienced cardiologists were more likely to classify an ECG as abnormal compared with experienced cardiologists (odds ratio, 1.44; 95% confidence interval, 1.03-2.02). Modification of ECG interpretation criteria improved interobserver reliability for categorizing an ECG as abnormal from poor (2010 European Society of Cardiology recommendations; κ=0.15) to moderate (refined criteria; κ=0.41) among inexperienced cardiologists; however, interobserver reliability was moderate for all 3 criteria among experienced cardiologists (κ=0.40-0.53). Inexperienced cardiologists were more likely to refer athletes for further evaluation compared with experienced cardiologists (odds ratio, 4.74; 95% confidence interval, 3.50-6.43) with poorer interobserver reliability (κ=0.22 versus κ=0.47). Interobserver reliability for secondary investigations after ECG interpretation ranged from poor to fair among inexperienced cardiologists (κ=0.15-0.30) and fair to moderate among experienced cardiologists (κ=0.21-0.46). The cost of cardiovascular evaluation per athlete was $175 (95% confidence interval, $142-$228) and $101 (95% confidence interval, $83-$131) for inexperienced and experienced cardiologists, respectively. CONCLUSIONS: Interpretation of the ECG in athletes and the resultant cascade of investigations are highly physician dependent even in experienced hands with important downstream financial implications, emphasizing the need for formal training and standardized diagnostic pathways.

Drug resistant TB: UK multicentre study (DRUMS): Treatment, management and outcomes in London and West Midlands 2008-2014.

OBJECTIVES: Detailed information regarding treatment practices and outcomes of MDR-TB treatment in the UK is required as a baseline for care improvements. METHODS: 100 consecutive cases between 2008 and 2014 were reviewed retrospectively at 4 MDR-TB treatment centres in England to obtain information on drug treatment choices, hospital admission duration and outcomes for MDR-TB. RESULTS: Initial hospital admission was long, median 62.5 (IQR 20-106, n = 92) days, and 13% (12/92) of patients lost their home during this period. Prolonged admission was associated with pulmonary cases, cavities on chest radiograph, a public health policy of waiting for sputum culture conversion (CC) and loss of the patient's home. Sputum CC occurred at a median of 33.5 (IQR 16-55, n = 46) days. Treatment success was high (74%, 74/100) and mortality low (1%, 1/100). A significant proportion of the cohort had "neutral" results due to deportation and transfer overseas (12%, (12/100)). 14% (14/100) had negative outcomes for which poor adherence was the main reason (62%, 9/14). CONCLUSIONS: Successful outcome is common in recognised centres and limited by adherence rather than microbiological failure. Duration of hospital admission is influenced by lack of suitable housing and some variation in public health practice. Wider access to long-term assisted living facilities could improve completion rates.

Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials.

Detecting treatment efficacy using cognitive change in trials of cerebral small vessel disease (SVD) has been challenging, making the use of surrogate markers such as magnetic resonance imaging (MRI) attractive. We determined the sensitivity of MRI to change in SVD and used this information to calculate sample size estimates for a clinical trial. Data from the prospective SCANS (St George's Cognition and Neuroimaging in Stroke) study of patients with symptomatic lacunar stroke and confluent leukoaraiosis was used (n = 121). Ninety-nine subjects returned at one or more time points. Multimodal MRI and neuropsychologic testing was performed annually over 3 years. We evaluated the change in brain volume, T2 white matter hyperintensity (WMH) volume, lacunes, and white matter damage on diffusion tensor imaging (DTI). Over 3 years, change was detectable in all MRI markers but not in cognitive measures. WMH volume and DTI parameters were most sensitive to change and therefore had the smallest sample size estimates. MRI markers, particularly WMH volume and DTI parameters, are more sensitive to SVD progression over short time periods than cognition. These markers could significantly reduce the size of trials to screen treatments for efficacy in SVD, although further validation from longitudinal and intervention studies is required.

Subclinical atherosclerosis in Behcet's disease: A systematic review and meta-analysis.

OBJECTIVE: To evaluate subclinical atherosclerosis in Behcet disease (BD), we performed a systematic review and meta-analysis of studies where atherosclerosis was determined by flow-mediated dilatation (FMD) and endothelial-mediated dilatation (EMD) and by measurement of intima media thickness (IMT) of carotid arteries. METHODS: Systematic search of EMBASE and PubMed databases from January 2000 to January 2014 according to PRISMA guidelines. RESULTS: Nine studies met the inclusion criteria on FMD/EMD, 11 on IMT and 4 on both. BD had lower FMD than controls (SMD = -0.89, 95% CI: -0.660 to -1.11, p < 0.001), which was confirmed by subgroup analyses on active and inactive patients (SMD = -1.17, 95% CI: -1.45 to -0.89 and SMD = -0.72, 95% CI: -0.97 to -0.46, p = 0.0001 for both). EMD was lower in BD but with a large estimate (SMD = 0.38, 95% CI: -0.79 to -0.03, p = 0.06, I(2) = 82.2%). IMT was greater in BD and the large estimate (SMD = 0.95, 95% CI: 0.63-1.28, p < 0.0001, I(2) = 87.6%) persisted after subgroup analysis on active and inactive patients (I(2) = 88.4% and 86.7%, respectively). Pooling IMT studies by a Newcastle Ottawa Scale of 5 and 6/7 yielded lower estimates (SMD = 0.54, 95% CI: 0.32-0.75, p < 0.0001, I(2) = 58.7% and SMD = 1.72, 95% CI: 1.35-2.09 p < 0.05, I(2) = 48.6%). CONCLUSIONS: FMD is impaired in BD even in inactive state and IMT is greater despite a degree of statistical heterogeneity that reflects the clinical heterogeneity of BD. Future prospective studies should account for risk stratification of atherosclerosis in BD.

Pharmacodynamic Analysis of a Fluid Challenge.

OBJECTIVE: This study aims to describe the pharmacodynamics of a fluid challenge over a 10-minute period in postoperative patients. DESIGN: Prospective observational study. SETTING: General and cardiothoracic ICU, tertiary hospital. PATIENTS: Twenty-six postoperative patients. INTERVENTION: Two hundred and fifty-milliliter fluid challenge performed over 5 minutes. Data were recorded over 10 minutes after the end of fluid infusion MEASUREMENTS AND MAIN RESULTS: Cardiac output was measured with a calibrated LiDCOplus (LiDCO, Cambridge, United Kingdom) and Navigator (Applied Physiology, Sydney, Australia) to obtain the Pmsf analogue (Pmsa). Pharmacodynamics outcomes were modeled using a Bayesian inferential approach and Markov chain Monte Carlo estimation methods. Parameter estimates were summarized as the means of their posterior distributions, and their uncertainty was assessed by the 95% credible intervals. Bayesian probabilities for groups' effect were also derived. The predicted maximal effect on cardiac output was observed at 1.2 minutes (95% credible interval, -0.6 to 2.8 min) in responders. The probability that the estimated area under the curve of central venous pressure was smaller in nonresponders was 0.12. (estimated difference, -4.91 mm Hg·min [95% credible interval, -13.45 to 3.3 mm Hg min]). After 10 minutes, there is no evidence of a difference between groups for any hemodynamic variable. CONCLUSIONS: The maximal change in cardiac output should be assessed 1 minute after the end of the fluid infusion. The global effect of the fluid challenge on central venous pressure is greater in nonresponders, but not the change observed 10 minutes after the fluid infusion. The effect of a fluid challenge on hemodynamics is dissipated in 10 minutes similarly in both groups.

A Randomised, Double Blind, Placebo-Controlled Pilot Study of Oral Artesunate Therapy for Colorectal Cancer.

BACKGROUND: Artesunate is an antimalarial agent with broad anti-cancer activity in in vitro and animal experiments and case reports. Artesunate has not been studied in rigorous clinical trials for anticancer effects. AIM: To determine the anticancer effect and tolerability of oral artesunate in colorectal cancer (CRC). METHODS: This was a single centre, randomised, double-blind, placebo-controlled trial. Patients planned for curative resection of biopsy confirmed single primary site CRC were randomised (n = 23) by computer-generated code supplied in opaque envelopes to receive preoperatively either 14 daily doses of oral artesunate (200 mg; n = 12) or placebo (n = 11). The primary outcome measure was the proportion of tumour cells undergoing apoptosis (significant if > 7% showed Tunel staining). Secondary immunohistochemical outcomes assessed these tumour markers: VEGF, EGFR, c-MYC, CD31, Ki67 and p53, and clinical responses. FINDINGS: 20 patients (artesunate = 9, placebo = 11) completed the trial per protocol. Randomization groups were comparable clinically and for tumour characteristics. Apoptosis in > 7% of cells was seen in 67% and 55% of patients in artesunate and placebo groups, respectively. Using Bayesian analysis, the probabilities of an artesunate treatment effect reducing Ki67 and increasing CD31 expression were 0.89 and 0.79, respectively. During a median follow up of 42 months 1 patient in the artesunate and 6 patients in the placebo group developed recurrent CRC. INTERPRETATION: Artesunate has anti-proliferative properties in CRC and is generally well tolerated.

Kielland's forceps: does it increase the risk of anal sphincter injuries? An observational study.

INTRODUCTION AND HYPOTHESIS: Rotational instrumental deliveries are thought to carry additional risks compared with non-rotational instrumental deliveries, including trauma to maternal tissues, and require specific expertise and training. We conducted a retrospective study to investigate the association between the type of forceps delivery and maternal perineal trauma, and in particular to investigate if Kielland's rotational forceps delivery increases obstetric anal sphincter injuries (OASIS). METHODS: This is a retrospective observational study of 1,515 women who attended a tertiary maternity unit over a period of 5 years and had operative vaginal deliveries primarily or completed by forceps. Data were obtained through the hospital's maternity reporting system. The severity of maternal perineal trauma, particularly third and fourth-degree tears in relation to the type of forceps delivery was explored. Multinomial logistic regression models were used to estimate the crude and the adjusted relative risks (RR) of sustaining third-degree tears compared with other types of vaginal tears. Univariate analyses explored the crude associations between relative risks and age, ethnicity, birth weight, type of instrumental delivery and operator's experience. A multivariate multinomial logistic regression model estimated the adjusted relative risks and included all the previous variables as independent covariates. RESULTS: Of the 1,492 women included in the study, 150 women (77 %) had sustained category 1 tears, 63 women (4 %) had sustained category 2 tears and 279 women (19 %) had sustained third-degree tears. There was no statistically significant association between the severity of maternal perineal trauma and the type of forceps delivery (failed ventouse vs Kielland's forceps RR 1.52, p = 0.159 CI 0.84-2.72, Wrigleys vs Kielland's RR 0.59, p = 0.249, CI 0.24-1.43; Andersons vs Kielland's RR 1.16, p = 0.603, CI 0.65-2.05) after adjusting for age, birth weight, BMI, ethnicity and operator experience (full list of covariates not included). CONCLUSIONS: The incidence of third- and fourth-degree tears following rotational Kielland's forceps delivery and other non-rotational forceps deliveries is comparable.