Although physician-rated health is emerging as a potentially useful variable in research, with implications in practice, it has not been analyzed. Moreover, one of its most important aspects, namely, concordance with patients’ objective health state, has not been investigated. This study sought to measure concordance between physician-rated health and an objective health measure, and assess both measures’ validity in predicting death.The data for the study were drawn from a 1998–1999 survey and subsequent mortality follow-up of residential and nursing homes in Madrid (Spain). Study subjects were 630 residents aged ≥65 years, and their respective facility physicians. Measures included agreement between physicians’ rating of residents’ overall health  and an objective measure of residents’ health , based on functional capacity, cognitive status, and number of chronic conditions. Overrating was defined as any case where health, rated as good by a physician, was objectively rated as poor.Whereas 45 % of physicians and 55 % of residents rated their health as good, only 4 % of such residents had good objective health. Of those who received a physician rating of good/very good health, 39.0 % had poor objective health. There was evidence of clear overrating in 18 % of the population, and clear to moderate overrating in 73 % of the population. In terms of power to predict mortality, the pattern of behavior shown by the objective health measure was good, graded and congruent, and better than that shown by physician-rated health.Physician overrating of the overall health of older persons in residential and nursing homes, would appear to be very high. Although some degree of contextualization by physicians in this setting might be considered reasonable, the degree of overrating in our population seems nevertheless excessive. Physiciysicians . Geest ed health . Giltay ortality . In termortality . Physiciariables ; and Mooe health .While self-rated health has an inherent value because it is a measure of subjective health, it is highly advisable that physician-rated health be checked against objective measures. Undoubtedly, physicians also incorporate some legitimate subjectivity and may appreciate subtle aspects not captured by objective indicators, yet their assessment is expected to be based on objective health factors to a greater extent than that of other actors, such as nurses, staff, caregivers, the residents themselves, and family members. In principle, congruence between physicians and their patients’ objective situation tends to be taken for granted and, to our knowledge, has not been systematically explored.e.g., by limiting iatrogenic actions. The first step however is to examine and explore the nature of physician rating. We were unable to find previous studies that compared physician-rated health against an objective measure of overall health. Consequently, our principal aim was to measure the concordance between physician-rated health and an objective health measure and, in particular, to provide evidence of a specific aspect of discordance, namely, the overrating of health in an institutionalized older population. Our study was essentially descriptive, and rather than seeking to test a specific hypothesis, sought instead to measure and describe potential discordance. In addition, criterion validity  for the key variables  could be established on the basis of its association with all-cause mortality.It is possible that a marked degree of discordance –particularly in the form of overrating- between patients’ objective health status and physicians’ perception of this could well lead to deficits in preventive interventions, diagnosis, prescribing, treatment and rehabilitation options, and ultimately to an unsatisfactory quality of care. Yet the opposite can also be true, Data were obtained from a survey conducted from June 1998 through June 1999, using a probabilistic sample of residents aged 65 years and older drawn from 25 public/subsidized and 30 private residential and nursing homes in Madrid (Spain). Study participants were selected by stratified cluster sampling. Of an initial sample of 800 subjects, 715 responded . Due to refusal, prolonged absence or sampling-frame errors, 39 subjects were randomly replaced by a resident of the same facility and sex, yielding a total of 754 interviews.Using structured questionnaires, data were collected by purpose-trained geriatricians or residents in geriatrics, during interviews conducted with participants, their main caregivers, and facility physicians. Informed consent was obtained verbally from study subjects or their next of kin. The Research Committee of the Carlos III Institute of Health approved the study: this met Spanish legal requirements because at that time there was no statutory need for an ethics committee report in the case of non-experimental research. Patient anonymity was assured through anonymization of the data set. The Carlos III Institutional Review Board also approved the study.Physicians were asked to rate residents’ health in a similar fashion: “What, in your opinion, is the resident’s health status: very good; good; fair; poor; or very poor?” We deliberately gave no instructions to subjects or physicians in this regard. Interviews with physicians were conducted with the aid of medical records and nursing annotations. For both variables we collapsed the extreme categories to create the following three-category version: good (the result of very good and good); fair; and poor (the result of poor and very poor).Subjects were asked about their health via the question, “In general terms, how would you describe your health: very good; good; fair; poor; or very poor?” Physicians were asked whether any resident had suffered from one or more of a list of diseases , and the number of diseases was then computed.et al. [We used the Barthel Index, as modified by Shah et al. . Subjectet al. : indepenCognitive status was evaluated using both the Short Portable Mental Status Questionnaire  [ errors) , 12, whiobjective health, based on the 3-category version of the following variables: functional status in basic ADLs ; number of chronic conditions ; and cognitive status . Subjects in the lowest severity level of the three variables were assigned to “good” health; those in the highest severity level of any of the three variables were assigned to “poor” health; and the remainder were assigned to “intermediate” health state. We applied this scheme in order to be congruent with the notion of these health dimensions being regarded as very important. If a person were to be classified in the severe category of any very important health dimension, no label other than “poor health” would be expected: and, following this same line of reasoning, if someone were to depart from the lowest level of severity in any of these very important dimensions, then such a person should not be assigned a “good health” label. It should be stressed here that only aspects of objective health are being considered. It is perfectly feasible for a person to be in an intermediate or poor (objective) category and yet have a good self-rating, with positive coping abilities and satisfactory social life.We created a single, ordinal, composite index of overrating was defined as good physician-rated health in cases of poor objective health; and moderate overrating was defined as fair physician rating in cases of poor objective health, or good physician rating in cases of intermediate objective health.Clear Study participants were followed up for mortality through September 15, 2013. Mortality was ascertained by mailing a survey to the participating facilities seeking data on residents’ vital status and through linkage to the Spanish National Death Index, which includes all deaths registered in Spain since 1987 [Weighted (quadratic weights) kappa coefficients were computed to assess agreement between pairs of the 3-category versions of self-rated health, physician-rated health, and objective health.In order to explore the association between the different components of the objective health measure and the physicians’ ratings, we fitted a multinomial logistic regression model with physician-rated health as the 3-category dependent variable. Six independent variables were included in this model: baseline age; sex; type of facility; and the 3 components of objective health , entered in a continuous form with values 1, 2, or 3 for the low, intermediate and high severity levels, respectively.Mortality for the different variables was studied using Cox regression models. We estimated hazard ratios, adjusted for baseline age, sex and type of facility. Non-parametric survival curves were obtained as the baseline survival functions from health-stratified Cox models  with years from the baseline interview as the time scale. Models were adjusted to the overall weighted percentages of baseline category indicators, including age , sex (women or men), and type of facility . Due to the complex sampling and different selection probabilities of the study participants (with residents of public facilities and men being oversampled), all analyses took into account the effect of stratification and clustering on estimates, and were weighted to reestablish proportionality. All analyses were performed using the Stata 13 statistical software package .i.e., 101 cases of clear overrating (18 % of the population), and 130 plus 174 cases of moderate overrating, amounting to 73 % of the population with some degree of overrating . Table i.e., functional dependency, multimorbidity, and cognitive impairment. Individuals are known to contextualize [e.g., short life expectancy). Then again there are times when physicians might be very familiar with their patient’s status and reckon that, despite the objective facts, their patient feels well. Having said this, however, there might well be instances where insufficient knowledge of the patient is also a real possibility. We did not find comparable works but a related approach is worth mentioning. Kroenke et al. studied how well physicians’ global estimates of disease severity (for patients with chronic cardiac or pulmonary disease) corresponded to more specific prognostic variables assessed by them in the same 6-item questionnaire, in an attempt to check physicians’ internal consistency [To our knowledge, this is the first time that physician-rated health has been assessed against an objective measure. There was a notable degree of discordance, and, in particular, a high fraction of clear overrating, inasmuch as near four out of ten of those rated by a physician as having good (or very good) health, were shown to have poor objective health Table , a propoxtualize , and thixtualize , 16. Whisistency . They fomortality indicated a good, graded pattern of behavior by the objective health measure, and an unexpected pattern of behavior by physician-rated health. It seems that physicians effectively use only two evaluations, namely, “good” or “not good”. Examination of mortality associated with physician ratings, with additional adjustment for important variables such as functional dependence, cognition and number of chronic conditions, showed a clearer association with the “fair” (HR: 1.15 (95 % CI 0.91-1.46)) than with the “poor” category (HR: 1.08 (95 % CI 0.61-1.92)). It should perhaps be recalled here that the latter category included “poor” and “very poor”. Other studies have focused on the predictive ability of physician ratings: Giltay et al. reported a better prognostic value for self-rated health than for physician-rated health when it came to predicting cancer mortality, while the opposite was true when it came to predicting cardiovascular deaths [Analysis of i.e., overrating. We observed a higher-than-expected number of residents with unquestionably poor objective health who received a good rating from a physician. By “unquestionably”, we wish to convey that this particular aspect of the measure does not necessarily require a formal validation process because, in our opinion, anyone suffering from a severe degree of cognitive impairment, a severe degree of disability in basic activities of daily living, or ≥4 chronic conditions should not and cannot be considered to enjoy good health by any health professional conversant with the meaning of these components. We thus feel that it could be a good measure for evaluating health-overrating phenomena.No similar measure was to be found in the literature. Our aim was to incorporate important, undisputed elements of health status, while excluding any subjective judgment. It is our considered opinion that the dimensions used  are essential in any health construct but this is open to discussion . Althouge.g., Katz’s ADL scale [Our measure would have some valuable advantages. Equivalent measures can be easily constructed by anyone with available data on any accepted measure of ADL dependency  and cogDL scale ), and a First, systematic information was not collected on relevant physician characteristics, such as personal attributes, medical specialty, work load, or frequency of visits. The majority of the medical practitioners interviewed were primary care or family physicians.e.g., transient ischemic attacks might be regarded as cerebrovascular disease by some physicians but not by others, and the same could occur in the case of mild hypertension. These add to the sources of misclassification in this study, which we do not see as being important in epidemiologic terms. Finally, the National Death Index might have missed some deaths that were not confirmed. Nonetheless, the random nature of these potentially missing deaths could be expected to have a minimal impact on most estimates.As with most measures, our objective health construct is liable to error. For instance, some residents may be misclassified and placed in the severe category of any of the three component variables constituting the measure, and so be wrongly assigned to poor objective health. Even in such a case, however, overall discordance will still be very notable because there are also many instances of “moderate” discordance . Furthermore, there is the possibility of some degree of subjectivity when physicians answer the questionnaire, There were notable discrepancies between physician-rated and objective health, particularly in the form of overrating, which may possibly have corresponded to an excessive contextualization process, with consequences that remain to be studied.i.e., underrating, along with its potential consequences of overdiagnosis, overtreatment, and related facts.Physician-rated health may be very valuable and is, in general, easy to obtain, but evidence of its real usefulness can only be furnished by further research into its properties. Although this study has highlighted a negative aspect of physician-rated health, adequate design and selected information may well serve to better understand it. In addition, other settings may possibly reveal the opposite manifestation of discordance, Much of the speculation regarding the reasons for discordance could be elucidated by research which targeted physicians, questioned them more closely and requested that they give an explanation for their ratings. Future research should collect data that focus on physician and facility characteristics. Research conducted in other settings would also be useful.


Boston's Museum of Science supports researchers whose projects advance science and provide educational opportunities to the Museum's visitors. For our project, 60 visitors to the Museum played “Fish Police!!,” a video game that examines audiovisual integration, including the ability to ignore irrelevant sensory information. Players, who ranged in age from 6 to 82 years, made speeded responses to computer-generated fish that swam rapidly across a tablet display. Responses were to be based solely on the rate (6 or 8 Hz) at which a fish's size modulated, sinusoidally growing and shrinking. Accompanying each fish was a task-irrelevant broadband sound, amplitude modulated at either 6 or 8 Hz. The rates of visual and auditory modulation were either Congruent (both 6 Hz or 8 Hz) or Incongruent (6 and 8 or 8 and 6 Hz). Despite being instructed to ignore the sound, players of all ages responded more accurately and faster when a fish's auditory and visual signatures were Congruent. In a controlled laboratory setting, a related task produced comparable results, demonstrating the robustness of the audiovisual interaction reported here. Some suggestions are made for conducting research in public settings. For more than a century, researchers have occasionally collected psychophysical data outside the laboratory, in public or quasi-public settings. Notwithstanding the logistical challenges they present, such environments can be attractive, especially for research focused on developmental trends and individual differences. Perhaps the best-known example of research done in a public setting is The Living Laboratory, located in Boston's Museum of Science, provides a unique research environment. The Museum invites scientists from local universities and hospitals to use the Laboratory as a venue for engaging visitors in ongoing research that also offers visitors a valuable educational experience. The Laboratory makes it possible to collect useful data from large and diverse samples of subjects across a wide age range, from school-aged children through senior citizens. For some time, we have been interested in audiovisual integration, particularly the ways in which a correlation between signals' temporal structures promotes their integration . So we tPsychophysical experiments are often time consuming and usually require many repetitions of the same measurement. As a result, test subjects must be available, attentive, and motivated for one or more lengthy testing sessions. Particularly when researchers want to study a wide age range of participants, the repetitive, sometimes monotonous aspects of an experiment can cause participants to withdraw before the needed data have been collected. Withdrawal before testing is complete can render data collected up to that point unusable. To minimize such risks, we embedded our experiment within a simple video game, which was designed to engage and amuse participants while also generating data on interactions between what subjects saw and what they heard e.g., .In our video game, “Fish Police!!,” players watched as computer-generated fish appeared one at a time and swam rapidly across a virtual river see . As it sOnce a fish appeared and began its journey across the river, a subject had just 2 seconds to respond before the fish would disappear from view. Then 3 seconds later, a new fish appeared and began its journey across the river. This schedule spawned about 12 fish per minute, which made the game challenging and seemed to promote sustained attention.In addition to a task design that would be accessible to subjects of all ages, this unique setting also required special considerations in terms of set-up. In laboratory environments, equipment needed for research can be set up and left unmolested for repeated use over an extended period. In public settings, that is usually impossible to do. The Living Laboratory's space is time-shared among multiple research projects, each of whom can use the space only a few hours each week. At the end of each day's assigned time, researchers must pack up and remove all the equipment and materials that had been used. To accommodate this requirement, our experiment's game was implemented in Python on an inexpensive touchscreen tablet computer (Samsung Note 10.1) running the Android mobile operating system.To boost players' enjoyment, Fish Police!! incorporated several features common to video games . For exaYou are going to be the police officer in charge of a river. One at a time, from either side of the tablet, a fish will appear. They are very nervous, though, because they don't want to be caught by you! The bad fish will be wiggling fast because they're scared, that's when you tilt the tablet towards you to catch them. If the fish is wiggling more slowly, then it's a good fish because it isn't as nervous, so you can tilt the tablet away from you to let it go. Remember though, since they've been swimming for a while, they're a little bored so they hum --you'll hear this through the headphones I'll be putting on you. Try as best you can to JUST focus on their wiggling to tell if they're a good or bad fish.As potential players of Fish Police!! would be unused to the attentional demands of psychophysical experiments, we decided to embed subjects' instructions in a narrative that would be engaging, easily understood, and easily remembered. After being shown the computer tablet on which the game would be played, subjects were told:Each participant played the game while holding the tablet with one hand on each side of the screen. This made it possible to implement a pair of responses, tilting the tablet either toward or away from the player that had an easily remembered correspondence to the judgment that each direction signaled.At the Living Laboratory's entrance, a video monitor advertized the game by displaying an image from Fish Police!!'s splash screen. Before commencing play, a player's basic demographic information, initials and age, was entered via the tablet's touchscreen. This information and all data generated during game play were de-identified and uploaded wirelessly by the tablet in real time to a secure server offsite. The tablet's built-in accelerometer sampled the tablet's angle of tilt at 60 Hz. The Python script controlling the video game defined a response as a rotation that was 17 ° or more relative to the tablet's orientation at the moment when a fish first appeared on the screen. This rotation threshold guarded against that possibility that spurious, unintended movements of the tablet would be mistaken for genuine responses to the fish. Once the Python script detected that the response threshold had been exceeded, it triggered the appropriate feedback for players, either the sound of coins clinking or a buzzing sound, and then, 3 seconds later, spawned the next fish. All accelerometer readings and responses were inserted into a data stream sent wirelessly from the testing area to the offsite server.Before beginning the game, a player was shown how to hold the tablet, with one hand on each side, and how the tablet was to be tilted in order to signal a response. Then, each player was given three practice trials with Congruent and Incongruent “good” and “bad” fish. Also included in these practice trials were some in which the fish was presented with no accompanying sound. These no-sound trials were meant to reinforce the point that the player was to judge a fish only on the basis of visual attributes. The practice trials provided an opportunity to ensure that a player understood the task. These trials were followed by a set of 10 practice trials in which conditions were randomized. Subjects scoring six or more correct on these randomized trials were allowed to move on to the game proper; 12 subjects who failed to reach that threshold received an additional set of 10 practice trials. Most of these 12 were among the younger subjects, who may have been particularly distracted by the presence of schoolmates and friends. After a player finished, the player's proportion of correct responses and mean response time, along with the initials and results of the previous 10 players, were displayed on a large computer monitor visible to the player and to any onlookers. Video 1 affords a player's eye perspective on the game.During the approximately 5 minutes of play, each player had the opportunity to judge and respond to 60 fish. For half the fish, the frequency of its size oscillation and the frequency of the concurrent amplitude modulation were Congruent, that is, both were the same, either 6 Hz or 8 Hz; for the other half of the fish, size and sound amplitude modulation were Incongruent, that is, they were at different frequencies. Specifically, the fish sinusoidally oscillated in size, either at 6 Hz or 8 Hz, while the concurrent sound amplitude modulated at the other frequency, that is, 8 Hz or 6 Hz. For indices of audiovisual integration, we contrasted players' performance with Congruent fish to their performance with Incongruent fish, using as metrics the proportion of categorizations that were correct, and the latency of response on correct trials; 60 test participants completed the entire 5-minute game; their ages ranged from 82 years down to 6 years, the youngest age we had permission to test. The 60 fish each player saw and heard were uniformly distributed across four categories defined by the two species of fish (good fish—6 Hz oscillation in size and bad fish—8 Hz oscillation in size), crossed with two types of congruence . For each subject, this 2 × 2 design produced just 15 trials per cell, too few samples for stable estimates of the dependent measures. For example, with only 15 samples and binomial variability, a change of just a single response would produce a swing of more than 13%. To reduce the impact of having so few samples per condition, while maintaining the focus on audiovisual interaction, we aggregated responses into just two categories: All fish whose audiovisual signals were Congruent and all fish whose audiovisual signals were Incongruent. In so doing, we ignored the frequency at which any particular fish varied in size.t test, producing t = 6.89, which corresponds to p = 4.128e-09 (with df = 59)  . Differedf = 59) .We next focused on response times from trials on which correct responses were made. Mental chronometry  treats at = 0.93, p > 0.35 (df = 59), . Note that the 60 Hz sampling rate of the accelerometer introduced some irreducible uncertainty into our mental chronometric estimates. Moreover, one subject continuously jiggled the handheld tablet, making it impossible to extract reaction time and MT from his/her records; that subject's data were excluded from further analysis.The mean MT for Congruent fish was 175.58 ms; the corresponding mean for Incongruent fish was 162.88 ms. The difference between these two means was not statistically significant, t test on the differences between the two sets of reaction times produced t = 6.00 (df = 59), for p = 1.277e-07. So both dependent measures, time and accuracy, produced reliable differences between players' processing of Congruent and Incongruent fish . A ent fish .r = −0.006; the . So, whatever factors contributed to differences in the way that players were affected by audiovisual congruence, these factors did not include adoption of some consistent speed-accuracy strategy.We were interested in the possibility that subjects might have been trading accuracy for speed of response . Viewingp = 0.13, and for accuracy, p = 0.82. The 95% confidence intervals around the slope of regression against players' age each included zero,  and , for accuracy and response time measures of congruence, respectively.Previous studies suggested that in humans, audiovisual integration emerges late in the first year of life , but conResults with each dependent measure were consistent with those from a comparable task studied in a controlled, laboratory setting . In addiMoreover, results from the Museum and from the laboratory show that the effect of temporal correlation of auditory and visual signals is strong enough to survive even with no corresponding spatial correlation between visual and auditory information. That is, the spatial information provided by vision  was not matched by a comparable change in auditory spatial information .As explained above, results from the two dependent measures  suggest In our video game, whenever a fish's auditory and visual attributes were not congruent, the rate at which the fish's sound was amplitude modulated not only did not match the rate of its size oscillation but also actually matched the visual modulation rate of fish from the competing type, either “good” or “bad” species. This particular form of mismatch between auditory and visual signals was intended to maximize stimulus-response interference , which wPlanning this project made us mindful of the many differences between a public or quasi-public research environment and the well-controlled dedicated research laboratories in which we have been studying various aspects of audiovisual interactions . AnticipOf course, visual distractions and background noise are unavoidable in public spaces. In the Living Laboratory, visual distractions included the Museum's nearby scientific attractions, the stream of curious passers-by, as well as players' friends, relatives and, for school age players, their classmates, and teachers. To minimize these and other potential visual distractions, we took the simple step of seating participants so that they faced a blank wall, with backs turned toward onlookers. Appreciable noise was generated by nearby interactive exhibits and by the chatter of excited visitors to Museum, particularly younger visitors. These sounds were consistently ∼76 to 80 dB SPL. To control the impact of audio distractions, participants wore Bose QuietComfort 15 Acoustic Noise Canceling Headphones while playing the game. These provided ∼30 dB attenuation. This reduction in background sound helped subjects focus on the task, with reduced influence from the occasional heckling or encouragement of family or friends, or by the general din of the Museum.As mentioned earlier, a publicly viewable video monitor displayed each player's initials, score, along with the scores of the previous 10 players. This leader board seemed to motivate players, particularly when a pair of museum-goers decided that they would be competing against one another. The leader board was helpful also to players who did not do well, as it showed them that there was considerable variation among players. In this regard, the leader board was particularly helpful to parents of children whose play was good, but not perfect. A less than perfect score made some players' parent ask what was “wrong” with their child. Seeing the scores of the preceding 10 players helped to provide a reassuring answer to that question. Finally, the leader board encouraged some players to ask a scientifically important, but difficult question, namely, why success varied as it did from one player to another. For that question, we have yet to develop a satisfactory answer.Even if some planned project does not entail auditory stimuli, researchers might still consider some technique to attenuate extraneous sounds. The noise canceling headphones worn while subjects played Fish Police!! were particularly useful, as they served two purposes. First, the headphones reduced the saliency of the extraneous sounds that were plentiful in the Museum setting; second, the headphones signaled to onlookers, particularly friends or family members, that the headphone's wearer was engaged in an important task and therefore should not be disturbed.In settings like the Museum of Science, many visitors are eager to take part in an activity that simultaneously is enjoyable and advances science. An experiment should be engaging and provide a vehicle for subjects to become interested in science and learn about real world applications of research. Embedding an experiment in a game is one effective way to achieve these goals. As researchers, we were gratified that so many of the Museum visitors who played Fish Police!! were interested in how their data would be used and how their results would impact science. For their participation and contribution, we are most appreciative.


The Wellcome Trust, the World Health Organization, and cardiologists have advocated for the idea of a “polypill” containing multiple cardiovascular drugs to be co-formulated into a single pill for over a decade. Some cardiologists have asserted that the drugs commonly considered for inclusion into such a polypill are older and therefore free of patent protection. We tested this assertion. This project was requested by the World Heart Federation (WHF).Two cardiologists from the WHF provided a list of 48 cardiovascular drugs for evaluation. We designated the United States and Canada as the base jurisdictions for this patent study. We linked patent data from these countries’ national medicine patent registers to patent information in over 96 other countries using Derwent and INPADOC via Thomson Innovation. We expanded our study beyond the aforementioned data linkage through a systematic search of the World Intellectual Property Organization’s PatentScope, which was based primarily upon the drugs’ active ingredient names.In the United States and Canada, eight of the drugs were only available in the patent-protected, brand name formulation in one or both countries. Another 21 drugs had relevant patents, but generic equivalents were nevertheless available. Only 19 drugs (40 %) appeared entirely post-patent. Broadening the co-formulation searches globally, the overwhelming majority of drugs (40/48) were mentioned in patent applications for cardiovascular drug combinations.The assertion that most of these cardiovascular drugs are post-patent is accurate, but only in the sense that many of the original patents on these active ingredients have expired and that generic alternatives are usually available. The landscape of patents covering novel (co-) formulations is far more complex, however. Most research and development for cardiovascular combination medicines are likely to be undertaken by companies whose original patents on the active ingredient will soon expire or have recently expired. Cardiologists looking to accelerate polypill development may consider approaching such companies to partner.The online version of this article (doi:10.1186/s12967-016-0997-3) contains supplementary material, which is available to authorized users. There is a major gap between the prevalence of hypertension, and recourse to effective treatment, particularly in developing countries, where 80 % of the disease burden lies , 2. To aBut while there is large appetite from the public health community for a polypill, no such thing is commonplace in today’s global pharmaceutical market. Why is this? Are there patent barriers to market entry? Experts on the treatment of CVD have stated that the drugs under consideration for inclusion in cardiovascular polypill prototypes are no longer covered by patents , 6, 18, We began by independently consulting two expert cardiologists —who both participated in a workshop on the polypill endorsed by the WHF—on what drugs are of particular interest for co-formulating. We used the union of their drug lists (n = 48 drugs) as the focal point for this patent study.As patent grants vary by country, it is necessary to designate a base legal jurisdiction for patent studies as a starting point for analysis. Consistent with other published methodologies –29, we sBoth countries have publicly available medicine patent registers—the United States Food and Drug Administration’s Orange Book  and HealNext, we consulted two commercial-grade international patent search databases covering over 96 countries—INPADOC  and DerwThereafter, we reviewed the title and abstract of each “Basic” patent identified by Derwent . We scored the type of protections typically covered by the patents contained in each family according to their proposal of a new co-formulation , a new compound , a new formulation , a new method of treatment , and/or a new manufacturing process.Both a strength and limitation of the above method is that all patents included are related to currently marketed products. To provide an impression of potentially relevant patent literature that may have been excluded, we conducted supplemental searches in the World Intellectual Property Organization’s (WIPO) PatentScope database . This daAll of the above patent searches were performed in May and June 2015. Note that there is no objective, definitive point at which such searches have identified all relevant patents. An expert judgment has to be made when to stop. Our results therefore should be taken as a preliminary appraisal, reflecting our search strategy, and should not be regarded by anyone seeking to commercialize these drugs as a substitute for obtaining independent legal advice. Our raw datasets are available in this article’s supplementary materials  were available only as a brand name, patent-protected formulation in one of the base jurisdictions (the United States or Canada)  products containing one or more of the 48 drugs of interest, we found ten drugs 21 %) for which the only co-formulation(s) available in the United States or Canada was the patent-protected, brand name product  were identified in the co-formulation patent applications returned from WIPO PatentScope, either by active ingredient name or by drug class. Only eight drugs were unmentioned, all of which were older diuretics . The remaining 3  were identified as the diuretic of choice in many proposed co-formulations, especially hydrochlorothiazide.Cardiologists’ perception , 6, 18 tWhat is the significance of this finding for polypill advocates like the WHF who see promise in that treatment in developing countries? Below we discuss two perspectives on the patent system—for shorthand, the “competitive” versus “cooperative” perspectives—which differently inform two corresponding courses of action based on the findings and data presented in this report.The “competitive” perspective is that patents represent strong, if temporary, barriers for others seeking to develop a technology and disseminate it widely. Patent owners possess exclusive rights to seek financial compensation in the law courts from those who infringe their technology. In this perspective, advocates of a CVD polypill should be prepared to deal with risk adverse pharmaceutical companies, who would likely not want to develop products that infringe upon these rights. Any patent is therefore a disincentive.Based on this view of the patent system, our results, such as those in Table The “cooperative” perspective is that the patent system serves to incentivize new innovation, products and commercial activities. Patent owners acquire rights so as to make a business case for investment and commercialization. In this perspective, advocates of a CVD polypill should try to piggyback onto efforts that maximize the revenue pharmaceutical companies can obtain from their patent holdings, but in such a way that allowances are made for access to medicines in poorer countries.Based on this view of the patent system, the shaded areas of Figs. exactly which medicine combinations are best for an FDC. That choice has to be based on strong scientific consensus of the most clinically rational combinations, but not necessarily unanimity, and must strike a balance between the best therapeutic outcomes (for patient treatment success) and widespread suitability of the formulation . Clear consensus is a true sine qua non, because whether seen through the eyes of a branded or generic company, advocates are calling on them to invest millions of dollars in FDC development and registration—and very simply put, companies will only sink that money when there is consensus guidance that says “the combination of A plus B plus C is satisfactory”, rather than equivocal guidance that says “the combination of A or B, plus C or D, plus E or F, but not if F is combined with C”.We do not consider the “cooperative” and “competitive” scenarios mutually exclusive; rather they are complementary and should both be pursued. But both of them require that advocates make it extremely clear The endorsement of advocates, or a coalition of advocates, to recommend a particular CVD co-formulation would likely appeal to drug makers and have a very significant impact on their willingness to invest. Since one would be endorsing a choice of co-formulation, and not a product, there is no conflict of interest in doing so. That would be a valuable step, whether pursuing a FDC built upon the “competitive” viewpoint of selecting only unpatented drugs over which nobody has exclusivity, or upon the “cooperative” viewpoint of selecting a drug precisely because it is patented and somebody has exclusivity. Our previous research in bringing low-cost new medicines to developing countries has shown that, depending upon circumstances, patent-centered strategies for improving access to medicines can be just as effective as patent-negating ones , 46, 47.Our study has tested the assertion that the drugs under consideration for polypill co-formulating are older, are post-patent, and have been genericized. For the original active ingredient patents, this is largely true, but our findings show that secondary patenting on these medicines is prevalent, and this includes large numbers co-formulation patents by generic and brand name companies alike.We have suggested two strategies based on the empirical data provided by this study for global public health entities like the WHF who are in pursuit of developing a polypill, and these strategies can be undertaken simultaneously. Our impression, however, is that others attempting to advance polypill development have relied most heavily upon variants of the first strategy. We suggest a more balanced approach, set upon two parallel tracks, in which patents are viewed both as barriers and as opportunities, depending who the commercial partner is.


Professional ethics refers to the use of logical and consistent communication, knowledge, clinical skills, emotions and values in nursing practice. This study aimed to explore and describe factors that affect professional ethics in nursing practice in Iran.This qualitative study was conducted using conventional content analysis approach. Thirty nurses with at least 5 years of experience participated in the study; they were selected using purposive sampling. Data were collected through semi-structured interviews and analyzed using thematic analysis.After encoding and classifying the data, five major categories were identified: individual character and responsibility, communication challenges, organizational preconditions, support systems, educational and cultural development.Awareness of professional ethics and its contributing factors could help nurses and healthcare professionals provide better services for patients. At the same time, such understanding would be valuable for educational administrators for effective planning and management. Nursing mission is to provide high quality healthcare and maintaining and improving community health . Ethics An inherent part of nursing is to respect human values, rights and dignity . From a et al. [Nursing ethics might also be considered as competency in nurses without any direct impact on their clinical activities, which could be separated from practical duties of nursing. However, such ethics are highly interwoven with clinical practices that cannot be alienated from them . Lemonidet al.  suggest Nowadays, health care settings are changing rapidly. Thus, nurses are facing ethical challenges in healthcare that put them at risk of ethical conflict . AlthougThis qualitative study was conducted using conventional approach of content analysis. It has been intended to explore and describe factors affecting professional ethics in clinical practice. In general, content analysis is used when the objective of a study is to describe a phenomenon, and there are limited ideas  or fragmParticipating nurses were selected by purposive sampling from hospitals affiliated to Jahrom University of Medical Sciences in Jahrom, Fars, Iran. A total of 30 nurses including 25 female and five male nurses with at least 5 years of experience participated in the study. The sample size was chosen based on the data saturation. Data were collected using individual face to face and semi-structured in-depth interviews. Each interview took between 60 and 100 min. All interviews were conducted in the participant’s workplace in a quiet setting. Firstly, interviews were started with main questions in accordance with participants’ statements. Then, it was continued by probing questions. All interviews were initiated with this question: “as a nurse please tells me about the ethical issues you have faced in your workplace”. As the interview progress, these questions were asked: what factors affect professional ethics in your clinical care? All interviews were recorded and transcribed immediately.Conventional approach for data analysis was implemented; no structure was used for categorizing data. This approach was carried out over three phases including: preparation, organizing and writing the report. In the preparation phase, each interview was treated as a unit of analysis. The recorded interviews were transcribed precisely and read several times to gain general impression. In the organizing phase, unites of meaning for each interview was highlighted, condensed, and openly coded. Then, codes with similar meanings were arranged into subcategories and main categories. Finally, the latent meaning of the data was reported in the reporting phase .Conformability of findings was evaluated to achieve the reliability of collected data . To achiThe approval of study was obtained from the Ethics Committee of Jahrom University of Medical Science. The participants were asked to sign a consent form; they were assured that they can withdraw from the study at any time.The findings highlighted two main themes: internal factors that deal with individual characters, responsibility and communication challenges; external factors that were reflected on organizational preconditions, support systems, educational and cultural development Fig. .Fig. 1FaIn this category, were extracted accountability, work conscience, positive energy associated with others, and self-control skills in conflicting situations. Most nurses pointed to professional ethics and accountability as important features that contributed to making a background for the ethical context of healthcare setting.Accountability: one of the participants with 11 years of experience mentioned that if nurses devoted themselves to their work sincerely, accepted their responsibility, and acted accordingly, the patients would receive medical care appropriately. For example, a nurse might use his/her hand (i.e. by putting it on the patient forehead) to see if the body temperature was normal instead of using a thermometer. Such inappropriate methods could jeopardize patient’s health, because there was high possibility of making mistake. Another participant with 10 years of experience about work conscience said: “I think that work conscience is a personal issue, and no one can be forced to accept it.” She continued “there are specific times when my shift at work is over, but I am still in the middle of the work. I take the responsibility of patients care and continue until I finish my duty, even if I have to stay more.” However, some nurses explain their shift is over and they have to wait for the next shift. In the interim, work conscience is another factor that is important in work discipline and generates sense of duty in the individual.By character, we mean a set of behavior and manners of thinking that individuals use in their everyday life situations. Character is also determined by other characteristics that are unique to that individual; it has been established in him/her and is predictable. Regarding the character of an individual, the participants believed that personality is formed during childhood in both family and society. However, they added that the environment is responsible for changing 40–50 % after the formative years. Manager can adapt to the environment; for example, with a little encouragement can be a very good influence.Regarding the possession of positive energy, a nurse said: “in my opinion, a nurse should work in an environment in which marginal issues are excluded. In addition, it is brimmed with positive attitudes and energy. Because patients admitted to hospital are often suffering from disruption in health condition, and this is uncomfortable for them and their families. Therefore, nurses should provide care with positive energy for patients and their relatives, reinforce their spirit to recovery and create a sense of hope.Regarding the internal control skills, a participant expressed: “A professional nurse has to be able to be considerate in different situations. For example, I had a patient suffering from multiple fractures. He was using bad words when he has severe pain. While I was doing his treatment, he even pushed me hard so that I felt down on the floor, but it did not make me upset. I did my best in spite of the patient’s behavior until I finally could reduce his pain.In this category, the following themes were extracted: communication between doctors and nurses, professional relationship among staff, nurse-patient relationship, and effective communication and interaction in the workplace.In this regard, a participating nurse with 8 years of experience said: “a doctor found an error in a patient’s medical records. Although it was not my fault, he insulted me verbally.” she added: “Unfortunately, reporting such cases is not beneficial. Because authorities do not attend or respond to such instances in the healthcare system.”Nurse- patient relationship: A participant with 12 years of experience stated: “I had an end stage patient. Even though the medical team was disappointed to him, and his level of consciousness was not at full stage, whenever I went to take care of the patient, I talked to him without receiving any response. The patients’ family told me that he opened his eyes when the nurse was giving medication and nursing care. I feel that the patient was waiting for someone who cared about him; the patient even in the absence of any communication could realize that someone had sympathy for him.”Nurse-patient communication: A participant with 8 years of experience said: “I believe that good communication with patients has miraculous results. For example, I had a patient with cardiac and respiratory diseases. He had an excruciating pain that made him scream. While I was doing my job as a nurse, I talked to him in a soothing manner and kept telling that he would be alright. I thought, based on his behavior, talking to the patient was effective enough to somehow make him relaxed.”In this category, the following themes were chosen: facilities and equipment; observance of nurse-patient ratio; heavy work load and shortage of staff; nurses’ right to choose an appropriate ward.Hospital facilities and equipment play an important role in establishing professional ethics. Non-standard equipment can interfere with providing proper care and may even mislead medical staff judgment about patients’ conditions. For example, we had a patient with kidney problems who had undergone surgery. While the patient was suffering from infection, temperature control device showed his fever lower than the actual degree. This seemingly simple incident could increase the length of hospitalization and hospital costs.Inappropriate nurse-patient ratio and heavy work load: a participant with 11 years of experience stated that once we had 40 patients, while only 5 nurses were available for care. Suppose from the above number, only 25 patients were in need of special care every few minutes, how could such a limited number of nurses be able to respond to required demands of the patients? It was absolutely infuriating. To make the situation still worse, add 25 more people to the list of the patients, those who accompany patients to the hospital and frequently go to the stations at hospital wards and expect to receive proper answers for their questions whenever they wish.Another participant with 14 years of nursing experience stressed on nurses’ rights to choose their own working places at hospitals. According to this person, this opportunity could affect the application of the professional ethics. He said: “I was supposed to work for 2 years as an obligatory practice after graduation. I worked in the emergency ward, in spite of my will.”In this category, the following themes were extracted: appropriate support system, flexibility and effective reward and punishment.A participant with 12 years of experience said: “I believe that an effective support system should encourage us to observe the professional ethics. Whenever I face a problem, supervisors should support me. Also, a proper system of reward and punishment could help enhance experience of the professional ethics.”Another participant highlighted flexibility as a necessity for nursing. He said: “nursing practice requires even if a patient is too much demanding or he has had challenges with us; we should never deprive him from our services.Another aspect of supportive system, according to a participant with 15 years of experience was an efficient way of punishment and reward system. He said “It would be helpful for nurses to get a positive or negative feedback based on their professional behavior. If the monitoring system rewarded me when I did my duties efficiently, I would be encouraged to work 10 times more than I supposed to; otherwise, I lose my motivation. Just try it for six months and see the results”.In this category, these themes were extracted: model educators and attention to practical ethics through modeling the environment, re-thinking about behavioral processes, cultural development focusing on ethics, and specialized practical and theoretical training courses in ethics.Regarding educator modeling and its impact on the development of morality, a participant with 13 years of experience stated that nursing instructors should be aware of the effects of training methods on trainees. He added “our instructor once forced male students to empty patients’ urine bags and change the bed sheets in the presence of patients’ companions and cleaning staff of the hospital. Meanwhile, he put the nurse under more pressure by repeating his order again and again. Such behaviors make negative impacts on our views of the job as a nurse.”For the issue of re-thinking about behavioral processes, a participant with 10 years of experience commented “I had a patient with ventricular fibrillation. As physicians were not available at that time, I started resuscitation. It was successfully performed, and the patient is still alive. As I reflect on my deeds, I found it very important.” The nurse continued, “In another instance, I found an error in a physician’s prescription and since I was sure about the exact medication dosage, I made the correction.”Regarding cultural development and ethics, a participant with 16 years of experience stated: “I had a critically ill patient who were supposed to be transferred to another hospital. I stayed with him until 4 pm, after my shift was over at noon; I had lunch after arriving home.” Such devotions or commitment to a profession can be strengthened by means of cultural development.”A participant emphasized on the importance of ethical courses for nurses. He said “training nurses in services expected from them is necessary. Every year, CPR training is repeated for us in accordance with new protocols to keep us updated.” However, another participant’s talk was focused more on educating nurses in professional ethics. He mentioned, “Such a course should be taught on location to make nursing students familiar with accepted patterns of morality in their interactions with patients.Factors effecting professional ethics in nursing practice have been identified in this study. The first main category of the findings was focused on the individual character and responsibility. It was emphasized on developing a sense of responsibility in nurses as a significant factor that influences professional behavior. Also, nursing literature indicated that creating professional commitment should be regarded as a necessary quality for nursing practice; nurses should be accountable for their decisions and outcomes. Such characteristics lead to better observance of professional ethics by nurses . Indeed,The second category is communication challenges among health care members. The participants highlighted effective relationship as the element of professional ethics. The researchers also believe that effective nursing is highly related to developing proper relationships among members of the health care system. In the absence of such attitudes, patient care will be adversely affected.This study also indicates that patient’s assessment is one of the important measures in establishing rapport between nurse and patient . In receOrganizational preconditions are the third category affecting professional ethics. Adib Haghbaghery et al.  stated tAlthough patient care is important for nurses, deficiency of clinical standards negatively affect nurses’ performance . This stThe fourth main categories in this study are support systems. Studies showed that elements of supportive environment in nursing contain an appropriate team work, accepting sense of personal identity, freedom to ask questions, and having a suitable working relationship. These factors can enhance professionalism and autonomy in nursing. From practical point of view, however, most nurses have not experienced such a supportive working environment; too much effort is needed to get support . In otheThe fifth main category of this study was educational and cultural development. Experts have explained that establishing bonds of commitment to nursing profession depends on cultural considerations , 38. ThiThe research findings have shown that both internal and external factors affect professional ethics in clinical practice. Therefore, professional ethics is not limited to the internal factors. External factors including instructors, administrators, health care providers, education, and culture can be applied in workplace in order to assist nurses in moral development.The acquisition of professional ethics is facilitated by internal and external factors. These factors could lead to legitimate norms and standards govern professional behavior of nurses in their relationships with patients. Furthermore, good communication among health care members, improvement of organizational preconditions, appropriate supportive system, and development of education and culture could lead to observing professional ethics in clinical practice.


Diatoms are unicellular algae with ornate silica shells. Their dazzling ability to build tiny structures could inspire applications in the semiconductor industry, drug delivery, and engineering Thalassiosira pseudonana (http://genome.jgi-psf.org/diatom/).Diatoms, unicellular algae with ornate silica shells, have fascinated amateur and professional biologists ever since the invention of the microscope. But these days, diatoms and their exquisite shells are also attracting the attention of nanotechnologists who hope that diatoms will teach them how to make minute structures currently beyond the capabilities of materials scientists. And now these nanotechnologists, together with ecologists interested in the global carbon cycle—in which diatoms play a central role—have a genomic blueprint to help them in their studies: the annotated genome sequence of Diatoms, microalgae that are found in all aquatic and moist environments, first appeared more than 180 million years ago. Since then, diatom diversity has literally exploded; no one is sure how many living species there are—probably about 100,000—or why there are so many different types. Plant molecular biologist Chris Bowler  explains that molecular phylogeny and morphological studies suggest that diatoms originated ‘probably as the result of a eukaryote being invaded or engulfed by a photosynthetic eukaryote, most probably a red alga’.The basic structure of all diatoms is similar: a single cell, often with a large vacuole, contained within a silica shell or frustule made of two overlapping halves or valves joined by girdle bands, which are also made of silica. The girdle bands form the rims of the two valves and allow unidirectional growth of the diatom during vegetative division. ‘The shell is rather like a Camembert cheese box or a petri dish’, explains marine ecologist Christian Hamm .There are only two main types of diatom: centric diatoms, which often have a circular symmetry, and pennate diatoms, which are usually bilaterally symmetrical. Nevertheless, diatom shells come in a dazzling array of forms and sizes ; Box 1. Richard Gordon, Professor of Radiology at the University of Manitoba in Winnipeg, Canada, somewhat accidentally laid the foundations of ‘diatom nanotechnology’ in 1988 when he was invited to give a lecture at an engineering conference. ‘I'm not an engineer’, explains Gordon, ‘but I knew engineers were interested in what was then called microfabrication so I told them about diatoms because they are so good at making small things’. Gordon, a keen diatom hobbyist, explained to his audience how diatoms could make a three-dimensional micro- or nanoscale structure for them without them lifting a finger. By contrast, says Gordon, ‘nanotechnology techniques then and now are tedious, involving painstakingly building three-dimensional structures up layer by layer’.Such tedious techniques are currently used in the semiconductor industry. At present, explains Michael Sussman, Director of the Biotechnology Center at the University of Wisconsin-Madison , ‘features are etched onto circuit boards using light. However, the wavelength of light limits the smallest size that can be achieved, and for the next generation of faster computers, engineers need to get denser features onto computer chips than is possible with light etching’. Diatoms, says Sussman, ‘are natural-born lithographers in the nanometre range. If we could work out how diatoms lay down micro lines of silica, then we may be able to simulate it’. The proteins that diatoms use to direct silica deposition could be very useful to the semiconductor industry, says Sussman.There are other ways in which diatoms could help us clumsy humans build nanoscale ‘widgets’. Molecular biologist Mark Hildebrand  is a member of a collaborative project trying to develop genetically engineered micro/nanodevices . Already, engineers are using diatoms to help them build extremely sensitive sensors based on microfluidic devices, he explains. Hildebrand is also interested in the optical properties of diatoms. ‘Information processing technology is moving from electronically to optically based hardware, which allows more information to be carried and stored. Optical systems need materials with regularly repeating structures with features below the micrometre size range. These are very difficult to make by standard manufacturing techniques, but diatoms make structures like this all the time’.It might also be possible to use diatom shells as delivery vehicles for drugs, suggests chemical engineer Tony Rogers, an assistant professor at Michigan Technological University . ‘They have a uniform nanoscale pore structure and are chemically inert and biocompatible’. Rogers envisages loading diatoms with a drug that would then leach out into the blood stream at a rate dependent on the diatom species used. By incorporating ferromagnetic particles within the diatom structure, it might be possible to use a magnet to guide the drug to the right organ, he suggests.Diatom structures are not just of interest to people interested in tiny objects. As Hamm comments, ‘in diatoms, Nature has solved many of the problems that engineers want to solve. For example, diatoms are particularly good at making lightweight but strong structures. Because it is possible to scale static structures like shells, diatoms can teach us how to make lightweight constructions for the aerospace and car industry’.Some of the potential applications of diatoms can be investigated right now, using naturally occurring diatoms. In addition, subtle but important changes can be induced in diatoms by varying the amount of silica in their environment or changing the water flow. Gordon also envisages a device he calls a compustat, which would be used to select diatoms for a specific purpose. Diatoms taken from the sea, for example, would be individually examined using a computer-controlled microscope. ‘We would tell the computer what characteristics we were looking for, and it would go through the culture, zapping those diatoms furthest from the ideal with a laser beam. The culture would then be allowed to grow up again and the process repeated until we got the sort of diatoms we wanted’, says Gordon.Gordon has not built a compustat yet—it may not work, he says, because we don't know how far we can push diatoms by forced evolution. And even if the compustat does work, to make the most of the nanotechnological potential of diatoms, we need to know exactly how diatoms make their shells. At present, all we know is that silicon transporters and a group of long-chain, polyamine-containing proteins called silaffins, which act as nucleation points for silica deposition, are involved. This is where the diatom sequencing project at the United States Department of the Environment's Joint Genome Initiative (JGI) at Walnut Creek, California, comes in.T. pseudonana, a marine centric diatom ‘We believe that knowing this genome will help us to figure out how to mimic the processes that diatoms use to construct their very precise structures, and that we can then learn how to create similarly precise structures ourselves’. Also, he adds, diatoms are extremely important on an ecological level.Daniel Rokhsar, Department Head for Computational Genomics at JGI, explains why his institute undertook the sequencing and computer annotation of the genome of T. pseudonana, explains further. Diatoms are responsible for between 25% and 40% of all the primary productivity of the oceans, she says. ‘They also keep the biological pump going. By fixing carbon dioxide and then sinking, diatoms draw carbon dioxide out of the atmosphere and take it into the deeper waters of the ocean, where it is retained for longer than it would be if the diatoms stayed near the surface’.Oceanographer Ginger Armbrust , Principal Investigator on the sequencing project for T. pseudonana, she continues, was chosen as the first diatom to sequence in part because it has a small genome, but mainly because it represents a cosmopolitan genus of diatoms and its physiology has been well studied. Once the primary sequence of the genome had been determined, molecular biologists, oceanographers, and ecologists from around the world gathered at JGI for a ‘genome jamboree’. ‘The first of these was in October 2002, a massive brainstorming session at which we all dug around in the genome for our favourite genes and tried to get a feel for what was there’, explains Bowler. ‘It was really refreshing to get the insights of oceanographers and ecologists into what this genome was telling us’.T. pseudonana genome can tell them about the difference between photosynthesis on land and in the sea. They also want to investigate how these organisms adapt to their environment. ‘Now that we have the genome’, says Armbrust, ‘we can investigate how gene expression varies at different places in the water column, for example. This will be the first time a eukaryotic genome has been interpreted in this ecological sort of way’.Among other things, Armbrust and her collaborators are interested in finding out what the T. pseudonana genome is that we can figure out quite a bit from it about how this diatom deals with organic materials, but it is hard to figure out what it is doing with silicon’, admits Rokhsar. ‘The only way we can really figure out what a gene is doing is by comparing it with known genes in other organisms, but because diatoms are so unique in their use of silicon, we don't have that option. We literally just have the parts list’.‘One of the striking things about the T. pseudonana genes is important in silicon metabolism, Sussman is using microarrays to investigate how silicon concentrations affect gene expression patterns in the diatom. ‘There may be a few hundred genes whose expression changes in response to silicon stress’, he predicts, ‘and we can then focus on the role that these genes play in silicon metabolism’. In another approach, Hildebrand is purifying the proteins present in diatom shells. ‘Once we have isolated these proteins, we can get a little bit of protein sequence, and from there go back to the genome to pull the gene out’, he explains.To get a hook on which of the 10,000 or so T. pseudonana. Unfortunately, this can't currently be done. ‘The only diatom we can genetically manipulate is Phaeodactylum tricornutum, a pennate diatom’, explains Bowler. P. tricornutum, he says, is the ‘lab rat’ of the diatom world but is much less important ecologically than T. pseudonana  by oceanographer David Thomas. ‘What we saw down the microscopes just blew our socks off’, says Parker-Eaton. ‘We could see how the plankton moved, the forms, the incredible different layers within the diatoms. What we particularly liked about diatoms was their complexity—they are totally unlike any other life form’.Navicula sp. The main body is sycamore, the ‘blobs’ are resin, and the object is coloured with inks. The piece is held together by magnets but splits in half to reveal two silver inserts at its centre. More examples of these artists' work can be seen at http://www.louiseandsarah.com.Parker-Eaton and Hibbert translate what they see down the microscope into objects made of wood and silver, usually small enough to hold in the hand.


The Allen Brain Atlas of gene expression in the mouse brain is poised to serve as an outstanding resource to neuroscience Armed with billions of cells, elaborate circuitry, and a seemingly animate anatomy, capable of growing as it learns, the brain is a marvelously enigmatic organ. Much to the chagrin of those that study it, the brain remains perhaps too mysterious.Although genetic information exploded out of the Human Genome Project, it has been of little consequence to neuroscience—a discipline still grappling with the boundaries and names for distinct brain regions. According to United States National Institute of Mental Health Director Thomas Insel, over 99% of the neuroscience literature focuses on only 1% of the estimated 15,000–16,000 genes expressed in the brain. David Van Essen, a neurobiologist at Washington University in St. Louis, Missouri, likens the current genetic map of the brain to a 17th century map of Earth. A voyage around the Earth had already proven it was round, but landmass resolution was still vague at best.Magellan's benefactors, though, never bankrolled a technical advance quite like the Allen Brain Atlas. Neuroscience's unlikely sugar daddy, Microsoft cofounder and the world's fifth wealthiest man, Paul Allen, created the $100 million dollar Allen Brain Institute in Seattle, Washington, two years ago. The first explicit goal of the institute was to create an open-access, visual, searchable online map of genes expressed in the brain, as well as of brain circuitry and cell location. Roughly one petabyte of data—equal to the memory necessary to hold the information held in about 50 Libraries of Congress—will be produced as a result.In mid-December, the first 2,000 genes were uploaded. By 2006, the Allen team plans to have as many as 24,000 genes online. While the ultimate goal is to map the human brain, the atlas ushers in a new era of neurogenetics—an attempt to make connections between anatomical, genetic, and behavioral observations.The initial effort will focus on the standard, inbred lab mouse strain known affectionately as C57BL6. Like it or not, mice are remarkably similar to humans—sharing 99% of our genes. Humans, at this time, provide too many hurdles—not the least of which is a lack of willing brain donors that are the same age. Since the C57BL6 strain is inbred, the mice are also much more uniform than humans—a key to constructing the most accurate representative map possible of one species' adult brain.dyspyndin, a gene linked to schizophrenia. Insel is banking on the atlas to locate genes linked to conditions including bipolar disorder, schizophrenia, and autism. Once identified, such critical genes can be examined in detail and used in studies aimed at disease cures or drug screens. Presumably, the atlas will be a boon for drug discovery and development by providing information on drug targets present within brain cells.With a map of mouse genes in hand, scientists will be able to develop informed hypotheses about genes that may affect human brain function and dysfunction. “People will be able to look first in the mouse atlas, then more selectively focus on human cases,” says Gregor Eichele, director of the Max Planck Institute for Experimental Endocrinology in Hannover, Germany. Indeed, researchers may do well to focus their efforts on those specific cells in which homologous genes are expressed in the mouse. Insel suggests an initial mental health application: find Eichele points out that the Allen Brain Atlas will eliminate time wasted testing fruitless hypotheses. “If you think gene X may be involved in [hippocampal-dependent] memory, but it's not expressed in the hippocampus, you shouldn't bother following that line of research,” he says. Insel agrees that where genes are expressed in the brain will be most telling. “In the brain, more than any other organ, function follows form,” he says.Cellular resolution of expression patterns will prove necessary to uncover as yet unknown relationships between circuitry, cell type, and gene expression in the brain, says Arthur Toga, a neuroscientist at the University of California, Los Angeles, and Allen Brain Atlas advisor. Ed Lein, a neuroscientist at the Allen Brain Institute, thinks that mapping at the cellular scale will also redefine anatomy. Traditionally, neuroanatomists have delineated brain regions pretty much by eye, identifying clusters of cells and patterns of connections that look the same. “We're starting to redefine boundaries of regions by cell type,” says Lein, defining cell type by gene expression pattern.The difficulty, according to Allen Brain Institute scientific advisor David Anderson, a neuroscientist at the California Institute of Technology in Pasadena, California, is in understanding how a gene mutation affects behavior. “It is impossible without a knowledge of the circuits in which a gene is expressed,” he says. Anderson himself studies innate behaviors such as fear responses. Specifically, he's most interested in understanding the function of different regions of the almond-shaped amygdala. Once he finds genes expressed in neurons within regions of the amgydala implicated in fear, he plans to determine neuron function by creating transgenic animals in which specific neuron activity has been silenced.Thus far, Anderson's laboratory has endured the slog of using microarray techniques to identify genes with expression patterns linked to fear behavior, followed by in situ hybridization, which traditionally involves twenty-odd complex, error-prone steps, to find just some of the genes expressed in different parts of the amygdala. “The Allen Brain Atlas will identify a whole set of genes that we would have had to spend several years to find,” he says. Indeed, locating where even one gene of interest is expressed in the brain eats up valuable research time, especially when there are so many potentially interesting genes. In most cells, 10,000 genes can be expressed.Eichele improved the slow error-prone process into an automated, fast, “high throughput” method that caught the attention of the Allen team because it was capable of meeting the needs of such an ambitious project. In situ hybridization uses labeled probes for specific messenger RNA sequences, allowing scientists to test individual brain tissue samples for gene expression.Automated in situ hybridization data will be generated for the entire mouse transcriptome—the full complement of activated genes in a particular tissue at a particular time—on a genome-wide scale. The mouse is a young adult at 56 days old, free from the confounding factors of development. After it is sacrificed, the mouse brain is immediately frozen, then sliced very thinly—to get forty sections from each millimeter of thickness—so that the probes for hybridization can expose gene expression in individual cells.The in situ data will be matched in a three-dimensional framework to the reference atlas developed by Allen's team. The resulting images will be turned into a virtual microscope, allowing users to focus down on genes expressed in regions of interest.While the Allen Brain Atlas is somewhat like other genomics projects in scale, it is unique. “No one's gone into a 3-D structure like a tissue and examined it in a systematic way,” says Allan Jones, senior director of Allen Brain Atlas Operations. In that way, he adds, it's a much richer dataset than the Human Genome Project. “As we're ramping up—fully by spring of next year—we'll be generating about 1,000 microscope slides a day with four mouse brain sections on each slide,” says Jones. Each day, those sections are scanned and stitched together electronically into 300-megabyte batches. “Scaling up a lab process is currently the biggest challenge,” says Jones. “In effect, we're turning an art form into something that gives high-quality data day in and day out,” says Jones. “If you are off slightly when cutting a 2-D brain slice, it becomes very difficult to map back into a 3-D context.”While it is a logical starting point, a spatial understanding of gene expression is just one way to mine the brain. Other avenues currently being pursued explore individual variability, development, and comparisons between species See . The sheThe Allen database will provide a spatial map of neurogenetic data, specifying where the 99% of shared mammalian genes are expressed in the brain. Other online databases are striving to provide alternative axes of information that will detail individual variability, species comparisons, and changes during development.Going deep on the genetic variability axis of understanding is Web QTL, a collection of images from 800 brains of 35 different strains of mice. “We're interested in genetic sources of variation,” says Rob Williams, a neurobiologist at the University of Tennessee in Memphis. “We study many strains of mice and map the upstream modulators that control expression differences.”Van Essen's online atlas strives to map the structural and functional areas of the cerebral cortex, believed to be the seat of thought, learning, emotion, sensation, and movement, for humans, macaques, rats, and mice. In constructing the SuMS (for “surface management system”) database, they've put most of their effort into comparing datasets between species.Finally, GenSAT (Gene Expression Nervous System Atlas) follows gene expression as it changes through the development of an organism. Using a method that manipulates “bacterial artificial chromosomes” to insert, change, or delete parts of large gene sequences, one transgenic mouse is created for each gene. When reporter genes are added to the bacterial artificial chromosomes, cells with selective gene activity glow. This advance takes a step towards relating gene expression patterns to connectivity between brain regions.“It's clear that they want to do a first-rate job of working with all this information, but I'm not sure they entirely appreciate how hard it's going to be to manage the staggering amount of information they're getting,” says Van Essen. As manager of his own comparative anatomy database, he understands the magnitude of the task. He points out that properly digitizing the data in electronic form and registering one particular slice to a standardized reference with meaningful coordinates is not trivial.“In an atlas, there will be considerable variability from one individual to the next—even in inbred mouse strains,” says Van Essen. Even if it's only 20% variability, it is still going to pose challenges for managing experimental data. Van Essen acknowledges that this isn't just an impediment for Allen's team, but for neuroscience as a whole. “These tools, in general, don't emerge from a vacuum. They emerge best when rich, challenging datasets are staring people in the face,” he says.An even larger problem is communicating the data effectively. Figuring out how to navigate the tremendous morass of data will be a bioinformatic stumbling block. Lein acknowledges that figuring out how to best annotate the data is one of the bigger challenges for the future—particularly in cases where gene expression doesn't match the agreed-upon boundaries of anatomical regions.For now, users will be able to mine the data by gene name only. The initial release consists of an image viewer to view the in situ hybridization data for one or several genes at a time, along with a reference atlas to determine the structures in which genes are expressed. Future releases will allow the user to conduct more sophisticated searches, such as by anatomical structures.“Not only is there this 3-D structure, but there are lots of studies where people are trying to understand what drives the turning on and off of genes,” says Jones. “At the end, if the atlas has a big impact, it will be in providing the precise coordinates for those people to tease apart what specific DNA elements drive expression within regions or structures.”And while the Allen Brain Atlas will provide a fine level of detail, there are limitations. Much like the Human Genome Project, the information will be the starting point and not the end point of understanding brain function. “It won't change strategy for doing experiments,” says Nobel laureate and Columbia University neuroscientist Eric Kandel. “The atlas will be a catalyst rather than a direction setter.”Overall, neuroscience is entering a new era. Insel notes that recent work has proven the brain to be extraordinarily dynamic, birthing neurons throughout a lifespan. Brain functions seem more modular than global. And there is no real separation between the mind and brain. “Mental disorders are brain disorders,” he says.Over the next 5–10 years, neurogenomics will fuel a golden age of discovery in neuroscience. In fact, scientists may even reach an overarching goal—understanding how the wild card of environment impacts brain function. “We want predictive genetics able to accommodate environmental differences,” says Rob Williams, neurobiologist at the University of Tennessee in Memphis.For Kandel, one thing is certain. “Most of the mysteries of the brain lie ahead of us.”


In mammals, males usually have one X and one Y chromosome and females have two X chromosomes. This crucial difference sets the sexes apart, but also creates a problem—female cells have the potential to turn out twice as much X-based gene product as necessary. Males with multiple–X chromosome syndromes face a similar problem. As if to avoid an overdose of X-related proteins, cells in the early embryo inactivate all but one X chromosome. The choice of which X (or Xs) to inactivate is apparently random, but once made, it persists across cell divisions and the specializations that determine a cell's ultimate fate, or type.Xist—which resides on the X chromosome—has a central role in X chromosome inactivation. It creates a special RNA molecule that spreads from its point of production down the length of the X chromosome, repressing its genes and inactivating the chromosome. After about one cell cycle, this gene silencing no longer requires Xist RNA. Daughter cells somehow remember which X to keep mute. In this month's PLoS Biology, geneticist Anton Wutz and colleagues at the Research Institute of Molecular Pathology in Vienna show that Xist expression during a critical period very early in embryonic development creates a chromosomal memory, independent of X silencing, that might help maintain X inactivation across cell generations.A gene called Xist gene mediates alterations to histones  along the X chromosome, which result in heterochromatin formation. As this structure is passed on to daughter cells, X silencing is perpetuated.The molecular underpinnings of X inactivation seem to center on histones, the protein spools around which DNA coils its length. DNA and histones form complexes called chromatin, which undergoes many structural modifications that have important effects on gene expression. For example, tightly packed chromatin inhibits gene expression in its closely curled segments. Not surprisingly, the inactivated X chromosome is coiled into this dense form, called heterochromatin. In the standing model of X inactivation, the Xist gene into the X chromosome of male mouse embryonic stem cells, so they could turn Xist expression “on” and “off” at will. The stem cells represent the earliest, unspecialized cells of a mouse embryo. Since the cells can be induced to differentiate in culture, they provide the opportunity to study the relationship between differentiation and X chromosome inactivation . Using this system, the authors have shown previously that Xist must act during a critical window very early during stem cell differentiation—within the first 24 hours. Wutz and colleagues now show that after that window the X chromosome inactivation can still be reversed, but after an additional 24 hours, it cannot. There appears to be a “memory” of Xist action, which leads to the permanent shutting down of the chromosome.To explore the molecular changes that mediate X chromosome inactivation, Wutz and colleagues inserted a special Xist and the establishment of irreversible silencing. By looking at the kinetics of histone modification, gene silencing, and Xist action, Wutz and colleagues further show that although certain histones are methylated at specific locations during this period in response to Xist, these modifications do not themselves constitute the chromosomal memory. The nature of the memory remains mysterious. Further experiments, perhaps looking at different histone modifications, will be required. Clarification of the events that lead to X inactivation will also improve our knowledge of how changes in the organization and structure of chromosomes can influence the activity of genes.The importance of this observation is that it establishes a new step in the process of X chromosome inactivation—between the action of


When a trip for food can require a three-mile flight, it pays to get the directions right, especially if you're a bee. Bees more typically forage within a 600- to 800-yard radius, expending a significant amount of energy—a fact they seem keenly aware of: for reasons that remain unclear, bees tend to ignore directions that send them to a target on water. It's been known since Aristotle's time that returning foragers dance a little jig for their hivemates, presumably regaling them with tales of nectar-laden flora. Some 2,300 years later, zoologist Karl von Frisch correlated dance choreography to the direction and distance of a food source, eventually winning the Nobel prize for his work. Since then, researchers have been working out the details of bee communication, such as how fellow foragers interpret the “waggle dance” and how dancers perceive and convey navigational details of a trip. A key aspect of this information exchange is how bees estimate distance.Recent studies suggest that bee odometers are driven by the “optic flow” experienced during flight—or, simply put, bees appear to log distance by measuring the rate that images of passing terrain move in their eye during flight. This theory comes from observations that when bees fly a given distance, they indicate a much longer distance—by performing a longer waggle—for low-flying trips than for those at higher altitudes, presumably because flying at higher altitudes limits the bees' ability to perceive changing images. Likewise, bees flying through short, narrow tunnels filled with visual elements waggle a disproportionately long distance. These observations also raise questions about which visual aspects of the environment—contrast, texture, distribution of objects—are most important to a bee's perception of image flow.To investigate the factors driving the bee trip odometer, Mandyam Srinivasan and colleagues trained bees to feed at locations along two different routes in a natural environment, then compared their waggle dances. One route was entirely over land; the other started on land, shifted to water, and ended back on land. Both routes were the same distance, about 630 yards. Bees trained to feed at a boat in the middle of a lake had no trouble getting there, which was no guarantee based on reports that bees have trouble flying across lakes, often plunging into the drink. They had less success recruiting their colleagues to share in the bounty, even though their waggles clearly placed the feeder on the lake. The length of the bees' waggle dance increased faster with distance when they flew over land than when they flew over water. This disparity indicates that land provides a stronger “odometric signal” than water. “The honeybee's odometer,” the authors explain, “runs at a slower pace when flight is over water.” Overland flights tend to offer high contrasts and rich textures, while flights over water tend to offer low contrasts and sparse textures. Most likely, it is the high contrast of land surfaces that triggers a stronger odometric signal. But land surfaces also show variation in contrast, which was reflected in the bees' dance. One section of the land-only route was a paved bicycle path, a low contrast surface that the bees waggled as a relatively shorter distance.The Life of theBee, deciding it must correspond “to senses and properties of matter wholly unknown to ourselves.” As Srinivasan and colleagues show here, the bee's view of the world indeed corresponds to a unique way of interpreting the landscape—and of sharing news of their travels with their hivemates.Whether or not the contrast theory holds, Srinivasan and colleagues conclude, differences in the visual environment trigger differences in odometric signal. The odometer racks up yards depending on the nature of the terrain, whether it be land or water, during flight. The great Belgian playwright and avid bee-keeper Maurice Maeterlinck wondered at the language of bees in his 1901 book,