To assess the impact of a clinical decision model for febrile children at risk for serious bacterial infections (SBI) attending the emergency department (ED).Randomized controlled trial with 439 febrile children, aged 1 month-16 years, attending the pediatric ED of a Dutch university hospital during 2010-2012. Febrile children were randomly assigned to the intervention  or the control group . The clinical decision model included clinical symptoms, vital signs, and C-reactive protein and provided high/low-risks for “pneumonia” and “other SBI”. Nurses were guided by the intervention to initiate additional tests for high-risk children. The clinical decision model was evaluated by 1) area-under-the-receiver-operating-characteristic-curve (AUC) to indicate discriminative ability and 2) feasibility, to measure nurses’ compliance to model recommendations. Primary patient outcome was defined as correct SBI diagnoses. Secondary process outcomes were defined as length of stay; diagnostic tests; antibiotic treatment; hospital admission; revisits and medical costs.The decision model had good discriminative ability for both pneumonia ) and other SBI ). Compliance to model recommendations was high (86%). No differences in correct SBI determination were observed. Application of the clinical decision model resulted in less full-blood-counts  and more urine-dipstick testing .In contrast to our expectations no substantial impact on patient outcome was perceived. The clinical decision model preserved, however, good discriminatory ability to detect SBI, achieved good compliance among nurses and resulted in a more standardized diagnostic approach towards febrile children, with less full blood-counts and more rightfully urine-dipstick testing.NTR2381Nederlands Trial Register  Fever is one of the most common symptom among children presenting to the emergency department (ED) –3 and acIn this study we aimed to evaluate the impact of a previously developed clinical decision model for febrile children in the daily practice of the ED. This model includes clinical signs, symptoms and the biomarker C- reactive protein (CRP).  Results We conducted a randomized controlled trial of a clinical decision model at the emergency department (ED) of the Erasmus MC-Sophia Children’s Hospital in Rotterdam, The Netherlands. The protocol and CONSORT statement are available as supporting information; see We prospectively enrolled all consecutive pediatric patients (≥1 month—<16 years) presenting with fever at our ED from the first of September 2010 until June 30, 2012. Febrile children were eligible if fever had been noted at home in the 24 hours prior to presentation, when body temperature measured at the ED was ≥38.5°C or fever was used as a positive discriminator of the Manchester Triage System (MTS). From theThe intervention consisted of the implementation of the clinical decision model, based on a polytomous logistic regression model of 2,717 febrile children who presented to the ED and included eleven predictors of pneumonia and other SBI versus no SBI 10]. Ins. Ins10].All children who attended the ED were routinely triaged with the Manchester Triage System (MTS)., 28, 29 Ethics was obtained by the institutional review board (IRB) of the ErasmusMC. According to IRB-review the intervention contained no additional risks as patients were not subjected to additional operations and no rules of conduct were imposed. Written informed consent was required by IRB and it was obtained from all caretakers, or guardians on behalf of the children enrolled (MEC-2008-071).Evaluation of the clinical decision model included diagnostic performance and feasibility of the model. Primary outcome measures were correct diagnoses (SBI) and their related false positive/negative diagnoses by using the clinical decision model in routine practice. Secondly, we measured process outcomes including length of stay (LOS) at the ED and items on diagnostics, treatment and follow-up as defined below.Previous research in the same setting showed that approximately 50% of febrile children at the ED were submitted to diagnostic procedures . To detecWe first assessed the performance of the clinical prediction model for our trial population by evaluating discriminative ability according to the area-under-the-receiver-operating-characteristic-curve (AUC) and calibration. PredicteSBI were defined according to a reference standard and included abnormal radiographic findings and positive cultures from otherwise sterile body sites  or excluded by uneventful follow-up by telephone three days after ED discharge. A consensus diagnosis was made if the reference standard was inconclusive . 35] All All35] At test analysis, P-values were two-tailed. All analyses were performed with SPSS PASW statistics software  and R statistical packages .[The impact of the decision model was analysed by intention to treat. We evaluated the impact of the clinical decision model by measuring correct diagnoses (SBI) and their related false positive/negative diagnoses,as our primary patient outcome, indicating effects of using the intervention strategy irrespective of overruling or non-compliance by the physician versus the usual care strategy. Primary patient outcomes of the decision model in intervention and usual care were compared using Chi-square analysis. We defined false positives as children without SBI incorrectly exposed to diagnostic tests and false negatives as children with SBI incorrectly refrained from diagnostic tests. We presented sensitivity (children with pneumonia/UTI and performance of chest-radiography/urine-culture), specificity (children without pneumonia/UTI and no performance of chest-radiography/urine-culture) and their related positive/negative likelihood ratios of the complete model. In the control group exposure to testing was based on judgment of the physician only; in the intervention group this was based on the recommendation of the clinical decision model and physicians’ judgment. LOS at the ED was based on the triage starting time and ED departure time as registered in the nursing record; Diagnostic procedures included chest-radiography, urine-dipstick, full blood-count and cultures . Treatment/follow-up included antibiotic prescriptions, hospitalization and revisits. Comparisons of process outcomes were tested with Chi-square or Student’s Austria).Out of 1,769 eligible febrile children 836 children were excluded because of chronic co-morbidity, emergent triage category, uncomplicated rhinitis/otitis or revisits within 7 days, resulting in 933 eligible children. 439 evaluable children were included for analysis  with a mThe discriminative ability of the clinical decision model was 0.83 (95% CI 0.75–0.90) for pneumonia and 0.81 (95% CI 0.72–0.90) for other SBI. The clinical prediction model had good calibration in the study population, except for the upper quintiles due to the limited number of cases with pneumonia or other SBI . We alsoIn 60% (25/42) of all children allocated to the intervention group chest-radiography was done but no pneumonia was diagnosed  . In the This impact analysis showed good compliance to the decision model recommendations and its good discriminative ability for detecting SBI was confirmed in febrile children presenting to the ED. Unfortunately, we could not demonstrate improved assessment of correct diagnoses by the intervention. Application of the clinical decision model resulted in a more standardized diagnostic approach towards the febrile child, with significantly less full blood-counts and more rightfully performed urine-dipstick testing in the intervention group.This randomized controlled impact trial provides the methodological step after external validation of a developed decision model with good discriminative ability for predicting the presence of pneumonia and other SBI. As an esFrom a literature review it is known that only a minority of new developed clinical prediction models underwent broad validation and no model had undergone impact analysis. The resuAlthough our study reports good compliance to and high accuracy of the clinical decision model, positive impact on routine care was lacking. A number of reasons have been described that explain why an accurate clinical prediction model may not result in improved patient care and processes.–42 One iOne major influence explaining the lack of impact on LOS was probably the availability of CRP bedside-testing in both study groups. Previous research showed that CRP bedside-guided decision making reduced the LOS at the pediatric ED by 19% (median LOS 148 minutes). The ratiCompliance to the recommendations of the clinical decision model was good. However, we did not include 379 children for unknown reasons, which may suggest some feasibility problems of the decision model itself, but also reflects the difficulties of performing a randomized controlled trial (with the need of informed consent) in emergency care. As we did not observe significant differences on median age (1.9 (IQR 2.0–3.0) vs. 1.8 (IQR 2.0–3.0)), gender  and prevalence of SBI (14.2% vs. 12.5%), when we compared non-included with included patients, we feel that this most likely did not affect generalizability of our results. Another measure of feasibility could be whether the model variables were completed directly after the patient’s triage. This was not the case for all patients, as some were seen by a physician directly during the triage process of the nurse. In more The main strength of this study is its randomized design to evaluate the last step required for translating prediction research into clinical practice. Second, as we modelled children’s age in a linear piecewise manner, we accouOur study has some limitations. First, reference tests were ordered based on the recommendations of the clinical decision model or at the physician’s discretion. However, to reduce verification bias we used a standardized follow-up period to ensure no clinically relevant SBI were missed in children who did not have chest-radiography or specimens bacterial culture., 49 In aFinally, our clinical decision model advised on performing chest-radiographies which is in contrast with recent advice of the British Thoracic Society  on limitThis impact analysis translates a validated clinical prediction model for febrile children into clinical practice. Although we observed well implementation, no substantial impact on patient outcome was perceived. Further evaluation may focus on impact in other settings with greater variability in experience in the assessment of the febrile child, in patient numbers, and in prevalence of outcome measures, or may include guidance on therapeutic management.S1 File(DOC)Click here for additional data file.S2 File(DOC)Click here for additional data file.S3 File(DOC)Click here for additional data file.


Based on the facts that chiral molecules response differently to left- and right-handed circular polarized light, chiroptical effects are widely employed for determining structure chirality, detecting enantiomeric excess, or controlling chemical reactions of molecules. Compared to those in natural materials, chiroptical behaviors can be significantly amplified in chiral plasmonic metamaterials due to the concentrated local fields in the structure. The on-going research towards giant chiroptical effects in metamaterial generally focus on optimizing the field-enhancement effects. However, the observed chiroptical effects in metamaterials rely on more complicated factors and various possibilities towards giant chiroptical effects remains unexplored. Here we study the optical-active second harmonic generation (SHG) behaviors in a pair of planar sawtooth gratings with mirror-imaged patterns. Significant multipolar effects were observed in the polarization-dependent SHG curves. We show that the chirality of the nanostructure not only give rise to nonzero chiral susceptibility tensor components within the electric-dipole approximation, but also lead to different levels of multipolar interactions for the two orthogonal circular polarizations that further enhance the nonlinear optical activity of the material. Our results thus indicate novel ways to optimize nonlinear plasmonic structures and achieve giant chiroptical response via multipolar interactions. Chirality is a basic characteristic of living matters. It has been widely studied in the field of biochemistry, biology, catalysis and pharmacology. Chiral object refers to a form lack of any planes of mirror symmetry and occurs as either left- or right-handed enantiomers. Characterization techniques to probe chirality are usually based on the facts that chiral molecules response differently to left- and right-handed circularly-polarized (LCP and RCP) light. Given many organic molecules are chiral and their handedness plays an important role in chemical reactions, chiroptical effects, such as optical rotation (OR) and circular dichroism (CD), have been serving as a spectroscopic tool for determining structural chirality, enantiomeric excess, or controlling the biological functions of complex molecules.Though optical-activity effects tend to be rather weak in all natural materials, it has been demonstrated that giant chiroptical effects can be achieved in chiral plasmonic metamaterials23416Giant chiroptical responses have been observed experimentally in chiral metamaterials built with various three-dimensional (3D)8910121314151617181920In this work, we employ planar sawtooth grating and its 2D mirror enantiomer to study the CD-SHG efficiency in chiral nanostructures. Large CD signals and asymmetric transmission have been observed in the visible range in our previous work2 in size and shifted with half lattice spacing horizontally (in the x-direction) between neighboring rows. The width of the sawtooth is ~110 nm. We define the N-type and mirror-N type sample by the patterns viewed from the air/grating side of the air/grating/substrate structures . 7To analyze the multipole effect, the nonlinear response tensor (NRT) approach2432ijk refer to the Cartesian coordinates in the laboratory frame. The coefficients Aijk are linear combinations of the macroscopic nonlinear susceptibility tensor components taking into account electric-dipole only interactions zzz, zxx, zyy, zxy = zyx, xxz = xzx, z is the surface normal. The first 5 terms of electric or/and magnetic interactions do not contribute to the far-field SHG signal since the polarization of the resulting second-harmonics directed along the direction of the wave vector of light and cannot propagate in the forward or backward direction. Accordingly, the output radiation field at the second-harmonic can be expressed as:where where the expansion coefficients The experimental results were then normalized to unity and fitted to the NRT model of equation z-direction. Upon LCP fundamental wave on the contrary, the microscopic nonlinear dipole sources locate more symmetrically on the upper and lower metal surfaces and thus reduce the radiation of quadrupole sources along the surface normal. As a result, the far-field SHG response was lower for the LCP case although it contains “hotter” spots in the nanogap between the neighboring rows of the sawtooth chain. We suggest the retardation of the electromagnetic field across the nanostructure gave rise to the multipolar terms in the nonlinear response of the gratings, while the relative oscillation strengths and phases between different multipolar sources depended on the polarization of the driven field. It modified the coupling efficiency of the incident field to different multipolar components and also led to different second-harmonic radiation intensity in the far field. Our experiments demonstrate that the CD-SHG response in chiral nanostructure can not only be enhanced by the field concentration effects but also by the difference in level of the higher multipolar interactions evoked by the two circular polarizations. It suggests another possible direction in optimizing the plasmonic structures for giant chiroptical effects. Compared to the surface-like electric dipole interactions, a large portion of multipolar response belongs to the bulk-type effects. Enhanced multipolar contribution may be implicated in thicker films or developing 3D helical structures or multi-layered materials with twisted unit structures. But the thickness of the nanostructures should be carefully chosen to balance the increasing of bulk effects and the decreasing of field retardation effects for thicker films35x- or y-polarized EM field can drive an effective magnetic field that lead to a transverse SHG component. Hence the interactions with magnetic dipolar moments are less important in our experiments.Among all these combinations, In summary, we have observed up to 60% difference in SHG from the planar sawtooth nanostructure between excitation with left- and right-handed circular-polarized fundamental wave. The CD-SHG response of the structure was enhanced significantly by multipolar interactions associated with asymmetric local field distribution and surface charge distribution. In additional to nonzero chiral optical susceptibility tensor components, the chirality of the structure also leads to different multipolar contributions to the second-order nonlinear process upon LCP or RCP illumination. Our results not only show that SHG allows an accurate determination of the chiral symmetry breaking in materials, but also suggest a way for the design of plasmonic structures with giant chiroptical response via manipulating the higher multipolar interactions through chiral symmetry.The Au-embedded sawtooth gratings were fabricated using an e-beam direct write technique as reported in our previous work2) cooled Spectrum One CCD head by an optical fiber. The SHG signal was depolarized by the optical fiber before entering the spectrometer to avoid polarization-dependent responses of the grating in our experiment. With the surface normal of the sample coincide with the wave vector of the input beam and the detecting direction of the emitted SHG signals, the experimental setup exhibits no extrinsic optical activity except the handedness of the light polarization vector7For the SHG-CD measurements, a Ti:sapphire laser at a wavelength of 820 nm, pulse width of 200 fs, repetition rate of 76 MHz, and average power of 60 ~ 80 mW was used as the pump radiation. The fundamental beam was focused on the sample using an objective lens to a spot approximately 5 μm in diameter. The wave vector of the laser beam was along the surface normal and its polarization was controlled using a linear Gran-Laser polarizer and a continuously rotating Newport achromatic zero-order quarter waveplate 10RP54-2). The QWP angles of 0, 90, 180 degree, etc correspond to linear input polarization and angles of 45 and 135 degree correspond to RCP and LCP circular input polarizations, respectively. After passing through a collecting objective lens and a band-pass filter (SCHOTT BG39), SHG signal generated from the sample was coupled to a Jobin Yvon SPEX500M spectrometer with the liquid nitrogen How to cite this article: Su, H. et al. Multipolar Effects in the Optical Active Second Harmonic Generation from Sawtooth Chiral Metamaterials. Sci. Rep.6, 22061; doi: 10.1038/srep22061 (2016).


Multimodality imaging is considered a cornerstone in the workup of catheter ablation for atrial fibrillation (AF). Advances in imaging modalities suggest a single modality approach could prove as effective as the current multimodality strategy. This could simplify the imaging workflow and potentially reduce financial and time burden upon the healthcare system.A literature review was performed to identify frequently used parameters for patient assessment prior to catheter ablation of AF. Subsequently, the role of four key non-invasive imaging modalities in performing this assessment was examined.A cost and time analysis was performed for two conventional multimodality imaging approaches and a cardiac magnetic resonance (CMR) only strategy. The cost of examination was according to the Netherlands standard care between July-2013 and December-2013.Five parameters  were identified in the workup of catheter ablation Table . Out of Comprehensive, providing all parameters required to perform a thorough assessment.Cost-efficient, saving up to €100 per patient in comparison to conventional strategies.Time efficient, acquiring all information in a single examination compared to the current (often fragmented) approach.A CMR based imaging approach for pre-procedural workup of AF ablation is:


Plants are under constant attack from pathogens and herbivorous insects. To protect and defend themselves, plants evolved a multi-layered surveillance system, known as the innate immune system. Plants sense their encounters upon perception of conserved microbial structures and damage-associated patterns using cell-surface and intracellular immune receptors. Plant lectins and proteins with one or more lectin domains represent a major part of these receptors. The whole group of plant lectins comprises an elaborate collection of proteins capable of recognizing and interacting with specific carbohydrate structures, either originating from the invading organisms or from damaged plant cell wall structures. Due to the vast diversity in protein structures, carbohydrate recognition domains and glycan binding specificities, plant lectins constitute a very diverse protein superfamily. In the last decade, new types of nucleocytoplasmic plant lectins have been identified and characterized, in particular lectins expressed inside the nucleus and the cytoplasm of plant cells often as part of a specific plant response upon exposure to different stress factors or changing environmental conditions. In this review, we provide an overview on plant lectin motifs used in the constant battle against pathogens and predators during plant defenses. In nature, plants are constantly exposed to a plethora of different pathogens including bacteria, viruses, and fungi. Whereas the interaction with some of these organisms can be beneficial, most microbial infection is harmful for the plant . In ordeMicrobial entry into the host tissue is a critical step in causing infection. Pathogens can enter plants through natural openings such as stomata, hydathodes, lateral roots, or through accidental wounds, but can also form specialized structures such as haustoria to penetrate directly into the plant surface . Many phThe first group encompasses the damage-associated molecular patterns (DAMPs) which are produced in the plant apoplast as a consequence of pathogen entry. Examples include cell wall fragments such as oligogalacturonides and cellulose fragments, cutin monomers, and peptides such as systemin, defensins, and phytosulfokines . PRRs arUpon PAMP/MAMP and DAMP perception by the PRRs, the so-called PAMP/MAMP-triggered immunity (PTI/MTI) response is activated which gives rise to downstream intracellular signaling events such as activation of mitogen-activated protein kinases, production of reactive oxygen species and transcriptional reprogramming ultimately leading to a complex output response of the plant that limits microbial growth .However, successful pathogens have elaborated a counter defense response to overcome PTI by means of expression of specific elicitors or effector proteins , and O  epitopes are bound with a higher affinity compared to high-mannose N-glycans. Based on inhibition studies, it was suggested that the EUL domain might contain two different binding sites  or of two tandemly arrayed EUL domains separated by a spacer sequence  and biotic  stresses GlcNAc], Lewis Y [Fucα1–2Galβ1–4(Fucα1–3)GlcNAc] and lactosamine  motifs  motifs . Similar) motifs . In cont) motifs . All theJacalin-related lectins (JRL). The family of jacalin-related lectins is named after jacalin, a 18 kDa T-antigen disaccharide-binding lectin domain first isolated from the seeds of jackfruit (Artocarpus integrifolia). Based on differences in molecular structure, subcellular localization, and carbohydrate binding properties, the large group of jacalins can be subdivided into two subgroups, further referred to as the galactose binding and mannose binding JRLs, residing in the vacuolar and nucleocytoplasmic compartment of the plant cell, respectively.A. thaliana, sequences composed of one or two jacalin domains C-terminally linked to five in tandem arranged Kelch domains are present. In addition, multiple Arabidopsis genes encode a putative F-box protein with a C-terminal jacalin domain , an AIG1 (avrRpt2-induced gene) domain (identified in Arabidopsis) or a kinase domain  or a Nictaba domain C-terminally fused to an N-terminal TIR (toll/interleukin-1 receptor) domain  tobacco lines demonstrated the entomotoxic activity of Nictaba. It was suggested that the entomotoxic effect of Nictaba is caused by interaction of the lectin with glycoconjugates present in the digestive tract of the insect , 2011. Wed genes .A. thaliana, PP2-A1, show high binding affinity for chitin oligomers (GlcNAc3-6). Similar to Nictaba, PP2-A1 also binds with the Man3GlcNAc2 core of high-mannose N-glycans  and poly-LacNAc structures as well as with Lewis A GlcNAc), Lewis X GlcNAc), Lewis Y GlcNAc), and type-1 B motifs Galβ1–3GlcNAc. Since these glycan structures have been reported in bacteria, viruses, and animals rather than in plants the physiological importance of this glycan interaction remains enigmatic  seeds, which was the very first lectin discovered in plants by Peter Hermann Stillmark in 1888. Ricin is a chimeric protein consisting of an A chain with enzymatic activity linked through a disulfide bridge with a B chain with lectin activity. This B chain consists of a duplicated ricin-B domain, responsible for the carbohydrate binding activity of the protein toward galactosylated structures. The enzymatic activity of ricin involves RNA N-glycosidase activity and is responsible for the removal of a highly conserved adenine residue from the sarcin/ricin loop of the 28S ribosomal RNA. As a result, the ribosomes are no longer able to bind elongation factor 2 and protein synthesis is blocked. Because of their catalytic activity these chimeric proteins are also referred to as type 2 ribosome-inactivating proteins (RIPs), and are considered as toxic proteins if they succeed in entering the cell. The uptake of the protein by the host cell is aided by their lectinic B-chain which can specifically interact with glycoconjugate structures on the cell surface. Except for ricin and abrin (from the jequirity bean Abrus precatorius), most type 2 RIPs are only moderately or even weakly toxic (ly toxic .R. communis (castor bean), Abrus precatorius (jequirity bean), Viscum album (mistletoe), and Sambucus nigra (elderberry). Unlike the other soluble lectins described above, most ricin-B related proteins accumulate in the plant vacuole or are secreted to the extracellular space  an extended family of ricin-B related proteins, including several chimerolectins and hololectins has been identified  linked to Gal/GalNAc. Finally, the type 2 RIP SNLRP represents a third specificity group with strong interaction with GlcNAc oligomers (Within the genus entified . Detaileligomers .S. nigra in transgenic tobacco (Samsun NN) plants enhances the tobacco plant’s resistance against infection with tobacco mosaic virus. Though the antiviral effect is clearly related to the amount of protein expressed it cannot be related to an increased expression of pathogenesis-related proteins . Ricin showed strong toxicity to several insects such as cowpea weevil , cotton boll weevil (Anthonomus grandis), house fly (Musca domestica), and larvae of the silkworm Bombyx mori , among which a large group of RLPs and RLKs some of which carry an extracellular lectin domain. Though different lectin motifs have been recognized, only the LysM domain was unambiguously shown to be dependent on carbohydrate interactions for recognition of fungal and bacterial components and subsequent signal transmission into the plant cell. Interestingly, the LysM motif shows high specificity for chito-oligosaccharides, an abundant component in different pathogens but absent from plants. Other (lectin) receptor kinases/proteins probably depend on protein–protein interactions to recognize specific ligands. Though our knowledge on receptor kinase function and signaling has greatly improved, several issues still remain with respect to the potential ligands for pathogen recognition and the downstream signaling events, especially for those receptors lacking the kinase domain.A first interaction between the pathogen and the plant occurs at the level of the cell wall and the plasma membrane where extracellular effectors, DAMPs, and P/MAMPs will be recognized by membrane-bound receptors (Table 3). Most of these inducible lectins reside in the nucleus and the cytosol of the plant cell and evidence is emerging for their role in signal transduction inside the plant cell as part of multiple plant defense pathways. Hence protein–carbohydrate interactions should not only be envisaged at the level of the interaction between the pathogen and the plant cell, but also play an important role inside the plant cell as part of the intracellular signaling resulting from the recognition of plant attackers. At least for some cytoplasmic lectins  it was shown that they are also translocated inside the plant nucleus. The Nictaba-related proteins in particular have been shown to interact with glycosylated histones, and therefore are suggested to act as chromatin remodelers, enabling altered gene expression as a result of stress signaling. Surveying the plant genome sequences also revealed that most lectin domains are part of larger proteins, consisting of one or more lectin domains linked to un-related protein domains, most often with unknown functions. Future challenges include the characterization of the ligands for these soluble lectins or lectin domains present as part of a larger protein to elucidate the biological relevance of these interactions. Large-scale experiments integrating genomics, biochemistry, cell biology, structural biology, and bioinformatics will enable to elucidate the physiological importance of the lectin motifs in protein–carbohydrate interactions in signal transduction and plant defense.In addition to the lectin motifs present at the level of the cell wall/plasma membrane, plants synthesize well-defined soluble lectins upon exposure to multiple abiotic and biotic stresses (The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Multivariate regression analyses showed an inverse association of the intake of vegetables and legumes, fruits and dried fruits, as well as vitamin C with the NAFLD prevalence (p<0.05). In conclusion, a better diet quality as characterized by a higher DQI-I and a higher consumption of vegetables, legumes and fruits was associated with a reduced likelihood of having NAFLD in Hong Kong Chinese.Dietary pattern analysis is an alternative approach to examine the association between diet and nonalcoholic fatty liver disease (NAFLD). This study examined the association of two diet-quality scores, namely Diet Quality Index-International (DQI-I) and Mediterranean Diet Score (MDS) with NAFLD prevalence. Apparently healthy Chinese adults  aged 18 years or above were recruited through a population screening between 2008 and 2010 in a cross-sectional population-based study in Hong Kong. DQI-I and MDS, as well as major food group and nutrient intakes were calculated based on dietary data from a food frequency questionnaire. NAFLD was defined as intrahepatic triglyceride content at ≥5% by proton-magnetic resonance spectroscopy. Multivariate logistic regression models were used to examine the association between each diet-quality score or dietary component and prevalent NAFLD with adjustment for potential lifestyle, metabolic and genetic factors. A total of 220 subjects (27.6%) were diagnosed with NAFLD. DQI-I but not MDS was associated with the prevalence of NAFLD. A 10-unit decrease in DQI-I was associated with 24% increase in the likelihood of having NAFLD in the age and sex adjusted model (95% CI: 1.06–1.45,  Nonalcoholic fatty liver disease (NAFLD) is the most common cause of abnormal liver biochemistry worldwide. Its prevalence is increasing in Asia –3. The wDiet may affect the development of NAFLD, and dietary alterations have been suggested as a cornerstone for the management of NAFLD . HoweverTo our knowledge, only few observational studies –29 have The present analysis was different from the findings regarding the possible link between dietary acid-base load and NAFLD of the same study population  in regar9/l, international normalized ratio above 1.3, or the presence of ascites or varices) (n = 147) were excluded . The multivariate adjusted association of DQI-I and the prevalence of NAFLD was stronger in male than in female, and in overweight or obese subjects than in normal weight subjects. Similar results were observed between the MDS and the prevalence of NAFLD, although the strength of the associations were not significant in comparison to those of the DQI-I with the NAFLD prevalence Click here for additional data file.S2 File(DOC)Click here for additional data file.


To update the Cochrane systematic review of exercise-based cardiac rehabilitation (CR) for heart failure.A systematic review and meta-analysis of randomised controlled trials was undertaken. MEDLINE, EMBASE and the Cochrane Library were searched up to January 2013. Trials with 6 or more months of follow-up were included if they assessed the effects of exercise interventions alone or as a component of comprehensive CR programme compared with no exercise control.33 trials were included with 4740 participants predominantly with a reduced ejection fraction (<40%) and New York Heart Association class II and III. Compared with controls, while there was no difference in pooled all-cause mortality between exercise CR with follow-up to 1 year (risk ratio (RR) 0.93; 95% CI 0.69 to 1.27, p=0.67), there was a trend towards a reduction in trials with follow-up beyond 1 year . Exercise CR reduced the risk of overall  and heart failure-specific hospitalisation  and resulted in a clinically important improvement in the Minnesota Living with Heart Failure questionnaire . Univariate meta-regression analysis showed that these benefits were independent of the type and dose of exercise CR, and trial duration of follow- up, quality or publication date.This updated Cochrane review shows that improvements in hospitalisation and health-related quality of life with exercise-based CR appear to be consistent across patients regardless of CR programme characteristics and may reduce mortality in the longer term. An individual participant data meta-analysis is needed to provide confirmatory evidence of the importance of patient subgroup and programme level characteristics  on outcome. People with heart failure (HF) experience marked reductions in their exercise capacity which has detrimental effects on their activities of daily living, health-related quality of life, and ultimately their hospital admission rate and mortality.6Based on evidence, including the previous 2010 Cochrane review,7The aim of this updated Cochrane review was to reassess the effectiveness of exercise-based CR on mortality, hospital admissions, morbidity and health-related quality of life of patients with HF. We also sought to explore how these effects may vary across differing modes of exercise CR delivery.We conducted and reported this systematic review in accordance with the PRISMA  statement.10The following databases were searched from January 2008 (the searching end date of the previous Cochrane reviewStudies were eligible if they were RCTs that included adult (≥18 years) patients with HFPEF or HFREF, and reported follow-up for 6 months or more postrandomisation. Trials in which participants had previously received exercise-based CR were excluded. The intervention group should receive exercise training either alone or as a component of the comprehensive CR programme . The control group must not undergo any form of exercise training but may receive active interventions  including usual medical care. Four categories of outcome were sought: (1) mortality ; (2) hospital admission or rehospitalisation ; (3) health-related quality of life assessed by a validated outcome measure ; and (4) costs and cost-effectiveness.Two reviewers  independently screened all titles and abstracts for eligibility. We obtained full-text copies of papers and contacted authors for more information when there was any uncertainty. Any disagreements about inclusion of studies were resolved by discussion.The following information categories were extracted from included studies: study design, participant characteristics, intervention group details , nature of control group, length of follow-up and outcomes. We assessed trial quality using the Cochrane risk of bias tool.2 statistic). The results from included studies were combined for each outcome to give an overall estimate of the treatment effect where appropriate. A fixed-effect model meta-analysis was used except where statistical heterogeneity was identified (I2 statistic >50%) and a random-effect model used.Data were analysed in accordance with the Cochrane Handbook for Systematic Reviews of Interventions.We explored the potential heterogeneity in the effect of exercise-based CR by two approaches: (1) within trial: subgroup analyses (supported by subgroup×treatment group interaction term), and (2) between trial: metaregression. Metaregression was used to examine the association between the effect of exercise on all-cause mortality, all-cause hospitalisation and health-related quality of life up to 12 months . Specific study level covariates included in meta-regression analyses included: dose of aerobic exercise ; type of exercise ; setting ; type of rehabilitation (exercise only or comprehensive); overall risk of bias ; single or multicentre; and publication date. Given the relatively small ratio of trials to covariates, metaregression was limited to univariate analysis and run using the STATA permute option.Our searches yielded 8746 titles. Following the review of titles and abstracts, we included 41 full papers. Eighteen of these papers were excluded resulting in 14 RCTs (23 papers) meeting the review inclusion criteria. The previous 2010 Cochrane review 2010 provided 19 RCTs (23 papers) giving an overall total of 33 included RCTs  or Borg rating of 12–18), and delivered over a duration of 15–120 weeks.The 33 trials randomised a total of 4740 patients predominantly with HFREF and NYHA class II and III see . DetaileA number of trials (particularly those published prior to 2000) failed to give sufficient details to allow complete assessment of their potential risk of bias . However552=0%, 2=34%, There was no significant difference in pooled mortality up to 12 months follow-up between exercise training and control groups  used the disease-specific Minnesota Living with Heart Failure questionnaire, the HF-ACTION trial used Kansas City Cardiomyopathy Questionnaire.et alet alThree studies reported economic data, two undertaking a formal cost effectiveness analysisThere were no significant associations in univariate metaregression for all-cause mortality, all hospitalisation and health-related quality of life with the exception of risk of bias and the setting for health-related quality of life . The meaAlthough, a number of studies reported that they had undertaken subgroup analyses, the methods used were often unclear (see e-supplementary table). Only the large HF-ACTION trial stated they performed a predefined interaction test of differences in intervention effects between subgroups. The HF-ACTION authors reported no evidence of difference in the intervention effects as assessed on either the primary outcome  or health-related quality of life  across a number of patient-defined subgroups.34There was no evidence of funnel plot asymmetry for all-cause mortality  or Minnesota Living with Heart Failure . The funnel plots for SMD health-related quality of life showed evidence of asymmetry .This systematic review shows that when compared to the no-exercise control, exercise interventions alone or as a component of comprehensive CR programme does not reduce or increase short-term (up to 12 months follow-up) all-cause mortality. We saw reductions in the risk of hospitalisation due to HF  and improvements in health-related quality of life following exercise interventions. In trials reporting the Minnesota Living with Heart Failure questionnaire, those undertaking exercise were on an average 5.8 points higher than controls. A difference of four points or larger on the Minnesota Living with Heart Failure questionnaire has been shown to represent a clinically important, meaningful difference for patients.Many trials included in this review have been conducted in the era of contemporary medical therapy for HF. For example, in the large multicentre HF-ACTION trial, 94% of patients were receiving β-blockers and angiotensin-receptor blocker or ACE inhibitors, and 45% had an implantable cardioverter defibrillator or implanted biventricular pacemaker at the time of enrolment.et alet al,et al was limited to three trials in 198 patients. Our metaregression analysis showed no difference in the magnitude of the reduction in hospitalisations and improvement in health-related quality of life with exercise training in those studies based in a hospital setting compared with those based in a home setting.The improvements in health-related quality of life with exercise training seen in this review are in accordance with the previous systematic review of van Tol The general lack of reporting of methods in the included RCT reports made it difficult to assess their methodological quality and thereby, judge their risk of bias. There appeared to be improvement in the quality of reporting in recent trials. Funnel plot asymmetry for health-related quality of life outcomes indicated evidence of small study bias and therefore, possible publication bias. Future trials need to also provide fuller details of the interventions and controls in accordance with Consolidated Standards of Reporting Trials (CONSORT) extension for trials assessing non-pharmacological treatments.64In conclusion, this updated Cochrane review shows that improvements in hospitalisation and health-related quality of life with exercise-based CR appear to be consistent across both patients with HF regardless of type of CR programme and may reduce mortality in the longer term. Individual participant data meta-analysis is needed to provide confirmatory evidence of the importance of patient subgroup and exercise programme characteristics on outcomes.In addition to improving the quality of reporting, future clinical trials of exercise-based interventions in HF need to consider the generalisability of trial populations  and interventions to enhance the long-term maintenance of exercise-based CR programmes, as well as the outcomes, costs and cost-effectiveness of programmes delivered exclusively in a home-based setting.


There is an evidence gap about how to best treat patients with prior coronary artery bypass grafts (CABGs) presenting with non-ST segment elevation acute coronary syndromes (NSTE-ACS) because historically, these patients were excluded from pivotal randomised trials. We aim to undertake a pilot trial of routine non-invasive management versus routine invasive management in patients with NSTE-ACS with prior CABG and optimal medical therapy during routine clinical care. Our trial is a proof-of-concept study for feasibility, safety, potential efficacy and health economic modelling. We hypothesise that a routine invasive approach in patients with NSTE-ACS with prior CABG is not superior to a non-invasive approach with optimal medical therapy.60 patients will be enrolled in a randomised clinical trial in 4 hospitals. A screening log will be prospectively completed. Patients not randomised due to lack of eligibility criteria and/or patient or physician preference and who give consent will be included in a registry. We will gather information about screening, enrolment, eligibility, randomisation, patient characteristics and adverse events (including post-discharge). The primary efficacy outcome is the composite of all-cause mortality, rehospitalisation for refractory ischaemia/angina, myocardial infarction and hospitalisation for heart failure. The primary safety outcome is the composite of bleeding, stroke, procedure-related myocardial infarction and worsening renal function. Health status will be assessed using EuroQol 5 Dimensions (EQ-5D) assessed at baseline and 6 monthly intervals, for at least 18 months.NCT01895751 . Patients with a prior coronary artery bypass graft (CABG) were excluded from some of the key clinical trials of routine invasive management versus conservative management. There is an evidence gap on the safety and efficacy of invasive management in these patients.We will obtain ‘proof-of-concept’ information on feasibility, safety and potential efficacy of a non-invasive approach including optimal medical therapy compared with a routine invasive approach in patients with an acute non-ST segment elevation acute coronary syndrome (NSTE-ACS) with prior CABG, including health outcomes beyond 1 year.The results of our trial will provide preliminary information on the rationale for routine non-invasive management in medically stable patients with prior CABG and a NSTE-ACS. The results of this pilot trial will inform the rationale for a substantive clinical trial that would be designed and powered to assess the effects of routine non-invasive versus routine invasive management on health and economic outcomes in this patient group. If our hypothesis proves correct, then routine non-invasive management could be initially adopted for patients except the minority with recurrent ischaemia. Results from a future substantive trial would have the potential to be implemented in routine clinical practice, with the potential to reduce variations in clinical practice, enable more efficient resource utilisation and allow patients with NSTE-ACS with prior CABG to reach critical points in the care pathway more quickly.Occlusive disease of saphenous vein coronary artery bypass grafts (CABGs) is a common occurrence within 10 years of surgery,In this article, we describe the clinical issues relating to the management of patients with a non-ST segment elevation acute coronary syndrome (NSTE-ACS). We then discuss the rationale and study design of a randomised controlled pilot trial of routine invasive management versus conservative non-invasive, and a prospective screening log and registry of patients who were not randomised.Epidemiology: CABG surgery is commonly performed worldwide based on historical evidence of benefit over medical therapy and recent evidence of prognostic benefits over percutaneous coronary intervention (PCI).7Scale of the matter: Chest pain is the commonest reason for hospital admission in the UK and more than 1 in 10–15 patients admitted to hospital with an acute NSTE-ACS have a history of prior CABG.(Lack of) clinical evidence, controversy, rationale: Pivotal clinical trials that compared routine invasive management versus conservative non-invasive management in unstable coronary syndromes, for example, Thrombolysis In Myocardial Infarction IIIb (TIMI IIIb),Clinical guidelines recommend a routine early invasive strategy in higher risk patients with NSTE-ACS.CT coronary angiography is useful for imaging graft patency; however, it has limited utility to resolve stenosis severity in chronic calcific coronary disease. Routine stress testing in patients with recent NSTE-ACS and known coronary disease is not evidence-based. Stress tests are used variably in clinical practice , according to clinician preference, patient eligibility and local availability. Stress perfusion cardiac MRI (CMR) might be diagnostically useful; however, it is impractical, since a routine strategy based on CMR would be qualified because of lack of availability , especially for patients in an urgent care pathway), patient ineligibility  or non-compliance .PCI continues to evolve through advances in technologies and technical skills. In recent years, specialist techniques have developed with ‘antegrade’ and ‘retrograde’ approaches to recannalise chronic totally occluded coronary arteries.Overall hypothesis: Considering efficacy, safety and health economics, a routine conservative (and selectively invasive) approach in patients with NSTE-ACS with prior CABG will be an acceptable alternative to the routine invasive approach, which is the current standard of care.Active efficacy hypothesis: Compared with a routine non-invasive approach, a routine invasive approach in patients with NSTE-ACS with prior CABG is associated with a lower rate of all-cause mortality, recurrent MI or HF.Active safety hypothesis: Compared with a routine invasive approach, a routine non-invasive approach in patients with NSTE-ACS with prior CABG is associated with a lower rate of adverse events related to safety during the index hospitalisation.Health economics hypothesis: Compared with a routine invasive approach, a routine non-invasive approach is cost-saving and associated with reduced resource utilisation.Pilot study objectives to inform a potential future clinical trial: To obtain information on: (1) the absolute number of patients admitted with an NSTE-ACS and a prior history of CABG; (2) number of screen failures (and the reasons); (3) enrolment rate; (4) randomisation rate; (5) reasons for failure to obtain informed consent in potentially eligible patients or failure to randomise ; (6) medical profile, including comorbidity; (7) revascularisation rates with PCI or CABG; (8) duration of index admission; (9) serious adverse events, including rehospitalisation (and the causes), and death (and the causes), as adjudicated by a Clinical Event Committee (CEC) blinded to treatment group assignment. Some pivotal clinical trials excluded patients with prior CABG, which we think qualifies the current guidelines that recommend invasive management in NSTE-ACS and prior coronary disease (including prior CABG).13Overall aim: To undertake a pilot trial of routine conservative non-invasive management versus routine invasive management in patients with NSTE-ACS with prior CABG who are treated according to standard care with optimal medical therapy (OMT) in NHS hospitals  Compared with routine non-invasive management, to assess if a routine invasive strategy is more effective in symptomatic patients with prior CABG compared with OMT; (2) compared with routine invasive management, to assess if a routine non-invasive strategy is associated with fewer major complications and hence is safer; (3) to prospectively quantify resource utilisation in the NHS with each treatment strategy, derive the difference in the quality-adjusted life years (QALYs) and hence provide preliminary health economic information.Secondary aims: To evaluate: (1) the components of the primary composite outcomes for efficacy and safety; (2) quality of life (EuroQol 5 Dimensions (EQ-5D) at baseline and six monthly intervals for a minimum of 18 months); (3) Canadian Cardiovascular Society (CCS) angina class at baseline and six monthly intervals for a minimum of 18 months; (4) repeat invasive management during follow-up; (5) freedom from coronary and/or bypass graft intervention; (6) secondary care costs; (7) the nature and extent of multimorbidity during the index hospitalisation; (8) the nature and extent of native coronary artery and graft disease, including culprit lesion characteristics; (9) a registry of the patients who were not randomised, including the reasons for not being randomised  and their clinical characteristics at enrolment and subsequent outcomes during follow-up.Elective;Non-elective unplanned (as adjudicated by the CEC).Accordingly, all invasive coronary interventional procedures will be reported:Health economics: Quality of life, direct healthcare costs, adverse events and their economic consequences over a patient's lifetime are key considerations to inform whether or not a routine conservative approach would be acceptable in patients with NSTE-ACS with prior CABG.24Value of information analyses will illustrate where additional information in a future trial will have the most value in increasing confidence in net monetary benefit. Such information will provide evidence for the optimal design of a future trial, including considerations of, but not limited to: whether it is needed, sample size, length of follow-up and relevant economic outcomes.Second, we are also uncertain on the optimal design of the future trial, including whether health economic results should be the primary objective. Pilot: We aim to prospectively gather information on the overall feasibility of conducting a clinical trial of routine non-invasive versus routine invasive management in recently hospitalised patients with an acute NSTE-ACS and prior CABG. The aim of the pilot is to mimic the main trial and assess whether or not random allocation of these treatment strategies and compliance with the protocol is feasible. Clinical research nurses will support enrolment and follow-up assessments on two of the four sites. NHS clinicians will support enrolment and follow-up assessments on all of the sites. We specifically aim to gather information on screening, recruitment, randomisation , cross-over rates and serious adverse events in patients with prior CABG and a recent NSTE-ACS to inform the feasibility and design of a future definitive clinical trial. Researchers and nurses independent of the clinical team will conduct follow-up for adverse events.Consent: All randomised and registry patients will provide written informed consent as soon as feasible after hospital admission and prior to referral for coronary angiography. Patients will be given an information sheet prior, and may opt out at any time.Setting and feasibility: The pilot study will involve 60 randomised patients recruited in two large urban hospitals  and two regional district general hospitals ). These hospitals were selected in order to reflect the diversity of secondary care in the UK NHS and different models of service provision. One of these hospitals (RBH) has an onsite cardiac catheterisation laboratory, whereas the other hospitals do not. In these hospitals, patients are triaged for invasive management by referral and transfer to the regional cardiothoracic centre ). The GJNH and RBH provide invasive care for the West of Scotland (2.5 million) and East Lancashire (0.5 million), respectively.Screening: The clinical research team on each site will screen for patients admitted during unscheduled emergency care with a suspected acute NSTE-ACS and prior CABG. Screening will take place in the acute medical and cardiology wards during the course of routine healthcare. Patients who are invited to participate should be eligible for either treatment option. Each patient will be given a corresponding site and study number, and entered into a screening log. Patients who do not provide consent will be included in the ‘screen failure’ log. Only de-identified information will be contained in the screening log including age, gender, medical history, date of admission, date of discharge, angiography (yes/no/date). The community health index (CHI) or NHS number will be recorded to enable electronic record linkage. Patients 18 years and older of both sexes, with a history of NSTE-ACS and who are eligible for either invasive management with coronary and graft angiography or non-invasive management will be invited to participate. Patients who fulfil the inclusion criteria and who do not have exclusion criteria  not controlled by medical therapy)Cardiogenic shockInability to give informed consentUnsuitable for invasive managementRandomisation: After informed consent, patients are randomised with an interactive voice recognition system from the trials unit, to one of two groups: initial medical management or initial invasive management. All patients will receive OMT with treatments prescribed at the discretion of the attending physician, and guidance on uptitration of anti-ischaemic drugs is provided in an investigator guideline. OMT includes dual antiplatelet, antithrombotic and anti-ischaemic therapies as per local protocols and international guidelines.13Non-invasive group: According to the trial protocol, study participants who have been randomised to the non-invasive group may be referred for invasive management if one of the following prespecified criteria are met: (1) recurrent or refractory (class III or IV) angina with documented ischaemic ECG changes while on ‘optimal’ anti-ischaemic therapy; (2) new ST-segment elevation in two contiguous leads without Q waves or T wave inversion greater than 3 mm or development of haemodynamic instability; or (3) a deterioration in HF status (consistent with Killip class 3 or 4) that the attending clinician judges to be ischaemia-related based on the presence of symptoms, ECG changes and cardiac biomarker elevation.Invasive group: Timed as appropriate according to local hospital protocols. Usually, invasive management is performed early  from hospital admission. Invasive management includes coronary and graft angiography and coronary and/or graft revascularisation with PCI and/or CABG, as clinically appropriate.Registry: Information will be prospectively recorded in a registry for patients with an acute NSTE-ACS and prior CABG who are not randomised. The reasons for non-participation in the randomised trial will be prospectively recorded. The reasons may be the presence of exclusion criteria, unsuitability for either invasive or non-invasive management, physician preference, patient preference, or a combination of these factors. The registry information will provide insights to reflect an ‘all-comers’ real-world population. The registry will also inform on the feasibility of a future substantive randomised trial. The baseline information and the follow-up assessments are intended to be collected in the same way for the registry and randomised trial participants. Information  in the registry patients will be obtained in the same way as the trial patients, that is, with case note review, telephone contact or a hospital visit and during the longer term by electronic record linkage.Screen failure: For screened patients who are (1) eligible but do not consent to participate in the randomised trial or registry, or (2) ineligible, then the reason(s) for not participating will be documented. No further clinical information will be recorded.Sample size calculation: The sample size in the CABG-ACS pilot trial is n=60 patients. We chose this number in order to gain reasonably representative information on the characteristics of patients with NSTE-ACS with prior CABG in contemporary practice to be enrolled in different secondary care settings in order to be representative of the diversity in UK hospitals. We included four hospitals differing in geographic location, availability of catheter laboratory facilities onsite (or not), and hospital type .The sample size was selected to enable the feasibility of randomisation, and the reasons for not being randomised were to be prospectively assessed on multiple occasions. As this pilot was an exploratory, proof-of-concept trial, a sample size calculation was not performed. The trial was designed but not powered to assess for between-group differences in the rates of the primary outcome.Outcomes: Serious adverse events during the index admission and follow-up will be evaluated from review of patient records obtained during usual care, and electronic health databases, including the CHI number and NHS number. The occurrence of all of these outcomes will be prospectively entered into an electronic clinical research form.An independent CEC is proposed to review the primary efficacy and safety end points. The CEC will review cases of interest to determine if they meet the criteria defined in this charter. Causality assessments will not be made by the CEC, nor will the committee possess governance authority. The CEC will be blinded where possible regarding all information relating to the randomisation group. The CEC will include four cardiovascular physicians who have expertise in the diagnosis and treatment of cardiovascular disorders and in the medical aspects of clinical trials. The CEC will have a Chairman and coordinator to assist with preparation of de-identified source clinical data, reports and communication with the Trials Unit. The CEC will follow a predetermined adjudication charter.Primary outcome: The primary outcome is the postrandomisation rate of major adverse events (co-primary composite outcome), including one composite outcome for efficacy and one composite outcome for safety. The comparison between the incidences of each outcome according to treatment group will assess the between-group difference in the proportion of major adverse events in patients allocated to non-invasive conservative management compared with invasive management. The trial is designed to assess the feasibility of recruiting and randomising such a population but is not powered to detect a between-group difference in clinical outcomes.Primary efficacy outcome: Defined as all-cause mortality, rehospitalisation for refractory ischaemia/angina, MI or hospitalisation for HF. The end points will be assessed during the study until the final randomised patient has completed 18 months follow-up.Primary safety outcome: Defined as bleeding (Bleeding Academic Research Consortium (BARC) types 2–4),Death: All-cause, sudden cardiac death, death due to MI, death due to HF, death due to stroke, death due to extra-axial haemorrhage, death due to cardiovascular operation, death due to other cardiovascular cause , presumed cardiovascular death (undetermined cause of death), non-cardiovascular death.38Procedure-related MI: According to the universal definition of MI. A postprocedure ECG will enable diagnosis of Q versus non-Q MI.Stroke is defined as the presence of a new focal neurological deficit thought to be vascular in origin, with signs or symptoms lasting more than 24 h; subdural haemorrhage.Major bleeding is defined according to the BARC criteria.36Worsening renal function is defined as deterioration in estimated glomerular filtration rate ≥25% of baseline during the index admission.Follow-up and timing of outcome evaluations: Follow-up  with completion of quality of life assessments (EQ-5D) will be maintained at six monthly intervals until a minimum of 18 months follow-up has been reached for the final recruited patient. Data will be held for up to 20 years to enable long-term follow-up analyses.Following randomisation, clinical assessments will involve gathering information from the standard-of-care clinical reviews  and also from clinical contacts recorded in the patients’ medical records. In West of Scotland hospitals, a single system of electronic patient records is used for all hospital attendances and correspondence with primary care.Cross-over: A cross-over between groups is defined as a change of treatment strategy from invasive to non-invasive management, or vice versa. In addition, we predefined cross-over as occurring within 30 days after randomisation.Quality of life ;CCS angina class;Hospitalisation for refractory ischaemia and/or angina: refractory ischaemia/refractory angina, defined as recurrent ischaemic symptoms lasting more than 5 min, while on OMT  with documented characteristic ECG changes indicative of ischaemia and requiring an additional intervention. An additional intervention is defined as reperfusion therapy for MI, cardiac catheterisation and insertion of intra-aortic balloon pump or revascularisation procedure (PCI or CABG surgery) within 48 h of the onset of this episode. This definition is in line with the Timing of Intervention in Acute Coronary Syndromes (TIMACS) trial;37Repeat invasive management during follow-up;Freedom from coronary and/or bypass graft intervention;Health economics: secondary care costs and procedure-related costs , hospital bed days including intensive care, high dependency unit, general medical.Estimate the cost-effectiveness of routine invasive approach versus conservative management for patients with NSTE-ACS with prior CABG;Identify where additional information in a future trial will have the most value in increasing confidence in net monetary benefit to the NHS.Secondary care and procedure-related costs , hospital bed days  will be recorded prospectively for index and subsequent hospitalisations. This information will be used to provide preliminary information on health economics.Early estimates of cost-effectiveness may exhibit a large degree of decision uncertainty. Designing a definitive trial to assess the relative clinical and economic outcomes is challenging given the paucity of evidence. Important considerations to consider are: whether it is needed, sample size, length of follow-up and relevant economic outcomes. Preliminary economic modelling and value of information methods can help identify where additional information in a future trial will have the most value.39The economic evaluation will be a cost-utility analysis will full incremental analysis.The analysis will be conducted from the perspective of the NHS and Personal Social Services (PSS). Differences in major adverse cardiac events may result in lifetime differences in cost and health effects. Thus, the analysis will use a lifetime time horizon. A 3.5% discount rate will be used for both health and cost effects.Value of information methods used to identify which outcomes affect the probability of cost-effectiveness and likelihood of NHS adoption under commonly used decision thresholds (£20 000–£30 000/QALY).Statistics: The Robertson Centre for Biostatistics will act as an independent coordinating centre for data management and conduct statistical analyses. The Centre is registered with a Clinical Trials Unit  Registration number: 16). Summary statistics will be performed with data from the pilot study and registry. The proportions of patients with adverse events will be assessed with a χ2 test. Summary analyses will be performed on the screening log data.2 tests (or Fisher’s exact tests) as appropriate.Baseline characteristics of the randomised participants (split by randomised group) and for the registry participants will be summarised using mean (SD for continuous measurement), or median  and count per cent for categorical variables. Baseline characteristics for randomised participants and registry participants will be compared using t tests, Mann-Whitney tests and χNumbers of events and numbers (%) of patients with events will be summarised. Time to first event of each type will be analysed using Cox proportional hazards regression models, with estimated hazard ratios, 95% CIs and p values using the Wald statistic. Time to event curves will be created using the Kaplan-Meier method.Numbers of events and numbers (%) of patients with events will be summarised. Relative frequency of event types will be compared using Fisher’s exact tests and ORs and 95% CIs for treatment effects estimated using exact logistic regression.Changes in quality of life over time will be analysed at each time point using analysis of covariance adjusting for baseline and using repeated measures analysis of postintervention data adjusting for baseline. The prespecified health outcomes will be analysed at each time point using ordinal logistic regression adjusted for baseline.All serious adverse events will be summarised according to system organ class and preferred term.The research study was reviewed and approved by the National Research Ethics Service (Reference 11-WS-0116).Potential benefits to participants include avoidance of harmful invasive management and avoidance of longer term stent failure. No additional interventions are proposed nor are procedures withdrawn that would be needed on clinical grounds. While the intention-to-treat in each group is either with non-invasive or invasive management, all treatment options remain available according to patient and physician preference, that is, patients initially randomised to medical therapy may undergo invasive management and vice versa.Data management and biostatistics: For confidentiality, patients shall be assigned an identification code at the time of recruitment.trial management group including the researchers and Local Principal Investigator on each of the four sites coordinated the study's activities on a day-to-day basis.A The NHS Sponsor monitored the trial. Since the trial was a pilot, there was no Independent Data and Safety Monitoring Committee (IDMC).The trial is publically registered:http://clinicaltrials.gov/ct2/show/NCT01895751.Expected value of results: Since clinical trials usually excluded patients with prior CABG, clinical guidelines are not evidence-based with respect to this group of patients meaning that clinicians lack knowledge, and a clinical decision in favour of invasive management (as per guidelines) is not well informed. Our project addresses this lack of evidence. If a future substantive trial confirms our overall hypothesis, then routine non-invasive management should be adopted generally, except for the minority with refractory angina who would be selectively referred for invasive angiography. The trial results will help reduce unnecessary and expensive diagnostic investigations  and provide clarity for decision-making. The results from a future definitive trial could be rapidly implemented in routine NHS practice. This research proposal will provide essential information to inform the design of the future substantive trial, including whether or not it should be performed and if so, its sample size and primary and secondary outcomes.


Promiscuous T-cell epitopes that can be presented by multiple human leukocyte antigens (HLAs) are prime targets for vaccine and immunotherapy development because they are effective in a high proportion of the human population. Although there are a number of epitope databases currently available online, the epitope data in these databases were annotated using specific MHC restrictions, and none of these databases was specifically designed for retrieving data on promiscuous epitopes.HLAsupE is an integrated database of HLA supertype-specific epitopes (promiscuous T-cell epitopes in the context of HLA supertypes). The source data for the T-cell activities and HLA-binding capacities of peptides with a specific HLA restriction were extracted from public epitope databases. After a manual curation, these allele-specific data were integrated into supertype-specific datasets based on the defined supertypes and corresponding alleles. Each supertype-specific peptide in HLAsupE is annotated in terms of its cross-reactivity to HLA molecules within the same supertype. Promiscuous peptides that can be presented by multiple HLA molecules across multiple HLA supertypes were also included in this database. Several web-based tools are provided to access and download the data.HLAsupE is the first database of promiscuous T cell epitopes that is organized based on the HLA supertypes. The main advantage of this database is the ability to search for promiscuous T-cell epitopes based on the cross-reactivity to specific alleles or supertypes. HLAsupE will be a valuable resource for the development of epitope-based vaccines and immunotherapies with broad coverage of human population. In the vertebrate immune system, short peptides derived from endogenous or exogenous antigens are presented by major histocompatibility complex (MHC) molecules on the surface of antigen presenting cells for recognition by T-cell receptors (TCRs). MHC-presented peptides that can trigger cell-mediated immune responses are termed T-cell epitopes and play a vital role in the development of epitope-based vaccines and immunotherapies against viral infections, tumors and autoimmune diseases –4. HowevAt present, a number of epitope databases, such as SYFPEITHI , MHCBN , AntiJenAlthough more than 10,000 HLA alleles have been identified to date , most HLHLAsupE is a web-based server that combines a MySQL database management system and Perl programs with a dynamic web interface based on PHP.Data on the T cell activity and HLA-binding capacity of peptides were mainly extracted from SYFPEITHI  and IEDBhttp://www.immunoinformatics.net/HLAsupE/downloads/alleles.xlsx). The curated T cell activities and HLA-binding capacities of the peptide data were integrated into supertype-specific datasets based on HLA restriction and supertype. Each peptide in the supertype-specific datasets was annotated in terms of its cross-reactivity to HLA molecules within one supertype.Most of the known HLA class I and class II molecules can be clustered into supertypes. The HLA class I supertypes for the HLA-A and B loci used here were defined by Sidney et al , and theHLA supertype-specific epitope data: the restriction of promiscuous epitopes to HLA molecules within one supertype and basic information on the epitopes ; (2) HLA supertype-specific binding peptide data: the cross-binding abilities of peptides to HLA molecules within one supertype and basic information on the peptides; (3) HLA-peptide binding data: detailed information concerning the binding ability of a given peptide to a certain HLA molecule; and (4) T-cell activity data: the T-cell activity of a given HLA restricted peptide. The quantitative HLA-peptide binding data and the detailed T-cell activity data available in HLAsupE were mainly extracted from IEDB, and hyperlinks to the source data are provided. The Source Protein (5) and Reference data (6) are also imbedded in this database, and hyperlinks to GenBank and PubMed are provided. An overview of the database and the contents of the data blocks are schematically represented in Fig. HLAsupE consists of six interrelated data blocks: 1)  HLA supeSource Protein dataset contains more than 14,000 proteins from approximately 1400 different source species and strains. The peptide datasets contained in HLAsupE can be freely downloaded at the download page (http://www.immunoinformatics.net/HLAsupE/download.htm).The latest version of the database maintains 17,889 unique records of HLA supertype-specific epitopes (SupEs) and 107,747 records of HLA supertype-specific binding peptides (SupBs). Non-redundant datasets on the detailed T-cell activity and HLA-binding capacity of specific HLA restricted peptides contain 31,793 and 196,510 records, respectively. Statistics based on HLA supertypes are shown in Table http://www.immunoinformatics.net/HLAsupE/tutorial.htm).To facilitate the use of HLAsupE, we provide several online tools allowing users to search for and analyze HLA supertype-specific peptides. The following options are provided: (1) retrieving and browsing supertype-specific peptides by peptide sequence, supertype, cross-reactivity to specific alleles and source species; (2) mapping supertype-specific peptides onto a specific protein sequence; and (3) searching for mutant analogues of a specific peptide. These servers are easy to use, and a tutorial is also provided on the tutorial page: . These data can be output based on the source species or/and the supertype selected by the user.In addition to HLA supertype-specific peptides, HLAsupE contains a large number of promiscuous peptides that can be presented by multiple HLA molecules within different supertypes . The collection of these promiscuous T-cell epitopes provides additional evidence for understanding HLA function and the development of epitope-based vaccines. The statistics on promiscuous peptides across every two supertypes are listed in Table HLAsupE is a database of promiscuous T cell epitopes that is organized based on HLA supertypes. Although promiscuous binding has been considered a hallmark of HLA class II restricted peptides –19 and tSupertype Epitope and Supertype-binding data blocks . As a result, users can instantly retrieve the promiscuous epitopes with multiple selected HLA restrictions. The query tools in HLAsupE now allow users to define the promiscuous binding ability using five different HLA molecules within one supertype. Moreover, HLAsupE can also be used for the query of promiscuous peptides with different binding affinities to multiple HLA molecules, e.g., peptides that can bind to HLA-A*0201and A*0202 but not A*0203 , which would be useful for the analysis of allele-specific recognition patterns. In addition to HLA supertype-specific peptides, HLAsupE also has a collection of a large number of promiscuous peptides that can be presented by multiple HLA molecules within different supertypes and provide corresponding query tools for these promiscuous data.T-cell activity and HLA-peptide binding data blocks; as a result, these peptide data can be displayed when a user inspects the detailed activity of a specific peptide, but a direct query of these peptides is currently unavailable in HLAsupE.There are large amounts of data on peptides presented by serological HLA molecules  included in SYFPEITHI and IEDB. However, the HLA supertypes in HLAsupE were defined based on the published data , 13, 15,The MHC restriction and population coverage are key questions in the development of epitope-based vaccines that contain at least two antigenic epitopes: a Th-epitope and an epitope that will either induce specific B-cell or CTL responses . PromiscWe will continue to update our database by extracting and curating HLA-restricted peptide data from all available epitope databases and published literatures. To make HLAsupE an even more powerful resource, we will further improve the functionality and architecture of HLAsupE to facilitate the use and analysis of promiscuous peptides.HLAsupE is the first database of promiscuous T cell epitopes and was constructed by integrating allele-specific data into supertype-specific data. The main advantage of this database server is the ability to search for promiscuous epitopes or binding peptides based on cross-reactivity to specific alleles or supertypes. This database is a valuable resource for the development of epitope-based vaccines with broad coverage of the human population and to obtaining a further understanding of the cellular immune response.HLA, human leukocyte antigen; MHC, major histocompatibility complex; SupB, supertype-specific binding peptide; SupE, supertype-specific epitope; TCR, T-cell receptor


In this paper, we propose a novel direction of arrival (DOA) estimation method for wideband signals with sensor arrays. The proposed method splits the wideband array output into multiple frequency sub-channels and estimates the signal parameters using a digital channelization receiver. Based on the output sub-channels, a channelization-based incoherent signal subspace method (Channelization-ISM) and a channelization-based test of orthogonality of projected subspaces method (Channelization-TOPS) are proposed. Channelization-ISM applies narrowband signal subspace methods on each sub-channel independently. Then the arithmetic mean or geometric mean of the estimated DOAs from each sub-channel gives the final result. Channelization-TOPS measures the orthogonality between the signal and the noise subspaces of the output sub-channels to estimate DOAs. The proposed channelization-based method isolates signals in different bandwidths reasonably and improves the output SNR. It outperforms the conventional ISM and TOPS methods on estimation accuracy and dynamic range, especially in real environments. Besides, the parallel processing architecture makes it easy to implement on hardware. A wideband digital array radar (DAR) using direct wideband radio frequency (RF) digitization is presented. Experiments carried out in a microwave anechoic chamber with the wideband DAR are presented to demonstrate the performance. The results verify the effectiveness of the proposed method. The problem of locating wideband emitters with sensor arrays is of growing interest in many applications such as sonars, radars, advanced satellites and cellular communication systems. Unfortunately, we cannot apply narrowband signal subspace methods such as multiple signal classification (MUSIC)  and estiThe incoherent signal subspace method (ISM)  decomposThe DOA estimation is transformed into a sparse reconstruction problem in recent research ,12,13,14The digital channelization receiver shows several desirable characteristics, including high broadband instantaneous frequency coverage, good sensitivity and dynamic range, simultaneous signal detection, arbitration and parameter encoding, and fine frequency measurement . DigitalWith the development of high-speed ADCs, direct sample to wideband intermediate frequency (IF) signal conversion is possible. Recently, the Science and Technology for Automatic Target Recognition (ATR) Laboratory developed a digital array radar (DAR) test-bed using direct wideband radio frequency (RF) digitization ,20. The kth sensor output kth sensor which is assumed to be statistically independent with signal sources. kth sensor:d is the spacing between adjacent sensors. The discrete-time Fourier transform (DTFT) of the kth sensor output is:Assuming a uniform linear array (ULA) of Decomposing the sensor outputs into several narrowband signals using a filter bank or the discrete Fourier transform (DFT), the output can be written in vector format at T denotes the transpose operator. K × P steering matrix. Its columns are the K × 1 array manifolds [·]Inspired by the digital channelization receiver, we propose a new DOA estimate flow shown in kth sensor output i-th channel is at:The wideband radar returns are directly digitized. A digital quadrature demodulation system ,22,23 isi-th sub-channel can be expressed as:The output of The order of prototype filter is Define Substituting Equation (9) into Equation (12), we can rewrite N is the number of snapshots of The output of digital channelization receiver T filter ,28.The frequency of received signals is not known in a real environment. Sometimes only part of the output sub-channels are within the wideband signal bandwidth. Before estimating the DOA, we need to find the sub-channels in which the wideband signals exist.The output sub-channels within the bandwidth of wideband signals always result in higher power output. The sub-channel power is a criterion to determine whether there signals exist in the sub-channel. We can compare the power of all the sub-channels to select out the sub-channels within the wideband signal bandwidth.Assume that The output ion γykn :(16)γykOnly the The SNR is improved approximately K × K covariance matrix can be expressed as:Assume that a total of Then we combine the estimated DOA The second estimator uses the arithmetic mean metric for the individual sub-channels and the geometric mean metric for the combination over the frequency range:The first estimator shows higher accuracy and lower resolution than the second one.Following the standard TOPS approach introduced in , we firsDefine a diagonal unitary transformation matrix whose size is Define a The channelization receiver shows several appealing characteristics such as wideband frequency coverage, high sensitivity and dynamic range, and accurate measurement of frequency resolution. The digital channelization receiver splits the wideband array output into multiple narrowband sub-channels and meanwhile estimates the parameters of the selected sub-channels. The estimation of the parameters including signal center frequency, pulse width and amplitude is very helpful to DOA estimation. Firstly, signals with different frequencies can be separated into different sub-channels. The DOA estimations of signals in different sub-channels can be obtained accurately without any influence of other signals. Secondly, to estimate the DOA of a signal, the knowledge of the signal parameters such as signal center frequency, pulse width and amplitude is necessary. The channelization receiver offers us a good way to obtain these parameters. Thirdly, the channelization receiver removes noises beyond the bandwidth of signals and selects the sub-channels within the bandwidth of signals with a high accuracy. The output SNR is improved approximately latforms ,30. In vlatforms , the ADCThe performances of the proposed method may degrade when the array manifold is affected by mutual coupling, sensor position errors and gain or phase uncertainties. Many calibration algorithms have been developed to compensate these uncalibration impairments ,32,33 InIn the DOA estimation procedure, we present the channelization-based ISM method and channelization-based TOPS method. The difference between these two methods is similar to that between the ISM method and TOPS, which is presented in . In thisIn this section, some computer simulations are conducted to demonstrate the performance of proposed algorithm for DOA estimation of wideband signals. Consider a ULA composed of eight sensors. The maximum number of resolved sources is 7  of the estimates from 200 Monte Carlo trials is defined as:In the first simulation, the accuracy performances of the ISM method  and the The second simulation considers the same scenario as the first simulation to compare the performances of the TOPS method  and the kth incident signal, respectively. This simulation considers the scenario where there are two sources with one source (weak source) being weaker than the other one by 20 dB. The simulation parameters are the same with those of the second simulation. To study the detection capability of week signal with the proposed Channelization-ISM method, the resolution probabilities versus SNR for the proposed Channelization-ISM and ISM method are calculated. By definition, a signal is resolved successfully when In the last simulation, the performances of the proposed Channelization-ISM method and Channelization-TOPS method against the number of sub-channels are studied. The SNR is fixed at 10 dB and the number of snapshots is 256. In this section, we present experiments carried out in a microwave anechoic chamber to further demonstrate the performance of the proposed algorithm.The wideband antenna is realized using eight tapered slot antennas (TSAs) shown in f0 = 2.7 GHz and bandwidth B = 500 MHz. The gain-phase and mutual coupling errors are calibrated by the method given in [The experiment is carried out in a microwave anechoic chamber. As shown in given in . The widIn this paper, we propose a hardware-efficient, channelization-based DOA estimation method for wideband signals. It splits the wideband array output into multiple frequency sub-channels and estimate signal parameters of each sub-channel. The sub-channels within the wideband signal bandwidth are selected on the basis of the power of every sub-channel. The channelization-ISM method applies narrow techniques to the selected channels and gets the final DOA estimate by averaging the results from all the selected channels. The Channelization-TOPS method measures the orthogonality between the signal and the noise subspaces of the output sub-channels to estimate DOAs. The proposed channelization methods outperform the conventional ISM method and TOPS method, which results from the proposed channelization method being able to estimate the signal parameters more accurately and improve the output SNR more. Besides, the parallel processing architecture makes it easy to implement on hardware. Simulations and experiments in a microwave anechoic chamber are carried out as well. The results illustrate that the proposed method can achieve better estimation accuracy and dynamic range performance than the conventional ISM method and TOPS method.


Most estimates of the incidence of acute otitis media (AOM) are based on general practitioner (GP) or pediatrician diagnoses. It is likely that these figures underestimate the community incidence of AOM since parents do not visit their doctor every time their child suffers from acute ear symptoms. The impact of these symptom episodes may be substantial since they affect the child’s quality of life and parents’ productivity.To determine AOM symptoms in the community, we measured parent-reported AOM symptoms daily for 12 consecutive months in 1,260 children participating in a prospective birth cohort in the Netherlands. The mean age of these children was at study enrollment 0.9 months (standard deviation 0.6). A parent-reported AOM symptom episode was defined as fever (temperature 38˚C or above) plus at least one of the following symptoms: ear pain and ear discharge. These febrile AOM symptom episodes were linked to GP-consultations and diagnoses in the GP electronic health records.With an estimated 624 parent-reported symptom episodes per 1,000 child-years (95% CI: 577 to 674) incidence of febrile AOM symptoms during the child’s first year is high. The GP was consulted in half of these symptom episodes and AOM was diagnosed in 49% of these consultations.The incidence of febrile AOM symptoms in the first year of life is high in Dutch children and leads to a GP-consultation in only half of the cases. This suggests that AOM symptomatology in the community is underestimated when focusing on GP-diagnosed AOM episodes alone, since a considerable proportion of febrile AOM symptom episodes are treated symptomatically by parents at home and do not come to the attention of the GP. Having data on community AOM symptomatology available for each country is important when the potential impact of preventive and therapeutic interventions for AOM are studied. Acute otitis media (AOM) is one of the most common childhood respiratory infections with most episodes occurring during early infancy . PublicaBeside a recent study , the fewPrevious studies on AOM have shown that parent-reported symptoms may have important diagnostic value in particular ear pain, fever and ear discharge, –15 althoRecognizing that accurate information on the incidence of AOM within the community is essential to provide valid estimates on costs and potential benefits of interventions to prevent or treat AOM, we monitored AOM symptomatology within a large prospective birth cohort study in the Netherlands and linked these data to general practitioner (GP) health records. In the Netherlands the GP is the gatekeeper to the Dutch healthcare system both during and outside of office hours and children need a specialist referral from a GP before visiting secondary or tertiary care.Data on AOM-related symptoms, GP-consultations and GP-diagnoses were retrieved from 1,260 children participating in a Dutch prospective birth cohort study (WHISTLER) from 2008 and onwards . The WHIA parent-reported AOM symptom episode was defined as a diary entry of fever (temperature > 38°C) in combination with either ear pain and/or ear discharge. An episode was counted if ear pain and/or ear discharge occurred within 24 hours after the onset of fever, irrespective of persistence of fever throughout the episode. A new episode was recorded after a symptom free interval of 7 days . Using tPneumococcal conjugate vaccination has been included in the Dutch National Immunization Program since April 2006 for all newborns. In March 2011 the 7-valent vaccine (CRM-PCV7) was replaced by a 10-valent vaccine (PD-PCV10). Although the individual vaccination status within the cohort under study is not known, the overall percentage of children fully vaccinated  is 95.5% for the municipality of Utrecht .Incidence of febrile AOM symptoms in the community per 1,000 child-years was calculated by dividing the number of parent-reported AOM symptom episodes by the total number of child-years. We calculated the proportion of parent-reported AOM symptom episodes that led to a GP-consultation by dividing the number of GP-consultations during the parent-reported AOM symptom episodes by the total number of parent-reported AOM symptom episodes. The proportion of GP-consultations that led to an AOM diagnosis was calculated by dividing the number of GP-diagnoses of AOM (H71) at time of GP-consultations by the total number of GP-consultations during parent-reported AOM symptom episodes. For the other diagnoses of interest  the same procedure was followed. In sensitivity analyses, we explored whether our main findings would change when stratifying our parent-reported AOM symptom episodes by three different symptom combinations: fever with ear pain, fever with ear discharge, fever with ear pain and ear discharge. In further sensitivity analyzes, we explored whether our results would change if we only included: (a) children whose parents completed all 12 questionnaires and (b) febrile AOM symptom episodes in which the onset of both fever and ear-symptoms were reported on the same day. All statistical analyses were performed with SPSS version 20.0  and OpenEpi: Open Source Epidemiologic Statistics for Public Health .For 51% (326 of 642 episodes) of parent-reported AOM symptom episodes the GP was consulted. Compared with all AOM symptom episodes (n = 642), the median duration of symptom episodes for which a GP was consulted (n = 326) was somewhat longer  AOM symptom episodes that led to a GP-consultation, a diagnosis was entered in the GP health records; a GP-diagnosis of AOM was recorded in 142 (49%) and a diagnosis of URTI, otitis media-related diagnoses , fever and cough was recorded in 44 (15%), 20 (7%), 14 (5%) and 7 (2%) of these consultations, respectively. The most common other GP-diagnoses were acute bronchiolitis/bronchitis (7), gastro-enteritis (6), other viral disease (5), varicella (4) and atopic eczema/dermatitis (4) (see In children younger than 6 months the GP was consulted in 30 of 56 (54%) parent-reported AOM symptom episodes and in 15 of these consultations the GP diagnosed AOM. In children aged 6–12 months the GP was consulted in 296 of 586 (51%) parent-reported AOM episodes and in 127 of these consultations the GP diagnosed AOM .Sensitivity analysis including only 680 children (54%) whose parents completed all 12 questionnaires, showed a similar incidence of AOM symptoms in the community as compared to the overall study population . Further sensitivity analysis including only parent-reported AOM symptom episodes with fever and onset of ear-symptoms occurring on the same day, showed an incidence of AOM symptoms in the community of 561 per 1,000 child-years (95% CI: 516 to 608).S. pneumoniae.Our study shows that the incidence of febrile AOM symptoms in the community is high during children’s first year of life, in particular in the second half of that year, and parents consult their GP in only half of the febrile AOM symptom episodes. To the best of our knowledge, this is the first prospective birth cohort studying the incidence of parent-reported AOM symptom episodes after the widespread implementation of vaccination against Compared to a recent survey among parents of children between 0–4 years conducted in seven European countries, we found a higher proportion of children with one or more parent-reported AOM symptom episodes per year, i.e. 32% versus 14–21% .Some aspects of our study need further consideration. First, the proportion of parents visiting their GP in case of AOM symptoms was relatively low. In the Netherlands, a watchful waiting strategy with supportive care  for the first 3 days has been advocated for decades in children with AOM  and the The incidence of febrile AOM symptoms in the first year of life is high in Dutch children and leads to a GP-consultation in only half of the cases. This suggests that AOM symptomatology in the community is underestimated when focusing on GP-diagnosed AOM episodes alone, since a considerable proportion of febrile AOM symptom episodes are treated symptomatically by parents at home and do not come to the attention of the GP. Having data on community AOM symptomatology available for each country is important when the potential impact of preventive and therapeutic interventions for AOM are studied.S1 Table*ICPC code entered in the GP electronic health record; ^Otitis media-related diagnoses include earache, ear discharge, otitis media with effusion and chronic otitis media; %, percentage.(DOCX)Click here for additional data file.