O(Nα), where α ∈  depends on the network topology and number of observers (N denotes the number of nodes in the network). Our Gradient Maximum Likelihood Algorithm (GMLA) reduces this complexity to O (N2log (N)). Extensive numerical tests performed on synthetic networks and real Gnutella network with limitation that id’s of spreaders are unknown to observers demonstrate that for scale-free networks with such limitation GMLA yields higher quality localization results than PTVA does.Spread over complex networks is a ubiquitous process with increasingly wide applications. Locating spread sources is often important, e.g. finding the patient one in epidemics, or source of rumor spreading in social network. Pinto, Thiran and Vetterli introduced an algorithm (PTVA) to solve the important case of this problem in which a limited set of nodes act as observers and report times at which the spread reached them. PTVA uses all observers to find a solution. Here we propose a new approach in which observers with low quality information (i.e. with large spread encounter times) are ignored and potential sources are selected based on the likelihood gradient from high quality observers. The original complexity of PTVA is  Increasing interconnectivity of the world exposes us to world-wide range of pathogens, viruses both physical and virtual, misinformation and rumors with often grievous consequences8. A good example is a fake tweet about explosion in White House in 2013, which caused $130 billion loss on the stock market9. Another example is the United States presidential election of 2016 when many rumors or fake news became viral on Facebook or Twitter and might have affected elections10. Many papers seek finding best conditions for spreading16 or sets of optimal spreaders20 but here we investigate an inverse problem. It became clear that one of the major challenges facing network and data scientists is to develop effective methods for detecting and suppressing spread of dangerous viruses, pathogens, misinformation or gossips. The basic component of such a system is undoubtedly a fast algorithm finding a source of such spread. The first widely discussed research on this subject has been done by Shah and Zaman21 and Pinto, Thiran and Vetterli22. In social networks, Shah and Zaman introduced rumor centrality of a node as the number of distinct ways a rumor can spread in the network starting from that node. They showed that the node with maximum rumor centrality is the Maximum Likelihood Estimator of the rumor source if the underlying graph is a regular tree. They studied also the detection performance for irregular geometric trees, small-word networks and scale-free networks. This method assumes that we know all the connections between nodes and additionally the infection states of all nodes. Pinto et al. relaxed some of these constraints since their algorithm requires information about state of not every node, but only about some fraction of nodes called observers. A further description of this algorithm is given in the next section and in Supplementary Information. After these two publications, the topic of the source detection became popular and many other variants of this problem have been studied. We can distinguish two main approaches to this issue: the snapshot-based25 and the detector-based27 source detection. The first one requires the snapshot of an entire network at a certain time instance, the second needs to monitor only a small subset of nodes but all the time. Regardless of the above division, researchers considered also different epidemic models28, spreading at weighted or time-varying graphs32 and multi-source detection problems34. In 2014 Jiang et al. described state-of-the-art and conducted comparative studies35. One of their conclusions is that current methods are too computationally expensive and they can not be use for a quick identification of the propagation source. The main goal of our research was finding the method which executes in reasonable time on large complex networks and delivers high quality of localization results at the same time.We live in the networked society. Every second we interact with many networks from which we collect, process and transmit a huge amount of information, which increases exponentially each year22. Then, we introduce our approach in which observers with low quality information (i.e. with large spread encounter times) are ignored and potential sources are selected based on the likelihood gradient from high quality observers. In order to measure the performance of the algorithms we use three different quality of localization measures: the accuracy, the rank and the distance error. The accuracy is the empirical probability that a source found by the algorithm is the true source. The rank is the true source position on the nodes list, which is sorted in descending order by likelihood of being the source. The distance error is the shortest path distance between the real source and the source found by the algorithm. Details on these measures can be found in the section Methods.Before demonstrating our main results, we present a brief description of Pinto-Thiran-Vetterli algorithm (PTVA)22 proposed a general framework for the localization of the spread source in which some of the nodes in network act as observers and report from which neighbor and at what time it received the information. However, in real life the identity of the neighbor that sent the message to the observer is not always available (like in the case of gossip spreading on the public square). For this reason, and for the sake of greater generality and applicability of our studies, we do not require data received by observers to contain the identities of nodes from which the spread came. We refer to tests in which PTVA is applied to such data as Pinto-Thiran-Vetterli Algorithm executed on data with Limited Information (PTVA-LI). This lowering of the requirements on input data increases applicability of the methods but reduces detection accuracy, and yet it does not affect the algorithm’s complexity or speed. Thus, PTVA-LI tests for the speed and complexity are valid also for PTVA.Pinto, Thiran and Vetterliθi for each edge are i.i.d Gaussian random variables, for which the mean μ and the variance σ2 are known. The algorithm’s complexity for arbitrary graphs is O (N(K3 + N2)), where N is the size of the network and K is the number of observers. If K ~ Nγ, PTVA complexity ranges from O(N3) when γ ≤ 2/3 to O(N4) when γ = 1. For more details on PTVA see Sup. Inf. Section PTVA calculates the likelihood of each node to be the source  with the arrival time tk, we can use only a small number K0 ≪ K of the nearest observers and drastically shorten the time needed for computing the score. The limited number of observers was used in earlier work36 where the search algorithm was run before all K observers get infected in order to limit the outbreak. In contrast, here we focus on the optimization of the algorithm’s complexity for large complex networks.Compared to the framework introduced by PTVA-LI we propose two improvements: a limited number of observers, and a gradient-like selection of suspected nodes. The first idea takes advantage of the fact that observers which are very far from the spread source make very small contribution to the score in comparison to the nearest observers Fig. . On the observer one). The procedure starts by calculating scores of the nearest neighbors of the observer one and then selects a neighbor with the highest score. Next, the algorithm jumps into this node and calculates scores for its nearest neighbors in order to find the one which has a score greater than or equal to the current maximum. The process is gradient-like and it is continued until all neighbors have a score lower than the current maximum  < 1  Fig. . It is wsee Fig. .Figure 1μ and σ2 denote the mean and the variance of the random propagation delay associated with one edge, {ok} is the set of observers and {tk} are the times at which they observed the spread. The score of a node is the likelihood that this node is the true source. We denote the score of a node v as ϕ(v). The formulas for ϕ(v), μv and Λv are given by equations  in Sup. Inf.The Gradient Maximum Likelihood Algorithm (GMLA) is summarized in Algorithm 2. K0 and N0 we reformulate the time complexity of GMLA as K0 ≪ N, which is true for our method, the complexity can be further simplified into O(log(N)N2).Using the symbols K0 is a crucial parameter of GMLA and should be carefully selected. If K0 is too small, the accuracy of the algorithm decreases. On the other hand, large K0 increases the time of computation. The optimal number of the nearest observers K0 needed to achieve maximal quality of the spread source localization. We test how 37 . It is easy to see a peak of the accuracy and the valleys of the rank and distance error. Figure K0 ≪ K nearest observers not only shortens the computation time, but it may also improve the quality of the source localization under certain circumstances. As we show further in Discussion, such a circumstance is the occurrence of the hubs in BA network. In the next paragraphs we present a numerical estimation of the complexity of GMLA as well as its performance in terms of the quality of results in comparison to PTVA-LI.The number of the nearest observers tio Figs . Figure entclass1pt{minimable Fig. . This alble Fig. . The facβ = 0.5 . Details on the baseline method are given in section Methods.We tested GMLA and PTVA-LI for various sizes of Erdös-Rényi (ER) random graphs and Barabási-Albert (BA) networks. We used Susceptible-Infected model (see details in section Methods) for the spread with the infection rate see Fig.  For compO(N3.46) to O(N1.15) for ER graph and from O(N3.49) to O(N1.32) for BA network. Furthermore, one can observe an initial difference between GMLA and PTVA-LI computing times for the networks of size 200, which is a factor 4.4 for ER graph and 3.6 for BA network.The most important feature of GMLA is a remarkable reduction of the computation time. Figures The quality of the source localization clearly depends on the network topology. In general, both algorithms achieve better results for ER graphs than BA networks. In the case of ER graphs, the accuracy of both algorithms is almost the same Fig. , but PTV40 contains N = 6299 nodes and has the average degree 〈k〉 = 6.6 (more details on data are in the section Methods). We examine the algorithms for different densities of the observers, but we keep a constant number of the nearest observers in GMLA (K0 = 30). During tests we use simple SI model to simulate spreading. The results are shown in Fig. ρ = 2.5% the computation time differs by a factor 61.5, but it increases with the density of observers since the computation time for PTVA-LI increases with ρ  per node in the worst case (where K denotes the number of observers). We avoid this drawback in out algorithm by reducing the number of the observers used to determine the score (the likelihood of being the source) and by limiting the number of suspected nodes. The latter is performed by the selection procedure which starts from the neighbors of the first observer and follows the gradient of the score. As a result of the selection, we get a limited number of the suspected nodes Vs = V). Thanks to this approach, the complexity of Gradient Maximum Likelihood Algorithm (GMLA) is O(log(N)N2) in the worst case and as far as we know this is the fastest algorithm for the spread source detection in generic networks with incomplete observations.We introduce a new algorithm (GMLA) for the spread source localization in the well-known Pinto-Thiran-Vetterli limited observers formulation. The main drawback of the Pinto-Thiran-Vetterli Algorithm (PTVA) is its time complexity. For large networks with many observers the complexity of PTVA is defined by the complexity of matrix operations, which is We test GMLA and PTVA-LI on Erdös-Rényi, Barabási-Albert and Gnutella networks and compare performance of these algorithms using three measures: the accuracy, the rank of true source, and the distance error. Both algorithms work noticeably better for ER graphs than BA networks. For ER graphs, the quality of source localization by both algorithms is similar , but for BA networks GMLA achieves much better results. The additional tests performed on Regular Random Graphs Fig. , ExponenAlthough GMLA does not use information from all observers, as PTVA-LI does, it achieves better results for scale-free networks in quality of localization tests based on three measures: the accuracy, the rank of true source, and the distance error. This is because GMLA acts like a filter and rejects low quality information from distant observers which are often “behind” the hubs.In summary, we proposed a new method for fast and accurate detection of spread source with incomplete observations which is capable to process timely large networks consisting of tens of thousands of nodes. Our algorithm is much faster and provides higher quality of localization results than Pinto-Thiran-Vetterli algorithm for scale-free networks. The key to this success is limiting the information sources to the most important observers, while ignoring excessive and noisy information from far observers, as well as use of likelihood gradient for selection of potential spread sources. The phrase “less is more” once again turned out to be truth here.λ as the ratio between the mean μ and the standard deviation σ of time delay associated with an edge in the network.For spreading process we define the propagation ratio 41. In this model each node can be in one of two states: susceptible or infected. At t = 0 only one random node is infected. We called this node the true source. At each subsequent time step each infected node has a chance to pass the information to its neighbor. The number of chances per time step is equal to the number of neighbors and for each neighbor the probability of success β is the same. The parameter β is called the infection rate. Since the number of time steps needed to pass the information from one node to its neighbor is equal to the number of independent trials (with the probability β) needed for first occurrence of success, it is described by the geometric distribution and therefore the mean propagation time per edge is μ = 1/β and the variance is σ2 = (1−β)/β2. It follows that the propagation ratio λ = μ/σ for SI model is We simulate the spread through the network using discrete Susceptible-Infected (SI) models*∈ Vtop or ai = 0 otherwise, where s* is the true source and Vtop is a group of nodes with the highest score (top scorers). The total accuracy a is an average of many realizations ai, therefore a ∈ . This measure takes into account the fact that there might be more than one node with the highest score (ties are possible).The accuracy of a single realization is The rank is the position of the true source on the node list sorted in descending order by the score. In other words this measure shows how many nodes, according to an algorithm, is a better candidate for a source than the true source. If the real source has exactly the same score as some other node (or nodes), the true source is always below that node (these nodes) on the score list sorted in descending order. The rank takes into account the fact that an algorithm which is very poor in pointing out the source exactly (low accuracy) can be very good at pointing out a small group of nodes among which is the source.Vtop| > 1, which means that an algorithm found more than one candidate for the source, the distance error is computed as a mean shortest path distance between the real source and the top scorers.The distance error is the number of hops (edges) between the true source and a node designated as the source by an algorithm. If |The baseline method serves as the benchmark for accuracy and distance error tests. It assumes that the real source is the first observer reporting the spread. The baseline method works in no time and its accuracy is expected to be equal to the density of observers; this follows from the fact that if the true source is among the observers, it has to be the observer with the smallest arrival time. One can expect a quite low value of the mean distance error in this case, because the baseline method never makes big mistakes in terms of distance from the true source. Apart the poor accuracy, the baseline method does not assign the scores to the nodes which means that it cannot be used to find the rank of the real source.40. This dataset consists of a snapshot of the Gnutella peer-to-peer file sharing network from 8 August 2002. Nodes represent hosts in the Gnutella network topology and edges represent connections which were established on 8 August 2002. The data has been anonymized by the researchers from Stanford University before it was made available. The graph contains Ntot = 6301 nodes and Etot = 20777 edges, but we use the largest connected component which consists of N = 6299 nodes and E = 20776 edges (〈k〉 = 6.6). The diameter of the network is 9, the average path length is 3.7 and the average clustering coefficient is 0.0109.We used the data from SNAP Datasets42 as a fast linear algebra library for Java.The time tests were performed in Java 7 using AMD FX-8350 4 GHz processor. We used jblas v.1.2.4Supplementary information


The early and timely recognition of dementia syndrome is a policy imperative in many countries. In the UK the achievement of earlier and timelier recognition has been pursued through educational interventions, incentivisation of general practitioners and the promotion of a network of memory clinics.The effectiveness of education, incentivisation and memory clinic activity are unknown. This article analyses data from different sources to evaluate the impact of these interventions on the incidence and prevalence of dementia, and the diagnostic performance of memory clinics.Three data sources were used: 1) aggregated, anonymised data from a network of general practices using the same electronic medical record software, The Health Information Network (THIN), 2) UK Health & Social Care Information Centre data reports and 3) Responses to Freedom of Information Act requests.Educational interventions did not appear to change the recorded incidence of dementia syndrome. There was no apparent effect of education, incentives or memory clinic activity on the reported incidence of dementia syndrome between 1997 and 2011 but there were signs of change in the documentation of consultations with people with dementia. There was no clear impact of incentivisation and memory clinic activity in prevalence data. Memory clinics are seeing more patients but fewer are being diagnosed with dementia.It is not clear why there has been no upturn in documented incidence or prevalence of dementia syndrome despite substantial efforts and this requires further investigation to guide policy changes. The performance of memory clinics also needs further study. Delays in the recognition of dementia syndrome are a common problem across the world, prompting Alzheimer’s Disease International to call in 2011 for earlier diagnosis and intervention [A number of attempts have been made in the UK to make recognition of dementia timelier, beginning in 1997 with educational activities aimed at general practitioners (GP) and other primary care professionals, coinciding with the launch of the cholinesterase inhibitors. In 2006 case finding/screening for dementia was added to the GP contract, introducing complex financial incentives calculated through a reimbursement system called the Quality and Outcome Framework (QOF) designed to improve dementia recognition and management. Finally, the implementation of the Dementia Strategy after 2009 saw the development of a network of National Health Service (NHS) memory services with diagnostic and support functions.A national education programme in 1997 which coincided with the launch in the UK of the cholinesterase inhibitors and memantine had only limited success in recruiting GPs  but therThe financial incentives for GPs, introduced in 2006, included payments for keeping a register of patients diagnosed with dementia, for developing care plans and reviewing them in a face to face consultation at least every 12 months and for carrying out appropriate investigations, e.g. full blood count (FBC), calcium, glucose, renal and liver function, thyroid function tests, serum vitamin B12 and folate levels, in those newly receiving a diagnosis of dementia. A financial reward per case diagnosed was included in this package for a short time. Payments also reflected how close GPs were to identifying the expected prevalence of dementia in their practice populations.The introduction in the UK of financial incentives for earlier diagnosis, and the promotion of memory clinics, remain controversial. These are interventions based on weak evidence. There is no simple, accurate, widely validated primary care screening tool except the mini mental state examination (MMSE) , the benStudies that have used aggregated, anonymised data from a network of general practices using the same electronic medical record software, The Health Information Network (THIN). These studies –9 have uUK Health & Social Care Information Centre  data reports.Responses to Freedom of Information Act requests made by a medical news journal, ‘Pulse’, in 2015.The primary care research group on dementia at University College London has investigated the impact of educational interventions and policy changes designed to promote timely or earlier diagnosis of dementia syndrome using different methodologies. Here we report data from three sources:Fig. The financial incentives introduced in 2006 did appear to change the way in which encounters with people with dementia were documented in the electronic medical records , shown in Fig. There is some evidence that memory clinics are diagnosing fewer cases of dementia. Data obtained from a Pulse magazine Freedom of Information request in February 2016 are shown in Fig. Educational interventions did not appear to change the recorded incidence of dementia syndrome, despite evidence from one contemporary trial that they could. This negative finding is supported by the results of a trial of practice-based education in the EVIDEM-ED study . There wMemory clinics are seeing more patients but fewer are being diagnosed with dementia. This is not surprising given the multiple causes of memory loss and the lack of specificity of memory loss symptoms. The emphasis on memory testing  and memory clinics may value subjective memory complaints over other features of dementia syndrome. A Swedish study by Palmer et al.  used a 3There are limitations in the use of routinely collected clinical data to judge effects of education, incentivisation and memory clinic performance, in that they cannot reveal changes in clinical practice that might be beneficial to individuals with dementia. Some data sources, such as the memory clinic performance data, are based on small samples and may not be representative. Nevertheless, these data provide insights into the impact that education, incentivisation and promotion of memory clinic may or may not have on the provision of care for people with dementia and prompt the question: after all these efforts, why is there no upturn in incidence or prevalence? It is possible that the educational interventions used did not improve knowledge or clinical confidence in GPs or that the financial incentives to recognise dementia syndrome were too small to change clinical work priorities. Similarly, all of these interventions may act more slowly than we expected and change clinical practice in the medium to long term rather than in the short term. Further investigation is needed to inform future policy changes related to the recognition of and response to dementia.


This novel design of a multilayered conveyor belt structure is fabricated in aluminium nitride (AlN) because of its outstanding thermal and electrical properties. This demonstration would pave a way for a compact and portable quantum device required for quantum information processing and sensors, where precise positioning of cold atoms is desirable.Here we report of a design and the performance of an optimized micro-fabricated conveyor belt for precise and adiabatic transportation of cold atoms. A theoretical model is presented to determine optimal currents in conductors used for the transportation. We experimentally demonstrate a fast adiabatic transportation of Rubidium ( The micro-fabricated wires and electrodes are lithographically imprinted on the atom chip to construct complex potentials using magnetic and electric fields to trap and manipulate the atoms6. Many aspects of integrated matter wave technology have been demonstrated such as combined magnetic/ electrostatic traps7, transportation of neutral atoms8, atomic beam splitters9, the creation of Bose-Einstein condensation (BEC)12, atom interferometer14, and the integration of optical15 and magnetic17 lattices with atom chip.A simple yet powerful technique to reach the quantum regime with neutral atoms has been demonstrated using atom chips18.For many applications, such as in quantum information and communication, quantum sensors and microscopes, and to study various short and long range interaction potentials, it is desired to precisely move trapped atoms in a three-dimensional (3-D) geometry along with temporal control. Indeed the realisation of a “qubit conveyor belt” is required for many implementations of quantum computing8. It is demonstrated that, by applying time dependent currents to the wires, the atom cloud could be split and transported parallel to the atom chip surface. In the second, an array of eight wires are used repeating on the chip surface. By manipulating the currents in those eight wires the atom cloud is transported20. Both these implementations have some advantages and drawbacks. In the first, using only two wires has the distinct advantage that wires can be placed in one plane. However, it won’t be easy to translate the trap without imperfections by modifying only the currents. Thus, adiabatic transport is difficult to achieve. In the second experiment, the use of a set of eight repeating wires would allow to eliminate even higher order trap imperfections by exploiting our approach. The implementation using eight wires however requires twice the number of power supplies compared to the scheme presented here.In this regard the transportation of ultra cold atoms using a magnetic “conveyor belt” should be adiabatic such that the atoms remain in the same state during the transport. The demonstrations of transportation of neutral atoms using a magnetic conveyor belt has been realised on an atom chip with two different patterns of conveyor belt wires. The first, using two wires in a repeating square wave type pattern on the surface of the atom chipvmax = 40 mm/s is demonstrated. This is almost an order of magnitude faster transport in comparison with the previous works as reported to be 5.3 mm/s8 and 2.6 mm/s20.In this article a theoretical model is presented to determine both the least number of conductors required for a conveyor belt and the optimised current through them to ensure adiabatic transportation of atoms. We present a new atom chip based conveyor belt design, which is simple to fabricate using printed circuit board (PCB) fabrication techniques. To achieve the adiabatic performance, our design utilises a repeating pattern of just four wires, though only three wires are strictly required. We outline the basic design of our conveyor belt and we experimentally demonstrate the adiabatic performance of the conveyor belt. With as few as three conveyor conductors, adiabatic transport of atoms with minimal loss at a maximum velocity of Our atom chip is comprised of a two component system with a science chip, connected underneath to a base chip. On the science chip, lithographically printed gold micro-wires in the shape of “U, Z, and I” are used Fig.  to creatAlN). AlN, a covalently-bonded ceramic, is chosen for fabrication due to its outstanding properties such as high thermal conductivity and high electrical resistivity. The science chip is designed and manufactured in-house 21. The base chip is manufactured by commercially available PCB fabrication methods techniques used for the heat sinks of LED and CMOS chips.The base chip performs two functions; first, the base chip has its own set of wires, which form the conveyor belt transport wires as shown in the Fig. 87Rb atoms are magneto-optically trapped (MOT) using a bias magnetic field and current through a U-shaped copper wire (U-wire) of 3 × 3 mm cross-section, approximately 4 mm directly below the U-wire on the science chip (and base chip), using the well known mirror-MOT technique2. The science chip’s gold (Au) surface acts as a mirror for the MOT. The current in the copper U-wire (not shown), initially 24 A for the MOT loading time for 10 seconds, is ramped down while the science chip’s U-wire  of optical molasses cooling is performed after the compression of the MOT, followed by an optical pumping before loading into the magnetic trap created by the Z-wire of the science chip (Z-MT). All the magnetic fields are turned off during the optical molasses cooling.The atoms are then compressed to mode-match with the magnetic trap created by the Z-wire Fig.  using a F levels of the MOT are optically pumped to the 52S1/2, F = 2, mF = 2 weak-field-seeking state. A circularly polarized To improve the loading efficiency of the magnetic trap, all the atoms from different m3 atoms are loaded into the trap, though it is possible to capture up to 1 × 106 atoms from the molasses. The temperature of the atom cloud in the magnetic trap is measured around 10 μK. The current through the I-wire is 0.9 A, the magnetic fields parallel and perpendicular to the I-wire are 5.4 G and 18.2 G respectively  on the science chip and the conveyor belt wires in the base chip. Typically 300 × 10For a smooth transport along the wire it is required that the trapping frequencies remain the same at all positions along the wire. To optimise the conveyor belt, we use a one dimensional model where we assume that the transverse and longitudinal trapping frequencies are independent. This approximation is valid when the principal axes of the trap are aligned with the trapping wires.Iw. A guide is formed when an external bias field Consider the situation illustrated in Fig. M is the mass of the atom and gF the Landé factor, r the distance from the minimum. The transverse field curvature around the minimum is given by,In such a guide the potential is a quadrupole field, where atoms would be lost due to the Majorana spin flips. Applying an additional field along the guide wire Ik, k = 1, 2, 3) through wires perpendicular to the guide wire that counteract and reduce the field y0 remains unaffected by the wires Ik, the field along the guide centre becomesL is the separation between the wires, and h the distance from the wires to the guide as illustrated in Fig. Trapping along the guide is formed by running currents  The current configuration provides a single minimum for Bx at any position between −L/2 and +L/2, ii) the magnetic field minimum should remain constant to maintain a constant transverse trap frequency, and iii) the axial curvature should remain constant to keep the axial trap frequency constant. These three conditions allow us to solve for the three currents. The equations are:B0 is the wanted trap bottom, and C is the desired field curvature.Here we calculate the currents that allows a smooth transport of atoms from −I1, I2 and I3 gives:Solving these equations for It is convenient to select a simple starting condition, for instance I2, I3, and I4 located at a distance L from wire I3. The currents for this is plotted in Fig. This also gives an important constraint on the geometry. For a wire separation At distances L = 800 μm, To test this approximation, we calculate the magnetic fields by integrating Biot-Savart’s law along the current carrying wires. Here we use the parameters close to our experimental values, i.e., h), which is the distance between the atom cloud and the conveyor belt wires. It is evident from the Fig. h), as provided in the equations To verify the model described in the above section, we have performed temperature measurements of the magnetically trapped atoms after transportation. An important parameter of the current waveforms is the height (h) should be set correctly in equations h in the following manner. We transport the atoms using current waveforms calculated for different choices of h. If the real distance between the cloud and the conveyor wires’ surface matches one of our choices of h, we would expect to see minimal heating of the cloud during transportation as that would satisfy all the three conditions given in equations h is incorrectly assigned in the calculation, we would expect heating.In order to move the atoms with a minimal change in curvature, the height . To eliminate any heating due to changing the loading conditions of the cloud, we perform a differential temperature measurement. We measure the difference in temperature of the cloud that is transported versus a stationary cloud loaded into the magnetic-trap under the same conditions. This differential measurement thus reveals the heating solely due to the transport.To verify this we assign several values for h = 1.2 mm. This is consistent with the distance between the cloud and the conveyor belt wires from the theoretical prediction. The distance of the cloud from the science chip surface (y0) is estimated to be around 100 h = 1.1, 1.2, and 1.3 mm, additional measurements are performed to verify the repeatability.Figure h, no measurable heating is observed. The trapping frequencies remain almost constant at all positions as predicted in the Fig. h = 1.2 mm, during the transportation.We observe that the heating follows the changes in curvature of the trap as shown in the Fig. Another important performance criterion for an atom chip conveyor belt, is to demonstrate that atoms are not lost due to the transport. When atoms are trapped in a magnetic potential, atoms are lost over time, due to collisions of background gas in the vacuum system. In order to confirm if the atom loss occurs during the transportation using the the conveyor belt, one needs to take into account the atom loss due to the magnetic trap’s lifetime. To verify, we measure the atom number for a transported cloud and for a stationary cloud held for same time as the transportation time, with the exactly same loading conditions. We then divide the measured atom numbers from each other and observe the atom loss due to the transport, independent of the natural trap lifetime. The measurement is then repeated over different distances of transport. The inset in Fig. h) is found, it is possible to move the atoms with any position-acceleration profile, limited only by the gradient and depth of the trap. We have found no significant heating dependent on the acceleration profile. In this experiment, the atoms are transported adiabatically almost without loss, with a maximum velocity of For an ideal conveyor belt one would like to move the atomic cloud not only adiabatically, but also as quickly as possible in order to minimise dead time and to avoid atom loss due to magnetic trap’s limited lifetime. Once the atom cloud to the conveyor wire distance (20, we expect it to be possible to perform ultra-quiet transport, or to accelerate atoms to very high velocities. The fast transport allows to overcome the atom loss due to the life time, as well as perform faster measurements. The minimalistic and optimized approach, towards the design of the conveyor belt, lends itself for easy implementation towards compact and portable atom chip devices required for quantum sensors, quantum optics and information.We have shown an analytical model of a minimalist magnetic conveyor belt for neutral atoms trapped using atom chip technology. Using this model we have calculated the optimal set of wire currents needed to transport atoms across the surface without changing the trap curvature or height, and thus maintaining the temperature of the atom cloud unchanged. The theoretical model and current optimization technique for adiabatic atom transport is not limited to a magnetic trap, this model could also be adapted for ion transport. We have built and characterised the conveyor belt, showing almost no heating or loss due to the transportation of the trapped atoms at a maximum velocity of


Clinical assessment of swallowing disorders (dysphagia) requires accurate and comprehensive medical history-taking to further tailor the diagnostic work-up, but functional health care questionnaires show a large variability and various limitations. The aim of this study was to assess the way in which international swallowing experts from various disciplines asses swallowing problems in order to improve the radiologist´s ability to take a thorough medical history in this specific patient group.A two-step Delphi method was used to collect swallowing experts’ ways of taking the medical history in patients with swallowing disorders. The questions obtained in a first interview round were pooled and structured by dividing them into general and specific questions, including several subcategories, and these were scored by the experts in a second step based on to their clinical relevance.Eighteen experts provided 25 different questions categorized as general questions and 34 dimension-specific questions  In the second interview round, the experts´ average predictive values attributed to those questions showed the varying importance of the presented items. Seven general and 13 specific questions (six of them attributed to ‘effect on life’ and seven ‘others’) were also added.This collection of questions reflects the fact that a multidisciplinary approach when obtaining the medical history in patients with swallowing disorders may contribute to an improved technique for performing a symptom-oriented medical history-taking for radiologists of all training levels. Swallowing disorders (dysphagia) are an increasing cause of disability and morbidity , 2. TheyVarying diagnostic examinations, including radiologic and non-radiologic techniques, are used to evaluate patients with swallowing disorders. Oropharyngeal and esophageal dysphagia are best evaluated with videofluoroscopic and fiberendoscopic imaging –7. HowevThe relevance of history-taking has long been established. About 60% to 80% of diagnoses in internal medicine are derived conclusively from an initial comprehensive interview . Murray To competently obtain the clinical history in a problem-solving manner, a thorough knowledge of the causes of each symptom and the symptoms of each disease is mandatory . ClinicaThe aim of this study was to enhance the radiologist´s ability to take a medical history-taking in patients with swallowing disorders by providing the core of experts´ knowledge and experience in this regard. Therefore, a group of interdisciplinary international swallowing experts participated in a two-step, questionnaire-based process.A two-step Delphi method  was usedFor step 1, a multidisciplinary expert panel was identified and selected based on their clinical background and their experience in patients with swallowing disorders, as evidenced by participation on the board or being invited to speak at the first congress of the European Society of Swallowing Disorders (ESSD) in Leiden/the Netherlands. In the first step, 18 swallowing experts were approached and consented to participate in an interview about their way of taking the medical history. This expert panel consisted of 14 out of 17 members of the original board of the ESSD and 4 invited speakers, attributable to the following medical speciality: eight swallowing experts from otolaryngology departments, four from radiology departments, four members of departments of speech and language pathology, one from an internal medicine department, and one from a department of surgery. The participants came from the following countries: Australia, Austria, Belgium, Canada, France, Germany, Greece, Ireland, Italy, the Netherlands, Spain, Sweden, the UK, and the USA. The experts reported that they saw about 500 patients per year, on average, ranging from 100 to 1500.x = 9; contacted personally: x = 16 during the ESSD congress in 2014). Eleven of these experts (44%) had also taken part in step 1. There were 8/25 experts in the field of ENT, surgery (n = 6), radiology (n = 5), internal medicine (n = 3), speech and language pathology (n = 2), and neurology (n = 1).For the second step, 25 experts with a comparable clinical backgrounds and experience in patients with swallowing disorders and a comparable number of patients investigated per year were contacted and invited to participate in a ranking of identified history-taking topics for swallowing disorders .For step 2, the themes and their respective questions covered during history-taking in patients with swallowing problems, as identified in step 1, were listed. Questions were accompanied by a scale of 1–6, where 1 represented a very important question for every patient with swallowing disorders, used in 100% of interviews, and 6 represented a rare question used only in specific situations in <10% of interviews. At the end of each theme, ‘missing questions attributable to the preceding theme’ could be entered as text. In addition, the experts were asked to indicate whether they approved of the given structure of the questions and whether they could imagine using a questionnaire based on this structure for their future work.For the first step, swallowing experts were interviewed by an experienced radiologist (P.P.) and a medical student in his final year (F.O.). During the first round, 18 interviews lasted for about 25–30 min each. Notes, taken immediately during the interview, were transcribed and subsequently mailed to each swallowing expert for review and specification.Swallowing experts were emailed the results of step 1 and invited to participate in a questionnaire where they rated the importance of each question.Step 1: In order to pool and structure the answers to the question “How do you take the history in patients with swallowing disorders?,” we performed a directed content analysis  , eight to ‘suspicion of aspiration,’ six to ‘globus sensation,’ four to ‘non-cardiac chest pain,’ and three to ‘effect on life.’The 18 experts provided 25 different items, categorized as general questions. Two items were assigned to ‘open questions,’ five to ‘symptom analysis, ’twelve to ‘nutrition,’ and six to ‘consistency.’ The dimension-specific questions about swallowing disorders comprised 34 different items: most of them attributable to ‘dysphagia’ .The results showed that 9/25 would definitely use a questionnaire based on the present structure in their daily routine; in a range of 1 (definitely would use the guide) to 6 (definitely would not use the guide), the overall average score of all interviewed experts was 2. Regarding the influence of the patients’ answers on the planning of an upcoming investigation protocol, the specialists assigned an average grade of 1.8, ranging from 1 (very high influence on investigation procedure) to 6 (no influence on investigation procedure).n = 8), the communication led to enough information to formulate a hypothesis (n = 8), and there was a correlation between the patient´s history and the results can be found (n = 3). The most frequently mentioned reason for a less successful patient–physician communication was shortage of time (n = 7).Regarding the average time needed to take the medical history in patients with swallowing disorders, three swallowing experts reported a duration of up to five minutes, six reported a duration of 5–10 min, four reported a duration of 10–20 min, three between 20–30 min, and two reported more than 30 min. Each of the 18 interviewees stated that they documented the history of the patient. Nine of 18 reported using at least one standardized questionnaire about swallowing problems in their clinical routine . All in all, 10 different questionnaires were mentioned. A history that went well was considered successful if the patient could participate and understood the questions (The goal of this study was to obtain a range of answers from a widespread, diverse group of experts from different disciplines about how to take a medical history in patients with swallowing disorders. Previously, various studies have revealed the relevance of the medical history for making a final diagnosis and showed a high agreement between the diagnosis made after taking the history and reading the referral letter and the final diagnosis , 9. In aWhile 21/25 experts rate the influence of patient history as “high” or “very high,” there are a number of challenges even with a well-tailored questionnaire. Patients’ perception of swallowing disorders is not always reliable, also reflected by the fact that the ability of the patient to participate in the taking of medical history is considered relevant for successful communication. In addition, the speed of onset and mode of progression of specific symptoms may not be helpful in predicting certain diseases. For example, patients with dysphagia associated with benign disease often report weight loss, which may be misleading . For thiAnother issue is the request to involve the patient in the decision-making process and further diagnostic steps. Patients want an effective dialogue with their physician and authentic caring in their clinical relationship –29. ThisFast-track investigation of dysphagia has a low success rate in diagnosing esophageal disease, and specialized physicians may facilitate an early diagnosis . GeneralThe advantages of questionnaires include the fact that they are easy to use, do not require a lot of effort compared to the information the physician obtains from the patient, and may be an important tool for evaluating problems and guiding further treatment decisions. Questionnaires for characterizing swallowing disorders vary largely among different institutions, and a review of the literature revealed many different screening tools . This waRadiologists will have contact with patients who have swallowing disorders during their training and career, and could benefit from structured guidance for a comprehensive interview. Determining the correct questions in a clear and simple way during the encounter, to ensure that the patient understands was one of the most important factors named when the experts were asked for examples of successful patient–physician communication. Therefore, a collection of questions that help to explore the diverse symptoms of swallowing disorders comprehensively may serve as an aid for radiologists of all training levels. A better understanding of the causes of swallowing problems, which could be achieved by asking the right questions, helps to customize the investigation of the individual patient, a prerequisite for a correct diagnosis. In addition, recognizing the patients’ problems enhances the interpretation of radiological imaging findings, thus leading to a correct diagnosis and suitable treatment for the patient.The number of gastrointestinal fluoroscopic examinations has declined during the last 20 years due to the increasing availability of endoscopy and cross-sectional imaging . HoweverThe experts interviewed reported a quite long time period for obtaining information about the individual patient´s symptoms. A detailed history may be important for several reasons: the accuracy of patient´s symptom localization in dysphagia is not precise  and a siOne limitation of this study is that the respondents of the first interview round were not completely identical with the experts of the second survey. Nevertheless, all experts of the second study round were dedicated experts in examining patients with swallowing disorders, with comparable clinical experience and working together with specialists in interdisciplinary deglutology centers.Although the number of experts is not very high, the topic of a comprehensive history-taking is important, and the presented collection of questions may serve as an aid in taking the history in this selected patient group. Another limitation is the fact that asking these questions is only suitable for patients who are not limited by neurological factors and are able to understand the content of the questions. We waived a third interview round, since the main aim of this study was not reaching consensus, but generated information about the experts´ way of obtaining medical history. Further research is required for consensual creation and validation of a multidisciplinary questionnaire for patients with swallowing disorders.This survey presents a collection of the methods used by interdisciplinary experts to perform the clinical interview in patients with swallowing disorders and a weighting of varying questions as an approach to this complex clinical challenge. It may contribute to improve the technique of radiologists of all training levels to take the history in patients with swallowing disorders in order to tailor the examination protocol of the individual symptomatic patient. Although radiologists often do not take a full history in an interdisciplinary setting, it is still important to know the relevant questions across the boundaries of individual disciplines to tailor the radiological investigation optimally and correlate the symptoms to the radiological findings.


Mismatch negativity (MMN) has been characterised as a ‘pre-attentive’ component of an event-related potential (ERP) that is related to discrimination and error prediction processes. The aim of the current experiment was to establish whether visual MMN could be recorded to briefly presented, backward and forward masked visual stimuli, given both below and above levels of subjective experience. Evidence of visual MMN elicitation in the absence of the ability to consciously report stimuli would provide strong evidence for the automaticity of the visual MMN mechanism. Using an oddball paradigm, two stimuli that differed in orientation from each other, a + and an ×, were presented on a computer screen. Electroencephalogram (EEG) was recorded from nine participants , mean age 21.4 years. Results showed that for stimuli that were effectively masked at 7 ms presentation, there was little variation in the ERPs evoked to standard and deviant stimuli or in the subtraction waveform employed to delineate the visual MMN. At 14 ms stimulus presentation, when participants were able to report stimulus presence, an enhanced negativity at around 175 and 305 ms was observed to the deviant and was evident in the subtraction waveform. However, some of the difference observed in the ERPs can be attributed to stimulus characteristics, as the use of a ‘lonely’ deviant protocol revealed attenuated visual MMN components at 14 ms stimulus presentation. Overall, results suggest that some degree of conscious attention is required before visual MMN components emerge, suggesting visual MMN is not an entirely pre-attentive process. The automatic detection of change in the visual environment is key to human survival and adaptive behaviour. The mechanisms for detecting changes in the absence of focal attention are beginning to be understood. However, how the brain detects change and orients to stimuli that may then come under focal attention is less well understood.Current literature suggests that the mismatch negativity (MMN) is an electrophysiological correlate of the brain’s ability to predict changes in environmental regularities. Current interpretations of the neural mechanisms that underlie the generation of the MMN posit the MMN within a predictive coding framework based on Bayesian principles. It is assumed that rather than passively registering environmental regularities the brain actively predicts the causes of sensory inputs Friston . Within The visual MMN is observed as a negative ERP deflection that usually peaks around 150–400 ms post-stimulus change and is maximal over posterior electrode locations. Recent interpretations of the component structure of the visual MMN suggest an initial negative component occurring between 150 and 200 ms and a later negative component between 200 and 400 ms Kimura . GeneratThe relationship between the elicitation of visual MMN and allocation of attentional resources is a controversial area in MMN research. The issue of how the automaticity of the MMN generation can be characterised is still to be understood Kimura . AlthougIn many studies, evidence of the pre-attentive nature of visual MMN is sought by the manipulation of the attentional resources of the participant away from task irrelevant stimulus sequences that are of interest to the experimenter, by asking the participant to focus their attention on a second task. For example, irrelevant stimuli are presented peripherally whilst the participant is asked to focus their attention in the middle of the visual field or to focus on an auditory task whilst ignoring visual stimuli presented  can still be analysed. The question of whether a visual MMN can be elicited by deviant stimuli that are reported as ‘unseen’ may provide insight into the relationship of the visual MMN on attention. Studies such as Hsieh and Colas  have shoA number of studies have used subliminal methods to explore ERP components to stimuli that have no emotional content. For instance, in a group of thirteen patients with intractable epilepsy, ERPs were recorded directly from the cortex to stimuli that were presented below and above subjective threshold of awareness . Participants reported no history of neurological disease and had normal or corrected-to-normal visual acuity.Two stimuli, comprising of black and white checkerboard elements, differing from each other only in terms of their orientation to form either a + or an ×, were presented in a behaviourally silent oddball paradigm where the ratio of standards to deviants was 8:2. The stimuli were embedded between masking stimuli consisting of complex images whose colours inverted. The background of the standard and deviant stimuli consisted of the same complex image as the mask. The two stimuli were presented at very brief presentation times, below levels of subjective awareness for 7 ms in the first instance and then above levels of subjective awareness at 14 ms. The masking stimuli were presented for between 486 and 500 ms, and details of stimuli, stimulus sequence and durations during experiment are illustrated in Fig. All stimuli were presented on a 21-inch cathode ray tube (CRT) monitor (Samsung Sync Master), with an NVIDIA GeForce 8800GT 320 MB graphics card, running with a screen refresh rate of 160 Hz. The stimulus presentation software (E-Prime V2.0 Psychology Software Tools Inc.) provided markers to be used during averaging of the electroencephalograph (EEG) to produce evoked potential waveforms.Participants were seated comfortably in a darkened room 1 m away from the computer screen and requested to fixate on a small red dot in the centre of the screen that was present throughout recording. Within the oddball paradigm, stimuli were presented in a pseudo-random sequence ensuring deviant stimuli were interspersed with standard stimuli. Five blocks of the 7 ms duration stimuli were presented. Each block contained 500 stimuli (400 standards 100 deviants). This was followed by one block of 100 stimuli where the masked deviant (the ×) was presented alone, i.e. with no standard stimulus. The same procedure was then carried out for the 14 ms duration stimuli. There was a break of 1 min between blocks. Following the first block of the 14 ms presentation, participants were asked if they observed anything different from the earlier presentations and prompted to describe what it was. All nine participants reported seeing the stimuli at 14 ms and were therefore included in the current study.Silver–silver chloride electrodes were used to record the EEG activity and were positioned at sites in accordance with the International 10–20 system Jasper   was compared to the evoked response to the same stimulus when presented alone. If a MMN is present, a relative negativity will be apparent only in the evoked response elicited in the context of the oddball paradigm and will not be present when the deviant is presented alone  and for each time window . Bonferroni corrections were applied. Results showed that there was an increased negative amplitude to the deviant stimulus compared to the standard stimulus at 14 ms stimulus duration for the early time window  and for the late time window  that was not apparent in other conditions  no visual MMN was recorded. Evidence of visual MMN components only appeared when the masked stimuli were presented for 14 ms and the participants were able to report their appearance, although some of the difference between the standard and deviant ERPs was accounted for by stimulus difference. The present study therefore revealed no evidence for the automaticity of the visual MMN.As proposed by Dehaene et al. , a conti


Biocidal products are mixtures of one or more active substances (a.s.) and a broad range of formulation additives. There is regulatory guidance currently under development that will specify how the combined effects of the a.s. and any relevant formulation additives shall be considered in the environmental risk assessment of biocidal products. The default option is a component-based approach (CBA) by which the toxicity of the product is predicted from the toxicity of ‘relevant’ components using concentration addition. Hence, unequivocal and practicable criteria are required for identifying the ‘relevant’ components to ensure protectiveness of the CBA, while avoiding unnecessary workload resulting from including by default components that do not significantly contribute to the product toxicity. The present study evaluated a set of different criteria for identifying ‘relevant’ components using confidential information on the composition of 21 wood preservative products. Theoretical approaches were complemented by experimentally testing the aquatic toxicity of seven selected products.For three of the seven tested products, the toxicity was underestimated for the most sensitive endpoint  by more than factor 2 if only the a.s. were considered in the CBA. This illustrated the necessity of including at least some additives along with the a.s. Considering additives that were deemed ‘relevant’ by the tentatively established criteria reduced the underestimation of toxicity for two of the three products. A lack of data for one specific additive was identified as the most likely reason for the remaining toxicity underestimation of the third product. In three other products, toxicity was overestimated by more than factor 2, while prediction and observation fitted well for the seventh product. Considering all additives in the prediction increased only the degree of overestimation.Supported by theoretical calculations and experimental verifications, the present study developed criteria for the identification of CBA-relevant components in a biocidal product. These criteria are based on existing criteria stated in the regulation for classification, labelling and packaging of substances. The CBA was found sufficiently protective and reliable for the tested products when applying the here recommended criteria. The lack of available aquatic toxicity data for some of the identified relevant components was the main reason for underestimation of product toxicity. Biocidal products are mixtures of one or more active substances (a.s.) and various intentionally added substances serving a broad range of functions in the formulated product. The authorization of biocidal products in the European Union (EU) is regulated by the Biocidal Product Regulation (BPR) , and furThe transitional guidance document particularly explains two different generic approaches for the mixture toxicity assessment. One approach is to conduct ecotoxicity tests with the biocidal product or, e.g. with the environmental mixture resulting from the use of the product (such as leachates from treated wood). The second, so-called component-based approach (CBA) is to calculate the ecotoxicity of the product or of the resulting environmental mixture using ecotoxicity data of the individual mixture components. The concept of concentration addition (CA) is recommended as default for this approach by the BPR as well as by the transitional guidance document, because CA is less data demanding and usually results in a more conservative assessment than the alternative concept of independent action (IA), demonstrated e.g. by Junghans et al. . In compa.s. from other product types (PTs) contained in the product (e.g. in-can preservatives), provided that a draft final Competent Authority Report (CAR) with an agreed risk assessment is available.Product components that intend to enhance the effect of the a.s. in the product (i.e. synergists) as well as organic solvents or surfactants (such as e.g. naphtha) that may enhance the bioavailability of the a.s. and thereby influence its toxicity (on a case-by-case basis).Product components that fulfil the criteria for inclusion in the candidate list established in accordance with the REACH Regulation Article 57 (f) and 59 (1) , as amenProduct components that meet two of the three PBT criteria in accordance with Annex XIII to Regulation (EC) No 1907/2006 .Product components for which an environmental quality standard (EQS) has been established under Directive 2000/60/EC  to be published by the end of 2017 and replacing the transitional mixture guidance, relevant by default are the active substance(s) and all substances of concern (SoC). SoC are defined in Article 3 (f) of the BPR as substances, other than the a.s., which are classified as “dangerous” according to Directive 67/548/EEC  and thatApplying the CBA in the authorization of chemicals is a rather new procedure that has been formally established for biocides by the BPR. While the predictability of mixture toxicity by CA and the rare occurrence of synergistic (i.e. greater than predicted additive) effects is supported by the literature , 5, 27, In this context, the objective of the present study was to assess the reliability and protectiveness of the CBA by comparing the predicted with the experimentally determined aquatic ecotoxicity of selected biocidal products. Additionally, the results of this study aim to inform the debate on the identification of ‘relevant’ components for the mixture assessment of biocidal products.In a first step, information on the composition of 21 different biocidal products (product type (PT) 08, wood preservatives) was compiled, and the components were classified for their ‘mixture relevance’ based on their aquatic toxicity following different tentatively defined criteria. The second step consisted in an experimental verification of the predicted aquatic toxicity of selected products, separately for the different sets of ‘relevant’ components established in the first step. The quantification of the deviation between experimentally observed and CA-predicted product toxicity for the different sets of “relevant” components aimed to identify the components that are indeed relevant for consideration in the mixture prediction. The protectiveness of the CBA approach was thereby assessed in comparison to the whole mixture testing approach.http://echa.europa.eu) for those substances among the other components in the formulated products (i.e. the additives) that were registered under REACH, from producer’s safety data sheets (SDS) obtained through Internet search, and from the ECOTOX database (http://cfpub.epa.gov/ecotox) provided by the US EPA. In case of multiple data for the same end point or a toxicity estimate given as a concentration range, the lowest value was used. With regard to aquatic toxicity, median effect concentrations (EC50) for invertebrates , fish , and green algae  were compiled. If data for the preferred end point were not available, other end points were taken as surrogate such as inhibition of yield in algae, effects in other algal species, immobilization of other crustacean species, EC50 for longer or shorter exposure times, and no observed effect concentrations (NOEC). In addition, information on ready biodegradability as defined in guidelines OECD 301 and OECD 310 was compiled for the additives. No quality assessment of the compiled data and no literature search to extend these data available within regulatory processes were performed. Data were compiled for the additives in the base formulations, i.e. pigments were not considered.For 21 biocidal products with complete dossiers available from the regulatory authorization process in the EU, confidential information on product composition and a base set of data were provided by the German Environment Agency. These data were complemented by retrieving information from the CAR for the a.s. prepared in the course of authorization in the EU, from the ECHA database  and EC50 i being the median effect concentration of the component i (mg l−1). This calculation was conducted separately for each trophic level, i.e. survival of Daphnia and fish and growth of green algae using the data compiled in the present study.Based on the CA concept, the relative theoretical contribution of each product component with the respective toxicity data was calculated in terms of toxic units (TU) and its relative contribution to the sum of toxic units (STU) of all considered components in the product as50,product as toxicity estimate relating to the summed concentration of the considered components was predicted for each trophic level asAccording to the CA concept, the EC50,product value was calculated separately for the various sets of selected product components  by including only these components with their EC50,i and Ci in the summed concentrations.The ECThe tentative identification of CBA-relevant components was based on existing regulatory approaches to be as much harmonized with regulatory procedures as possible. It was not the aim of the present project to check the existing assessment or classifications of the selected biocidal products.Three different sets of criteria were established to tentatively identify additives as ‘relevant’ for a CBA of the product. This was done separately for each product, resulting in multiple counts for additives that were present in several products. All known additives with at least one available end point for aquatic toxicity were allocated to one or more of the established categories  or to none of these categories. All additives for which aquatic toxicity data were unavailable were assigned to the category ‘no data’, and consequently not included in any mixture predictions.The category ‘HAZ’ related to the labelling of product components on the product SDS, which is regulated under REACH. According to the relevant guidance , all proThe lowest of the compiled aquatic toxicity end points was ≤ 1 mg/l and the concentration in the product  was ≥ 0The lowest of the compiled aquatic toxicity end points was > 1 mg/l and ≤ 100 mg/l and the concentration in the product was ≥ 1% w/w.The category ‘CLP’ used criteria for the identification of ‘relevant’ mixture components based on the definition stated in Annex I, Part 4 of the CLP regulation . AccordiConsideration of biodegradability in the environment is important for the classification of the ‘Chronic’ categories and, hence, also for the identification as ‘relevant for the mixture’ according to CLP: a component that is rapidly degradable is only considered as relevant for the mixture if its lowest aquatic toxicity end point is ≤ 1 mg/l. However, degradability (in the present study: readily biodegradability) was not taken into account in the categorization as ‘CLP’ or ‘not-CLP’, because excluding readily degradable components from the prediction would interfere with the planned comparison of experimentally observed and CA-predicted product toxicity. Yet, readily degradability as fate-related criterion was included in a second step.Differences between categorization as ‘HAZ’ and ‘CLP’ in the present study may result from various circumstances such as that SDS may have been issued according to the former directive or that data triggering the classification as ‘hazardous’ by the producer were not available within the scope of the present study for ‘CLP’ categorization. One key difference is that the categorization as ‘CLP’ is more conservative than ‘HAZ’, as it does not require the additive to be present at a concentration that leads to classification of the product as hazardous to the environment.n components of the mixture (MCR = n). Hence, an MCR could enable a yes/no decision on the relevance of a mixture assessment as such, but does not provide criteria to decide which components need to be taken into account in a CBA.The third tentative category, ‘> 10% STU’, relates to the predicted contribution of the individual additive to the joint toxicity  as predicted by CA. In the context of plant protection products, a substance may be deemed as dominating the mixture if it contributes > 90% to the overall toxicity . Hence, Seven wood preservative products with water-based formulations were tested in three different bioassays . All products were well miscible with water, and therefore no solvents were used to prepare test solutions. The tested products were either provided by the producer or obtained from commercial suppliers via Web-based shops. SDS obtained along with the products were compared with confidential dossier data (if available) to ensure consistency of information.Raphidocelis subcapitata (Culture Collection of Algae at the University of Göttingen) was tested based on OECD guideline 201 [−2 s−1. Test vessels were placed randomly on a shaker and constantly shaken with 100 ± 5 oscillations min−1. All tests were started with an inoculum of 5000 cells ml−1 obtained from a preculture in its exponential growth phase. There were six replicate vessels for the control and three replicate vessels for each of the five test item concentrations, prepared as a geometric dilution series with a spacing factor not exceeding 3.2. After 72 h of static exposure, algal cell density was determined by measuring fluorescence (Multiple Plate Reader Tecan ULTRA). The results (relative fluorescence units) were converted into biomass concentration (cells ml−1) based on a calibration curve that was generated from a dilution series of the preculture at the day of the test start. The average specific growth rate was calculated as end point according to OECD 201.The growth of the freshwater green algae line 201  using stDaphnia magna Straus (clone M 10) according to the OECD guideline 202 [D. magna after 48 h exposure was calculated as end point according to OECD 202.Immobilization  was tested with the freshwater microcrustacean line 202  using Elline 202 . Test coDanio rerio) maintained at conditions as prescribed by the guideline. Exposure was started within 1 h of fertilization by transferring the eggs to pre-test crystallizing glass dishes containing the respective test solutions. Eggs were checked for fertilization using a microscope and fertilized eggs were transferred to final test dishes. There were four replicates per treatment, control and positive control , each with ten embryos. Five test item concentrations were tested in a geometric dilution series with the spacing factor between 2.0 and 2.2. Test dishes were incubated at a constant temperature of 26 ± 1 °C in a climate-controlled incubator with light conditions of 300–700 lx and a light:dark cycle of 12:12 h. The test vessels were not aerated and the medium was not renewed during the test. The test duration was 96 h in three tests , but 48 h for the other products due to changes in legislation regarding animal welfare during the time of the project. According to OECD 236, the following parameters were used as indicator of mortality: coagulation of fertilized eggs, lack of somite formation, lack of detachment of the tail bud from the yolk sac, and lack of heartbeat. An embryo was scored as dead if one of these four criteria was fulfilled. If scored dead at the daily inspection, the embryo was removed to prevent deterioration and impact on the remaining embryos. Mortality as proportion of dead embryos after 48 h in relation to inserted eggs was used as end point according to the guideline.Fish embryo toxicity tests were conducted according to guideline OECD 236 . The eggSamples for chemical analysis were taken for the lowest, a medium, and the highest test concentration level from freshly prepared test solutions and in most tests also from test solutions at the end of the exposure period and stored in brown glass flasks at ≤ − 18 °C until analysis. The a.s. and selected additives  were analysed by direct injection of the samples into a liquid chromatographic system with tandem mass spectrometer (HPLC 1260 Infinity from Agilent Technologies coupled via an electrospray interface to an API 5500 tandem mass spectrometer from AB Sciex). Quantification was done against a calibration in the test medium. Limits of quantification were low enough to detect the residual concentrations of the analytes in all test samples under investigation (except for the blanks).50), i.e. the estimated concentration causing 50% effect by means of concentration–response modelling for the key response variables growth rate, immobilization and mortality. Concentration–response was based on nominal concentrations of the product using individual replicates in the software R, version 3.1.3 [The observed product toxicity was estimated as the median effect concentration  by fixing the upper limit d at 1. The confidence intervals (95%) for all EC50 values were obtained with the implemented function “ED” of the “drc” package using the delta method and the t distribution.The parameter 50 values for the products (mg product l−1) were re-calculated to the sum of the considered components (mg considered compounds/l) for defined sets: (i) only the a.s., (ii) the a.s. and all additives categorized as ‘HAZ’ or ‘CLP’, and (iii) the a.s. and all additives for which toxicity data were available for the respective end point. For this re-calculation, the maximum allowed concentrations of each of the substances in the product were assumed for deriving nominal test concentrations. It is important to note that maximum concentrations are established for each component of a product during the authorization process, while the actual concentration of a component in a marketed product may be lower . Hence, the exact actual concentrations of a.s. and additives in the tested products were not known, and the maximum allowed concentrations were therefore assumed as nominal concentrations. Still, to verify if deviations of the actual from the maximum allowed concentrations hampered CA predictions, the actual test concentrations of a.s. and some additives were determined and considered in the CA prediction in a second step. To this end, the observed EC50 values and CA-predicted EC50 values were re-calculated based on measured concentrations   was calcAn MDR above 1 indicates that the toxicity of the product is underestimated by the CA prediction based on the considered set of components, while an MDR below 1 indicates that it is overestimated.Statistical hypothesis testing and correlation analysis were conducted in Statistica, version 12.Based on CA prediction, growth inhibition of algae was the most sensitive end point in the majority of products Table  for whicSeven of the overall 23 products Table  were notp > 0.05) between the number of additives per product and the predicted combined aquatic toxicity or the predicted relative toxicity contribution of the additives with respect to the most sensitive end point , but the proportion of predicted joint toxicity contributed by additives was significantly greater in the solvent-based products . Hence, solvents were significantly contributing to the proportion of overall product toxicity attributable to their additives, particularly in the case of Daphnia.There were eight solvent-based formulations among the 21 products with organic solvents amounting to more than 50% of the total mass . All products for which algae were not the most sensitive species were solvent based. The 13 water-based formulations contained organic solvents up to a mass proportion of 7.1%. The predicted combined toxicity (STU) for the most sensitive end point did not significantly differ among water- and solvent-based formulations  with regard to the most sensitive end point in 9 out of the 21 products. This clearly indicates that additives can contribute significantly to the aquatic toxicity of formulated wood preservatives based on mixture toxicity predictions and the degree of this contribution varies among products.The total number of additives in the 21 products amounted to 273. When repeated counting of the same additive in different products was removed, 122 different additives (based on CAS numbers) remained together with 50 ‘unknowns’, i.e. additives with confidential identity or lack of CAS number. For 30 of the 122 different known additives, no data were available for any of the three aquatic toxicity end points. Based on available aquatic toxicity data, about half of the known individual additives (63 of 122) were not assigned to any of the three categories of tentatively relevant additives with regard to their presence in any of the products. The remaining 29 individual additives (53 cases including double counts for presence in different products) were allocated to one or more of the three categories of tentatively relevant components with regard to their presence in at least one product. The Venn diagrams in Fig. The ten additives identified as “hazardous to the environment” in the SDS of the products were all contained at less than 1% w/w in the respective product Table . Six of There were five cases (three different additives based on CAS numbers) where an additive was categorized as > 10% STU, but not ‘CLP’ or ‘HAZ’. All these additives contributed less than 20% STU to the overall toxicity, and two of them were readily degradable. Among the 38 cases of ‘CLP’ but not ‘HAZ’ were more additives classified as readily degradable, and 27 of them would be removed from the category ‘CLP’ . In the end, however, the selection of products for testing was mainly driven by their availability. Two more products 22 and 23) beyond the 21 products with detailed information were selected for testing to include a.s. with a different mode of action (MoA) and fish or daphnids as the most sensitive species  did not change the results for the most sensitive end points, while the trend for overestimation was slightly increased for the other end points  were additionally taken into account Fig. d. This fDaphnia and/or fish, leading to categorizations as ‘HAZ’ or ‘CLP’. The two additives with lacking algal data were both amines trimethylenediamine), a group of compounds for which high algal toxicity is known [Products 16 and 20 represent examples where the consideration of additives categorized as ‘CLP’ or ‘HAZ’ along with the a.s. did not cure the underestimation of product toxicity for the most sensitive end point , (ii) the lowest value was used in case of a toxicity range (e.g. 1 mg/l in case of EC50 between 1 and 10 mg/l), (iii) NOEC or EC10 was used if EC50 was not available, and (iv) toxicity estimates for the a.s. were taken from the CAR and thereby represent the most sensitive species for each taxon group, but not necessarily the one used for product testing. Thirdly, concentration addition tends to overestimate toxicity for mixtures of dissimilarly acting components. However, the degree of overestimation by CA compared to IA is relatively small [While underestimation of product toxicity was rare for the selected products, overestimation of toxicity was relatively frequent and increased slightly with the consideration of additives. There are a number of possible reasons for this trend. First of all, nominal (maximum) concentrations were assumed for all product components, while measurements for the a.s. and some additives indicated that actual concentrations in the products were often lower and never exceeded the maximum allowed concentration levels. Secondly, the toxicity data for the single substances can be deemed rather conservative, as (i) exact values were used in case of censored data  compared to an adult fish mortality test (from which the input data for single substances originate). While reported correlations between acute toxicity in fish embryos and adult fish are highly significant , 25, 29,Since the present study dealt exclusively with aquatic toxicity, it remains open whether the results and conclusions regarding identification of relevant components and reliability of a CBA could be extended to the risk assessment for the terrestrial environment or human health.Overall, the present study provides extensive evidence that a component-based assessment derives sufficiently reliable and, in terms of an ERA, protective estimates for the aquatic toxicity of biocidal products. To achieve this, the consideration of all additives in a product was clearly not required. Yet, the criteria for identifying additives as relevant for a CBA stated in the current draft guidance  may needAll active substances in the product.All additives (i) with a relevant aquatic toxicity end point ≤ 1 mg/l and a product concentration of ≥ 0.1% w/w (after consideration of the M-factor according to CLP), (ii) with a relevant aquatic toxicity end point > 1 mg/l and ≤ 100 mg/l and a product concentration ≥ 1% w/w, and (iii) those that are (or should be) labelled as hazardous or dangerous to the environment on the SDS of the product according to REACH.Applying the here tentatively established criteria for ‘relevant’ additives (‘CLP’ and ‘HAZ’) would improve the predictability of product toxicity and thereby the protectiveness of the CBA, since additionally those components would be considered that significantly contribute to the product toxicity without triggering the classification of the product as hazardous to the environment. Hence, it is recommended to consider the following components of a biocidal product in a CBA:Based on the here investigated dataset, the components that contribute more than 20% to the overall joint toxicity as well as relevant a.s. from other biocidal product types are covered by these criteria. Using a set of criteria based on the REACH and CLP regulations for the identification of additives relevant for a CBA of a biocidal product has the great advantage to improve consistency and harmonization with the existing regulatory guidance. In terms of workload, the number of additives to be considered would increase compared to the current set of criteria . HoweverWhile a CBA based on such criteria for identifying the relevant components appears to deliver reliable and protective assessments, the greatest deviation between the observed and predicted product toxicity was found to result from unavailability of aquatic toxicity data for some additives (particularly amines) with regard to the presumably most sensitive end points. This underlines the often-stated general constraint of any component-based risk assessment: the result of the assessment critically depends on the availability of data for all relevant components.


Objective The study aims to assess whether unintended children experience slower growth than intended children. Methods We analysed longitudinal data linked to the Karonga Health and Demographic Surveillance Site collected over three rounds between 2008 and 2011 on women’s fertility intentions and anthropometric data of children. Using the prospective information on fertility intention we assessed whether unintended children are more likely to be stunted than intended children. We applied Propensity Score Matching technique to control for endogenous factors affecting both the probability that a family has an unwanted birth and a child with poor health outcomes. Results We found that 24 % of children from unwanted pregnancies were stunted compared with 18 % of mistimed pregnancies and 17 % of those from wanted pregnancies. However, these differences in probability of children being stunted, though in the expected direction, were not significant either for large or small families, after controlling for age. The number of children in the household was associated with stunting and boys were substantially more likely to be stunted than girls. Conclusion We found no significance difference in probability of being stunted by mother’s fertility intention. In addition, in cross-sectional studies it is problematic to establish a causal link between unintended childbearing and child health. This is the first prospective study in Africa to assess the health consequences of unintended childbearing on child growth, we analyse longitudinal data on children growth and data on fertility intentions collected before the birth of the child.Studies that assess health consequences of unintended childbearing using retrospective data on fertility intentions such as the Demographic and Health Surveys suffer from Although there is wide agreement that the promotion of family planning lowers fertility, it is not clear to what extent greater contraceptive use and smaller family sizes will enhance health and family welfare or what are the consequences of unintended childbearing on children’s life chances Lloyd . UnintenIn this paper, the effects of unintended childbearing on child growth are examined. Under nutrition is the underlying cause of 35 % of the burden of disease in under-five children; low weight-for-age, low-height-for age and low-weight-for-height are all associated with increased risks of death  in Karonga District in Northern Malawi. Malawi is one of the poorest countries in the world; it has high fertility, with a Total Fertility Rate (TFR), according to the 2010 Demographic and Health Survey, of 5.7 births per woman, with 42 % of married women using any method of contraception. It is estimated that 26 % of women have an unmet need for contraception  and ICF Macro This is the first prospective study in Africa to assess the health consequences of unintended childbearing on child growth. Married or cohabiting couples were asked whether they wanted more children and the preferred timing of future births. Over the 3 year follow-up period, new births could thus be classified as intended (wanted), or unintended (unwanted or mistimed). Using these data on prospective fertility intentions, which were reported before the conception leading to the birth of the children, we assessed whether unintended recently born children are more likely to be stunted than intended children and if these differences are greater for children living in large families than in small families. Stunting was chosen as the key outcome, because it can be measured objectively and because it is the best overall indicator of longer-term health and nutrition.This study uses data collected between October 2008 and October 2011 from a module on fertility intentions linked to the on-going Karonga DSS in Northern Malawi, and repeated anthropometric data of children aged 10 years or younger collected in three rounds in 2008–2009, 2009–2010 and 2010–2011. The DSS baseline census was conducted in 2002-2004 following which the population has been under continuous surveillance. Details of the demographic data collection procedures have been documented  and piloted from September to October 2008. Data collection began on October 28th 2008.Women and men of reproductive age were asked questions on their current fertility and their marital status. A section on fertility preferences was introduced in order to assess separately whether or not the husband and wife wish to have another child and the preferred timing of the next birth. Together with anthropometric data from each survey round, we are able to analyse the effect of being unintended on the growth of a newly born child.As some mothers were either pregnant or did not respond to all the three rounds of the fertility intention study, we use the first available statement on preferences to define subsequent births as wanted, mistimed or unwanted. Unwanted births were defined as births occurring to women who wanted no more children. Mistimed births are those occurring within 6 months to women who wished to wait 1–2 years, those occurring within 18 months to women who wished to wait 2–3 years and those occurring within 30 months to those wishing to wait 3 or more years. The intendedness of the children with missing information on the mother’s fertility intention and those born before the mothers’ first report on fertility intention were classified as ‘unknown’. All other births were defined as intended. In this study, husbands’ preferences are not analyzed; this is justified by the high level of agreement (80 %) between spouses on desire for another child which has already been described  analysis. This method controls for the fact that ‘exposed’ children  are also more likely to be from lower socio-economic groups; hence in order to establish the ‘true’ effect of exposure on child health outcomes, it is necessary to control for this confounding. PSM creates a propensity score for each child in the ‘exposed’ group (given a set of background characteristics) and then matches the child to a control, those not exposed to the event with a similar score. We then can compare the outcome (i.e. stunting) for the ‘exposed’ and ‘unexposed’ children.To achieve this matching, the PSM technique uses a logistic regression based on a set of background characteristics to calculate the probability or propensity of each respondent of being exposed , and the ethics committee of the London School of Hygiene & Tropical Medicine, UK. Before the start of the demographic surveillance the Traditional Authority that covers the area, and all village headmen and traditional advisors in the study area were informed about the aims of the study and the nature of the data to be collected, and their approval and verbal authorisation was sought. All household members were given a similar explanation and interviews were only conducted if verbal consent was given by the household head and by the respective household members. The socio-demographic data for this study come from the basic demographic surveillance for which the ethics committees agreed that written consent was not needed. For the fertility intentions survey and for HIV testing, separate individual written consent was sought from the individuals with information sheets in the local language, Chitumbuka.Among 8768 women under 50 years old who participated in the fertility intentions survey, 3978 mothers had at least one child during the 3 year period of the study (28 October 2008–13 October 2011). Of this sample, 12 % of children did not have anthropometric data or had a biologically implausible value of height for age. We excluded from the analysis children who were under 1 year of age because the stunting level are low during this period and their growth pattern is influenced by breastfeeding. We analysed the remainder of 1704 children to 1701 mothers in this study (Table The probability of being stunted was significantly higher for children in households with 4 or more children 25 vs 19 %), children of HIV positive mothers (38 vs 21 %), and children of mothers who experienced a prior child death (29 vs 19 %). The prevalence of stunting declined monotonically with increasing maternal education. Stunting also depended on household income with children living in poor and agricultural households being more likely to be stunted than richer households or households with a salary employment as their main source of income  in the matched sample. However, when we simulated the standard errors of these estimates with bootstrap and we found that these difference was not statistically significant.In the United States a large, complex and inconclusive literature exists on the possible disadvantages that children whose conception was unintended may have in comparison to children who were intended (Brown and Eisenberg post-facto rationalisation encountered when retrospective preference data are used. Nevertheless, no statistically significant difference was found in the nutritional status according to whether the child’s conception was wanted at that time, was mistimed or not wanted at all, according to the mother’s reported preference stated before conception. Differences were in the expected direction and it is possible that a larger sample size would have established a significant effect but one of modest magnitude. It is reasonable to conclude that unintended children suffer no subconscious or conscious discrimination in terms of food allocation or health care. It is more surprising that the stress of the advent of an unintended birth on household income and food security in this poor and under-nourished population was not reflected in the growth of the index child; however this effect might appear in older siblings.This study was conducted in a poor rural setting where under-nutrition is common. Unlike most previous studies, it has the advantage of prospective fertility preference information, thus circumventing the problem of A possible explanation for this negative result is that questions on fertility intentions are poorly understood by women in Karonga or that responses fluctuate over time. In a society where contraception is absent the former hypothesis would be convincing but, in Karonga, 43 % of married women reported use of a method and thus the idea of volitional childbearing and reproductive control is not alien. The fact that a high level of agreement was found between spouses concerning desire for another child also indicates that fertility intention data are valid. We were also able to check consistency of women’s intentions over the course of the study. Among women who said at baseline that they wanted no more children, 35 % were pregnant at round 3 or had given birth, 13 % had changed their intention to wanting another child or were unsure while 53 % gave the same response (Machiyama et al. Other interpretations are more plausible. As throughout sub-Saharan Africa, traditions in Karonga no doubt place a high value on children and positive emotional reactions to a new birth may outweigh any prior intentions to avoid or delay further births. Moreover, unwanted and mistimed births are commonplace in this population. One of the remarkable findings of the study is that over one-third of young children were born to mothers who had earlier stated a desire for no more and a similar proportion were mistimed. In a setting where fertility control is weak and unintended childbearing is so common, it is perhaps unsurprising that no adverse effect of unintendedness was found relative to other children.The analysis found that boys are more likely to be stunted than girls, confirming similar results from other studies (Griffiths et al. What are the policy implications? Malawi has a national family planning programme whose ultimate purpose is to reduce unwanted childbearing. The apparent absence of any link between unintended births and nutritional welfare found in this study in no way undermines investment in family planning. Greater and more effective use of contraception will inevitably lead to a reduction of unintended pregnancies and to smaller family sizes, where there is less competition between siblings for scarce resources. Improvements in family welfare are likely to result from this transition.