Spinal manipulative therapy (SMT) has been shown to have an effect on spine-related pain, both clinically and in experimentally induced pain. However, it is unclear if it has an immediate noticeable biomechanical effect on spinal motion that can be measured in terms of an increased range of motion (ROM).To assess the quality of the literature and to determine whether or not SMT is associated with an immediate increase in ROM.A systematic critical literature review.Systematic searches were performed in Pubmed, the Cochrane Library and EMBASE using terms relating to manipulation, movement and the spine. Selection of articles was made according to specific criteria by two independent reviewers. Two checklists were created based on the needs of the present review. Articles were independently reviewed by two reviewers. Articles were given quality scores and the data synthesized for each region treated in the literature. Findings were summarized in tables and reported in a narrative fashion.Fifteen articles were retained reporting on experiments on the neck, lumbar spine, hip and jaw. The mean quality score was 71/100 (ranges 33/100 - 92/100). A positive effect of SMT was reported in both studies where mouth opening was assessed after cervical manipulation. In five of the nine studies on cervical ROM a positive effect was reported, whereas the remaining four studies did not show improvement. None of the three studies of the lumbar spine showed an effect of SMT on lumbar ROMs and one study of sacroiliac manipulation reported no effect on the ROM of the hip joint.In relation to the quality score, the seven highest ranked studies, showed significant positive effects of SMT on ROM. Continuing down the list, the other studies reported no significant differences in the outcomes between groups.SMT seems sometimes to have a small effect on ROM, at least in the cervical spine. Further research should concentrate on areas of the spine that have the potential of actually improving to such a degree that a change can be easily uncovered. It is well known that back pain is highly prevalent in the general population, with serious economic consequences both on an individual and societal level. One of the treatments frequently used for back pain is spinal manipulative therapy (SMT). Although it has been shown that SMT is a reasonable treatment option for some people and some conditions, the mecA manipulation is said to occur when a joint is brought to the extreme of its passive range and thereafter submitted to a rapid but shallow thrust, a so-called high velocity low amplitude (HVLA) manipulation. The manSMT is usually differentiated from mobilization, which is described as more of a slow, long-lasting stretch of an articulation at the extreme of its passive range,9 and usTo better understand the true role of SMT in health care, more information is needed regarding the effects of SMT on the articular and peri-articular structures, and joint function; i.e. movement. Theoretically, SMT could have an effect on a number of structures and tissues within and surrounding the spinal articulation. These structures include muscles, aponeuroses, peri-articular receptors, tendons, discs, and ligaments, which all, singly or in combination, would have the capacity to cause dysfunction and pain as they are all potential starting points of proprioceptive and nociceptive pathways. For SMT to have a positive effect on vertebral movement, it must modulate the function of some or all of these structures/tissues. SMT has, in fact, been shown to modify spinal reflex excitability, paraspiDesign: systematic critical literature review.Searches were conducted in PubMed, the Cochrane library and EMBASE without any date limitations and using the following combinations of search terms: •“spinal” + “manipulation” + “range” + “motion” •“chiropractic” + “manipulation” + “range” + “motion” •“spinal” + “manipulation” + “stiffness” •“spinal” + “mobilization” + “range” + “motion” •“spinal” + “mobilization” + “stiffness”Thereafter, two of the authors (MM and CLY) independently applied specific inclusion criteria to select the potentially relevant articles from the titles, abstracts, and keywords of the references retrieved in the literature search. These inclusion criteria were: •Languages: English, French, Spanish, Danish, Swedish and Norwegian. •Spinal Manipulative Therapy (SMT), anywhere in the spine. •Humans or animals. •Experimental studies with at least one control group. Thus, studies without a random allocation procedure were accepted. •ROM had to be one of the outcome variables. •Immediate effect was reported. The following studies were excluded: •Studies of subjects with specific pathologies, such as inflammatory diseases, tumors or severe spinal degeneration, because these might influence the spinal structures in such a way as to limit ROM permanently and therefore confuse the results. •Studies of combined/concomitant therapies , as it would not be possible to know if the results were obtained from SMT or the other therapies. •Literature reviewsTwo authors (MM and CLY) extracted data from each article, independently of each other, into two check-lists, one descriptive and one qualitative. Data were later compared in order to minimize reading errors. The other authors were designated as judges in case of disagreement between the first two reviewers.The descriptive checklist for the selected articles ; •Duration of symptoms (if any); •Description of the SMT/mobilization group and the type(s) of control group . •Number of experiments performed on each study subject; •Time when ROM was measured (immediately after the SMT or later); •Whether SMT was performed at the level of a spinal complaint; •Type of measurement (distance or angle) ; •Method of measurement; •Approval from ethics committee (yes/no)A number of issues related to quality of study were identified by consensus among the authors and used to develop a quality checklist  or if the article did not mention this condition (”?”), no point was given. However, if the item was not applicable (“N/A”), this was not counted in the denominator. Thus the maximum total score could be different from one article to the next. Finally, the total score was normalized to a 100 point scale in order to compare quality across studies.Although a summary quality score was calculated, no cutoff-point was defined for acceptable or unacceptable level of quality. This allowed us (and the readers) to use the quality scores and the information on each individual quality item as a guide to determine whether articles would be considered more or less credible. In other words, the quality assessment was meant to be informative rather than proscriptive. Because we decided not to use a scoring system to establish levels of quality, we have not defined any discrete levels of evidence, e.g. high, moderate or low.Four data tables were constructed according to the area of the spine where treatment was provided and ROM assessed: 1. cervical treatment and ROM, 2. lumbar treatment and ROM, 3. cervical treatment and range of mouth opening, and 4. sacroiliac treatment and hip ROM. The tables were scrutinized, one by one, to obtain answers to our research question. Results were thereafter interpreted and reported in a narrative fashion.FigureTableOf the 15 selected studies, two measured the effects of SMT on mouth opening, nine studied effects about the three cervical axes of movement, one measured only the range of cervical rotation, three studied flexion/extension in the lumbar spine, and one investigated the ROM of the hip. There were nine randomized controlled trials and six cross-over studies. All of them measured the ROM before and immediately after treatment. No papers on the thoracic spine satisfied the inclusion criteria.ROM was measured differently depending upon the spinal region under study. Mouth opening ( and35]35]) was Some researchers (n=11) performed their experiments on people with symptoms, either patients (n=8) or volunteers with symptoms recruited by advertisements (n=3), whereas the remaining four studies dealt with healthy students.Eight authors performed only one experiment, five reported two experiments, and two studies reported on three and four experiments, respectively.Only one article did not report whether approval had been received from an ethics committee.TableAll articles fulfilled the following four quality criteria: “Random allocation”, “SMT well described”, “Estimates reported and shown in tables/graphs” and “Results tested for statistical significance”. The item “Age distribution similar in studies with study sample consisting of people older than 45” was applicable to six studies  of whNine articles dealt with “disinterested/naïve study samples”. Ten studies included what we considered a credible sham treatment in comparison to the spinal manipulation. However, some studies investigated differences in outcome in relation to different types of manipulation (such as manipulating in different planes), i.e. not comparing manipulation to a sham treatment making this issue superfluous. Eleven authors specified that SMT was performed by an experienced person , theIn none of the studies were the experimental conditions stated to have been equal for treatment and control groups or before and after the manipulation. Only six studies reported if there were any exclusions or losses during the study.The results for mouth opening, cervical ROM, lumbar ROM and hip ROM are shown in TablesOutcomes were reported as either degrees or millimeters and there were generally no large improvements in ROM. In fact, although a statistically significant effect of SMT was seen in several studies, the differences between pre and post treatment, when clearly reported, were, for the best results, in the order of 3.5mm for mouth opening  and 10°A positive effect of SMT was reported in both of the studies where mouth opening was assessed after cervical manipulation . The Finally, if articles are listed by total quality score, the seven highest ranked studies  rather than changes in the total ROM. It is also possible that changes in one manipulated joint among several in a spinal region would not contribute greatly to changes in regional movement.In this review, SMT only showed discernible effects in the cervical spine. There may be several explanations for this. First, gross ranges of motion are largest in the cervical spine and so there is the potential for treatment in that area to cause a larger, hence measureable, effect. Secondly, more than 50% of the total rotation of the cervical spine is attributed to movement at a single level, the atlanto-axial joint. Hence, In order to investigate this matter further, all articles that tested the effect of SMT specifically in the upper cervical spine were re-analyzed, in relation to the size of the effect. Two studies,40 treatThere are also some technical issues that have to be taken into account in interpreting the results presented herein. For example, measurements of ROM face the problem of where to start and stop; i.e. how to identify the neutral or starting position. Therefore, measurements are probably more accurate when the full ROM is reported. Although most studies in our review did measure the full range, for some reason they reported on each individual movement component (e.g. left rotation and right rotation).It is also possible that ROM does increase immediately following treatment but that the methods used in the reviewed studies did not capture this effect. In this regard, most of authors either claimed to be using a previously tested and acceptable instrument in relation to reliability, or they presented their own reliability study with acceptable results.Interestingly, many studies of cervical ROM seem to concentrate on the reliability of measurement tools, but construct validity and what has been referred to as ‘responsiveness’ - the ability to capture change - are studied less often. WhetherAs with all systematic literature reviews, it is likely that not all relevant articles were found, and the review process itself has a subjective element even with the systematic approach of using checklists. Other researchers may prefer to scrutinize other methodological items and may judge the contents differently. However, as there were no disagreements between the two primary reviewers, the protocol appears to have been appropriate and clearly defined.Research findings are of course dependent on the study methodology; it is often seen that the weakest studies have the “best” results. However, in this review, the methodological score was, generally, associated with study outcome in the opposite way, i.e. studies with better quality scores were more likely to show statistically significant differences, suggesting that the effects of SMT on ROM are robust, albeit not very large. Nevertheless, the fact that there was no set cut-point for methodological acceptability and because the evidence tables report on both descriptive and quality items, the reader is able to make his/her own additional analysis of the data, should this be relevant.It has been shown that it is difficult to evaluate ROM if there is pain. On the The results do not support the concept that SMT has an immediate, strong and obvious effect on ROM in the human spine. In clinical practice, it is possible that measurements of ROM should be clearly separated from the experience of pain in relation to movements.Based on the studies reviewed herein, SMT sometimes seems to have a small effect on ROM, at least in the cervical spine. The studies reviewed did not reveal an effect of SMT on temporomandibular, lumbar or hip ROMs. Future studies into ROM should take into account various stages of degeneration, should standardize the experimental situation, and should include both pain and ROM as outcome variables. It would also be useful to include study subjects who actually have a decreased ROM, in order to have the potential for improvement. Also, it seems obvious that the measured movement should have the potential to improve with the treatment. Therefore, the effect of SMT on the upper cervical spine should be tested in relation to rotation and treatment to the lower cervical spine in relation to lateral bending, flexion and extension. The full ROM should be measured with validated instruments and all estimates should be clearly reported, including full statistical analysis.Authors declare there are no conflicts of interest.All authors instigated this review. MM and CLY designed the check-lists. MM and BB searched in the databases. MM and CLY reviewed the literature and wrote the first draft. BB, MDC and MAA provided expertise on the topic, assisted with the literature review and provided critical comments to the first draft. All authors reviewed the final manuscript and approved the final version.


Sir,Scientific publishing capabilities, both in terms of quality and quantity, to a great extent reflect the strength of science and technology of a country. Many developing countries, including India, are yet to achieve success in this aspect. In the recent past, the order of global leaders is on a transition and the “east” is now giving a tough competition to “west” in terms of scientific and technological poweretc., should recommend the researchers to publish their work preferably in relevant Indian journals. The funding bodies should announce a special package/reward/prize, in some form or the other, for researchers who publish their research in Indian journals.The prestigious funding bodies under the Government of India, such as Department of Science & Technology, Department of Biotechnology, Indian Council of Medical Research, Council of Scientific & Industrial Research, etc.) and their preference should shift to “good-will factor” rather than “impact factor”.It is now a well accepted fact that the Asian scientific power is soaring at a rapid pace, and a sense of “look east” has developed in the minds of global community. But, unfortunately, the Indian research community (both scientists and students), though aware of the above fact, still believe in “west-first” approach to get a good impact factor (IF)One cannot blame the scientific community for their “west-first” tendency to get high IF papers. The existing recruitment policies make them more focused on their personal career over national pride. For example, if a Ph.D. scholar, having publications in Indian journals (with zero/lower IF), applies for a position (either post-doc or any permanent/temporary job) in any institute, the chances of selection are slim. Even the scientists/ faculty with regular appointment also would like to improve their IF to get promoted to a higher grade. Hence, unless and until government makes a policy to regulate “IF” as a criteria for selection/promotion of a candidate, researchers are forced to plan work which has a potential to get a high IF rather than work for problems inflicting the nation. Only when amendments in recruitment criteria are made, the researchers would try to balance between “good-will factor” and “impact factor” and thereby would be able to balance “personal career” and “national pride”.The government should initiate an agency/body to develop and maintain a single window web portal for hosting all Indian journals. The best example of such kind is J-STAGE  developed and maintained by JST (Japan Science and Technology) Agency of Government of Japan. J-STAGE is a huge collection of research articles reflecting the science and technology strength of Japan. Currently, it includes 639 journals , 125 proceedings, 10 reports and 42 JST reports The government should fund the publishers or societies  for “open access” publication. Consequently, the research published in Indian journals reach every corner of the globe free of cost, and hence, attracts the global scientific community to Indian journals.etc. The best examples are websites like NPG, Elsevier, Wiley, Springer, etc., which provide such facilities.There is a tremendous scope for private sector groups in scientific publishing in India. With the help of indigenous IT sector, private venture capitalists should take initiations towards launch of a single window portal for all Indian journals including providing access to full text, searching options, submission and peer-review, Besides the solutions suggested in a recent editorial by Satyanarayan & SharmaThe journals should adapt to the regular changes happening in their fields and should think of expanding the aim and scope as per the demands of scientific community.On a regular basis, the journal team should send circular/poster inviting submissions to various research institutes (Indian and foreign). Again ethically, this should be an unbiased invitation.The journals should put more efforts in making a user-friendly web based system for accessing full text content, searching, submission and review. For this, the journals can attract funds by hosting third party advertisements.Journals should provide templates for various forms of articles that they publish. This will help the researchers to a great extent, especially those in the early stages of their career.Global outreach and impact factor is all what a researcher expects. So, editorial team should seriously think on this issue.etc., encourage such self-citations.Last but not the least, a journal should encourage the authors to give citations to work published in that particular journal. It is not a good option, but not a bad one too! Many journals belonging to NPG, Elsevier, etc. to bring their journals in the forefront of global community and thereby improving their standards. Recent trends in science and technology all over the world clearly indicating that China is on rise at a rapid paceChina, Japan and Korea are collaborating with agencies like NPG, Elsevier,


Regenerative strategies that facilitate the regrowth and reconnection of neurons are some of the most promising methods in spinal cord injury research. An essential part of these strategies is an increased understanding of the mechanisms by which growing neurites seek out and synapse with viable targets. In this paper, we use computational and theoretical tools to examine the targeting efficiency of growing neurites subject to limited resources, such as maximum total neural tree length. We find that in order to efficiently reach a particular target, growing neurites must achieve balance between pruning and branching: rapidly growing neurites that do not prune will exhaust their resources, and frequently pruning neurites will fail to explore space effectively. We also find that the optimal branching/pruning balance must shift as the target distance changes: different strategies are called for to reach nearby vs. distant targets. This suggests the existence of a currently unidentified higher-level regulatory factor to control arborization dynamics. We propose that these findings may be useful in future therapies seeking to improve targeting rates through manipulation of arborization behaviors. Search and pursuit problems have been studied extensively, leading to optimal strategies, for example search for food in an unpatterned landscape During normal development, controlled growth and elaboration of neuronal extensions  are central to establishing a functional nervous system Axonal connectivity between neurons is complex and varied, involving morphologies that facilitate connections to very different types of targets in silico synthesis of dendritic trees as well. These can be characterized either as Growth Models or Reconstruction Models. Growth Models are based on principles of dendritic development, utilizing rules of outgrowth associated with dynamic growth-cone behavior, microtubule-mediated neurite elongation, and actin meshwork branch formation in vitro experiments toward asking the question: how successful are neurons with similar growth properties in reaching their targets?Mathematical and computational studies within the field of neuroscience have previously been used to examine the spatio-temporal organization of post-synaptic potentials within a dendritic network. For example, quantitative models of the detailed branching patterns in dendritic trees have investigated the impact of network topology on firing patterns and neuronal signal processing in vitro studies and potential future therapies involving adult CNS regeneration. For these purposes, time may be less of an issue than limitations in resources. In order to maximize the space explored under this constraint, a neuron that seeks to reach a target could branch as often as possible and prune as seldom as possible. In practice, however, this would create an arbor whose cumulative length of all of its branches would grow exponentially rapidly and which would at some point inevitably exhaust any cell's resources. In the present paper, therefore, we focus on optimal search strategies for a neuron with a fixed resource limitation; that is, for a neuron that produces an arbor with a specified maximum cumulative length.Two types of optimization strategies present themselves when context-dependent constraints are placed on a neuron during growth. In the first scenario, neurites may aim to reach targets in the shortest time possible. Strategies which minimize search time may be at work in certain developmental stages, e.g. during pyramidal The issue of neural connections across extended spatial scales has been also examined in depth in the context of neural wiring for the brain structures, such as hippocampus or cortex, in vitro studies of Dorsal Root Ganglia were dissected from the lumbar region of embryonic chicks at day E11. Dissociated neurons and glial cells were isolated by digestion in 0.25% trypsin followed by mechanical trituration through a polished glass pipette and purification through a 10% BSA in PBS gradient. Neuro-glial suspensions were plated onto Poly-L-lysine/laminin coated plates and grown at 5% CO2/37°C in N3 complete serum-free media. Time-lapse movies of cocultures were acquired at 15 minute time intervals, 24–48 hours post-plating, with a 10× objective (N.A. 0.35) using an inverted Zeiss 200 M deconvolution microscope mounted with an on-stage incubation chamber and heating plate. Neurite tracing and morphometric analysis of live-cell phase contrast images were performed using ImageJ software. For each neuron, individual neurites were tagged, tracked, and traced across time frames. In the in silico numerical simulations that follows, with a focus on evaluating how branching, advancement and retraction of neurite tips, as well as branch elimination affect axonal pathfinding and targeting strategies.Illustrative examples of both branching and branch elimination are shown in max, is achieved; (b) can bifurcate periodically with defined probability, Pbranch; and (c) are subject to pruning of available neurite tips with fixed probability, Pprune. Each of these functions are described here.The simulation used here is straightforward, and involves elements that have been described elsewhere i(t) is assigned an interim value:max as follows:max = 1 for convenience, and max.Growth begins at a fixed location, defining a cell ‘body’, and each neurite tip grows according to an integrated random walk branch – this is accomplished by simply choosing a random number, ri, between 0 and 1 for each neurite tip, and if ri<Pbranch, a new tip is spawned. When a tip is spawned, this new tip is assigned a higher order than the prior tip, so the original neurite has order 1, its daughter has order 2, and so forth. When branching occurs, both parent and daughter have identical starting locations, but the newly-generated neurites acquire separate additional random additions to their velocities, of magnitudes amounting to 30%·Smax. This addition gives the secondary branches a tendency to diverge, or in other words, to have a non-zero branching angle, as is seen in in vitro experiments . Thus, the completed distal branch (with length one) is no longer active and is replaced by two new proximally extending branches. The only way for the distal branch to increase its length is to continue to extend instead of bifurcating. This process is illustrated in 2, the tree will have length 3. It is easy to check that the sum of all probabilities, (p+p·q+q2) = (p+q·(p·+q)) = (p+q) = 1. By induction, we can obtain the probability distribution at time step N listed in After 2 time steps, the length of the elongating branch, in units of VIf we assume that the number N has a large value, it follows thataverage.At first glance, it would seem that the probability distribution of these branches and the average branching length could be obtained from performing statistics on neural trees grown from simulations, but the overall picture is more complex. In fact, the sample mean for the branch length of the trees is a biased estimator, one which consistently underestimates Ltip·Δt = 1). The latter tree has a sample mean for average branch length of 1. As a result, after the second time step (first branching decision), the expected value for the average branch length obtained from tree statistics is p*1 = p. Note that this is in agreement with the analysis in the previous section where we tracked the evolution of a single branch.In order to prove this point we will compare the expected branch length for trees that were allowed to evolve for 4 time steps, with the expected value for the sample mean of the tree branches. The possible instantiation of the evolving trees are shown in At the third time step, six types of trees are possible. These trees possess morphologies ranging from completely unbranched (probability q*q) to exuberantly branched (probability p*p) geometries. Note that it is also possible to retain trees of similar geometries using symmetry transformation. These “trees isomers” are contained within gray boxes in For purposes of computing the sample mean, we can consolidate the geometrically-undistinguishable structures into a single shaded entry. These tree isomers are therefore listed once, but their probability is doubled . Based oAgain, this is in agreement with the results from the single branch analysis. After four time steps, however, the estimates are no longer in agreement. Using the trees generated after four time steps, we can create a table that contains the probability of generating each type of tree, the list of its mature branches, as well as the average branch length . Since eaverage = This sum is no longer equal to the expected value for the single tree branch: Laverage tree−Laverage)/Laverage , derived in the previous section.Furthermore, it is expected that this divergence depends on the branching probability. Indeed, in the extreme case of setting the branch probability equal to one, all branches of the tree will have the same value, hence both the theoretical prediction and statistics from numerical simulations must agree. For the trees that are allowed to evolve for 4 time steps, we can compute these values exactly , as wellLaverage . The sumaverage tree−Laverage)/Laverage , depends linearly on the branching probability , with larger values for the ‘effective’ branching probability, equal to approximately 2/3 here, instead of the simulation value of ½ (Results from lue of ½ .0 = Vtip Δt) produce bushy arbors that explore the nearby space thoroughly, but exhaust their resources rapidly and as a result cannot travel far from the originating point. Here L0 plays the role of the quantity Laverage derived in the previous two sections: we assume a neurite travels exactly a length L0 then it branches with probability 1. Using this convention, trees that branch often will have a small L0, creating a dense tree, while branches that have low branching probabilities will extend for a long distance before bifurcating. As illustrated in the figure, targets located in a gray band at a fixed distance from the origin will not be reached by such an arbor. By contrast, a standard tree that branches less frequently (0 = Vtip Δt) could travel further from the starting point using the same resources as before, but would explore intervening space more sparsely, passing only at a couple of points through the grey target region shown. It follows that given a target distance, an intermediate branching rate , could maximize the number of branches that explore targets at a desired distance  the number of targets hit per unit time doubles, which continues until the daughter branches travel on average L0 = vtip Δt, at which point the number of targets hit per unit time doubles again, and so on until the cumulative branch length reaches Lmax. At the moment of the first branching, the cumulative branch length, Ltotal, is L0; at the second branching Ltotal = L0+2L0; at the third, Ltotal = L0+2L0+4L0, etc. Thus, the number of targets reached grows exponentially as a function of distance from the origin as shown in max is reached. Ltotal itself grows according to (2N−1) L0, where N denotes the number of times the standard tree has split before it runs out of resources, which ideally occurs when Lmax = (2Nmax−1)L0, or when Nmax = log2(1+Lmax/Lo). The condition  with L0 = Lmax = 6. Alternatively , Eq. [3] allows us to determine the optimal branching rate (which in turn determines L0) needed to optimize the chance of striking a target at a given distance, D.Given a branching probability, we can use this averaged approach to derive the number of targets reached as a function of distance from the cell body in a straightforward manner. As shown in shown in  that allshown in , using L0, obeys Eq. [3].We reiterate that the solution shown here only presents a simplification of the neurite targeting problem. For example, actual neurite branches do not appear at constant distances and neurites do not travel in straight lines separated by fixed angles. Furthermore, when neurites do branch, their trajectories cease to be centered at the origin and the value of number of branching points N calculated above will in general not be an integer. Additionally, the simplified calculation above ignores redundant hits and finite target sizes. Nevertheless, these examples predict the behavior expected under idealized conditions: namely that the most effective standard trees should be the ones that finish the search at the required distance, defined to lowest order by Eq. [3], and not the ones that run out of resources too early or that extend too far from the origin. On average, we expect the branching rate to be such that the mean branch length, LTheoretical analysis becomes more complicated when branches can be pruned. Qualitatively, pruning permits regions of space to be explored transiently after which the resource expenditure is recouped for subsequent exploration elsewhere. On the other hand, pruned branches can no longer explore downstream regions of space; and consequently, it is not at all obvious what the ultimate effects of pruning may be. To develop some insight into some of the functional effects of pruning, we provide in max = 20, with average branch length L0 = 0.9. The target zone is divided into targets of fixed size. In this simple example, targets to the right of the origin are uniformly struck, with 8 targets hit in total. By comparison, in In These illustrations show that pruning permits additional space to be explored – for example, widening the coverage of targets  as the number of cubes of Size 3 that are located at distance r away from origin and are being visited by the expanding neural tree. Obviously, the theoretical derivations, which constitute an upper bound for the distance where the standard tree can target efficiently, should outperform the trees obtained in numerical simulations the vast majority of the time. They always peak at the right time, just as the tree is about to run out of resources. To facilitate the comparison between theoretical and simulation methods, we consider another approach that is situated in between these models and is expected to generate intermediate targeting results. More precisely, this model allows the neural trees to branch stochastically at any moment in time, while still maintaining linear trajectories. In the upcoming sections, we use the variable S(r) to compare these three types of neural trees: standard theoretical, stochastic, and numerical.Apparently, the effects of pruning are complex, since it is possible to obtain neural trees that extend below or above neurons generated with similar parameters but without pruning. To analyze these effects systematically, we resort to simulations. First, we examine the case of stochastic branching without pruning. Then, we turn to studying the effects of pruning on targeting, both in terms of overall targeting effectiveness and of the time required to reach the target.branch, of branching into two free tips in a unit time, and a second fixed probability, Pprune, of being pruned and dying back to the nearest branch point in the same unit time.As mentioned in the methods section, we use an arborization model to examine complex structures of axons observed in sensory neurons with the goal of exploring the implications of axonal morphological variations on target-finding capabilities. In particular, we focus here on examining the effects of pruning – i.e. elimination of some projections – on targeting. As an illustration, we compare two typical simulated neuronal arbors in branch = 0.2, meaning that an average of 20% of free tips, chosen at random, will branch at constant time intervals, but Pprune = 0, meaning that branches never prune. By comparison, in branch = 0.4, and Pprune = 0.2. After 130 computational time units, the two simulated neural arbors are superficially similar, but as shown in In a first scenario, shown in In these simulations, we assume that resources available to cells are limited, which we mimic by imposing the constraint that the total length of the neuronal arbor cannot exceed a maximum. The total arbor lengths are therefore are identical in branch = 0.3, 0.5, and 0.7, which as discussed are unimodal, with a peak at moderate distance, rather than at the maximum distance shown in green for the uniformly branching case. Contributing to the spreading of the distribution results is the existence of some rare events in which branching seldom occurs, and the tree can reach far beyond the maximum distance defined by Eq. [3]. The red and the green plots, shown for three values of branching probability in When branches prune stochastically, rather than at fixed uniform intervals, the targeting distribution changes significantly. Rarely does the majority of branches reach higher order arborization simultaneously. Consequently, the dominant peak at long distances is considerably diminished in favor of a single mode at a moderate distance. We can estimate how stochastic variations in branching should affect targeting simply by repeating the calculation made in As we have mentioned previously, the theoretical (green) and stochastic (red) results are approximations of the simulation conditions, neglecting neurite curvature, angle variations at branching, redundant branches, finite target size, etc. As a consequence of these approximations, optimal targeting occurs at lower distances in the simulations (blue line). Nevertheless, both approximation cases reveal the essential mechanism at work in targeting when branching is also manifest in the simulation results. More explicitly, the region of optimal targeting shifts to locations that are situated farther away as the branching probability decreases. As demonstrated by the numerical simulations, exponentially more targets are reached by higher order than by lower order branches. The relative paucity of very high order branches, however, as well as the existence of occasional trees that reach long distances, combine to produce smoother targeting curves with a single maximum performance peak. In the presence of pruning, this result changes significantly, as we describe next.max = 1000. Accordingly, we expect that an increase in pruning probabilities should reduce the effective rate of producing new branches, thus increasing the range at which a standard tree can search for targets, as well as the overall search time. Numerical simulations are in agreement with this intuition, as indicated by results with Pbranch fixed at 30% and varying Pprune, which are shown in The previous results demonstrate the intuitive result that standard trees which branch more often can travel shorter distances, but cover the intermediate range better than do branches that bifurcate less frequently. A quantitative summary of these results appears in branch = 0, 0.1, 0.2, …, 1, and Pprune = 0, 0.1, 0.2, …, 1. Note here that the number of simulations have been increased from 100 to 500 to allow for more statistical confidence in comparison of performances for adjacent regions of the map. The target size is 3 units on each dimension. In addition, simulations are performed only if Pbranch−Pprune>0, that is, the targeting success is deemed to be zero if Pbranch−Pprune≤0.The theoretical considerations that we have described indicate that optimal branching and pruning rates can be established to construct standard trees that maximize probabilities of striking particular targets. To confirm these results, we perform a factorial design of simulations in which branching and pruning rates are varied, and the number of fixed size targets is evaluated as a function of distance to the target. Results are shown in branch−Pprune is constant. Deviations from the expected parallel line can be observed in numerical simulations for high values of Pbranch and Pprune, due to the increased incidence of accidental imbalances in local branching and pruning events. Second, for nearby targets . This represents an advantage that trees which prune have over trees that only branch, thus pointing to potential functional roles of pruning. We note, however, that by operating in a high branching/pruning regime, a cost incurs due to an increased likelihood that putative successful branches might be prematurely cut off or that the tree may waste its resources on premature growth if the pruning is deficient at early stages. In this sense, a moderate amount of pruning would strike a balance between too little intermediate exploration and too many premature pruning events. We also note that by comparing trees which have similar total length for their final structures, we implicitly assume that there is no penalty for pruning of neurites. This simplification permits us to perform an explicit analytical treatment. Different options for assessing cost can be employed in higher order models, such as fixed terms, factors that are proportional to the length of the neurite pruned or factors that depend on the distance from the starting point.Results from the numerical simulations support the notion that branching and pruning may work as opposing agents to collectively help a neural tree find its target. In other words, as long as there is a set difference between probabilities of branching and pruning (P_branch−P_prune), the expected targeting success at a distance D away from the origin should be similar. To further explore this, we recognized that the search for targets at a certain distance from the initial starting point can be formulated as an optimization problem, in which a neural tree attempts to advantageously use the limited resources by generating a structure that maximizes the number of active neurites in the region of interest. We used theoretical methods to generate an upper bound estimate for the target performances for neurons that have a fixed probability of branching and a fixed total length, showing that the tree optimally targets at a specific distance.branch−Pprune and plotting the number of targets hit versus Pprune and distance. As shown in branch−Pprune = 0.2) indicates that trees generated under this parameter regime are most effective at targeting at distances around D = 50. While in general, the performances are similar for different parameters, trees that have very high branching and pruning probabilities loose their effectiveness at targeting at this distance. Hence, prune>60% and Pbranch>80%, few targets are reached at any distance. This appears to be associated with the fundamental exponential nature of iterative branching. That is, at high branching rates, the number of branches along with total arbor length grows exponentially in time. A small stochastic reduction in pruning can therefore cause a large growth in total arbor length and a premature exhaustion of available resources. On the other end of the spectrum, a tree that prunes overeagerly by a small amount produces slender and sparse arbors that make inefficient use of the resources in the intended target area. In contrast, as shown in While the requirement that a fixed difference between branching and pruning rates is indicative of the optimal targeting distances, these trends may exhibit some variations. We can investigate this directly by examining the effect of pruning on targeting as a function of distance to the target by fixing Pin silico model to reflect the complex arborization morphology of DRG neurons observed in vitro. While individual branches were allowed to evolve independently, a length-bound scenario was assumed to realistically reflect the finite amount of cellular structures that can be sustained by a neuron as it expands. In contrast to the traditional method of estimating targeting success by employing a single stationary target, we mapped the entire search space covered by the neural trees. The resulting “landscape profiles” obtained for neurons with differing pruning and branching capabilities allow for a more informative measure of how arborization dynamics change the topography of the space searched and consequently, the ability for a neuron to innervate a potential target located within those coordinates.In this paper we have constructed a computational model of a growing neuron with stochastic capabilities to evolve individual branches. The growth dynamics within the simulations were adjusted according to observations of sensory neurons isolated from the dorsal root ganglion (DRG) and grown on a featureless growth-permissive substrate. Live cell imaging demonstrates that neurons dramatically restructure their arbor architecture as they grow in culture . These pOur work is different from the traditional search and the pursuit problems in the sense that the target does not attempt to evade the search. Instead, they are hidden at the beginning of the search. Although there are similarities with complex search problems e. g. , the timin-vitro neurons. Since similar-looking neurons can be obtained over a range of parameters . For example, if a neuron is stimulated by external factors to branch, it may recover the optimality of search by increasing its internal propensity to prune. The number of possible  combinations that exist for successful targeting also suggests that branching and pruning do not function as independent processes within an optimized search strategy. For any branching rate, a pruning rate exists to match and to create the appropriate balance to facilitate efficient search. A reasonable way for a neuron to achieve balance is by employing a coupling factor that operates on a higher level of control, simultaneously regulating both pruning factors and branching factors to maintain the critical difference, or constant delta. As revealed by the numerical simulations in this study, the importance of a balanced Pbranch−Pprune rate, which allows families/classes of neurons generated using same set of parameters to optimally target at a specific set distance away from the origin, suggests that a regulatory hierarchy for control of arbor formation may exist within the neuron.These findings indicate that absolute pruning and branching probabilities are less relevant to a neuron, than its capability to sustain a tightly coupled relationship between its branching and pruning probabilities  pairs in which P


Older patients often experience sub-standard communication in the palliative phase of illness. Due to the importance of good communication in patient-centred end-of-life care, it is essential to understand the factors which influence older patients’ communication with physicians. This study examines older patients’ attitudes towards, and experiences of, patient-physician end-of-life (EoL) communication in three European countries.A secondary analysis of interviews from British, Dutch and Belgian patients over the age of 60 with a progressive terminal illness was conducted. Cross-cutting themes were identified using a thematic approach.Themes from 30 interviews  included: confidence and trust; disclosure and awareness; and participation in decision-making. Confidence and trust were reinforced by physicians’ availability, time and genuine attention and hindered by misdiagnoses and poor communication style. Most participants preferred full disclosure, though some remained deliberately ill-informed to avoid distress. Patients expressed a variety of preferences for and experiences of involvement in medical EoL decision-making and a few complained that information was only provided about the physician's preferred treatment.A variety of experiences and attitudes regarding disclosure and participation in decision-making were reported from each country, suggesting that communication preferences are highly individual. It is important that physicians are sensitive to this diversity and avoid stereotyping. In regard to communication style, physicians are advised to provide clear explanations, avoid jargon, and continually check understanding. Both the ‘informed’ and the ‘shared’ patient-physician decision-making models assume patients make rational choices based on a clear understanding of treatment options. This idealized situation was often not reflected in patients’ experiences. The majority of deaths in Europe occur over the age of 65. However, the needs of older patients are often neglected during end-of-life (EoL) care . Older pSub-standard communication is both a cause and an outcome of poor EoL care. Poor communication affects physicians’ ability to recognize patients’ palliative care needs and make referrals to specialist services . FurtherDue to the importance of good patient-physician communication in EoL care, it is essential to understand the factors that influence communication between older patients and physicians. European surveys that explore patient-physician communication and participation in decision-making at the EoL have revealed that country of residence is a strong determinant of practices and attitudes -12. For Although surveys are excellent for mapping differences in practices and attitudes across Europe, a deeper understanding of patients’ and physicians’ experiences, attitudes and preferences surrounding EoL communication is most readily achieved through qualitative rather than quantitative research ,16. UnfoBy reporting the results of an exploratory secondary analysis of older patients’ interviews from three northern European countries, this paper begins to address the paucity of cross-country qualitative research on EoL communication in Europe. The interviews analyzed were conducted as part of studies that explored terminally ill patients’ attitudes towards, and experiences of, death, dying and EoL care. As the primary studies varied in their specific foci, this cross-country comparison only examines common themes surrounding patient-physician EoL communication. In light of calls to implement European-wide EoL care policies and for best practice models to be used across Europe ,20, suchThis study therefore aims to examine older patients’ attitudes towards, and experiences of, patient-physician EoL communication in the United Kingdom, the Netherlands and Belgium. Specific objectives include: 1) to examine common themes surrounding patient-physician EoL communication from British, Dutch and Belgian interviews with older patients on attitudes to death, dying and EoL care; and 2) to identify similarities and differences in attitudes and experiences within these common themes.This study is part of a two part project. The first part consisted of a detailed reflection on ethical and methodological challenges in interviewing older adults about EoL issues, comparing experiences from six qualitative studies in four European countries . This arThis secondary analysis therefore draws upon data from these three qualitative studies conducted in the United Kingdom, the Netherlands and Belgium Table . ParticiA sub-sample of available interviews was purposively selected from each study: participants over the age of 60 with a range of socio-demographic characteristics, health statuses and care locations were included. One of the studies (Ethnicity and Cancer) compared the views of older Chinese and white patients resident in the UK. From this study Chinese participants (n = 24) were excluded, leaving only white older patients (n = 47), in order to make the sample’s ethnic composition comparable to the samples from the Netherlands and Belgium. A final sub-sample of 30 interviews  was selected from 94 interviews .The selection and construction of data are intertwined with the assumptions and procedures of the intended analytical approach . ThematiAfter a reading of the English language interview transcripts by the first author (NE), and of the Dutch and Flemish interview transcripts by the second author (RP), a preliminary coding scheme was developed. Both researchers used this coding scheme to code all interviews. Interview segments from the non-English language transcripts that dealt with patient-physician interactions were identified by the second author (RP) and translated into English by professional translators. The language expertise provided by the professional translators, combined with the authors’ language skills and understanding of the research topic enabled a sensitive and nuanced translation of the interview data . The preEthics approval was obtained for all of the primary studies Table . Either Although the secondary analysis of datasets is most readily associated with quantitative research, there is increasing interest in the secondary analysis of qualitative data . There aVan den Berg  however The majority of participants had cancer, whereas just under a quarter suffered from non-malignant conditions Table . The medThe analysis provided insight into the nature of the patient-physician interaction for older patients receiving EoL care. Cross-cutting themes included: confidence and trust; disclosure and awareness; and participation in decision-making.The physician-patient encounter is affected by patients’ expectations, which are shaped in part by their past experiences with physicians and other healthcare professionals. Factors that reinforced older patients’ trust and confidence in their physician included availability, time and genuine concern.Participant’s wife: But if we call him, he’s there for us. It’s true. He doesn’t count it. He says, “I’m getting up and I’m there,” and ten minutes later there he is. He doesn’t live far away, but he still has to come here.Participant 8, Male, 65 – 74 years, BelgiumInterviewer (I): Are there any things regarding the doctor about which you are less satisfied?Participant (P): No, not at all. Nothing with regard to the general practitioner or with regard to the lung specialist. That’s a really nice woman. I can call her at any time of the day. Even in the middle of the night, at her home number!Participant 10, Male, 75 – 84 years, the NetherlandsP: […] I think in general principle, this place [the hospice] has been superb. The ordinary hospital sort of stuff that you get is in and out, flash, bang, wallop and really has nothing, there's nothing humane about it whatsoever.Participant 21, Male, 75 – 84 years, United KingdomParticipants frequently commented on their physician’s availability, the amount of time the physician dedicated to them and if the physician appeared to be in a hurry. Furthermore, older patients emphasized how important it was that their physician gave them their full attention and, even if they had only a little time to spare, that their concern was genuine.Negative experiences also greatly impacted older patients’ trust and confidence in their physician. Some participants specifically criticized the manner in which physicians spoke to them, describing a lack of empathy and sensitivity. Whereas others criticized physicians’ use of medical jargon and expressed satisfaction with physicians who were prepared to explain difficult to understand medical terms.I: [ …] did you still trust that general practitioner?P: No, I had asked for a walker then. And then he said, 'that’s not worth the trouble anymore.'Participant 12, Male, 75 – 84 years, the Netherlands.P: I said "he’s [the physician] a Canadian and he's as cold as a bloody fish that they pull out of the sea in Canada" […] So he is a cold fish and I mean that sincerely, but what does he deal with? Death constantly. And all he's ever got to say to some poor bugger is "I'm afraid that you're on the way out". […] [b]ut I do wish that he'd sort of look at me as if to say "well, I do appreciate how you feel", but I understand how he has to cope with it and that's it. So we beg to differ at times, you know. If he says something I don't agree with, I'll bloody tell him so. Because I've got nothing to lose, have I?Participant 21, Male, 75 – 84 years, United KingdomP: But you’d prefer a doctor to speak to you as a human being, and not use all these formal terms.I: They use too many formal words?P: Yes, when my daughter was here too, she even said so to the specialist.Participant 5, Male, 65 – 74 years, BelgiumOlder patients’ confidence in physicians and the efficacy of biomedicine were also negatively affected by experiences of misdiagnoses and inappropriate treatments.I: Yes, you were on the wrong track really weren't you [in reference to a misdiagnosis by Dr. Smith]?[…] So that's the difficult one is the fact it wasn't picked up;P: That's the difficult one yes.Participant 22, Male, 60 – 64 years, United KingdomOlder patients frequently expressed a preference for open and honest disclosure of diagnoses and prognoses. Indeed, the one woman who knew that she had not received a prompt disclosure of her diagnosis stated that she would have preferred full disclosure.P: My GP, when he’d got the letter [from the specialist]…He said, “Look, Denise, I’ve had this letter a while. I’ll give it to you now,” he said, “but Denise, I should have told you in January; that you needed another scan… but it would’ve been the same. We couldn’t do anything about it anyway.” And he said that my morale was still so good that he didn’t want to… because that’s what he said, this doctor, that you can’t do anything about it. If I’d been three months earlier, then yes. And so I asked my GP why he hadn’t done anything with the letter for so long…I: And you think your doctor should tell you?P: (hesitantly) Yes, I do think so… although to be honest, Dr R. did do it in a gentle way.Participant 1, Female, 60 – 64 years, BelgiumPatients also expressed dissatisfaction with the amount of information provided by their physician about their illness and treatment options. A common complaint was that information was something that needed to be sought and was not routinely provided.In contrast, other patients preferred to remain deliberately unaware about their illness and treatment options in an attempt to avoid distress.I: Did they [the GP] discuss it with you?P: Not much. Those doctors don’t say much.I’d prefer not to know. Otherwise it breaks my heart.I: Did they tell you what to expect?P: No. I prefer not to know; it would make me sick.I’ve already had a fever for three days. I don’t want to know.I: Have you talked about what you want to say or decide?P: There’s no point in asking me anything, I can’t answer you. Unfortunately. I don’t know…I: Is there a doctor who has explained things when you’ve asked anything?P: No. They don’t say anything.I: Have you ever asked anything or would you like to have asked anything?P: No, if they don’t say anything, then I don’t ask. I don’t say anything. They definitely don’t say anything.Participant 2, Female, 75 – 84 years, BelgiumP: Yes, well when I came here I saw the doctor the same day. And the doctor said, ‘Now I’m going to…’ I was in an hour. ‘Now I said when you’ve gone I shall be writing to your GP’, and he said, ‘you’ve got every right to ask to see the letter. Now what do you want to do?’ So I said, ‘I don’t. Whatever you say to him, I don’t want to read… hear about it you see.’Participant 29, Female, 85 ≥ years, United KingdomWhen asked if a physician should provide full information about diagnosis and prognosis, some older patients were pragmatic and stated that a physician should know when and for whom full information is appropriate. Others stated that a physician should always be open and direct in communication.An additional complaint was that, when information on treatments was given, the physician only provided information concerning the treatment option they recommended and did not discuss the consequences of other actions.P: Yes convinced, he didn’t leave me any choice, they don’t leave you any choice. My reward is that I’m not given any choice […] So there were two possibilities: chemotherapy or not. And I already knew that chemotherapy could also have physical consequences and stuff, vomiting and feeling bad and everything. But what actually happened if I refused chemotherapy. I didn’t actually hear anything about that. So I think that was missing. So I didn’t actually make a decision, err, with any conviction. Yes. Correct me if I’m wrong.Participant 6, Male, 65 – 74 years, BelgiumP: And I regret that. That they pushed me [to get started with a treatment]. You just grasp at a straw. So when they tell you: 'You are terminally ill; you have cancer and the only possibility is surgery' then you want to seize that possibility, right? However, afterwards, it turned out that it was so radical. When I had to go to the hospital and that they first told me that: first with that doctor, then with that internist, to the surgeon, and that only then I found out that it was way too radical […] Every time I make a phone call, I have to recover my breath. At those times, I’m jealous that I was not told about the possibility of being ‘taped’ [an alternative procedure] from the start [instead of surgery] […]Then I went to the lung specialist and I said: 'I changed my mind, I'm not going to do it'. And she said: 'I'm glad you didn't go through with it.' Because they push you to do it! [to become a study subject] However, they just need people. Because, in twenty years, there will be an explosion of asbestos victims who have all worked there.Participant 10, Male, 75 – 84 years, the NetherlandsIn each country older patients expressed a variety of preferences for and experiences of involvement in medical EoL decision making. Levels of involvement included: active involvement in decisions; involvement with family support; and no involvement in decisions. Many older patients described joint discussions about treatment options, including non-treatment decisions, with their physician.I: Did you talk with the doctor about you not wanting euthanasia or resuscitation? Did this take place on your initiative or on the doctor's initiative?P: Yes, on my own initiative. I’ve witnessed a resuscitation in the hospital and I thought it was horrible. And I do not want surgery either any moreParticipant 12, Male, 75 - 84, the NetherlandsSome participants believed that patients should make decisions in collaboration with, or with the support of, their family and saw the physician as having more of an advisory role. The presence of a spouse or adult child at the physician-patient interview who provided emotional support or aided the understanding of options available was often mentioned.R: […] I said, 'Would you mind if my son came. Can you explain everything to him?' 'Oh no that's a good idea.' So my son came and they told him what's what.Participant 26, Male, 75 - 84, United KingdomWife: No, no, it’s us who decides that [treatment], together with the specialist. But if you don’t want to, you don’t have to continue. They’d continue. They say it makes no difference anymore, but they want to continue anyway.Participant 5, Male, 65 - 74, BelgiumFamily involvement in decision-making was not however universally positive or supportive. Family members have their own hopes and expectations, which may differ from those of an older patient. The presence of family members was described by one participant as having a coercive effect on his decision to choose a more aggressive, experimental treatment, which he later regretted. P: All my children were there. So you are anxious all the time. Normally, you have a meeting with the general practitioner, but when all the children also have to be present, and they are going to make a decision and are all enthusiastic: "Dad, you have to get surgery' […] So, looking back, I actually regret this.Participant 10, Male, 75 - 84, the NetherlandsIn some cases the participant deferred decision-making responsibilities to the physician, whereas others were simply told what their treatment would be rather than being included in treatment (or non-treatment) decisions. This lack of involvement often went unchallenged and was treated fatalistically by participants.P: So I was told in my case that they weren’t going to operate. And I accept that. OK? Yes, I can run from one hospital to the next and… err… to Aalst [Belgian city] or what’s it called?Participant 6, Male, 65 - 74, BelgiumThis exploratory secondary analysis of older patients’ interviews from three northern European countries highlights some common issues in patient-physician EoL communication. Furthermore, it represents the first step in addressing the paucity of qualitative cross-country research on patient-physician EoL communication in Europe. The identification of the common themes of ‘confidence and trust’, ‘disclosure and awareness’ and ‘participation in decision-making’ from Dutch, Belgian and British older patients’ interviews implies that they are relevant across diverse social and cultural settings.Within each of these common themes, a diversity of participant experiences and attitudes were reported from each of the three countries. This suggests that attitudes and preferences of older people regarding EoL patient-physician communication are highly individual. The variety of preferences for information provision and decision-making (including the involvement of family members), revealed in the findings, highlights the lack of an ‘idealized’ preference for older patients. For example, although older patients frequently expressed a preference for open disclosure of their diagnosis and prognosis, others remained deliberately unaware by rejecting information offered by their physician. These patients can be considered in a state of self imposed ‘partial awareness’ of dying. Partial awareness, according the typology of Glaser and Strauss, includes the suspicion of dying or the pretence of not dying . This fiWhereas more quantitative approaches reveal that country of residence is a strong determinant of practices and attitudes -12, thisPatients reported a variety of experiences of communication with physicians, ranging from caring to coercive. Trust and confidence were reinforced by physicians’ availability, time and genuine concern, and negatively impacted by previous negative experiences such as misdiagnoses and poor communication style (lack of sensitivity and empathy) in all three countries. These findings highlight the importance of continued EoL communication training for physicians.The themes revealed by the secondary analysis are supported by the findings of international research on patient-physician EoL communication. Nolan et al.  describeThe studies, from which the interviews were derived, varied in their foci . As such the secondary analysis only looked at common themes on patient-physician EoL communication in three northern European countries. The variation found in the primary studies’ main foci does however make the identification of common themes even more remarkable.Decontextualization is a major risk in secondary analysis of qualitative data. A number of steps, therefore, were taken to ensure sufficient contextual information was available to inform the analysis. These steps are outlined in Table This secondary analysis only begins to address the paucity of cross-country qualitative research on patient-physician EoL communication in Europe. Furthermore, in Europe, EoL attitudes and practices are often discussed in terms of northern/southern, Protestant/Catholic, or Anglo-Saxon/Mediterranean dichotomies. However, all the interviews included in this secondary analysis come from northern European countries. Further research is required to ascertain whether the themes identified in this study are applicable in other European countries. There remains a need for primary cross-country research to better understand both the similarities and differences in attitudes, preferences, physicians’ practices and patients’ experiences across the continent, as well as the role of socio-economic characteristics and past experiences of illness, death or bereavement, to ensure the flexibility of patient care and the accommodation of a variety of patient preferences.This study highlights that older patients’ attitudes and preferences concerning patient-physician EoL communication are highly individual and that there is no ‘idealized’ preference for disclosure or participation in decision-making. Physicians must therefore be sensitive to a diversity of preferences amongst older patients and avoid stereotyping. In regard to communication style physicians are advised to be mindful to provide patients with clear explanations, avoid jargon, and continually check patients’ understanding. Physicians must also be careful to avoid partial information provision or any other attempt to manipulate older patients’ treatment choices as such actions can compromise patient autonomy and trust.The findings have implications for the dominant patient-physician decision-making models. In both the ‘shared’ and the ‘informed’ decision-making models the doctor informs the patient of the benefits and risks of all treatment options . In the NE designed and carried out the secondary analysis and drafted the manuscript. HRWP contributed to the study design, analysis and helped to draft the manuscript. SAP, JS, SP, RD, BDOP contributed to the conception of the study, the gathering of data and helped draft the manuscript. All authors read and approved the final manuscript.a, Meeussen Koena, Brearley Sarahe, Caraceni Augustog, Cohen Joachima, Costantini Massimoh, Francke Annekeb, Harding Richardc,d, Higginson Irene Jc,d, Kaasa Steinf, Linden Karenk , Miccinesi Guidoi, Onwuteaka-Philipsen Bregjeb, Pardon Koena, Pasman Roelineb, Pautex Sophiej, Payne Sheilae, Deliens Luca,bVan den Block LieveThe authors declare no competing interest.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-684X/11/24/prepub


The European CHOICE study was a cross-sectional survey that evaluated women’s combined hormonal contraceptive choices before and after contraceptive counseling in Austria, Belgium, Czech Republic and Slovakia, the Netherlands, Poland, Sweden, Switzerland, Israel, Russia, and Ukraine. The changes in method selection before and after counseling were reported previously. In this paper we present the reasons given by the 18,787 participating women for selecting their contraceptive method of choice, as well as their perceptions about the contraceptive pill, patch, and ring after counseling.Women with an interest in a combined hormonal contraceptive method  were counseled using a standardized counseling leaflet. The women completed questionnaires, which included questions on why they had selected a particular method of contraception, and the extent to which they agreed with statements about the attributes of the pill, patch, and ring. The results for each country were compared with the percentages for all countries combined by using a binomial regression model. Multiple logistic regression models were used to investigate the extent to which the probability of choosing a method was related to prespecified aspects (i.e. perceptions) of each contraceptive method.‘Easy to use’, ‘convenience’, and ‘regular menstrual bleeding’ were important selection criteria. ‘Nondaily administration’ was one of the main reasons women selected the patch or ring. ‘Daily use’ and ‘will forget to take it’ were the primary reasons for not selecting the pill, while the main reasons for not choosing the patch included ‘not discrete, visible’ and ‘can fall off’. In a small number of instances, the ring was rejected because some women don’t like to use a ‘foreign body’. Women’s perceptions influenced their contraceptive decisions: positive perceptions about a method increased the likelihood that a woman would select it. After counseling, many women associated the pill with forgetfulness, and many still did not know about the patch or ring’s key attributes. Women’s knowledge about a particular method was generally greater if they had chosen it.To support informed contraceptive decision-making, healthcare professionals should realize that a woman’s view of a method’s ease of use is more important than perceived efficacy, tolerability, health benefits, or risks. Innovation in reversible hormonal contraceptives beyond the pill  has given couples more contraceptive choices. Although women in more affluent countries generally have access to a wide range of hormonal contraceptives, combined oral contraceptives (COCs) remain the most popular form of reversible contraception in Europe and the United States-3. ParadInformed health care professional (HCP)–client dialogue and information-sharing may help women select a contraceptive method that best suits their needs and lifestyles, thus maximizing contraceptive compliance and helping to prevent unintended pregnancies. In the The Contraceptive Health Research of Informed Choice Experience (CHOICE) study was modeled after the TEAM-06 study and was designed to evaluate women’s contraceptive choices before and after contraceptive counseling in 11 mostly European countries OR would be > 1). Conversely, we expected that women who had a negative opinion about a particular method (i.e. they disagreed with its advantages and agreed with its disadvantages) would have a lower probability of choosing that method (OR < 1).The CHOICE study (began in April 2009 and ended in October 2010) included 1730 HCPs. The HCP study logs from nine countries (HCPs in Israel and the Netherlands did not keep logs) indicated that 65,603 women consulted their HCPs for contraception during the study period. Of those women, 18,787 expressed an interest in starting or switching to a new CHC method and completed Part B of the study questionnaire. The target number of participants per country was exceeded  in all countries except the Netherlands, where only 727 women were recruited. The mean age (± standard deviation) of participating women was 25.8 ± 6.4 years , condoms (25.2%), natural family planning (5.5%) or no method (10.2%)  and the ring  , other combined methods , and for women who were undecided regarding which method they preferred to use . The difference in proportions for each individual country was also calculated.In the 11 countries combined, a statistically significant increase was noted in the proportion of women who chose the method after counseling versus those who intended to use it before counseling for the patch . In Ukraine, women who selected the pill were less likely to state ‘daily use’ as one of the reasons they selected the pill. Women in Russia and Ukraine who selected the pill were more likely to state they chose it because it was ‘recommended by my doctor’ and was a ‘well-researched method’. If they chose the patch or ring, women in Russia and Ukraine were more likely to state that they selected these methods because they were ‘not dangerous’. Conversely, women in Belgium and the Netherlands who selected the pill were less likely to cite ‘well-researched method’ as a reason for choosing it. In Austria, ‘convenience’ mattered to fewer women who selected the pill, patch, or ring. ‘Convenience’ also mattered to fewer women in Switzerland who selected the patch and ring. In the Czech Republic and Slovakia, women were more likely to cite ‘weekly use’ and ‘monthly use’ as reasons to choose the patch and ring, respectively. In the Netherlands, women were less likely to state they selected the patch and ring because they are ‘easy to use’. In Poland, ‘discretion’ was more frequently given as a reason for women choosing the pill and ring relative to the percentage in all 11 countries combined.Reasons for choosing a method were similar in most countries. However, within certain countries, the most prominent reasons varied from the percentage in all countries combined by a statistically significant margin (Reasons for not choosing a method are shown in TableP < 0.001 for each reason listed in this paragraph). In Belgium, Israel, and the Netherlands, women were less likely to cite ‘daily use’ as a reason for not selecting the pill. Women in Austria, Belgium, Israel, and the Netherlands were less likely to cite ‘more convenient methods are available’ as the reason they did not select the pill. In Poland, women who did not select the ring were more likely to state they were ‘not interested in monthly contraception’. In Russia, women who did not select the patch were more likely to cite that the patch ‘can irritate skin’. Women in the Netherlands were more likely to avoid selecting the patch because they did not know anybody else who used it. Women in the Czech Republic/Slovakia and Ukraine were more likely to cite cost as a reason for not choosing the ring. In Russia and Ukraine, women were more likely to state that they ‘do not like to use a foreign body’ as a reason for not choosing the ring. In contrast, women in Belgium, Sweden, and Switzerland were less likely to cite ‘do not like to use a foreign body’ as the reason for rejecting the ring. In Ukraine, women more often stated that their partner did not like the ring.Within certain countries, many of the reasons that women cited for not choosing the pill, patch, or ring varied from the (pooled) response across all countries combined by a statistically significant margin , many stated that hormonal contraceptives may cause negative side effects and damage to the body, especially during puberty. The curIn a recent study that surveyed women in France, Germany, Italy, Spain, and the United Kingdom, social and cultural differences between these countries influenced women’s decisions regarding their method of contraception. Among tAlthough ‘easy to use’ and administration frequency were rated highly as selection criteria for the pill, patch, or ring in all countries, ‘convenience’ was cited less often by Austrian and Swiss women who selected the patch or ring compared with women in Poland, Russia, and Ukraine. We speculate that longstanding use of the pill may have contributed to a more negative image regarding the pill’s health risks , which could have prompted women (even in countries where convenience is less important) to seek alternative contraceptive methods.A recent study assessed women’s perceptions about the safety of COCs. Of 794 In the CHOICE study, the analyses of the association between women’s choice of method and their perceptions were, among other factors, corrected for women’s age, HCP's most frequently recommended method, women's last (main) contraceptive method, as well as other factors. These factors influenced a woman’s decision-making process. However, we also assume that cost played a decisive role in women’s selection of a CHC method. In most of the 11 participating countries, the patch and ring are indeed considerably more expensive than generic COCs, but in general their price is quite similar to the newer, branded COCs. Surprisingly, only 13% and 22% of participants did not choose the patch or ring, respectively, because of cost. Nevertheless, in the Czech Republic and Slovakia and Russia, cost was a significant deterrent that prevented many women from selecting the ring.Our analysis of the association between a woman’s selection of the pill, patch, or ring and her perceptions about these methods after counseling indicated that ease of use was the most important knowledge factor. In addition, women who chose a method had a positive impression about the method's efficacy, tolerability, safety, and cycle control. It was disappointing to see that, following counseling, so many women still indicated that they ‘did not know’ or had ‘no opinion’ about the advantages and disadvantages of the patch and ring (unless they had chosen this method). Furthermore, most women had an opinion (positive or negative) about the pill, irrespective of whether they had chosen it.The CHOICE study had several limitations. First, the study focused on women who were considering a combined hormonal method – women considering other forms of contraception or who indicated prior to the counseling they would not consider one of the three CHC methods did not complete the questionnaires and were counseled in the usual way. This was a deliberate decision, in consultation with the ESC, since we wanted to assess to what extent women consider alternatives to the method they were contemplating, provided it was a viable alternative for them. Nevertheless, this focus limits the generalizability of the findings only to women in the same situation. Secondly, we did not assess contraceptive compliance, discontinuation rates, or user satisfaction. This would have necessitated the need for a follow-up visit, which would have been costly and was not the primary interest of the program. Furthermore, in Belgium, Russia, and Ukraine, HCP’s favorable attitudes towards the patch and ring may have influenced the information and advice they provided, leading to a greater proportion of women who selected the patch or ring. The queThe results from the CHOICE study allow us to draw several conclusions. Informed dialogue between HCPs and women encourages women to select alternative contraceptive methods. The majority of women who selected the pill, patch, or ring stated that daily, weekly, or monthly use was an important consideration that factored into their final choice. ‘Daily use’ was the main reason why women who selected the patch or ring did not select the pill. ‘Easy to use’ was the most significant factor affecting women’s choices. Reasons beyond frequency of administration, including visibility of the method (e.g. patch), placement of foreign body inside the body (e.g. ring), and use of a well-known method versus use of a new, more innovative method, were important and varied significantly between countries. Additional knowledge of the various methods following counseling also played an important role. Surprisingly, a woman’s negative feelings about a particular method, especially the pill, did not always dissuade her from selecting it. In Central and Eastern Europe, women’s contraceptive decisions were more driven by safety concerns and HCP recommendations, whereas in Western Europe, women’s decisions were more driven by a less favorable opinion about the pill. While patch and ring use increased in all countries after counseling, women’s reasons for selecting or not selecting a particular method varied considerably between countries.In conclusion, we suggest that the results of our study demonstrate that awareness of the decision-making factors that affect women’s choices regarding methods of contraception may enable HCPs to make more informed recommendations that are targeted to the needs of each of their female patients.CHC: Combined hormonal contraceptive method; CHOICE: Contraceptive Health Research of Informed Choice Experience; COCs: Combined oral contraceptives; ESC: European Society of Contraception and Reproductive Health; HCP: Health care professional.Merck, Sharp & Dohme (MSD) provided financial support for this study. The authors received no compensation or honoraria in association with this manuscript and exercised sole and complete editorial responsibility for this paper. BJO and MMP are employees of MSD and may potentially own stock and/or hold stock options in the company. CE has received payments for consulting and lecturing for MSD, Pfizer, and Sanova and has received research funding from MSD, a company that may have a commercial interest in the results of this study. BF and JB have received consulting fees and honoraria for lectures by MSD. SW has received consulting payments from MSD. SW has received consulting payments from MSD.The authors of this manuscript all provided expert advice regarding the design and conduct of the CHOICE study and the interpretation and presentation of the data; they also contributed to the writing of this manuscript. In addition, JB led a team of representatives selected from the European Society of Contraception and Reproductive Health, a group that reviewed the study plan and provided input into the creation of a counseling leaflet that contained information about the pill, patch, and ring. BJO was the international project leader of the study, while MMP was responsible for statistical analysis. All authors read and approved the final manuscript.The International Steering Committee of CHOICE included Dr. Christian Egarter (Austria), Dr. Steven Weyers (Belgium), Dr. Tomáš Fait (Czech Republic), Dr. Arie Yeshaya (Israel), Dr. Frans Roumen (the Netherlands), Prof. Leszek Pawelczyk (Poland), Dr. Marina Anatolyevna Tarasova (Russia), Prof. Vera Prilepskaya (Russia), Dr. Vladimir Cupanik (Slovakia), Prof. Kristina Gemzell-Danielsson (Sweden), Prof. Johannes Bitzer (Switzerland), Dr. Brigitte Frey Tirri (Switzerland), and Dr. Vyacheslav Kaminskiy (Ukraine).The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6874/13/9/prepub†.Four most frequently cited reasons women selected the pill, patch or ring after counseling  Click here for file†.Four most frequently cited reasons women did not select the pill, patch or ring  Click here for file