Consumption of antibiotics in food animals is increasing worldwide and is approaching, if not already surpassing, the volume consumed by humans. It is often suggested that reducing the volume of antibiotics consumed by food animals could have public health benefits. Although this notion is widely regarded as intuitively obvious there is a lack of robust, quantitative evidence to either support or contradict the suggestion. As a first step towards addressing this knowledge gap, we develop a simple mathematical model for exploring the generic relationship between antibiotic consumption by food animals and levels of resistant bacterial infections in humans. We investigate the impact of restricting antibiotic consumption by animals and identify which model parameters most strongly determine that impact. Our results suggest that, for a wide range of scenarios, curtailing the volume of antibiotics consumed by food animals has, as a stand-alone measure, little impact on the level of resistance in humans. We also find that reducing the rate of transmission of resistance from animals to humans may be more effective than an equivalent reduction in the consumption of antibiotics in food animals. Moreover, the response to any intervention is strongly determined by the rate of transmission from humans to animals, an aspect which is rarely considered. The notAntibiotic consumption by food animals occurs for the purposes of herd health, prophylaxis and growth promotion. Growth promotion, often involving sub-therapeutic doses, is particularly controversial. It has been banned in European Union (EU) countries since 2005 and is the subject of a more recent voluntary ban in the USA. Currently, 51% of the OIE member countries who report on antibiotic consumption/usage have a complete ban on using antimicrobials as growth promoters, and a further 19% have a partial ban . There hA key challenge for understanding the expected impact of reducing drug usage is that the relationship between antibiotic consumption by food animals and levels of resistant bacteria in humans is complex. First, food animals are far from the only source of human exposure to antibiotic resistant bacteria: high levels of antibiotic use in hospitals, clinics and the general population are also major drivers of resistance in humans . QuantifAs a first step towards addressing this knowledge gap, here we develop a simple mathematical model for exploring the generic relationship between antibiotic consumption by food animals and levels of resistant bacteria in humans. Our objective is to better understand the dynamics of antimicrobial resistance moving between food animal and human populations and to identify which model parameters have the greatest influence on levels of resistance in humans and for which parameter combinations we expect to see the greatest impact of reducing antibiotic consumption by food animals.By using the simplest possible mathematical model as a starting point, we hope to be able to make a first step in understanding this highly complex system and gain some robust and useful insights into its behaviour.2.2.1.RH, the fraction of humans with antibiotic resistant bacteria (so a measure of the ‘level of resistance’); and RA, the fraction of food animals with antibiotic resistant bacteria. The rationale of the model is that humans or food animals can acquire antibiotic resistant bacteria from different sources:(1) within host selection for resistant bacteria in response to direct exposure to antibiotics;(2) direct or indirect exposure to antibiotic resistant bacteria or mobile genetic elements containing resistance determinants carried by other individuals within the same population (e.g. humans acquiring resistance from a human source); and(3) as (2) but between different populations .The dynamics of RH and RA is given by the coupled ordinary differential equations:ΛH is the per capita rate at which humans acquire antibiotic resistant bacteria through direct exposure to antibiotics and ΛA is the equivalent in food animals; (1 − RH) and (1 − RA) are respectively the fraction of humans without antibiotic resistance and the fraction of food animals without antibiotic resistance. βHH is the per capita rate at which humans acquire antibiotic resistant bacteria as a result of exposure  to other humans harbouring resistant bacteria and βAA is the equivalent for animals; βAH is the per capita rate at which humans acquire antibiotic resistant bacteria as a result of exposure  to food animals harbouring resistant bacteria and βHA is the reverse; µH is the per capita rate at which humans with resistant bacteria revert to having only susceptible bacteria  and µA is the equivalent in food animals. The time unit is arbitrary and does not affect the equilibrium values. We assume that all transmission parameters  combine transmission of both antibiotic resistant bacteria and transmission of mobile genetic elements. Although these rates could be disaggregated, this would (for our study) have no impact on the system dynamics for a given set of parameters.Our mathematical model is intended to be as simple as possible while still capturing the nonlinearities inherent in infectious agents spreading between two host populations. To achieve this, we consider two variables: RH in terms of the eight model parameters. Although we do not consider the real-world system to be at equilibrium, largely because antibiotic consumption patterns have changed considerably in recent decades (from zero before 1932) and continue to do so, we regard µH and µA are high, i.e. the mean duration of resistant infections is short (Studying the system in a steady state (i.e. at equilibrium) allows us to explore the long-term effects of changing different parameter values. To obtain an equation for the equilibrium value, ΛA = 0  and define impact, ω, as 1—the ratio of As an indication of the potential impact of curtailing antibiotic usage in farm animals on the level of resistance in the human population we define athematica v. 10.3 [All analyses were carried out in Wolfram M v. 10.3 .2.2.βHA. For the low impact scenario, βHA = 0.1, and for the high impact scenario, βHA = 0.001. These values were chosen to maximize the differences while minimizing changes in the baseline levels of resistance between the two scenarios. The baseline parameters for the two scenarios are given in To identify key parameters and capture the nonlinearities of the system in more detail, we consider two distinct scenarios in this study, a low impact scenario and a high impact scenario. The difference between these two scenarios is the choice of baseline value for 2.3.DTi using the extension of Fourier amplitude sensitivity test (FAST) as described in Saltelli et al. [DTi. It therefore captures the overall effect of parameter variations on equilibrium levels of resistance over a pre-specified range (i.e. including first- and higher-order interactions between model parameters). For example, a value of DTi = 0.10 indicates that 10% of the total observed variation of the prevalence is explained by the parameter under consideration. The sensitivity analysis was carried out using R [We determine which model parameters have most influence on the outcome value by computing the total sensitivity index i et al. . The exti et al. ,17 for e using R . For the3.RH and RA in time. βHA in the high impact scenario .The sensitivity analysis on the equilibrium equation for and βHH, . FurtherΛA, but is more sensitive to changes in βAH, suggesting that reducing the former without addressing the latter may have limited impact on the prevalence of antibiotic resistance in the human population. Furthermore, the figure shows that the change in βAH is nonlinear, which suggests that partial reductions of βAH may only have limited impact when a with figure 3b shows that the effect of reducing the rate at which animals acquire antibiotic resistant bacteria as a result of exposure of animals to antibiotics (ΛA) is also strongly influenced by the per capita rate at which food animals acquire antibiotic resistant bacteria as a result of exposure to humans carrying resistant bacteria (βHA). For the higher value of βHA  lowering ΛA by itself has little influence.ω (defined above). ΛH, the rate at which humans acquire antibiotic resistant bacteria as a result of exposure of humans to antibiotics, followed by μH, μA and βHA. ΛA and βAH have less influence. βAH and ΛA on the impact, ω, of curtailing antibiotic use in food animals. The difference between the low impact scenario and the high impact scenario is immediately clear from these graphs as there is virtually no impact of reducing ΛA in the low impact scenario , while in the high impact scenario (with relatively low βHA) there is a much more obvious benefit.Figures 4.per capita rate at which humans acquire antibiotic resistant bacteria as a result of direct exposure to antibiotics (ΛH). Of much greater interest is the importance of the per capita rate of transmission of antimicrobial resistance from humans to animals (βHA) (figures βHA) and a high impact scenario (low βHA). If βHA is high (figures a and 5a) then the effects of reducing the rates at which animals acquire resistance as a result of antibiotic usage (ΛA) and humans acquire antibiotic resistant bacteria from animals (βAH) are limited . This contrasts with the situation where βHA is low (figures 3b and 5b). This indicates that whenever the rate of transmission of antibiotic resistant bacteria from humans to animals is high it is more difficult to curb the antibiotic resistance problem, a rather counterintuitive result and often overlooked in discussion about this topic.It is often implied that the high levels of consumption of medically important antibiotics by food animals is contributing significantly towards the global public health problem of antibiotic resistance. Therefore, we tested the potential impact of curtailing the use of antibiotics in food animals on the (long-term) prevalence of humans carrying resistant bacteria using a mathematical model designed to capture the nonlinearities inherent in the transmission of infectious agents between two populations as simply as possible. Our results show that, as expected, the system is sensitive to changes in  figures  and 5. F figures a and 5a ΛH to 0), we can only reduce the long-term prevalence of antibiotic resistance in humans to 0.56 for the low impact scenario and 0.54 for the high impact scenario . In other words, if resistance dynamics in human and animal populations are coupled, as is generally thought to be the case in practice, substantial impacts on levels of resistance requires coordinated interventions across both populations.Also of interest is that a failure to address the agricultural usage of antibiotics severely limits what can be achieved by tackling the problem from the human side, i.e. even if no resistance is acquired via direct exposure to antibiotics in humans  different results. Similarly, for the β's we combined the rate of acquiring resistance through transmission of  bacteria and through the transmission of mobile genetic elements. Although it is possible to disaggregate these modes of transmission, this would require an additional parameter and would not alter the system dynamics for a given set of parameters . However, if the separate contributions of the different transmission paths were of interest, such disaggregation would be necessary. Lastly, for the recovery rates (µ) we assumed that these combine recovery from infection with a resistant strain with demographic replacement by hosts with susceptible ones. The scenarios considered here assume high recovery rates and so emphasize the former .Our study has several limitations that should be recognized. The first limitation is the simplicity of the model used. As indicated in the introduction, antibiotic resistance is a highly complex problem with numerous routes of transmission and with dynamics that will vary qualitatively and quantitatively for different drug-bug-animal combinations. Accounting for all these different routes and combinations separately is challenging. However, by taking the simplest possible mathematical model as a starting point, we are able to make a first step in trying to understand this highly complex system and gain some robust and useful insights into its behaviour. These findings can then be used as stepping stones for the development of more complicated (and perhaps more precise) models. As with all models, several assumptions have been made in this study. For example, Key aspects of future models might include: (i) information on geographical distance and contact structures between and within populations; (ii) explicit consideration different modes of inheritance of resistance; and (iii) quantitatively relating rates of gain of resistance to historical data on antibiotic consumption. Also, the dependency of resistance on demographics should be taken into account as human and livestock demographics can be very different (for example the batch structure that is common in poultry has an influence on infectious disease ).As with all models, parametrization is an important issue. In this study, we chose our baseline parameter values such that the long-term prevalence of the fraction of the human population that is affected by resistant bacteria is roughly 70%. This mimics, for example, the situation of ampicillin resistance in both human and livestock in the United Kingdom where antibiotic resistance is well established but still leaves room for improvement or deterioration of the levels of resistance. However, knowledge of the prevalence of resistance in the two populations is not by itself sufficient to parametrize this model, as there are eight parameters to be estimated. Independent estimates of parameter values are required, but are not currently available, even for any specific drug-bug-animal combination in a defined setting. In practice, the many different combinations of antibiotic, bacteria strain, food animal species and setting will represent many different points in parameter space, each of which would need to be determined individually—a significant challenge. That said, the results of the simple, generic model presented here are robust in the sense that they apply over a wide range of parameter space that we expect to cover many real-world scenarios.5.To conclude, we have shown in this study that we can obtain useful insights into a highly complex problem like antibiotic resistance by using a simple mathematical model. Although it is widely regarded as intuitively obvious that reducing antibiotic consumption in animals would decrease levels of antibiotic resistance in humans this is, in fact, not the case for a wide range of scenarios (i.e. parameter space), especially if this intervention is made in isolation. Reducing the rate of transmission of resistance from animals to humans may often be more effective. In addition, the behaviour of the system, and so the response to any intervention, is strongly determined by the rate of transmission from humans to animals, but this has received almost no attention in the literature. It is thus not enough to only lower the consumption of antibiotics in food animals, the transmission both from and to food animals should also be limited in order to maximize the impact of this and other interventions. We recommend that formal, quantitative analyses are needed to assess the expected benefits to human health of reducing antibiotic consumption by food animals. In some circumstances, these benefits will be very small and other measures will be needed to reduce the public health burden of antibiotic resistance.


Prescribing policy recommendations aimed at moving immunosuppressant prescribing for renal transplant patients from primary to secondary care may result in benefits of increased safety and reduced cost. However, there is little evidence of patients’ preferences for receiving their immunosuppressant therapy from hospitals compared to community dispensing. The aim of this study was to elicit patient preferences for different service configurations focusing in particular on home delivery versus collection of medication from hospital.A discrete choice experiment was administered to 265 renal transplant patients in North Wales. Respondents were presented 18 pairwise choices, labelled as either home delivery or hospital collection, and described by the attributes: frequency of supply, waiting time (for delivery or collection) and method of ordering . Data were analysed using a random-effects logit model and marginal rates of substitution calculated based on the waiting time attribute.p < 0.05). Results indicate that patients are willing to increase waiting time by nearly 10 h to have a home delivery service.A response rate of 63% was achieved, with 5332 usable observations from 150 respondents. Method of delivery , frequency of supply  waiting time , provider contact (desirable) , patient contact by telephone (desirable)  and patient contact electronically (undesirable)  were statistically significant  contains supplementary material, which is available to authorized users. The safe and effective use of immunosuppressants in the prevention of organ transplant rejection requires careful prescribing, and a high degree of adherence. Adverse events may arise from missed doses , medicatPrescribing policies that promote the safer use of immunosuppressants in the UK have centred on increased specialist input from secondary care or tertiary centres to meet the pharmaceutical care needs of patients , 7. PatiDiscrete choice experiment (DCE) is a quantitative technique for eliciting patients’ stated preferences. It has been applied extensively to assess service users’ preferences for health care service delivery and organization , to infoThe health board in North Wales is responsible for three major hospitals, located in the West, Central and East of the region. The East region is mostly urban or semi-urban, whereas the West and Central areas are more rural with distances from patients’ homes to the nearest hospital being up to 60 miles and requiring up to 2 h of travel time. Current supply of immunosuppressants is via collection alongside other medication prescribed by the general practitioner (GP) on a monthly basis from a local community pharmacy. However the policy recommendation is a change of prescribing responsibility from the GP to hospital (secondary care) based nephrologists. This means that the supply of immunosuppressants has to be arranged by the hospital pharmacies, which can be direct collection from the hospital or provision of home deliveries.A mixed methods approach was taken, which involved qualitative research methods (focus groups) to inform the design of the DCE. Ethics approval was granted by the North Wales Research Ethics Committee (West) reference 11/WA/0244.Initial attributes and levels of the prescribing service were based on clinical experience with home delivery services of erythropoiesis stimulating agents, a programme which initiated in North Wales in 2007, and a patient satisfaction questionnaire administered to 198 patients in 2008 (response rate 76.8%). Responses to the questionnaire highlighted the importance to patients of the location of medication delivery  and identified a prolonged waiting time as a cause of patient dissatisfaction . In the Focus groups were convened to discuss the attributes and refine how they were to be presented as part of the DCE, to identify relevant levels, to ensure that they were important and relevant to the patient population and understood by DCE respondents . Twenty The purpose of the first focus group was to assess the relevance and importance of the identified attributes  in the UK), and to identify any further attributes using a thematic analysis. The second focus group considered the attribute list and again considered the relevance and importance, with a focus on phraseology, and potential attribute levels.Focus group participants did not identify any further attributes; however there was concern that the inclusion of a price proxy would result in different interpretation of the meaning of cost  in the context of healthcare being free at the point of delivery. It was decided, therefore, not to include a price proxy in the DCE. Waiting time was considered as an attribute to estimate DCE respondents’ willingness to give up time for improvements on other attributes. Clinical experience with home delivery of medicines and data on local hospital dispensary waiting times were considered when assigning levels to this attribute. Although the attribute pertaining to prescribing safety/ risk of errors was considered to be important to some focus group participants, it was identified as not suitable for inclusion in the DCE as no meaningful levels could be established as no comparative risk data were available for the different service models. The final selection of attributes and levels used in the DCE are detailed in Table A labelled design was used to keep choice sets realistic , and to 3 × 21) profiles and 1431 choice sets, hence a fractional factorial design was used to arrive at a manageable number of choices. The design was based on an orthogonal main effects design taken from a published design catalogue (Design 19a)   were the least important attributes. Patients were more likely to choose infrequent delivery of medicines and initial contact for ordering made by the health care provider. Increased waiting time and the need for patients to initiate the medication ordering process themselves –either by phone or online– decreased the probability of patients choosing a method of medication delivery.The absolute values of coefficients indicate their relative importance on patients’ choice. Method of delivery had the greatest absolute value of the coefficient , the results indicate that patients will accept an additional 26 min  of waiting time if the interval between medication supplies was increased by one month. Home delivery supplies were valued at almost 10 h of waiting time. A reduction in waiting time of over 2 h would be required for patients to accept online ordering of their medications.Total utility for home delivery was 0.458 (95% CI 0.316 to 0.601). Hospital supply yielded a significantly lower utility of −0.410 (95% CI −0.514 to −0.302).p < 0.01).Four subgroups satisfied the criteria for analysis: region , distance to clinic, experience with home deliveries, and employment status. All subgroups were shown to be significant in terms of model fit, compared with the base case  regional nephrology centres within the Health Board show a higher preference to home deliveries than patients in the east, with a willingness to wait an extra 711 min (more than 11¾ hours) and 444 min  for home delivery, respectively. The travel attribute was not significant for patients living within 30 min of their local hospital clinic; but for those living 30 min or more away, were willing to wait an extra 347 min (5¾ hours) for home delivery.Patients with previous experience of home deliveries show a weaker preference for home delivery supply compared to those who have not received medication deliveries to their homes. They were willing to increase waiting time by 531 min (nearly 9 h) compared to 623 min (over 10 h), respectively. Of all subgroups, patients in full time employment showed the lowest preference for home deliveries and willing to increase waiting time by only 271 min (4½ hours) for this service.Marginal rates of substitution . A second potential limitation was the use of a forced choice format which, while being appropriate to the policy context, does not allow for patients to indicate that they did not prefer one supply method over the other. Inclusion of an option of “no preference”, however, would have impacted on the number of discrete choices to the extent that response rate might have been adversely affected. Labelling the choice sets with the two possible supply methods represented a third limitation as this led to a significant number of patients exhibiting a dominant preference by choosing home deliveries irrespective of the levels of other attributes in the choice set. We also note that when analysing data on waiting time, no distinction was made between time waiting at the hospital versus time waiting at home, and no account was made for travel time to the hospital, however given that patients collect their prescriptions following an appointment, this is not an additional expense. No attributes describing adherence to treatment or medication safety were included in this DCE. While there is no difference in the frequency of clinic appointments with either method of medication delivery, collection of medicines at hospital pharmacies might provide an opportunity for patient counselling, including matters relating to adherence. Finally, a transcription error meant that 2 of the 18 choice sets did not correspond to the original design; but extensive testing for level balance and orthogonality confirmed that neither were compromised nor affected the validity of the results.Waiting times are often used as a key performance indicator to measure workload and performance in pharmacy outpatient medication supplies. However, this study showed that patients are willing to accept a significant increase in waiting time for other preferred attributes describing a medication supply service. This should be considered by policy decision makers when evaluating services affecting medication supply. Recent changes to commissioning of solid organ transplantation by NHS England (2014) will result in a significant shift of immunosuppressant prescribing from primary care to transplant centres or secondary care providers with assumed benefits on prescribing safety and cost . The impThese first insights into the preferences of renal transplant patients suggest that patients have a preference for home-delivery of their immunosuppressant medications. The strength of this preference is increased for patients who live in more rural areas, but decreases in patients who are in full time employment. These findings and influencing factors should be considered in arriving at policies aimed to maximise adherence and patient safety.


Given a complete graph branch and cut approach. Usually the integrality constraints are relaxed first and all separation processes to identify violated inequalities are done on fractional solutions. In our approach we try to exploit the impressive performance of current ILP-solvers and work only with integer solutions without ever interfering with fractional solutions. We stick to a very simple ILP-model and relax the subtour elimination constraints only. The resulting problem is solved to integer optimality, violated constraints  are added and the process is repeated until a feasible solution is found. In order to speed up the algorithm we pursue several attempts to find as many relevant subtours as possible. These attempts are based on the clustering of vertices with additional insights gained from empirical observations and random graph theory. Computational results are performed on test instances taken from the TSPLIB95 and on random Euclidean graphs.The  Traveling Salesman/Salesperson Problem TSP is one of the best known and most widely investigated combinatorial optimization problems with four famous books entirely devoted to its study , which forbid solutions consisting of several disconnected tours, and finally . Then we check if the obtained integer solution contains subtours. If not, the solution is an optimal TSP tour. Otherwise, we find all subtours in the integral solution (which can be done by a simple scan) and add the corresponding SEC to the model, each of them represented by the subset of vertices in the corresponding subtour. The resulting enlarged ILP model is solved again to optimality. Iterating this process clearly leads to an optimal TSP tour.The general approach works as follows (see Algorithm 1). First, we relax all SEC  from theiteration. We define the set of violated SEC as the set of all included SEC which were violated in an iteration (see line 7). Figures Every execution of the ILP-solver see line 3) will be called an  will be see line . FiguresIt should be pointed out that the main motivation of this framework is its simplicity. The separation of SEC for fractional solutions amounts to the solution of a max-flow or min-cut problem. Based on the procedure by Padberg and Rinaldi , extensiThis approach for solving TSP is clearly not new but was available since the earliest ILP formulation going back to Dantzig et al.  and can Miliotis  also conG, d) there exists a minimal set of subtours From a theoretical perspective, the generation of subtours involves a certain trade-off. For an instance   5) by pimentclass2pt{minimIt turned out that the three versions sometimes  lead to huge differences in running time (up to a factor of 5). This is an interesting experience that should be taken into consideration also in other computational studies. From our limited experiments it could be seen that version  in compaAs pointed out above, the focus of our attention lies in the generation and selection of a “good” set of SEC, including as many as possible of those required by the ILP-solver to determine an optimal solution which is also feasible for TSP, but as few as possible of all others which only slow down the performance of the ILP-solver.Trying to strike a balance between these two goals we followed several directions, some of them motivated by theoretical results, others by visually studying plots of all subtours generated during the execution of Algorithm 1.BasicIntegerTSP.Many ILP-solvers report all feasible integer solutions found during the underlying branch-and-bound process. In this case, we can also add all corresponding SEC to the model. These constraints can be considered simply as part of the set of violated SEC. Not surprisingly, these additional constraints always lead to a decrease in the number of iterations for the overall computation and to an increase in the total number of SEC generated before reaching optimality  and add iteratively edges in increasing order of distances until the desired number of clusters c is reached (see lines 5 and 6). In each iteration the current clustering is implied by the connected components of the current graph (see line 7). We denote this clustering approach by Metric TSP or the Euclidean TSP.First, we fix the number of clusters c and thus a rough estimation of c is sufficient. The behavior of the running time as a function of c can be found for particular test instances in Fig. It was observed in our computational experiments that the performance of the TSP algorithm is not very sensitive to small changes of the cluster number Although the clustering algorithm (see Algorithm 2) decreases the computational time of the whole solution process for some test instances, we observed a certain shortcoming. There may easily occur clusters consisting of isolated points or containing only two vertices. Clearly, these clusters do not contribute any subtour on their own. Moreover, the degree constraints , but add an edge only, if it is incident to one of the vertices in a connected component (i.e. cluster) of size one or two. This means basically that we simply merge these small clusters to their nearest neighbor with respect to the actual clustering. Note that this is a step-by-step process and it can happen that two clusters of size 1 merge first before merging the resulting pair to its nearest neighboring cluster. The resulting restricted clustering approach will be denoted by To avoid this situation, we want to impose a minimum cluster size of 3. An easy way to do so is as follows: After reaching the c.Against our expectations, the computational experiments  Core(TM) i5-3470 CPU @ 3.20GHz with 16 GB RAM under LinuxC++SCIP MIP-solverCPLEX as LP-solver. It has often been discussed in the literature  were especially prone to unstable behavior, such as widely varying running times for minor changes in the parameter setting. This seems to be due to the fact that these instances contain many 2-matchings with the same objective function value, and thus the search process for a feasible TSP tour can vary widely  are defined as point sets in the Euclidean plane with distances corresponding to the Euclidean metric or as a set of geographical cities, i.e. points on a sphere. Moreover, they often contain substructures like meshes or sets of colinear points and finally, since all distances are rounded to the nearest integer, there are many instances which have multiple optimal solutions. These instances are relatively unstable with respect to solution time, number of iterations, and—important for our approach—cardinality of the set of violated SEC. For our approach instances with a mesh geometry  TSPLIB instances and one random instances for every number of vertices t (s)) in wall-clock seconds (rounded down to nearest integers), the number of iterations (#iter), i.e. the number of calls to the ILP-solver in the main part of our algorithm (without the TSP solutions for the clusters) and the number of SEC (#SEC) added to the ILP model in the last iteration, i.e. the number of constraints of the model which yielded an optimal TSP solution. We often compare two approaches in a table by taking the mean ratio, i.e. we compute the quotients between the particular columns t (s)/#iter/#SEC of the compared method over the first “reference” method on the same instances and then we report the arithmetic mean of these quotients.All our running time tables report the name of the instance, the running time  in Fig. u159 is much more structured and has many colinear vertices. Here, we can observe a different behavior. While the standard clustering is actually beaten by BasicIntegerTSP for smaller cluster numbers and has a more or less similar performance for larger cluster numbers, the restricted clustering is almost consistently better than the other two approaches. For c between 2 and 10 there exists a large component containing many mesh substructures which consumes as much computation time as the whole instance.Instance Consist of more clearly separated clusters andNot contain mesh substructures and colinear vertices.These two instances give some indication of how to characterize “good” instances for our algorithm: They shouldA summary of the computational results for BasicIntegerTSP and the most promising variants of clustering based subtour generations can be found in Table pr299). For instances with mesh substructures it is difficult to find an optimal 2-matching which is also a TSP tour. For random Euclidean instances the results are less clear but approaches with fixed number of clusters seem to be better then the hierarchical ones.As already mentioned, best results are obtained with u . The lower graph of Fig. We started with extensive computational tests, some of them presented in Figs. It was proven by Beardwood et al.  that the by Rhee  and Yuki by Rhee . We usedcomplete convergence, Yukich (converges completely (c.c.) to a constant C if and only if for all  A sequeLet See our accompanying technical report, Pferschy and Staněk . \documen, one would obtain that also Based on these results the following idea might lead to a proof that the expected cardinality A different approach is illustrated in Fig. lazy cuts and invoke them only when a new integer solution is found. However, since the number of generated constraints remains moderate in our test instances we found no advantage in pursuing this option.In this paper we provide a “test of concept” of a very simple approach to solve TSP instances of medium size to optimality by exploiting the power of current ILP solvers. The approach consists of iteratively solving ILP models with relaxed SEC to integer optimality. Then it is easy to find integral subtours and add the corresponding SEC to the ILP model. Iterating this process until no more subtours are contained in the solution obviously solves the TSP to optimality. It would also be possible to treat subtour elimination constraints as so-called In this work we focus on the structure of SEC and how to find a “good” set of SEC in reasonable time. Therefore, we aim to identify the local structure of the vertices of a given TSP instance by running a clustering algorithm. Based on empirical observations and results from random graph theory we further extend this clustering-based approach and develop a hierarchical clustering method with a mechanism to identify SEC as “relevant”, if they appear in consecutive iterations of the algorithm.Concorde, Applegate et al. (We mostly refrained from adding additional features which are highly likely to improve the performance considerably, such as starting heuristics (cf. Sect. e et al. , which hFinally, we briefly discussed some theoretical aspect for random Euclidean graphs which could lead to polyhedral results in the expected case.


In this first issue of the Netherlands Heart Journal in 2017, I would like to introduce to you a new editorial board, consisting of an editor-in-chief and five deputy editors. It is an Amsterdam-based editorial board to facilitate close interaction between the board members. It is the ambition of the new editorial board to further improve the journal’s current impact factor as an index of its quality and success. The attractiveness of the journal for authors may be enhanced by offering a rapid review system, which requires close collaboration between the associate editors and the national editorial and international advisory board. Moreover, the Netherlands Heart Journal is an open access, peer review journal offering services without payment for authors in contrast with numerous other open access journals.Professor Jan J. Piek Fig.  completeYigal Pinto Fig.  was traiThe main research interest of the Pinto group  is to identify novel mechanisms that can help treat or diagnose cardiomyopathies, such as genetic forms of DCM. His group focuses on RNA biology in relation to genetic variants that are related to heart failure and translates findings to biomarkers or therapeutic targets.Robbert de Winter Fig.  studied The main research interest of his research group relates to acute coronary syndromes, diagnostics, risk prediction and outcome in STEMI and NSTEMI patients and biomarker studies. In addition, there is increased involvement in structural and congenital heart disease both in percutaneous procedures and in research projects.Ron Peters Fig.  had all cum laude), and defended his PhD thesis at that same institution in 2001. He was a research fellow with Michael R. Rosen MD  and with José Jalife . After his training as a cardiologist (2008) he subspecialised as a clinical electrophysiologist (2010), both at the AMC. The research interests of his group consist of mechanisms and treatment of atrial fibrillation, closely intertwined with the thoracoscopic atrial fibrillation ablation program and the Laboratory of Experimental Cardiology. Furthermore, his group publishes on arrhythmias in adult congenital heart disease.Joris de Groot Fig.  was bornJolanda van der Velden Fig.  studied The editorial board would like to take the opportunity to thank the previous board members and in particular Professor E.E. van der Wall, who served as editor-in-chief for almost three decades, initially as the editor-in-chief of the Nederlands Tijdschrift voor Cardiologie followed by the journal Cardiologie and finally the Netherlands Heart Journal. These efforts led to the current position of the Netherlands Heart Journal among the top of the 60 national society journals of the ESC-related countries. The editorial board acknowledges the support of the Netherlands Society of Cardiology in its endeavour to further improve the quality of the Netherlands Heart Journal.


Refractive optical elements for X-rays that vary the size of the focal spot of an X-ray mirror are reported. X-ray mirrors are widely used at synchrotron radiation sources for focusing X-rays into focal spots of size less than 1 µm. The ability of the beamline optics to change the size of this spot over a range up to tens of micrometres can be an advantage for many experiments such as X-ray microprobe and X-ray diffraction from micrometre-scale crystals. It is a requirement that the beam size change should be reproducible and it is often essential that the change should be rapid, for example taking less than 1 s, in order to allow high data collection rates at modern X-ray sources. In order to provide a controlled broadening of the focused spot of an X-ray mirror, a series of refractive optical elements have been fabricated and installed immediately before the mirror. By translation, a new refractive element is moved into the X-ray beam allowing a variation in the size of the focal spot in the focusing direction. Measurements using a set of prefabricated refractive structures with a test mirror showed that the focused beam size could be varied from less than 1 µm to over 10 µm for X-rays in the energy range 10–20 keV. As the optics is in-line with the X-ray beam, there is no effect on the centroid position of the focus. Accurate positioning of the refractive optics ensures reproducibility in the focused beam profile and no additional re-alignment of the optics is required. It is frequently desirable to be able to broaden the focus size in order, for example, to allow larger sample areas to be imaged more rapidly at lower spatial resolution or to allow the beam size to be matched to a diffracting crystal in order to reduce the sample radiation dose and minimize radiation damage during a measurement. Ideally this should be done with no significant reduction in the overall beam intensity in the focal spot and the change should be fast in order to meet the demands of rapid data collection at modern synchrotron radiation sources.et al., 2016et al., 2016et al., 2007et al., 2013et al., 2013et al., 2014Existing methods for increasing the focus size include changing the surface profile of a bimorph mirror in order to change the mirror focal length  in order to reduce the focus size of the optics of an X-ray beamline  can be met in the geometrical optics regime by A and i indexes the wavefront section) and ensuring that within the ith section the wavefront distortion is given byith section, the angle of the wavefront normal is w requires Q = 0.4 m is shown in Fig. 1Within the limits of geometrical optics, the wavefront distortion yy) maps onto a distinct point at the focal plane and therefore each point on the focal plane receives a geometrical ray from a single point in each section of the initial wavefront. Physical optics, however, predicts that interference fringe structures caused by interference of the X-ray amplitude propagating from these spatially separated points will be present on the focal spot.While arguments based on geometrical optics can predict the size of the focal profile, physical optics which takes into account the wave nature of the X-rays is required to correctly model the intensity distribution for the focused highly coherent X-rays from a modern storage ring source. In each section of the initial wavefront P is the distance from source to the focusing optical element and Q is the distance from optic to the focus. The effect of the incoherent source is shown at the top of Fig. 2It can easily be shown that two points separated by a distance et al., 2015The width of each parabolic section of the initial wavefront at the focusing optical element  is calculated from equation (4)A inserted into equation (3)E and equation (2)In order to design the refractive structure to obtain a given focal spot size For the test measurements, we required that the focused beam size should be varied in the range 1–10 µm at X-ray energies from 8 keV to 24 keV. This required a sequence of refractive optics with structures of varying amplitude, the smallest amplitude being required for achieving the smallest focused beam size at the lowest X-ray energy and the largest amplitude for achieving the largest focused beam size at the highest X-ray energy. The change in beam size could then be executed by translating the required refractive optical element into the X-ray beam.3.The refractive optical elements made by the LIGA process are planar structures with near-vertical side walls and high aspect ratios. The structures are composed of the polymer SU8 which for X-rays has a favourable ratio of refraction to absorption and low surface roughness and they are well suited for X-ray refractive optics deflecting the X-rays within the plane of the structures. The structures are laid down on a flat single-crystal silicon wafer substrate allowing a range of structures to be inserted into the X-ray beam by translation of the wafer. The structures were initially drawn using CAD and then converted to a photo mask which was used to produce the LIGA structures. The fabrication process allows a large number of refractive optical elements (many hundreds) to be laid out on a wafer. In our initial test design, we arranged the structures in ten columns on the 100 mm wafer which were then separated by slicing the wafer into ten strips, each containing about 20 refractive optical elements arranged on a vertical line along the length of each silicon wafer strip. A wafer strip could be mounted in the X-ray beam with horizontal translation and vertical translation being used to position the selected refractive optic in the X-ray beam. The initial structures had a depth of about 200 µm; however, it is expected that this will be increased in the future.et al., 2010Measurements were made using the Diamond Light Source Test Beamline  integrating X-ray detector. The intensity distribution of the beam is then found by taking the intensity difference at each step of the wire. The mirror had been characterized previously by Diamond NOM  used to calculate the profile of the refractive structure [equation (4)Fig. 45.This new optics will find applications for experiments at X-ray sources where a variable focused beam size is an advantage. Macromolecular crystallography experiments require the ability to match the focused beam size to the size of the crystal sample in order to minimize radiation damage. For microprobe experiments a variable-sized probe would allow different length scales to be measured efficiently. For diffraction experiments from polycrystalline samples an increased focused beam size could be used to improve sample averaging over crystallite orientations.The results clearly show that these fabricated refractive structures, which deliberately modify the X-ray wavefront, can be used to provide a variable-sized focused beam. The features of this new optics are:(i) Simplicity of implementation: the optics is in-line with the X-ray beam and requires only a small longitudinal space before the focusing mirror. The exact position along the beamline is not critical for the operation of the devices. This would allow the devices to be installed as an upgrade to an existing beamline.(ii) The optical axis does not change when the devices are inserted. As a result, the focus position does not move as the refractive structures are moved into the X-ray beam and no realignment of the focusing optics is required.(iii) Low cost. The fabrication process is well established and is well suited to making custom designs. Using wafer substrates of diameter 3 inches allows hundreds to thousands of unique structures to be fabricated. The alignment requires two translations and two rotation axes. A standard mounting for the devices would allow the structures to be easily replaced and upgraded as design and fabrication improves.(iv) Having the possibility of a large number of available structures gives a quasi-continuous control of the beam size.(v) The X-ray absorption in the structures is low. The highest absorption occurs at the lowest X-ray energy for the largest amplitude structures needed for achieving the highest broadening. Even at 10 keV and for a focused beam size of 20 µm the X-ray transmission was over 95%. Future designs would be able to reduce the amplitude of the structures by adopting a shorter repeat period.et al., 2011(vi) Fast changes in beam size are possible. With suitable goniometry, it will be possible to move the structures into position in significantly less than 1 s. This will be essential in order to meet the demands for automated high-throughput macromolecular crystallography experiments when the beam size must be altered to match each crystal sample (Evans While the focus broadening from a given structure is energy dependent because of the dispersion in the refractive index, we have shown that a sequence of structures of increasing amplitude can be used to generate a range of beam sizes from 1 µm to over 10 µm over an energy band of 10–20 keV on the Diamond Test Beamline. The same principle could be used with thinner LIGA structures to broaden the sub-100 nm focus size on a nano-probe beamline to cover the range to 1 µm and we expect future generations of the structures to also extend the broadening range to beyond 20 µm. It is also our aim to increase the depth of the structures to cover the aperture of a two-dimensional focusing optic such as a Kirkpatrick–Baez mirror system. This will allow the beam size to be independently controlled in the horizontal as well as vertical directions using two crossed refractive structures in-line with the X-ray beam. The structures present on the focused beam profiles are predicted by the physical optics simulations and it is hoped that by subtly changing the profiles of the refractive structures, for example changing the width of each section


We attribute this in part to directionally dependent group velocities of optical phonons in the different crystallographic directions. For interfaces comprised of materials exhibiting diamond cubic crystal structures, higher conductances are observed for interfaces where there is a better overlap of acoustic phonons on either side of the interface, whereas, acoustic phonons directly coupling with high frequency optical phonons is shown to lower the overall conductance, especially at high temperatures where anharmonic interactions become important. Unique to the interfaces formed between the materials with diamond cubic crystal structures studied in this work, the presence of localized interfacial optical modes mediate thermal conductance across these interfaces.We investigate the influence of optical phonon coupling across interfaces comprised of different materials with varying crystallographic orientations on the overall thermal boundary conductance. We show that for interfaces formed between a fcc solid and a L1 The relation between the nanoscale temperature discontinuity, ΔT, at the interface between the materials and the impinging heat flux, Q, at the interface quantifies the thermal boundary conductance (hK = Q/ΔT)3, which is a measure of the efficacy with which heat propagates across the interface. Over the past few decades, hK has been shown to be mostly limited by the acoustic impedance and mismatch of phonon spectra between the materials comprising the interface, to a first approximation11. Moreover, prior works have also demonstrated the influence of extrinsic factors such as defect concentration and roughness around the interface16, strength of cross-species interaction and chemistry around the interface22 and the relative crystallographic orientations of the two materials comprising the interface25 in dictating interfacial heat flow. However, despite these advances in understanding interfacial heat flow, relatively few studies have focused on understanding the role of optical phonons on thermal boundary conductance at solid-solid interfaces, even though optical phonons can make up to 90% of the available vibrational modes in some materials.In most modern-day nanoscale devices, thermal transport is limited by the high densities of interfaces rather than the materials that comprise the device27. The advent of rigorous computational approaches such as first principles calculations, molecular dynamics simulations and solutions to the phonon Boltzmann transport equation, however, have highlighted the important contributions of optical modes on the thermal conductivity of bulk materials and nanostructures34. In this regard, surely, the understanding of the role of optical phonons on thermal boundary conductance across solid-solid interfaces will be crucial in designing and optimizing thermal transport across nanoscale devices with high densities of interfaces that are composed of semiconducting materials with optical branches making up a significant proportion of the dispersion relations. As such, theoretical models based on the diffuse mismatch theory have been reformulated to account for optical phonons, which can contribute significantly to the total thermal boundary conductance across interfaces of several representative material systems due to elastic and inelastic scattering36.Historically, theoretical calculations have suggested that optical phonons do not contribute to dominant mean free paths and resulting thermal conductivity of crystalline solids due to their relatively small group velocities and short lifetimes relative to acoustic phonons0 crystal described by 6–12 Lennard-Jones (LJ) potentials; and 2) between a homogeneous diamond cubic crystal and a layered zincblende crystal described by the Stillinger-Weber (SW) potentials. We show that for interfaces formed between a fcc solid and a layered L10 solid, optical phonons from the L10 crystal preferentially couple to acoustic phonons of the monatomic crystal when the interface is comprised of the layered crystal oriented in the direction which accommodates for the higher group velocities of the optical modes . A better overlap between these optical modes (in the in-plane direction) and the acoustic modes in the homogeneous crystal is shown to dramatically enhance the thermal boundary conductance. In contrast, interfaces comprised between diamond cubic and zincblende crystal structures demonstrate higher conductances for interfaces formed with a better overlap of acoustic phonons on either side of the interface. Moreover, at higher temperatures where anharmonic interactions become important, acoustic phonons directly coupling with high frequency optical phonons is shown to lower the overall conductance for these structures. Furthermore, the presence of localized optical modes at the interface mediate thermal conductance across these interfaces, which are unique to the diamond cubic crystal structures studied in this work.In this work, we use molecular dynamics simulations and lattice dynamics calculations to investigate the role of optical phonons on thermal boundary conductance across interfaces comprised of materials with different crystallographic configurations. In particular, we study interfaces formed: 1) between a homogeneous fcc crystal and a layered L1p-3 branches of the optical variety populate the vibrational spectrum, where p denotes the number of atoms forming the basis37. In order to accommodate for optical phonons in the dispersion relation, we create a L10 crystal with a four-atom basis  with the lattice constant a0 = 1.56 σ. The sizes of the computational domains are 10 a0 × 10 a0 × 80 a0 with periodic boundary conditions applied in the x- and y-directions, whereas, fixed boundaries with 4 monolayers of atoms at each end are placed in the z-direction. Figure For the cubic fcc and L138 for Si and only the mass of the atoms are altered for simplicity. We note that as the main purpose of this work is to understand the general effect of optical modes on the thermal boundary conductance as opposed to predicting material specific properties, the use of the LJ potential for the fcc and L10 crystals and SW potential for the diamond cubic and zincblende crystals will provide sufficient qualitative insights into the role of optical phonons on thermal boundary conductance across these structures.Similarly, for the diamond cubic crystal structures, a layered domain  is constructed by replacing the four basis atoms that form the unit cell with atoms of different mass  and 160 g mol−1 (mB = 4 mAr), respectively, for the LJ-based crystals. For the thermal boundary conductance (hK) calculations, the computational domains are separated midway to create atomically smooth and perfectly matched interfaces with the difference in mass between the materials creating the acoustic mismatch. The computational domains for the AB alloy oriented in the cross-plane or in-plane directions in contact with the cubic A or B materials are shown in Fig. 39, the number of atoms, volume and temperature of the simulation is held constant followed by the NPT integration  for another 1 ns at 0 bar pressure. The time step for all simulations is set to 1 fs throughout the simulations.To begin, we prescribe the masses of materials A and B to 40 g mola0 in the z-direction) under a microcanonical ensemble with the number of particles, volume and energy held constant. This procedure establishes a steady-state temperature gradient and the temperature of atoms in each atomic monolayer in the direction of the applied heat flux are averaged for a total of 20 ns. The temperature profiles for the first 5 ns are discarded in order for the systems to reach steady state after which the time-averaged temperature profiles are used to calculate the thermal boundary conductances. As NEMD simulations are known to exhibit size effects due to scattering of phonons with the heat baths41, we have simulated all systems with two different sizes along the direction of the applied heat flux to make sure that our MD-predicted thermal boundary conductances are not artifacts of the simulated system sizes. Figure −1 from the hot and cold baths, respectively). Along with these temperature profiles, we also include the temperature profile obtained by applying a lower applied heat flux . As is clear from the figure, neither the computational domain size nor the applied heat flux alter hK, which suggests that the results are independent of the system size as well the applied heat flux for our simulations. Note, to reduce the uncertainty in determining the temperature drop at the interface, linear fits to the temperature gradients are performed for the two materials on either side of the interface (excluding the nonlinear regimes near the boundaries and that comprising the heat baths).After equilibration, a fixed amount of energy is added per time step to a warm bath at one end and removing the equal amount of energy from a cool bath at the other end  is analyzed in the[001] direction, which corresponds to Γ → X. Note, the dispersions in the [001], [010] and [100] directions are the same for the isotropic fcc solid. For the AB alloy, we use the conventional unit cell with four atom basis and a simple cubic lattice to specify the unit cell. This description results in a simple cubic Brillouin zone with a length of π/a0, where a0 is the lattice constant. As the AB alloy are oriented in the [001] and[010] directions to form interfaces with the isotropic solid  alloy in the cross-plane and in-plane directions are also plotted in Fig. The phonon dispersion relations of material A, B and the AB alloy (chosen in the direction of high symmetry) are determined via harmonic lattice dynamics calculations carried out with the General Utility Lattice Program (GULP)π/a0 (k* = k/(2π/a0)) for all phonon dispersion relations shown in Fig. k* value of unity, the branches have been folded at k* = 0.5 to be consistent with the dispersions for the L10 AB alloy. For comparison, we have also plotted the dispersion relation for the material A with the four atom conventional unit cell  in the [001] direction. The additional dispersion curves  structures. The DOS for the AB alloy is also distinct from that of materials A and B with the formation of stop bands arising between frequencies of ~0.5 and ~1.3 THz, which is attributed to the two atom basis in the unit cell of the AB alloy  demonstrates an overall better spectral overlap with the AB alloy in terms of their cutoff frequencies since the optical phonons in the AB alloy extend from ~1 to 2 THz. Also, the group velocities, The wave-vectors are normalized by 2 hK across the material A/material B interface is also plotted. The uncertainties in the MD-predicted hK are calculated from three independent simulations and taking into consideration the uncorrelated fluctuations in the data sampling. For the A/B interface, we have considered the effect of different crystallographic orientations on hK and found no correlation between the different crystal orientations within uncertainties of the MD-predictions. This result is in agreement with previous simulations and experimental results on cubic crystals where hK does not depend on the relative orientation45.Figure 0 AB alloys, hK demonstrates clear anisotropy with the in-plane direction showing considerably higher conductances as compared to the cross-plane direction for both AB/A and AB/B interfaces. In the cross-plane direction, the conductance across the AB/B interface is higher than the AB/A interface, even though material A has a better overlap in the DOS with the AB alloy as noted earlier. However, as material B has a better overlap with the acoustic phonons in the AB alloy, hK across the interface comprising of AB alloy oriented in the cross-plane direction and material B is greater in comparison to that across the AB(cp)/A interface. This points to the fact that a better relative match between the cutoff frequencies (or Debye temperatures) of two materials does not necessarily result in a high conductance when the two materials have different crystallographic configurations and corresponding phonon dispersions. While the cross-plane conductances are higher for the case with the better match in the acoustic modes (across the AB(cp)/B interface), the conductances for the AB(ip)/A interface with better overall spectral overlap are relatively higher at lower temperatures. At higher temperatures (>20 K), the linear increase in hK for the AB(ip)/B interface leads to higher conductances as compared to that for the AB(ip)/A interface (where the conductance at higher temperatures studied in this work are similar within uncertainties).For the interfaces comprised of the L1hK  could sufficiently describe phonon transport across interfaces. However, Gordiz and Henry have shown that the vibrational properties of the interface  need to be considered in order to properly describe the energy transport mechanisms occurring at the interface49.The temperature dependence for the AB(ip)/A interface is unique as all other interfaces considered show a linear increase in ces refs  and 47. hK with temperature is related to multiple-phonon inelastic scattering events at the interface51. This would suggest that the ability of inelastic channels to increase interfacial conductance for our AB(ip)/A interface saturates at ~20 K for the temperature range studied in this work. Although, the optical modes in the AB alloy are “elastically accessible” to material A due to the DOS overlap in both cases when the AB alloy is oriented in-plane or in the cross-plane directions, one of the reasons for the difference in the large anisotropy in hK might potentially be due to higher group velocities of the optical modes in the in-plane direction as compared to that in the cross-plane direction.Generally, the linear increase in To understand the differing temperature trends in more detail, we calculate the DOS of atoms in the bilayer of the AB alloy that are immediately adjacent to the interface for the two orientations  is the spectral heat current. For pairwise interactions between an atom i and j, the heat current is proportional to the correlation between the interatomic force 54. To this effect, under the NVE integration at 30 K, velocities of atoms near the interface for the AB alloy are tabulated for a total of 10 ns with 10 fs time intervals along with the forces due to atoms on the other side of the interface. The resulting heat current accumulations from the AB alloy to the other side of the interfaces are shown in Fig. To quantitatively support the observations presented in the above paragraph, we turn to the spectral decomposition method at the interface (the details of which are presented in our previous work)hK as a function of mass of the fcc solid for interfaces comprised of in-plane and cross-plane configurations of the AB alloy. For the cross-plane configuration, hK increases monotonically up to a mass of 130 g mol−1 and decreases thereafter. In Fig. m = 130 g mol−1 is plotted along with the DOS for the AB alloy. For comparison, we also plot the DOS for the solid with m = 55 g mol−1, which represents a lighter solid with a broader spectrum of frequencies that can elastically accommodate the optical phonons in the AB alloy. The acoustic modes in the heavier solid (with m = 130 g mol−1) better overlap the acoustic modes in the AB alloy, which results in an increase in hK when the AB alloy is oriented in the cross-plane direction. This suggests that for interfaces comprised of AB alloys in the cross-plane configuration, interfacial heat flow is mainly mediated through acoustic phonons. However, a further increase in the mass leads to a mismatch in the heat carrying acoustic phonons between the solids, which could potentially be one of the reasons for the decrease in hK. In contrast, for the in-plane configuration, the maximum in hK is observed for m = 55 g mol−1, which has a better overall spectral overlap. In this case, the high frequency acoustic modes in the fcc solid coincide with the high frequency optical modes in the AB alloy (in the 1.25 to 1.75 THz range). Going back to the phonon dispersion relations and group velocities shown in Figs hK when the optical modes are “elastically accessible” to the acoustic modes in the fcc solid across the interface, as noted earlier. It is also worth noting that the anisotropy in hK is pronounced for comparatively lighter masses with broader frequency spectrums that can elastically couple with the optical phonons in the AB alloy.To better understand the role of relative match of the cutoff frequencies (or Debye temperatures) on the interfacial heat flow, we performed additional simulations by varying the mass of the isotropic fcc solid while the AB alloy remains unchanged; note, increasing the mass decreases the cutoff frequency via the relation, m = 72.6 g mol−1 (which we refer to as Ge) arranged in a 1 × 1 layered structure with the atoms placed in a fcc lattice with a 2 point basis with a0 = 5.44 Å, which we have referred to as the zincblende structure. Similar to the LJ structures, we vary the mass of the homogeneous crystal  to gauge the effect of DOS overlap  between the two materials. Figure m = 50 and 112 g mol−1. Similar to the dependence of hK on the mass of material B for the AB(cp)/B interfaces in the LJ systems, hK increases linearly up to 50 g mol−1 and decreases thereafter. As is clear from Fig. −1 perfectly coincide with the acoustic phonons in the SiGe alloy. This suggests that acoustic phonons are the primary heat carriers mediating interfacial transport across these diamond structured materials. This is in line with the modal decomposition of thermal boundary conductance across Si/Ge interfaces carried out in ref. As most of the semiconductor devices are based on Si, we also investigate the role of optical phonons across interfaces comprised of diamond cubic crystal structures defined by the SW potential. The AB alloy in this case is formed from a combination of Si and mass-heavy Si with hK for interfaces comprised of solids with m = 112 and 20 g mol−1 and the SiGe alloy. Within uncertainties, hK values for the two interfaces are similar for almost the entire temperature range. However, at 1400 K, hK is greater for the interface comprised of m = 112 g mol−1 due to the relatively stronger anharmonic interactions of the acoustic phonons that are better overlapped with the acoustic phonons of the SiGe alloy as compared to that of the solid with m = 20 g mol−1.Figure m = 12 g mol−1 and an AB alloy with the two atoms defined by m = 120 g mol−1 and m = 160 g mol−1. The band gap for the alloy with the lower mass ratio between the atoms is relatively smaller as compared to that of the SiGe  are similar for the two cases, whereas, the increase in anharmonic interactions at the interface comprised of the SiGe alloy leads to greater conductances as compared to the case where the acoustic phonons in the homogeneous solid are coincidental with the high frequency optical phonons in the AB alloy at higher temperatures. It is also worth noting that the interfaces composed of diamond and zincblende structures demonstrate linear temperature dependencies for the temperature range studied, even when the acoustic phonons are “elastically accessible” to the high frequency optical phonons, which is unlike in the interfaces formed between the fcc and L10 structures where the conductance of the AB(ip)/A interface deviates from the linear dependence  were observed in ref. 22.To investigate the effect of acoustic phonons in the homogeneous solid coupling with the high frequency optical phonons in the AB alloy, we run additional simulations on interfaces comprised of SiGe alloy and solid with m = 20 g mol−1 and m = 112 g mol−1 that comprise the interface, the results of which are plotted in Fig. m = 20 g mol−1) or the homogeneous diamond structure (for the interface comprised of SiGe and diamond structure with m = 112 g mol−1). This suggests that the contributions to hK from these modes are a direct result of inelastic energy exchange due to the anharmonicity at the interface. Similar results for interfaces comprised of Si and Ge have also been reported, where considerable amount of heat is carried by interfacial modes at 12–13 THz region that are beyond the cutoff frequency of Ge57. The large DOS for the interfacial modes is also not an artifact of the SW potential used in this work as similar results , optical phonons are preferentially better coupled for the case when the interface is comprised of the layered crystal oriented in the direction which possesses higher group velocities of these modes, thus increasing the overall thermal boundary conductance. In contrast, interfaces comprised of diamond cubic crystal structures demonstrate higher conductances for interfaces formed with a better overlap of acoustic phonons on either side. At high temperatures where anharmonic interactions become important, acoustic phonons directly coupling with high frequency optical phonons is shown to lower the overall conductance for these structures, which is in contrast to the results obtained for the LJ-based solids. Furthermore, the presence of localized interfacial optical modes, which in this work are unique to the diamond cubic crystal structures are shown to mediate thermal conductance across these interfaces.We assessed the role of optical phonons on the thermal boundary conductance across materials with different crystal structures and orientations. We show that for interfaces formed between a fcc solid and a L1


Pogona vitticeps). Incubation temperature did not influence the gaze following ability of the bearded dragons; however, lizards incubated at colder temperatures were quicker at learning a social task and faster at completing that task. These results are the first to show that egg incubation temperature influences the social cognitive abilities of an oviparous reptile species and that it does so differentially depending on the task. Further, the results show that the effect of incubation environment was not ephemeral but lasted long into adulthood. It could thus have potential long-term effects on fitness.Recent work exploring the relationship between early environmental conditions and cognition has shown that incubation environment can influence both brain anatomy and performance in simple operant tasks in young lizards. It is currently unknown how it impacts other, potentially more sophisticated, cognitive processes. Social-cognitive abilities, such as gaze following and social learning, are thought to be highly adaptive as they provide a short-cut to acquiring new information. Here, we investigated whether egg incubation temperature influenced two aspects of social cognition, gaze following and social learning in adult reptiles ( Geneticinter alia growth rate, sex determination and many aspects of behaviour (for a review see [Bassiana duperreyi). However, it is currently unknown whether incubation temperature impacts upon other aspects of cognition and the duration to which it might influence cognitive processes.Reptiles are especially interesting in this context because of their dependence on behavioural thermoregulation  and theiview see ). Recentview see  and perfview see –9 in youSocial cognition encompasses all cognitive processes involved in acquiring knowledge from another individual and is typically studied in two categories, social intelligence and social learning . One claSocial learning, in its broadest sense, can be considered as ‘learning that is influenced by observations of, or interaction with, another animal  or its products’ . Social Pogona vitticeps) as a result of incubation temperature, with animals from the hot group initially appearing bolder than those in the cold group. However, these differences did not last into adulthood [The long-term effects of egg incubation temperature on cognitive traits in oviparous reptiles are currently unknown. Typically, experiments use animals that are a few days or a few weeks old –9,32. Hodulthood . It is, Incubation temperature is known to influence the development of behavioural traits and the learning ability of oviparous reptiles –9,32,33,2.n = 7) incubated at an average temperature of 30 ± 3°C, and the ‘cold group’ (n = 6) incubated at an average temperature of 27 ± 3°C . The egribed in  and hencribed in  but had 2.1.a). The experimental set-up consisted of a square arena measuring 73 × 73 cm with 19 cm high walls. A visual barrier (41 × 16 cm) was placed so that the lizard could see the screen but the barrier obstructed the view of the lizard to one side of the arena. A computer monitor was positioned in one end of the arena, this was used to present video stimuli to the observer animal (a). Bearded dragons have been shown previously to respond to videos of conspecifics [To assess gaze following, the lizards were placed facing towards a computer monitor within a familiar arena containing a barrier on one side a. The exr animal a. Beardepecifics .Figure Prior to the onset of the experiment all lizards were habituated to the arena. Each habituation trial lasted 10 minutes. During this time, the lizards had access to the entire arena including the barrier. Mealworms were placed inside the arena and the animals were considered habituated if they readily explored and ate all the food on two consecutive trials. All the lizards were habituated within two trials.During the experimental trials, the observer animal was placed facing towards the screen. If the observer was not looking at the screen (classed as at least one eye facing towards the screen) or the lizard moved off before the video was played, then the trial was terminated and repeated on another day. Exactly 5 s after the bearded dragon had been placed in the arena, a video was presented. The video footage, described in more detail below, showed an unfamiliar female bearded dragon doing one of four things; looking up, looking to the side, looking to the side behind a barrier and looking straight ahead (the control). The gaze movements were recorded by presenting a favoured food in a specific position (above or to the side) relative to the demonstrator bearded dragon. The average length of the video clips was 2.33 ± 1.23 s and a different video was used for each trial. Once the clip was finished, the demonstrator bearded dragon remained on the screen and continued facing in the same direction. All trials were recorded on a video camera (Sony HDR-CX22OE) and were analysed using VLC media player.2.1.1.Each video showed a demonstrator lizard, positioned in the centre of the screen, looking up by moving its head upward with at least one eye looking upwards. An observer look-up was counted if the observer dragon looked up by either extending its head and neck upwards or by turning its head so one eye was directed upwards in the 5 s following the stimulus presentation.2.1.2.Each video showed a demonstrator lizard, positioned in the centre of the screen looking to the side by moving its head either to the left or the right  without tilting its head upward. The observer lizard was considered to be looking sideways if its head moved sideways in either direction in the 5 s following the stimulus presentation. Bearded dragons have binocular vision meaning that in order to follow the gaze of a conspecific the lizard could move its head to the side in either direction.2.1.3.look sideways into distant space condition; as such, the specific videos used for the two conditions were counterbalanced across subjects. The side was also counterbalanced (and the barrier was moved accordingly) across subjects.Each video showed a demonstrator lizard looking sideways behind a barrier. This meant that the observer lizard had to reposition itself in order to follow the gaze of the demonstrator lizard. The lizard was considered to have moved past the barrier if it moved so that its head was positioned so it could clearly follow the gaze of the demonstrator lizard or if it climbed over the barrier within the 1 min trial time. The video stimuli used in this condition presented identical information to those used in the 2.1.4.To control for the influence of the presence of a conspecific we included a condition in which the video showed a demonstrator lizard facing towards the observer but did not shift its gaze direction. When presented with the control condition, observers were expected to show fewer shifts in their gaze in the 5 s following stimulus presentation and move around the barrier less often than in the geometric gaze following condition.Each lizard received one session of three trials a day repeated over four days. When an animal moved before the start of the video the trial was repeated the next day, hence it took five days to test all lizards. Each trial was separated by an inter-trial interval of at least 10 min, during which time the lizard was returned to its enclosure. Each animal received 12 trials in total and three trials per condition. The order of the trials was counterbalanced between animals and across sessions.2.2.k = 0.913, p = 0.001). All statistical analyses were carried out using Minitab (v. 17).All trials were coded from video recordings. If the lizard responded within the appropriate time period (5 s after the start of the video for gaze following into the distance and 1 min for the moving around the barrier), it was coded as 1 and if it did not then it was coded as 0. These numbers were used as the dependent variable in a general linear model while incubation temperature and test condition were used as fixed factors as was the interaction between them. The individual was used as a random factor. We also used time to respond to gaze as a dependent variable in the same model to assess if incubation influenced the time it took the subject to respond to the demonstrator gaze. Ten per cent of the data was analysed by a second individual who was blind to condition and the inter-observer reliability was excellent (Cohen's 2.3.b). After watching the video, the animals were given access to the sliding door and they had 5 min to open the door themselves. Each lizard was presented with 10 trials. The experimental arena  was divided into two parts by the test apparatus (figure 1b); the test area (where the subjects were located) and the demonstration area . The test apparatus was a wooden board (41.5 × 51 cm) with a horizontally sliding door with vertical bars in front of the hole (12 × 12 cm). The door could be opened to either the left or the right side. The sides of the arena were opaque and the floor was lined with newspaper. All testing was recorded with a digital camera (Panasonic HC-V100) on a tripod positioned above the arena.To investigate social learning, we used a bi-directional control procedure  in whichfigure 1All animals were habituated to the arena in a similar manner to the previous experiment. During the experiment the lizards received up to two trials per day, with a total of 10 trials per animal. At the onset of each trial the lizard was placed in the arena for 30 s. They then watched a demonstration video lasting 11 s in which they observed an unknown female demonstrator opening a horizontally sliding door to either the left or the right side, using a specific head movement . After the screen was raised the lizard had five minutes to open the sliding door to access a reward of a mealworm that was located behind the door. The trial was terminated when the lizard successfully opened the door and ate the reward or after five minutes had passed. Lizards were returned to their vivarium between trials.et al. [The lizards were considered to have successfully opened the door when the door was moved enough, to either the right or left side, to create a visible gap . The time taken before a successful opening was measured, as was the latency before attempting to open the door; latency ended when the subject first moved to make contact with the door. To investigate whether differences in motivation could account for any differences in performance between the two groups we assessed motivation by recording the sum of the amount of head and claw interactions with the door prior to its opening and measuring the latency to approach the door. A control condition was not included in this experiment as Kis et al.  showed t2.4.t-test assuming unequal variances. A general linear model was used to see if there was a difference in the speed of social learning for the hot and the cold group. The time it took to open the door was used as a dependent variable, temperature was used as a fixed factor and the trial number was used as a covariant. Ten per cent of the videos were second coded and the correlation of results was excellent . All the statistical analysis was calculated on Minitab (v. 17).For the door opening the data for the hot and the cold groups were compared using an independent 3.3.1.F1,23 = 10.89, p = 0.003; figure 2a) or looking sideways . Egg incubation temperature did not influence their propensity to follow gaze into the distance . Lizards incubated at colder temperatures, however, were quicker to respond in general in the looking upwards but not the looking sideways condition . There was no evidence of geometric gaze following in the bearded dragons; individuals were equally as likely to move around the barrier on a control trial as they were when they observed the stimulus animal looking behind the barrier ; this was also unaffected by incubation temperature .Bearded dragons followed the gaze direction of the stimulus animal significantly more than they looked in that direction during the control trials when both looking upwards (3.2.a) this difference was not significant . However, over the course of 10 trials, the cold group completed the task significantly quicker than the hot group  and spent significantly less time (92.3 ± 7.2 s) than the ‘hot group’ (199.0 ± 30.3 s) attempting to open the door . The number of times the animals touched the door (figure 3c), significantly differed between the ‘hot’ and ‘cold group’  but the latency to touch the door was not significantly different between the hot and cold groups .Although the ‘cold group’ opened the door more times than the ‘hot group’ a this di4.Our findings reveal that egg incubation environment impacts upon some aspects of social cognition in adult bearded dragons. We found that the lizards were able to follow the gaze of a conspecific into distant space, but that both incubation groups performed similarly in this task and neither group were able to follow the gaze of a conspecific around a barrier. By contrast, there was an effect of incubation temperature on social learning, with the cold-incubated animals performing significantly faster than those that were incubated at a warmer temperature over time.Gaze following into the distance is thought to be controlled by an innate orienting response, which can be modulated by experience ,18. ThisWe found a significant influence of egg incubation temperature on social learning. Over the course of the experiment, the cold-incubated animals opened the door significantly faster than the hot-incubated animals. The nature of this difference supports the idea that the contrast observed between the groups in this experiment may be the result of differences in associative learning abilities caused by incubation environment. It, therefore, provides further evidence for the idea that associative learning mechanisms may underpin social learning. This is supported by research in a number of areas. The medial cortex is thought to play a central role in reptile learning  and receThere was a difference in the number of interactions with the door between the conditions, with the cold-incubated animals interacting with the door more than the hot-incubated animals. This suggests that there may be a difference in motivation between the two groups. However, there was no difference in willingness to approach the door. This, in combination with recent work with the same animals, which revealed that there was no difference in food motivation between the two groups , makes iChelydra serpentina) is affected by incubation temperature [All previous research in this area has used very young animals –9,32 andperature , which ivice versa. Further research is required to test these ideas. As such, it is possible that variation in the sensitivity of oviparous reptiles to external environmental factors may provide a behavioural buffer that allows individuals to better cope with heterogeneous and changing environments.The mechanisms that underlie temperature-dependent differences in the phenotypes of oviparous reptiles remain poorly understood ,36. One


Treatment informed consent aims to preserve the autonomy of patients in the clinician – patient relationship so as to ensure valid consent. An acceptable method of evaluating understanding of consent information is by assessing the extent of recall by patients of the pieces information believed to have been passed across. When concerns are not satisfactorily addressed from the patients’ perspective, recall of consent information may be low.This study is a questionnaire – based cross – sectional interview of consecutive adult surgical patients who could give their respective medical histories and who were booked for elective major surgical procedures over a period of 7 months in a tertiary health institution in southeastern Nigeria. Four to five days after a formal consent session, during ward admission, extent of recall of information on the nature of the disease condition or diagnosis, the nature of the planned procedure and the risks involved in the planned procedure were assessed and analyzed on the background of how satisfying the consent sessions were from individual patient’s perspective.Generally, the recall of nature of disease condition and nature of planned procedure is better than recall of risks involved in the planned procedure. More specifically however, recall in these 3 domains is significantly better among the patients that affirmed that their concerns were satisfactorily addressed.The findings from this study support that no effort should be spared in ensuring that the consent information are satisfying to the patients from the patients’ viewpoint.The online version of this article (10.1186/s12910-017-0227-4) contains supplementary material, which is available to authorized users. In modern clinical practice, there is a conscious effort by health care teams to carry patients along in all decisions concerning the latter’s medical care. Over the years, the principal-agent relationship in healthcare services has undergone some modifications through the concept of consent with a shift from ‘obtaining consent’ from patients to educating patients to ‘give informed consent’ prior to any intervention with the aim of improving patients’ satisfaction and quality of care . The conSeveral strategies are deployed in achieving the desired goals of giving an informed consent and several sessions may be needed. These strategies include oral discussions, handing out of manuscripts containing needed information to the patients, referring patients to appropriate education materials and websites, and the playback of appropriately structured audio and video recordings –8. The iThe extent of comprehension of the consent information and the subsequent recall of this information believed to have been given are related to the extent of interactions with and exposure of the patient to the care-givers in the health care facility . BecauseThe informed consent process has largely been introduced into clinical practice, but the strategies employed in achieving it vary from society to society. In Nigeria, a lower medium-income country, literacy level of patients is on the average low, belief in the theology of predestination is strong, infrastructural development of the health institutions is mostly rudimentary, and the influence of the extended family system is strong , 13. In As part of evaluation of each patient for elective surgery in the outpatient clinics, standard operational procedure demands that the surgeon gives to the patient all the information necessary for the latter to give an informed consent. Such information includes, but not limited to, the nature of diagnosis and the nature of the treatment options available with the attendant risks and successes. On the day of admission into the ward for the planned surgical operation, on the premise that all necessary information has been well-received, the consent form is signed by the patient.This cross sectional survey was conducted in the University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu, in south-east Nigeria. Approximately 1606 elective surgeries were carried out on patients 18 years and above in the institution’s main theatre complex in the preceding year (2014). Based on this number therefore, we estimated a sample size of 310 using Survey System® software. From February 2015 to August 2015, a total of 401adult patients 18 years and older were scheduled for elective surgeries. Nine patients declined to participate while 23 patients did not meet an inclusion criterion to participate in the study. This inclusion criterion is that the patient must have been able to give his clinical history himself at presentation. The resultant 369 participants were drawn from the Urology, General Surgery and Orthopaedic units, and these gave consent to participate in the study.Each patient was given procedure-specific consent information verbally by the surgeon as part of care protocol about 4 or 5 days prior to the date of the intended procedure: on an outpatient clinic visit preceding the date of the proposed procedure. Expositions on the nature of the disease condition, the nature of the planned procedure and the risks involved in the procedure form part of the content of each consent session with the objective of addressing all concerns arising from any pre-conceived notions. For the purposes of this study, the study questionnaire was administered to each participating patient on admission into the ward a day prior to the procedure day. The response to the questionnaire revealed the extent of recall of information believed to have been given earlier to the patient, and hence the areas that required ‘top up’ information by the surgeon before the eventual endorsement of the consent form by the patient. The questions in the questionnaire were non-leading and options with respect to answers to the questions were not provided. Four Intern doctors, who scored highest in a quiz after tutelage on the administration of the questionnaire assisted with administering the questionnaires to the various patients, translating and explaining the items therein whenever there was need. There were questions on the nature of the diagnosis, the nature of the planned procedure and the risks involved in the procedure. The response to each of these questions was documented. Where the patient had forgotten what he believed was the answer, ‘forgotten’ was noted; and where he believed he was not given that information during the consent session, ‘uninformed’ was noted. The last question sought to ascertain from the patient (respondent) the extent to which the patient’s concerns during the consent session were addressed by the surgeon, and the response to this particular question was ‘satisfactory’, ‘not satisfactory’ or ‘unsure’. The documented responses were adjudged to be ‘correct’ or ‘incorrect’ by the surgeon during data collation. Patients whose procedures were carried out in the outpatient clinics, wards or emergency theatre complex were not included in the study. The University of Nigeria Health Research Ethics committee gave approval for this study.For ease of analysis, responses that were judged incorrect’, ‘forgotten’ or ‘uninformed’ were classed as ‘Inappropriate Response’ while responses that were judged ‘correct’ were classed as ‘Appropriate Response’. Similarly, with respect to the last question, ‘Affirmative’ was used for ‘satisfactory’ responses while ‘Negative’ was used for ‘not satisfactory’ and ‘unsure’ responses. The data obtained was analyzed using crosstabs descriptive analyses of SPSS version 20. The figure was produced with MS Excel 2007.There are 369 respondents between the ages of 18 years and 82 years (mean 44.1 ± 17.7 years). Among them, 207 (56.1%) are <45 years, 173 (46.9%) are females, and 279 (75.6%) acquired at least a secondary level of formal education. They are mostly Nigerians (99.7%), of the Igbo tribe (91.9%) and residing in the south-eastern region of the country. Table About 78.3% of the 369 respondents recalled appropriately the nature of the disease condition, 63.7% recalled appropriately the planned surgery, and only 21.7% recalled the risks involved in the planned surgery. This is summarized in the Fig. n = 207) and 63.6% of those ≥45 years of age (n = 162); 74.0% of females (n = 173) and 62.2% of males (n = 196); and 50.0% of those with no or primary level of formal education (n = 90) and 73.5% of those with post-primary level of formal education (n = 279) affirmed that their concerns were satisfactorily addressed. Further analysis was done with respect to the three questions under consideration and the results displayed in Tables Responses from respondents who admitted that their concerns were satisfactorily addressed constituting the ‘Affirmative’ group of responses was matched against the ‘Negative’ group of responses from the other respondents who did not admit that their concerns were satisfactorily addressed. Seventy-one percent (71.0%) of those <45 years of age n = 07 and 63It is standard operative procedure just as it is an ethical principle that patients are given adequate information to allow for rational decision making prior to their signing of the consent form. In doing this, the patients are made to possess adequate knowledge of their health condition and the treatment options available; guided by the ethical principles of autonomy, beneficence, non maleficence and justice , 17. PatOften patients would acknowledge having discussions with their surgeons about their health challenges and treatment modalities. They (patients) are usually able to recollect as well, the chain of referrals including interventions leading to the present point of healthcare . HoweverIn all, 78.3% of our respondents could recall appropriately the nature of their disease conditions while 63.7% recalled adequately the nature of the planned procedure Fig. . Mexas ep = 0.10), the nature of the planned surgeries (p = 0.83 or the risks associated with the planned surgeries (p = 0.13) more appropriately than older respondents (Table p = 0.03), but not nature of planned surgery (p = 0.45) or risks involved in planned surgery (p = 0.32) is better in the younger age groups. Our finding may be due to limited access of our younger patients to other sources of appropriate medical information including the internet which leaves both younger and older patients with similar knowledge base.There is no significant evidence from this study that younger respondents < 45 years) considered in isolation recall the nature of the disease conditions p = 0.0, the na5 years cp < 0.001) and the planned surgical procedure (p = 0.01), but no evidence with respect to the risks involved in the planned surgical procedure (p = 0.38). The reason for this difference is not obvious from this study, but may be related to the observation that 80.9% of the 173 female respondents had at the minimum a post-primary level of formal education as against 70.9% of the 196 male respondents with a post-primary level of formal education. Now, considering the responses from female and male respondents that could not affirm that their concerns were satisfactorily addressed, there are no significant differences in recall in the three domains of interest. However, among the respondents who affirmed, extent of recall of nature of disease condition (p = 0.001), but not the nature of planned surgery (p = 0.24), or risks involved in the planned surgery (p = 1.00) by females appears to be significantly higher.Comparing in general, the responses obtained from the female respondents to the responses from the male respondents, there is strong evidence Table  that a gp = 0.02).There is strong evidence from this study that higher level of formal education attained by respondents positively influences the extent of recall of consent information across all domains of interest Table . This isFormal education is expected to reduce the paternalistic tendencies of individuals who have acquired it. Invitation to ask questions is a recognized approach to increasing understanding . The conThe findings from this study suggest that satisfying consent from the patients’ perspective is associated with better recall of consent information for surgical procedures in low income setting. Therefore, no effort should be spared by the surgeons  in ensuring that the consent information is satisfying to the individual patient from the latter’s viewpoint. Appropriate recall of consent information as an index of understanding by the patients is better among patients whose concerns relating to the disease conditions and treatment decisions are satisfactorily addressed than those whose concerns are not.