Globally, almost 40% of tuberculosis (TB) patients remain undiagnosed, and those that are diagnosed often experience prolonged delays before initiating correct treatment, leading to ongoing transmission. While there is a push for active case finding (ACF) to improve early detection and treatment of TB, there is extremely limited evidence about the relative cost-effectiveness of different ACF implementation models. Cambodia presents a unique opportunity for addressing this gap in evidence as ACF has been implemented using different models, but no comparisons have been conducted. The objective of our study is to contribute to knowledge and methodology on comparing cost-effectiveness of alternative ACF implementation models from the health service perspective, using programmatic data, in order to inform national policy and practice.We retrospectively compared three distinct ACF implementation models - door to door symptom screening in urban slums, checking contacts of TB patients, and door to door symptom screening focusing on rural populations aged above 55 - in terms of the number of new bacteriologically-positive pulmonary TB cases diagnosed and the cost of implementation assuming activities are conducted by the national TB program of Cambodia. We calculated the cost per additional case detected using the alternative ACF models.Our analysis, which is the first of its kind for TB, revealed that the ACF model based on door to door screening in poor urban areas of Phnom Penh was the most cost-effective , followed by the model based on testing contacts of TB patients , and symptomatic screening of older rural populations .Our study provides new evidence on the relative effectiveness and economics of three implementation models for enhanced TB case finding, in line with calls for data from ‘routine conditions’ to be included in disease control program strategic planning. Such cost-effectiveness comparisons are essential to inform resource allocation decisions of national policy makers in resource constraint settings. We applied a novel, pragmatic methodological approach, which was designed to provide results that are directly relevant to policy makers, costing the interventions from Cambodia’s national TB program’s perspective and using case finding data from implementation activities, rather than experimental settings. Tuberculosis (TB) control remains a critical global challenge, becoming the leading cause of death from an infectious disease in 2014. TB principally affects adults in lower income countries, with 10.4 million new cases estimated in 2015, of which more than half occurred in people living in South-East Asia and Western Pacific regions .It is indeed likely that the current DOTS passive case finding (PCF) strategy, which relies on patients presenting to the health facility for screening of their own accord, has limitations in contexts where primary health services are weak and awareness of TB is low; evidence from a multi-country analysis indicated that DOTS programs may have no impact on improving case detection . PCF appAlthough referred to using the same terms, numerous different ACF implementation models exist, ranging from population-wide screening to targeted case-finding in high-risk groups . CompareCambodia presents a unique opportunity for addressing this gap in evidence on relative cost-effectiveness of alternative ACF implementation models. The country has one of the highest TB incidence rates in the region, at 380 per 100,000 population and approximately 40% of smear-positive patients remain undiagnosed . Many diWe compared three ACF programs using retrospective data on case-finding during the implementation period of the pilot program, and primary data collected on costs of implementation, as described below.To initiate the cost-effectiveness comparison, we first compiled a list of all ACF interventions implemented in Cambodia over the past 5 years, through discussions with officials at CENAT and the Cambodia WHO office which had held a meeting of all ACF implementing agencies, supplemented with searches of peer reviewed literature, grey literature and organizational websites. We identified nine different approaches to delivering ACF services across the country by CENAT and various non-governmental organisations (NGOs): symptom screening in prisons; testing contacts of TB patients; testing patients with HIV; door to door symptom screening in urban slums; symptom screening focusing on elderly members of the community; and using community based volunteers for identification of symptomatic patients in rural areas.For this study, we selected ACF interventions meeting the following criteria, to allow for a comparison across implementation approaches: large-scale (covering more than three districts), primarily targeting adults in the community, seeking to diagnose bacteriologically confirmed (B+) cases using smear-microscopy or Xpert MTB/RIF (GeneXpert) and implemented for a similar time period (10–14 months). We identified three distinct ACF interventions implemented by different public health organisations for inclusion in the analysis. Implementation approaches applied to deliver ACF services are summarized below and in Table Screening contacts of index cases (CENAT) (2)Screening of urban poor (HOPE) The national TB program in Cambodia, CENAT conducted an ACF program for 10 months (2012–2013) in 15 operational districts (ODs), using a neighborhood and household contact tracing strategy. Any smear-positive TB cases registered for treatment during the preceding 2 years were located and their household contacts were referred for chest X-Ray (CXR) testing irrespective of presence or absence of symptoms. In addition, people living in the neighbourhood of a confirmed TB case who demonstrated symptoms consistent with TB were referred for the same CXR testing. Community health workers, known as Village Health Support Group (VHSG), were responsible for referring individuals for CXRs. Any person with an abnormal CXR or with persistent symptoms suggestive of TB and a normal CXR underwent GeneXpert sputum testing alone in order to identify B+ TB cases.(3)Targeted screening in older rural population (CATA)Sihanouk Hospital of Hope (HOPE) conducted ACF over a 14-month period (2012–2013), covering four ODs within Phnom Penh city. They targeted poor urban communities, which had a presumed higher prevalence of TB related to socioeconomic factors and reduced access to TB treatment. VHSG, managed by salaried ‘TB workers’, conducted verbal door to door symptom screening and sputum samples were requested from those reporting TB symptoms. Sputum samples were transported for smear-microscopy testing at referral hospitals and the HOPE hospital in Phnom Penh. GeneXpert and sputum culture were utilized when subjects were suspected of having HIV co-infection, being at higher risk of multi drug-resistant (MDR) TB and in those who were negative on microscopy but had persisting symptoms.The Cambodia Anti-Tuberculosis Association (CATA) organisation conducted a 12 month ACF program (2013–2014) covering five ODs. They focused, non-exclusively, on people aged 55 years or older, due to the known higher TB case notification rates in this age group . CATA stWe defined the effectiveness of ACF interventions in terms of the number of new, adult TB cases diagnosed. To allow a comparison between interventions, we applied a standard definition to assess the number of new cases diagnosed: confirmed B+ cases based on smear-microscopy or GeneXpert testing, pulmonary TB, aged 15 or above.We extracted data from internal reports, published papers, as well the raw data on case finding activities from each program. Published research papers were available for two of the ACF strategies  perspective. First, interviews were conducted with key implementation staff involved in the ACF activities of each organization (two per organization) to understand resources used, applying a standardised data collection template Table ; this waWe then shared data on all the resources required by each ACF intervention with CENAT, who supplied their cost estimates for each type of resource, according to their budget predictions for the coming year (2016), this method, along with the exclusive use of USD dollars, avoided any need to adjust figures according to historic inflation or exchange rates, respectively.Once we had a unit cost for all of the resources used and activities conducted we calculated the overall costs for each of the three strategies, from the perspective that activities would be conducted by CENAT as part of their programmatic strategy for TB control. If there were additional activities or trainings that CENAT would insist on as part of any ACF strategy they conducted - for example, training relevant staff on GeneXpert equipment - this was added to the budget for HOPE and CATA’s activities.In addition to the costs incurred during the data collection period, the cost of all trainings and preliminary meetings for each program were calculated and included. The preparation and post data collection activities were not included as each organisation took variable lengths of time with overlapping resources for other activities, making the calculation of accurate times and costs for each activity difficult.We sought to estimate the cost per additional B+ case diagnosed for the three different ACF strategies, using a health system cost perspective based on the assumption that the ACF strategies would be implemented by CENAT. We assessed cost-effectiveness using the standard approach used by researchers and funders such as TB REACH, defining the cost per TB case detected as the total cost of activities related to diagnosis divided by the total number of TB cases diagnosed .The method of analysis employed in this study assumes that the effectiveness achieved for each dollar spent is comparable between the programs, meaning there is an assumption of equivalent efficiency across the three implementing groups. A further assumption made in the comparison, is that the cases detected would not have been detected had the ACF activities not taken place. It should be noted that due to the different contexts of each strategy the consequences of this assumption is likely to vary between the programs.Our comparison of three distinct ACF models in Cambodia revealed that the cost per case detected was 249 USD, 308 USD and 316 USD, for the HOPE, CENAT and CATA ACF models, respectively   to USD 4Increased case detection and high treatment success rates are the cornerstones of global TB control policy  and as oOur study provides timely information in light of calls for cost-effectiveness data from ‘routine conditions’ to be included when programmatic recommendations for TB diagnosis are made . Such coA potential limitation relates to the estimation of costs by CENAT and an assumption that scale up of CATA and HOPE strategies by CENAT will be possible and provide the same efficiency, without substantial extra investment in the current services and health centres. However, there were also advantages to the method employed for cost calculations, with the unit costs being standardized according to national program estimates. We acknowledge that reductions in patient costs owing to outreach activities are not accounted for, and that the cost-effectiveness comparison does not consider equity and accessing of hard to reach populations, which may justify a higher cost per case detected. Finally, we recognize that wider questions regarding ACF itself still remain and highlight that ACF strategies will only be effective if cases are identified early such that onward transmission is prevented. Thus, before launching into large ACF programs in resource-limited settings, pragmatic comparisons of different ACF models – looking not only at cost per case detected as we have done but also at forecasts of long term impact on TB incidence- are required to inform resource allocation decisions.Alternative ACF implementation models for TB are being introduced in numerous resource-constraint settings, but evidence on relative cost-effectiveness, which is essential to inform resource allocation decisions of national policy makers, is lacking. We applied a novel, pragmatic methodological approach to compare the cost-effectiveness of three ACF implementation models that had been implemented between 2012 and 2013 in Cambodia, allowing the models to be ranked in terms of potential to identify the largest number of new bacteriologically-positive TB cases per unit of investment. We found that implementation of ACF activities in urban areas was slightly more cost-effective than in rural areas, and that the pragmatic cost-effectiveness assessment approach provided information that was called for by local policy makers.


There are three times as many outer hair cells (OHC) as inner hair cells (IHC), yet IHC transmit virtually all acoustic information to the brain as they synapse with 90–95% of type I auditory nerve fibers. Here we review a comprehensive series of experiments aimed at determining how loss of the IHC/type I system affects hearing by selectively destroying these cells in chinchillas using the ototoxic anti-cancer agent carboplatin. Eliminating IHC/type I neurons has no effect on distortion product otoacoustic emission or the cochlear microphonic potential generated by OHC; however, it greatly reduces the summating potential produced by IHC and the compound action potential (CAP) generated by type I neurons. Remarkably, responses from remaining auditory nerve fibers maintain sharp tuning and low thresholds despite innervating regions of the cochlea with ~80% IHC loss. Moreover, chinchillas with large IHC lesions have surprisingly normal thresholds in quiet until IHC losses exceeded 80%, suggesting that only a few IHC are needed to detect sounds in quiet. However, behavioral thresholds in broadband noise are elevated significantly and tone-in-narrow band noise masking patterns exhibit greater remote masking. These results suggest the auditory system is able to compensate for considerable loss of IHC/type I neurons in quiet but not in difficult listening conditions. How does the auditory brain deal with the drastic loss of cochlear input? Recordings from the inferior colliculus found a relatively small decline in sound-evoked activity despite a large decrease in CAP amplitude after IHC lesion. Paradoxically, sound-evoked responses are generally larger than normal in the auditory cortex, indicative of increased central gain. This gain enhancement in the auditory cortex is associated with decreased GABA-mediated inhibition. These results suggest that when the neural output of the cochlea is reduced, the central auditory system compensates by turning up its gain so that weak signals once again become comfortably loud. While this gain enhancement is able to restore normal hearing under quiet conditions, it may not adequately compensate for peripheral dysfunction in more complex sound environments. In addition, excessive gain increases may convert recruitment into the debilitating condition known as hyperacusis. The audiogram is often considered the gold standard for assessing sensorineural hearing loss (HL). Individuals with pure tone thresholds of ≤20 dB HL would be classified as having normal hearing. However, there is growing awareness that the pure tone audiogram fails to detect certain forms of cochlear pathology and auditory processing deficits. This has led to the concept of “hidden hearing loss,” i.e., the realization that significant auditory perceptual deficits can exist in listeners with normal hearing thresholds, a condition that can exist when there is considerable IHC and/or auditory nerve fiber degeneration  can be used to interrogate the functional status of different structures in the cochlea and identify “hidden” damage to inner hair cells (IHC), outer hair cells (OHC), the IHC/type I auditory nerve fiber synapse, and spiral ganglion neurons (SGN). Sensorineural hearing loss is a complex phenomenon that not only involves the cochlea, but also numerous structures in the central auditory system capable of partially compensating for these cochlear deficits. Therefore, a more complete understanding of sensorineural hearing loss not only requires assessment with ECochG, but also examination of the neurophysiological changes occurring in the central auditory pathway. In this review, we will discuss our results from a comprehensive series of electrophysiological, neuroanatomical, behavioral, and neuropharmacological experiments in a chinchilla animal model of carboplatin-induced ototoxicity in which there is selective damage to the IHC and type I auditory nerve fibers that exclusively innervate the IHC. These studies illustrate how ECochG can be used to identify damage to the IHC and type I neurons that goes undetected  by the pure tone audiogram. Electrophysiological recordings from the inferior colliculus (IC) and auditory cortex (ACx) reveal how weak neural signals from a damaged cochlea are amplified as they ascend through the central auditory pathway. Finally, we discuss a few simple psychophysical tests we have shown can identify hearing deficits associated with damage to IHC and type I neurons.Cisplatin and other platinum based anti-cancer drugs are generally more toxic to OHC than IHC, with hair cell lesions generally progressing from the base toward the apex as the dose and duration of treatment increases  , which depend on OHC somatic electromotility , an AC receptor potential that mirrors the waveform of the acoustic stimulus, is predominantly generated by the OHC with only a small contribution from IHC , reflected as a sound-evoked DC shift near stimulus onset, is thought to be generated predominantly by the IHC receptor potential with a much smaller contribution from OHC , consisting of two negative peaks (N1 and N2), is the most widely studied component of ECochG. The CAP is most effectively elicited by acoustic stimuli with rapid rise time and is thought to reflect the synchronized onset response of type I auditory nerve fibers Dallos, . Since tHigh impedance microelectrodes can be used to record the all or none spike discharges from single auditory nerve fibers as they leave the cochlea and enter the cochlear nucleus. Since each type I auditory nerve fiber contacts a single IHC, the neural output of a fiber reflects the activity from a discrete region of the basilar membrane. When tone bursts are used to measure the response of a single auditory nerve fiber, one can map out the frequency-intensity combinations that are just capable of evoking a response, the so-called frequency-threshold tuning curve , inferior colliculus (IC), and auditory cortex (ACx) of awake chinchillas before and after carboplatin treatment ; a plot of threshold vs. frequency in the presence of the masker defines the NBN masking profile  based on the neural responses seen in the damaged cochlea Figures . The larWS, DD, GC, EL, JW, KR, and BA finished the experiment. RS, WS, DD, GC, EL, and KR analyzed the results. RS, BA, and WS wrote and edited the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We develop a theory of grounded and embodied mathematical cognition (GEMC) that draws on action-cognition transduction for advancing understanding of how the body can support mathematical reasoning. GEMC proposes that participants’ actions serve as inputs capable of driving the cognition-action system toward associated cognitive states. This occurs through a process of transduction that promotes valuable mathematical insights by eliciting dynamic depictive gestures that enact spatio-temporal properties of mathematical entities. Our focus here is on pre-college geometry proof production. GEMC suggests that action alone can foster insight but is insufficient for valid proof production if action is not coordinated with language systems for propositionalizing general properties of objects and space. GEMC guides the design of a video game-based learning environment intended to promote students’ mathematical insights and informal proofs by eliciting dynamic gestures through in-game directed actions.GEMC generates several hypotheses that contribute to theories of embodied cognition and to the design of science, technology, engineering, and mathematics (STEM) education interventions. Pilot study results with a prototype video game tentatively support theory-based predictions regarding the role of dynamic gestures for fostering insight and proof-with-insight, and for the role of action coupled with language to promote proof-with-insight. But the pilot yields mixed results for deriving in-game interventions intended to elicit dynamic gesture production. Although our central purpose is an explication of GEMC theory and the role of action-cognition transduction, the theory-based video game design reveals the potential of GEMC to improve STEM education, and highlights the complex challenges of connecting embodiment research to education practices and learning environment design. Commercially available motion-based programs for improving mathematical reasoning through action  have long attracted the attention of educators, but with little basis in the psychological theory of how actions can reliably influence cognition. Evaluation of these programs seldom accounts for variations in learning and performance due to variation in influences such as pedagogical support . Early work exploring grounded and embodied mathematical cognition (GEMC) through video game performance showed some areas of promise. As predicted, dynamic gestures reliably predicted mathematical insight, even when players were not consciously aware of the mathematical relevance of their in-game actions. GEMC also correctly predicted that proof validity would improve when players’ directed actions elicited during game play were explicitly connected to mathematical conjectures through pedagogical language. However, some findings that were at odds with our initial hypotheses reveal the gap between embodied learning theory and using theory to design effective learning environments aimed at promoting science, technology, engineering, and mathematics learning. Generally, learning theories under-constrain designs of effective instruction and learning environments, which fundamentally constricts the impact of research on practice. Engineering-based approaches of iterative design generation and refinement are needed to translate research to practice.Principles of grounded and embodied cognition address the role of the body and body-based resources to shape cognition. Our objective is to present a theory of grounded and embodied mathematical cognition (GEMC) consistent with Stokes’  ‘use-insGeometric proof is a valuable content area for making strides for theories of GEMC. First, geometry is seen as the study of the properties of space and shape, and therefore should be suitable to a GEMC perspective. Second, it is an area of advanced mathematics, typically studied by students planning to attend college and other post-secondary educational programs  body actions affected the generation of appropriate mathematical intuition, insight, and informal proof for two different tasks. They looked at intuition and informal proof for a conjecture on properties of the lengths of sides of all triangles. They also looked at insight and informal proof for a task involving parity for a train of gears. Mathematical insights are defined as partial understandings of the key ideas underlying a mathematical system. Insight is related to but distinct from intuition , directed actions on their own did not lead to superior informal proofs compared to irrelevant actions. Rather, adding pedagogical language in the form of prompts (prospective statements) and hints (retrospective statements) that explicitly connected the directed actions to the tasks significantly enhanced proof performance on the Triangle task. The authors interpret the findings as raising questions about the reciprocal relations between action and cognition: actions on their own facilitate insight, while actions coupled with appropriate pedagogical language explicitly connecting the actions to the mathematical ideas foster informal proofs.Our third finding is that actions from earlier training opportunities leave a historical trace that is evident when people later solve problems in new, related contexts. Body-based training on the Tower of Hanoi task led participants to integrate their motor experiences into their mental encoding of the objects and their subsequent solution processes  interventions. Specifically, ‘action-cognition transduction’  can yield the recitation of valid proofs  will predict the production of dynamic gestures.H3. Performing mathematically relevant directed actions  will predict student performance on mathematical insights.We offer testable hypotheses about the nature of GEMC. As illustrated in Fig. H4. A language intervention, in the form of pedagogical cues about the mathematical relevance of game-based directed actions, predicts the production of dynamic gestures during proof production that co-occur during transformational speech production.H5. An intervention consisting of language cues coordinated with mathematically relevant directed action predicts the performance on production of valid transformational proof-with-insight.H6. Co-speech dynamic gestures predict the production of transformational proof-with-insight.As illustrated in Fig. The Hidden Village, designed as a platform to investigate these hypotheses. The pilot study is provided as an initial, illustrative example of how the GEMC framework can be empirically tested and iterated upon. Given the small sample size and early operationalization of the relevant outcome measures, we make only tentative conclusions from these findings, and offer them as a means to refine our ongoing empirical investigation.A pilot study was conducted using a prototype version of a new video game, The Hidden Village utilizes a standard built-in laptop camera and specialized image processing software developed by Extreme Reality, Ltd. (xtr3d.com) to determine in real time whether the player successfully executes each action sequence. The software generates a wireframe skeleton (invisible to players) to track the coordinates of the user’s joints  attending a video game design summer camp on a university campus individually tested the game; three had previously taken a geometry course. In the second round of data collection, 17 high-school students from the same city  in 9th or 10th grade enrolled in a geometry class at a private school participated in the study. The population at the high school has a mean college admissions American College Testing score of 26, matching the national average.Students were given a pre-assessment measuring their knowledge of geometric properties of circles, triangles, and quadrilaterals. Students then played the game, experiencing six conjectures in random order. Upon finishing, the interviewer revisited two to four conjectures (depending on time remaining) that the student had received relevant motions for, and revealed that the motions had been relevant by displaying an image that showed the game motions and the conjecture. Participants were asked to think about how their motions might have been connected to the conjecture, and given an additional opportunity to provide a justification following this pedagogical hint.For scoring student responses, we adopted Harel and Sowder’s  notion oVideos of students playing the game were divided into segments of each student proving each conjecture, and were transcribed. Students’ responses to each of the six conjectures were scored either 0 or 1 along four dimensions: (1) whether they made any spontaneous depictive gestures while attempting their proof, (2) whether they made any spontaneous dynamic depictive gestures while attempting their proof, (3) whether they recognized the key mathematical insight behind the proof, and (4) whether they formulated a valid informal transformational proof. As noted above, mathematical insights involve an intuitive yet not fully elaborated understanding of the key ideas behind a conjecture. By coding for insight in addition to informal proof, we sought to capture instances where students seemed to have some limited understanding of how the geometric system worked, but were unable to fully formulate and articulate their thinking.D-type effect sizes were calculated using the method in Chinn  to be included for both participant and conjecture. Predictors included gender, pre-test score, highest mathematics course , how many conjectures the participant had proved previously as an ordered factor variable (to account for tiring), and sample (video game camp or private high school). in Chinn . In Cohein Chinn , effect d = 0.6, p = 0.007), but not formulate an informal proof (p = 0.11). However, making dynamic depictive gestures predicted both insight  and proof . This suggests that producing any depictive gesture may help students glean some key ideas behind the conjecture; however, dynamic gestures may be associated with reasoning about relationships between geometric objects. This supports H1, a novel process claim, which stated that dynamic gestures would predict mathematical insight.Results of the regression analyses support the trends that are visually apparent from the descriptive statistics in Table d = 0.8, p = 0.008). Counter to H2 and H3, in trials where participants performed relevant directed actions they were not more likely to make dynamic gestures (H2), or demonstrate mathematical insight (H3), than in those trials in which they performed irrelevant directed actions . Relevant directed actions seemed to activate participants’ motor systems and leave a trace in the form of depictive gestures during proof, but these gestures were often not coded as dynamic gestures. As described above, depictive gestures only predicted insight (not proof), whereas dynamic depictive gestures predicted both insight and informal proof. Note that for these comparisons, most participants (n = 27) reported not being consciously aware of the relationship between the directed actions they performed and the conjectures. When participants who did report some conscious awareness were omitted from the analysis (n = 8), the pattern of results was the same. In sum, we see the predicted association between dynamic gestures and insight (H1). However, while video game trials cuing mathematically relevant actions were more likely to elicit overall gesture production among players, cuing relevant actions as an in-game intervention did not reliably increase players’ production of the all-important dynamic gestures (H2) or lead to a significant increase in mathematical insights (H3).The relevance of the directed actions cued by the video game was manipulated within subjects. Participants were more likely to make depictive gestures on trials for which they had performed relevant (versus irrelevant) directed actions  and more likely to make dynamic depictive gestures , supporting H4 which stated that directed actions combined with pedagogical language would promote dynamic gesture production. In support of H5, when coupling directed actions to pedagogical language, participants were more likely to produce favorable mathematics outcome measures, including expressing the insight  and formulating a valid informal proof . In addition, we saw support for our theoretical claim that dynamic gesture production reliably predicts the performance of formulating a valid proof , supporting H6. Overall, receiving pedagogical language connecting the directed actions to the conjecture was highly beneficial for players’ mathematics performance, both for insight and for proof production.As noted, players often had no awareness that the actions they were asked to perform related to the mathematical conjectures. When comparing participant performance before and after the intervention of a pedagogical hint explicitly linking actions to the conjectures (H4 and H5), findings emerged that support GEMC. Following the pedagogical hint, participants were more likely to make depictive gestures , and that making depictive gestures predicts mathematical insight (d = 0.6). However, surprisingly, performing relevant actions (versus irrelevant actions) did not predict insight, as would be expected. Supplementary analyses showed that the ‘extra’ depictive gestures induced by relevant directed actions tended to be static, non-moving gestures that did not display transformational reasoning. Although trials where participants performed irrelevant actions were less likely to have gestures, responses from irrelevant action trials showed a greater proportion of the all-important dynamic gestures .Our results suggest that performing relevant directed actions during game play fosters depictive gestures  and more likely to generate correct insights and valid informal proofs (H5) after receiving verbal hints. This provides tentative support for the GEMC theory and its call for coordinating language and action systems in service of mathematical reasoning. It raises a question of why the pedagogical hints improved insights, which we take as nonverbal. One indicator is that pedagogical hints were found to influence insight performance directly, and to increase the production of dynamic gestures, which, as hypothesized earlier (H1), promotes mathematical insight and the formulation of valid informal proofs (H6) through a mechanism such as transduction. As predicted, we also found support for H5, the applied path that bypasses the meditational influence of dynamic gestures and predicted a direct relationship between pedagogical language coordinated with directed action and our primary outcome measure of interest, proof-with-insight. Although these results need to be replicated and generalized across a broader set of mathematical conjectures and student populations, these initial findings are encouraging for future game designs that instantiate this direct pathway.A qualitative analysis of contrasting cases highlighted the significant challenges involved in transforming a directed motion into a meaningful dynamic gesture that makes sense to the learner in the context of the task. This transformation has the potential to support students’ proving activities and give them powerful new body-based resources with which to confront the task, as shown in the first transcript. However, making the mapping between directed actions and the sequence of key mathematical ideas needed to prove a conjecture is fraught with difficulty, as shown in the second transcript. This reveals a central challenge in the use of directed actions as an embodied intervention for learning: how to select and design the actions such that the mapping is as sensible and accessible to the learner as possible.The current study provides empirical support for an emerging theory of cognition-action transduction for embodied mathematical cognition. The production of dynamic depictive gestures is strongly predictive of mathematical insight (H1) and informal mathematical proofs (H6), providing support for the GEMC process account. While game-initiated directed actions increased depictive gesture production, this did not translate to improved mathematical reasoning because these depictive gestures were often not dynamic (H2), suggesting that the directed motions utilized by the intervention may need further development.This highlights the challenges of designing theory-based learning technologies, and reinforces the importance of iterative design approaches for effective educational games.Our findings also support the hypothesis that pedagogical language directing students to the relevance of the game-directed actions improves both dynamic gesture production (H4) and proof performance (H5), which suggests that the language aspects of the intervention were effective. This supports the view that integrating language systems with nonverbal motor-based forms of knowledge can enhance analytic forms of mathematical reasoning.This work offers several contributions, both theoretical and practical, for promoting mathematics education. By focusing on geometry and proof, we contribute to an area of mathematics that makes substantial interconnections across the STEM fields, including classic fields such as physics, chemistry, and biology, as well as more recent advancements, such as nanotechnology and fractals.From a theoretical perspective we have begun to articulate and investigate a theory of embodied cognition. Our theory makes an overt distinction between insight, or System 1 thinking, as a nonverbal, unconscious form of knowing of mathematical relationships, and conscious, analytic formulation of propositional knowledge, or System 2 thinking, that supports the production of logically valid transformational proofs. While action systems and language systems each contribute to both insight and proof, proof-with-insight, it is hypothesized, depends on a coordination of these two systems. On these matters, we showed partial success. However, the shortcomings offer up valuable direction for future models and research.On a practical level, our work contributes to issues concerning the design of theory-motivated interventions for improving STEM education, and the proliferation of commercial body-based programs in STEM and language education. One important take-away is that GEMC is not about thoughtless movement. Rather GEMC considers the integration of nonverbal and verbal forms of  thinking.Lee  observesThe Hidden Village served as an intervention medium for these design principles, and attained partial success on the impact of language cuing. We were also able to add further empirical support for the theoretically inferred role of dynamic gestures on insight. However, we were not successful at effectively eliciting dynamic gestures on demand through elicitation of relevant directed actions by copying the motions of in-game characters.GEMC offers theoretical guidance for the design of effective learning environments. Working from this paradigm, Lindgren and Johnson-Glenberg  offer siOne of the key design challenges when creating an environment that directs motions for a sophisticated conceptual area like geometric proof is determining which actions to direct to best facilitate students’ reasoning. One idea is to examine the gestures, particularly the dynamic gestures, that competent problem-solvers tend to make, and then turn these gestures into directed actions given by the game for particular conjectures. However, this is complicated by limitations in current technology for accurately detecting certain types of motions. While subtle hand gestures are more difficult for our prototype video game to identify, large arm movements are less problematic. Thus our general approach is to examine the gestures that competent problem-solvers make when they prove our geometric conjectures, and then re-imagine these gestures as large arm movements that the technology can reliably capture. However, some of our motions designed in this way certainly worked better than others.One finding in the intervention used in Nathan et al.  that hasPedagogical language connecting relevant motions to the mathematical task at hand are clearly critical to the success of such an embodied learning environment to promote valid reasoning, but little is known about how the pedagogical prompts should be delivered. Nathan et al.  exploredF = ma) can help analyze why a bridge stands or falls, but does little to inform bridge design. That is the purview of engineering; for it is within the carefully monitored process of the iterative design cycle that one can rapidly explore, test, and converge on successful designs. Research methods such as design-based research  and thereby inhibited the associated conceptual and spatial relations. Irrelevant actions would, by design, be unrelated to the geometric relations, and therefore may be easier to ignore when learners are confronted with a statement to prove using their already-taxed motor system. Our remedy here is to vary the number of times players have to match the directed actions and see how this impacts insight performance.Our future research is informed by the findings and limitations of the current study. One immediate action item is to replicate our findings with a larger, more uniform sample of participants from an age/grade-appropriate context. To this end, we will conduct classroom studies with Our preliminary results suggest that directed actions in combination with pedagogical language promoted valid informal proofs, and that dynamic gestures played a key, mediating role. While pedagogical prompting yielded some of the strongest findings in support of GEMC, we still understand very little of how these cues foster valid proof production. In future studies we will vary the kinds of pedagogical cues, self-cueing, and the timing of cues in order to understand the robustness of this for promoting mathematical reasoning. We also plan to look at the impact of providing language input alone, without directed actions, on proof performance. Finally, our near-term interest is to introduce this video game to high-school geometry classrooms to support collaborative proof production and collaborative authoring of new mathematical conjectures to provide a generative learning environment for exploring mathematical reasoning about objects and space.One final point addresses the proliferation of motion- and body-based interventions for promoting mathematics learning. There is currently no definitive compendium of these programs, or a systematic inventory of their claims. But programs such as The Action Based Learning™ Lab, MATHS DANCE, and Math in Your Feet generally share intertwined goals of incorporating movement into mathematics instruction for intellectual, physical education and health, and interest purposes. Most of these programs lack the research reporting that would support the claims made about advancing academic goals. However, they are tapping into a growing awareness of the role the body plays in learning and engagement. As our current work matures, we hope to provide sound, empirically tested, and theoretically motivated design guidelines for programs that use embodiment to advance STEM learning. With such a vast design space before us, scholars working in embodied cognition for education will find value and inspiration in programs developed by mathematics educators, dancers, biomedical engineers, and mathematicians, as well as those designed by psychologists and educational researchers. Theoretical advancements in GEMC have the potential to provide a common framework for future efforts to design embodied learning experiences to enhance STEM education.


Sex-related differences have been noted in cardiovascular anatomy, pathophysiology, and treatment responses, yet we continued to drive evaluation of vascular device development in animal models without consideration of animal sex. We aimed to understand sex-related differences in the vascular responses to stent implantation by analyzing the pooled data of endovascular interventions in 164 Yucatan mini-swine . Bare metal stents (BMS) or drug-eluting stents (DES) were implanted in 212 coronary arteries . Histomorphological parameters were evaluated from vascular specimens at 3–365 days after stent implantation and evaluated values were compared between female and male groups. While neointima formation at all times after implantation was invariant to sex, statistically significant differences between female and male groups were observed in injury, inflammation, adventitial fibrosis, and neointimal fibrin deposition. These differences were observed independently, i.e., for different procedure types and at different follow-up timings. Only subtle temporal sex-related differences were observed in extent and timing of resolution of inflammation and fibrin clearance. These subtle sex-related differences may be increasingly important as interventional devices meld novel materials that erode and innovations in drug delivery. Erodible materials may act differently if inflammation has a different temporal sequence with sex, and drug distribution after balloon or stent delivery might be different if the fibrin clearance speaks to different modes of pharmacokinetics in male and female swine. Cardiovascular disease (CVD) is the main cause of death in women and men around the world . HoweverConcern has been raised that these differences might herald sex-related difference in therapeutic outcomes. Drug therapies for atherosclerosis and CVD have made great advances, but women have not derived as much benefit as men. Women tend to experience more drug-related adverse events than men, perhaps from differences in body mass, volume of drug distribution, liver metabolism, and/or kidney function . Some clIn addition, sex-related differences in the outcomes of stent implantation have been studied –43; howeThe National Institutes of Health now use consideration of sex as a biological variable as a dominant criterion in evaluation of research funding proposals and yet sex has rarely been evaluated in animal model systems. These systems are an essential bedrock of research into vascular biology and in the determination of the safety/efficacy of endovascular interventions. Animal systems are ideal for testing specific hypotheses that drive vascular disease and much of what we know of vascular biology is derived from animal work. Endovascular therapies require evaluation in animal systems before clinical evaluation can commence. Yet, few if any studies are concerned with the choice of sex in preclinical studies. It is for this reason that we pooled data from extensive experience in preclinical studies to determine if sex-related differences could be identified in the vascular responses to the stent implantation.All animal studies were performed at GLP AAALAC accredited animal facility  and adhered to the Guide for the Care and Use of Laboratory Animals under an Institutional Animal Care and Use committee-approved protocol. We pooled data from 164 Yucatan mini-swine (4-month old). Among all mini-swine, 87 (53%) were nulliparous female and 77 (47%) were castrated male. BMS or DES was implanted in the three main coronary arteries with standard procedure. The procedure is described in NA) and lumen area (LA) were measured, and luminal occlusion (LO) was calculated as follows: LO = NA/(NA+LA). Histomorphological parameters, i.e., injury score, inflammation score, adventitial fibrosis score, neointimal fibrin score, neointimal maturation score, and endothelialization score, were also evaluated from each specimen  after stent implantation. From each histology specimen, neointima area , the single- or overlapped-usage, and the follow-up timing. We could not subcategorize the data based on the artery and its region  because of the limited sample size. Average and standard deviation (SD) were calculated for all evaluated values in each subcategorized group. The statistical significance between female and male groups was evaluated in each subcategorized group by applying Student’s Though mean neointima area did not reach statistically significant differences between female and male mini-swine under any procedure protocols at any time after implantation Figs  and 2, tSimilarly, though vascular injury was minimal (injury scores less than 1) for both sexes, injury was more statistically persistent and elevated at later times in the females; 180 days after single BMS implantation, 365 days after single DES implantation, and 180 days after overlapped DES implantation . PerhapsNeointimal fibrin is a maker of drug delivery as it correlates with vascular fragility from local drug depots. Statistically higher neointimal fibrin scores were observed in male swine arteries with DES 30 and 180 days after single and 90 days after overlapped implantation . Fibrin Sex differences in vascular responses to catheter-based intervention have been sought with just cause. Several studies observed the sex-related difference in onset of cardiovascular events , 11, whiWe pooled data from an extensive database of studies with stents and looked across a wide array of histomorphometric responses segregated by sex. While there were no major sex-related differences in neointima formation as the primary determinant of vascular repair in any of stent implantation procedures, there were statistically significant differences on a variety of parameters that might well emerge as important in specific instances. For example, injury and inflammation persisted for longer in the female swine and adventitial fibrosis and neointimal fibrin deposition were greater in in the males, which is consistent with the clinical trial results.We need though to careful contextualize our findings since we seek not to recapitulate the human condition in the animal or even to answer whether vascular interventions are different in women and men but rather to understand if the biology in animals is sex-dependent. Accordingly let us first comment on what it means to be a male and female animal, second to understand if any confounding variables like arterial dimensions or device type could have biased the results, and then to understand the biologic consequences of variations in component parts of the repair pathways and final lesion formed.Animals are not humans and indeed animal models are used to investigate mechanisms and hypotheses not to predict responses in people. Animals in experimental model departs from the humans in clinical trials. Aside from the obvious age difference and environmental exposures, the notions of sex are different in experimental models and trial subjects. Almost all the animals used in this study are 4 months old and are often raised on carefully controlled chow in carefully modulated and monitored environments. There is no hypertension or diabetes mellitus unless introduced artificially, or there is no tobacco abuse or “unhealthy” lifestyle. More importantly for us, femaleness and maleness have different insinuations. Male animals in experimental systems are most often neutered and female swine most often pre-menarchal placing animals on the different extreme of the natural spectrum of sex hormonal exposure than older human subjects. Although the mini-swine reproductive system is similar to that of human, mini-swine are sexually matured at 5–6 months old, while these animals are usually 4 months old at the initiation of preclinical studies. In addition, these studies mostly follow up to 12 months, when sexual maturation begins. As studies go longer and longer, especially when we begin to examine stents with erodible coatings or backbones, the sexual maturation may overlap with follow-up and we may understand the influence of sex on the outcomes. Thus, our data are valuable to scientists especially in an era where federal mandates to consider sex as a biological variable are ubiquitous but we are careful not to claim association with the human condition.Preclinical experiments are carefully mandated and especially as all the experiments represented here were performed not only in an AAALAC-accredited facility but under GLP guidance as well. Sex-related difference in clinical outcomes of stent implantation may well have arisen from anatomic differences between women and men as arterial dimensions are smaller in women than in men –5. This Different hemodynamic patterns could potentially influence the outcomes of stent implantation. In the pooled data, the stents were implanted in all three coronary arteries and we and others have shown differential physical forces and hemodynamic patterns on the different coronary arteries . AlthougOne important element from this work is that overall cumulative effects on an artery like ultimate neointimal hyperplasia and thrombosis are no different in female and male swine though different pathways and elements of the response to injury do show differential effects. This is an important finding and not contradictory. Neointima or clot formation are the end result of a multitude of processes and are subject to the full range of biologic, biochemical, physical and hemodynamic effects. The metrics integrate all of the net biologic effects that confront the artery, and it is impossible to predict the end result from isolated component parts. This may well explain why effects like fibrin deposition cannot predict overall thrombosis, or inflammation and proliferation cannot predict ultimate neointimal mass. Cumulative effects integrate many events such as arterial geometry and flow as well as physiology and biology and it is essential that these two sets of effects are reported independently and precisely.That differences in specific biological pathways after stent implantation bare metal and drug-eluting, with regard to sex is important in helping investigators plan and justify future studies. This is especially the case as subtle sex-related differences may be of increasing importance as interventional devices meld novel materials that erode and innovations in drug delivery. Erodible materials may act differently if inflammation has a different temporal sequence with sex, and drug distribution after balloon or stent delivery might be different if the fibrin clearance speaks to different modes of pharmacokinetics in male and female swine.In this study, we used a pooled data of catheter-based interventions in more than 200 coronary arteries of Yucatan mini-swine to understand sex-related influence on vascular repair after stent implantation. Animals were split almost equally between males and females and both bare metal and drug eluting stents were considered in single and overlapped configurations. While several clinical studies observed sex-related differences in cardiovascular events, our pooled data showed no sex-related differences in the major bulk properties of thrombosis, neointima formation or luminal occlusion at all times in follow-up from 1 month to 1 year after stent implantation. Statistically significant differences between male and female swine were observed in histomorphological parameters directed at resolution of fibrin deposition after drug delivery and degree of inflammation. These issues speak to the mandate to consider sex as a biological variable in animal experiments and will likely become important when we consider complex convergence technologies such as erodible materials where the dynamics of vascular repair after initial events determine late effects.S1 Appendix(PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S3 Appendix(PDF)Click here for additional data file.S1 Table(XLSX)Click here for additional data file.


Are there key attributes of leaders? Extrovert versus introvert? Charismatic? Detail oriented? Visionary? How do past leaders of the Medical Library Association (MLA) stack up? What leadership skills will MLA’s leaders need in a complex information future? Leadership attributes of MLA’s past and current presidents were studied to determine the common characteristics shared among these leaders. An examination of the leadership literature identified critical leadership characteristics essential to successful future leaders. MLA’s past, current, and future leadership development efforts were examined. Finally, all members were encouraged to consider leadership with a small “l” and become leaders based on their own strengths, interests, and environments.A text analysis was performed on past presidential profiles, the past twenty-five years of MLA presidents were surveyed, and conversations with MLA’s current presidents were held to determine commonalities among leadership characteristics. These were compared and contrasted with characteristics in the current leadership literature regarding the qualities of future leaders.The text analysis of past presidential profiles was not particularly revelatory regarding leadership qualities of early MLA presidents although several generalized traits emerged including collaborative traits; management traits such as effectiveness and efficiency, innovation, and vision; personal traits such as humor and energy; and finally, a passion for the work were revealed. These aligned with traits identified in the survey of the past twenty-five years of MLA presidents and with the thoughts of the president-elect, president, and past president. Additional qualities identified were communication skills, political acumen, creativity, courage, and respect for the opinions and concerns of all members. MLA’s current leadership programs were reviewed in the context of examining traits needed by leaders of the future. A lack of focus on the needs of middle managers and the development of individual leadership skills was identified.As an organization, MLA should focus on leadership development in contrast to management training to prepare members as leaders in careers and work that may be vastly different than current situations. Equipping members with the skills enabling them to lead and thrive in these diverse situations, whether as the heads of programs or middle managers, or exploring and empowering individual leadership development while maintaining a passion for the profession, will be essential. Appendix AClick here for additional data file.Appendix BClick here for additional data file.


Accessibility and affordability of evidence-based medicines are issues of global concern. For low-income countries like Nepal, it is crucial to have easy and reliable access to affordable, good-quality, evidence-based medicines, especially in the aftermath of natural or manmade disasters. Availability of affordable and evidence-based high quality medicines depends on the medicine procurement procedure, which makes it an important aspect of healthcare delivery. In this study, we aimed to investigate medicine procurement practices in hospital pharmacies of Nepal within the framework of International Pharmaceutical Federation [FIP] hospital pharmacy guidelines “the Basel Statements”.We conducted semi-structured interviews with hospital pharmacists or procurement officers in hospital pharmacies of four major regions in Nepal to explore procurement practices. Data were collected until saturation of themes, analysed using the framework approach, and organised around the statements within the procurement theme of the Basel Statements.Interviews conducted with 53 participants revealed that the procurement guidelines of the Basel Statements were adopted to a certain extent in hospital pharmacies of Nepal. It was found that the majority of hospital pharmacies in Nepal reported using an expensive direct-procurement model for purchasing medicines. Most had no formulary and procured medicines solely based on doctors’ prescriptions, which were heavily influenced by pharmaceutical companies’ marketing strategies. Whilst most procured only registered medicines, a minority reported purchasing unregistered medicines through unauthorised supply-chains. And although the majority of hospital pharmacies had some contingency plans for managing medicine shortages, a few had none.Procurement guidelines of the Basel Statements were thus found to be partially adopted; however, there is room for improvement in current procurement practices in hospital pharmacies of Nepal. Adoption and regulation of national and international policies is recommended for enhancing medicine accessibility, as well as improving preparedness for health emergencies during natural disasters and health epidemics. A hospital pharmacy is an integrated part of healthcare in health institutions and is responsible for all medicine-related and management health processes to optimize outcomes and enhance the safety and quality of health services provided to patients . There iWith the objective of developing global consensus statements for advancement of hospital pharmacy practice, the Hospital Pharmacy Section of International Pharmaceutical Federation (FIP) developed the first set of international consensus statements, named the Basel Statements, in 2008 . The BasThe procurement theme of the Basel Statements  highlighPharmaceutical procurement is a multi-disciplinary process requiring medical, pharmaceutical, managerial, financial and often political expertise An effective pharmaceutical procurement process should ensure availability of the right drugs in the right quantities, at the right time, for the right patients at reasonable prices, and at recognizable standards of quality .PharmaceRational selection of medicines is also considered one of the important factors associated with medicines use . Data frClinical and pharmaceutical advancements and innovations around the world are causing incremental increases in medicine and total health expenditure . These iAdditionally, the quality of medicines is one of the key components of pharmaceutical procurement because of increasing availability of counterfeit, substandard and contaminated medicines on the market, that have the potential to pose serious health threats . A surveMedicine shortages is another challenging issue that can have serious implications on healthcare delivery, economy of the hospital and patient’s health . There aMore than half the population of low-income countries in Africa and Asia do not have regular access to essential medicines, either due to absence of regulatory authorities or limited capacity to regulate medicine distribution . Medicinth in the Human Development Index . All documents, including Participant Consent Form and Interview Guide were approved by the ethics committee. Written consent was obtained for each interview.Hospital pharmacists or procurement officers at hospital pharmacies in private and public hospitals throughout Nepal were included in the study. Samples were collected using a passive snowballing technique. In the snowballing technique, informants refer prospective participants and these participants again refer other participants making a chain of referral . PassiveThe Hospital Pharmacists’ Association of Nepal, a private company of pharmaceutical products, and prominent figures in the profession such as the Vice President for the Hospital Pharmacy Section of International Pharmaceutical Federation (FIP) in the South East Asian Region were the key contact points for searching and reaching out to prospective participants. The only inclusion criterion was involvement of the participant in the procurement process. Hospital pharmacies that were based inside the premises of a hospital, and were run either by the hospital itself or leased by the hospital to a private organization, were included in the study. Hospitals from the five major regions in Nepal as well as those in major cities were targeted for inclusion in the study.Semi-structured interviews were conducted with key stakeholders using a standard interview guide  based onInterviews were conducted in either Nepali or English, based on the participant’s preference. All participants provided written consent. All recorded interviews were transcribed verbatim by the ground researcher [MS]. Transcripts of interviews conducted in Nepali were translated to English by a Nepali translator and verified by another Nepali co-author. All transcripts were verified by the interviewees before analysis. Each interviewee was posted or emailed transcripts for approval, and followed up to confirm reliability of the transcript. Data collection continued until saturation of themes occurred .Data were analysed thematically utilising the framework analysis approach  based onInterviews were conducted with 53 participants; 52 were from hospital pharmacies  in four different regions of Nepal. One participant worked at the Logistic Management Division under the Department of Health Services of the Ministry of Health and Population, and was responsible for procuring free supplies for public hospitals and associated health institutions of Nepal. Out of 53 participants, 46 were male and 7 female. As the central region of Nepal has several major cities and a larger number of hospitals, the majority of participants (n = 33) were from this region. Twelve participants belonged to the eastern region, 7 to the western region and 1 belonged to the far-western region .Our findings showed the existence of two types of hospital pharmacies, irrespective of the type of hospital: 1. those run by the hospital and 2. those run by a private organization under a lease agreement. Statements pertaining to the need for pharmacist-controlled procurement, information systems, existence of funding mechanisms, and proper storage conditions were all satisfactorily implemented, however, some guidelines were implemented only partially.Notably, procurement practices were found to be affected by the nature of ownership of the hospital pharmacy: hospital-regulated hospital pharmacies tended to be more adherent to the Basel guidelines, while privately owned pharmacies deviated.Utilising the Basel Statements relating to procurement processes, we organised the data under three main themes: Procurement Model, Medicines Selection and Contingency Plans. Below are the details of some important findings; all major findings are listed in Our study revealed that hospital pharmacies in Nepal tended to use either one or both of two types of procurement models: 1.a direct-procurement model or 2.a competitive-procurement model. In the direct-procurement model, adopted by the majority of hospital pharmacies, medicines were purchased directly from wholesalers based on established business relationships, incentives, and/or recommendations of pharmaceutical companies, at prices allocated by manufacturers/wholesalers.“If we buy from the supplier allocated by medical representatives, they will provide us with schemes and facilities. I want to maintain relationships and earn profit. Since price is always the same, we negotiate on facilities. When we will buy in bulk quantities they may offer us some extra facilities. Therefore, while purchasing medicine, bargaining will be done on such things.” [PP40]On the other hand, some hospital pharmacies operated under the competitive-procurement model, following a well-defined written procedure, through either an open-bidding process with predefined terms and conditions or competitive negotiations for best prices.“We call for registration of suppliers with predefined criteria. If the applying suppliers meet all those criteria, we will shortlist them through initial screening. Then we will ask for quotation from them and will select who offers us the best price.” [PP53]These differences in procurement models were directly related to pharmacy ownership: the competitive-procurement model was typically adopted by hospital pharmacies owned by the hospital, while the direct-procurement model was implemented by privately-owned hospital pharmacies.The study highlighted that pharmacists or trained technical staff were responsible for procurement processes in the majority of hospital pharmacies. In a few hospital pharmacies, the pharmacy owner, (not necessarily a pharmacist or trained) supervised procurement processes.The study also revealed that procurement officers in most of hospitals utilized the internet, books , company brochures and databases to gather information about medicines.“We have all sources; primary, secondary and tertiary sources.” [PP18]Some hospital pharmacies reported not having access to such resources.Almost all interviewees reported that funds for procurement in their pharmacies were generated by sales of medicines. Where medicine sales were low, participants reportedly used credit or returned unused stock.“We can request from the account section which collects bills of purchased medicine and money collected from the sales. We can also purchase medicine on credit from our regular suppliers.” [PP11]Our study confirmed that the majority of hospital pharmacies did not have a formulary. Of the few that did adopt a formulary list, it was either devised by a formal Pharmacy and Therapeutic (P&T) Committee, or by an informal group of employees. An informal group of employees would be non-officials, mainly doctors or health professionals working in hospital, requesting or suggesting medicine purchases in a hospital as needed. Some procurement officers also mentioned considering the national EML while purchasing medicines.Participants almost unanimously reported that doctors’ prescribing, irrespective of the formulary and EML, drove procurement.“We have to keep medicines according to doctors’ prescriptions.” [PP30]Additionally, almost all of the participating procurement officers reported that aggressive marketing strategies of pharmaceutical companies affected medicine selection, effectively creating undeclared conflicts of interest."Yes, there are influences. If you look at the whole of Nepal, there are influences. Since we don’t have Pharmacy and Therapeutic Committee, medicines are selected based on doctors’ prescriptions. Therefore, pharmaceutical companies have become successful in influencing doctors." [PP25]One participant stated that some pharmaceutical companies donated to the hospital, and therefore it was desirable for procurement to be conducted through these companies.We are practising in this way because we want to provide opportunities to all pharmaceutical companies. Sometimes, some companies may have invested in the hospital, and then we can discuss with even directors and can use medicines of such companies… Everyone’s interest is met. The pharmaceutical companies are also here for business… They conduct Continuing Medical Education (CME), conferences and other programs. Therefore, we will keep medicines from those companies on rotation basis ". [PP2]Amidst the prescription-driven and commercially-influenced procurement practices, a small minority of hospital pharmacies confirmed that procurement was conducted in accordance with the Public Procurement Act 2007 without influence of companies."It is very transparent; 100% as per the law. Due to this Commission for the Investigation of Abuse of Authority (CIAA), things are very tough now. Public Procurement Act is there and we have to follow each and every step as per guidelines." [PP8]Majority of hospital pharmacies showed no regulations or policies for managing influences of pharmaceutical companies."This is almost impossible in the context of Nepal because doctors are given more priorities and doctors are controlling the hospital rather than being controlled by hospital…Therefore, it is impossible to regulate doctors. This is more of a national issue rather than a hospital issue. The government has published Medicines Promotional Act for managing this and they can implement this act; then only will there be some control over this promotional strategy…otherwise they are free to continue with their marketing strategy." [PP4]However, a few reported to manage influence by restricting pharmaceutical companies’ access to decision-makers."Medical representatives are not allowed to visit doctors. We have that rule to restrict medical representatives’ visit to our hospital; but meeting outside the hospital might happen." [PP50].An interesting observation was that such hospital pharmacies tended to be run by the hospital and were often owned by the government or International Non-Governmental Organizations (INGOs).On the issue of safety, only a few officers mentioned prioritising safety of medicines. Many pharmacists noted that they confirmed the registration status with national regulatory authorities before procuring."If medicines are registered in Department of Drug Administration (DDA) then we trust that they are of good quality. We only buy registered medicines.” [PP2]However, a few hospital pharmacies, especially in cities near the Indian border, admitted that they had to procure unregistered medicines from unauthorised sources if prescribed by doctors or if medicines required were in shortage."Some medicines are important to patients and are life-saving medicines. Doctors have to prescribe such medicines and most of them are not available in Nepal. In such conditions when doctors prescribe them, we do purchase from India, even from black market. Such medicines are not kept here in the pharmacy; we stored them separately and even dispense secretly to patients. It is illegal but we are saving patients’ lives." [PP44]When asked about adoption of a quality assurance system for controlling entry of substandard medicines, some respondents answered that they trusted doctors’ prescriptions and recommendations, and/or reputations of the manufacturers for ensuring quality of medicines."No, we don’t do that. If doctors prescribe then it must be of good quality. If they prescribe then we will sell anything, even stones." [PP20]A few participants had a system in place for quality control, including seeking certificates of analysis and/or testing of samples."There is a pre-shipment inspection, post-shipment inspection, checking of Good Manufacturing Practice and analysis certificates. We appoint a third-party inspection agency for inspection…It is done for each product and each company that won the bid for supply. There is post-shipment inspection at the time of delivery. We randomly select medicines and send to national medicines laboratories for inspection" [PP15]The study revealed that medicines in most hospital pharmacies were stored in appropriate conditions. Many had facilities for maintaining room temperature (20–25°C) and other conditions necessary to preserve the quality of medicines during storage.Our results showed that the majority of pharmacists used brand-substitution, emergency-purchasing , and borrowing from other pharmacies, as strategies to manage medicine shortages."We will borrow from other hospital pharmacies or request suppliers to manage medicines for us. If it is not possible to manage from these sources then we will go for second option. We will discuss with doctors and substitute. We also control inventories and try to manage stock.” [PP52]Several hospital pharmacists also claimed that they had a separate emergency fund, for pricier substitutions needed during emergencies. A few pharmacists stated that they did not have a shortage management system in place.“If medicines are not available then we have to say no and request patients to search in other places.” [PP13]Some hospital pharmacies managed inventories by stockpiling up to 3 months’ worth of medicines based on past consumption or seasonal changes and epidemics, as well as gathering prior information from suppliers/manufacturers to help manage medicine shortages.“We usually maintain stock for 3 months so shortage does not happen that frequently. Sometimes supplier will inform us about upcoming shortages and ask whether we want to order in larger quantities. And in such conditions, we will order in larger quantity.” [PP14]To our knowledge, this is the first study to explore procurement practices in hospital pharmacies in Nepal within the framework of the procurement guidelines of the Basel Statements. Our findings revealed mixed results regarding implementation of guidelines, which included partial adoption of guidelines in the majority of hospital pharmacies. This shows that, by and large, Nepalese hospital pharmacies have many good processes in place however there is room for improvement. Accordingly, several recommendations are proposed.It is important to note that compliance with the Basel Statements may not always be in the best financial interests of private pharmacy ownership. This could therefore have contributed or explained lower compliance with the guidelines by some privately owned hospital pharmacies. Given the apparent correlation between pharmacy ownership and guidelines implementation, enforcement of the Nepalese National Health Policy 2014  and HospThe study found that the majority of hospital pharmacies followed the direct-procurement model, which is considered one of the most expensive models by WHO , and is Furthermore, barriers to utilization of the tendering process were identified, such as size of purchase order, stock levels, and administrative workloads, which are similar issues reported by WHO  and ArneAlthough the Nepalese National Good Pharmacy Practice Guidelines 2005  insists Furthermore, and in contrast to the Basel Statements, the Nepalese Hospital Pharmacy Directives 2013  do not sReliance on unreliable sources of evidence-based healthcare was also a concern. Utilization of readily available online information sources provided by national and international organisations providing evidence-based guidelines  should be encouraged. Finally, procurement officers should be educated about international guidelines developed by WHO and other international pharmaceutical associations [such as FIP] to improve their procurement practices.Another challenging issue in pharmaceutical procurement was medicine selection. This study found that the majority of hospital pharmacies in Nepal are being operated without a hospital formulary to facilitate patient care and medicine procurement. This finding suggests that the Basel Statements 18, 21 and 22, the WHO , AmericaFurther, occurrences of undeclared relationships between decision-makers and suppliers/manufacturers were also uncovered in this study. The lack of a Pharmacy and Therapeutic (P&T) Committee, authority of doctors in medicine selection, and influences of aggressive pharmaceutical marketing strategies were reported by interviewees as major barriers for formulary-based selection.The dominance of doctors driving procurement based on what they prescribe without specific prescribing guidelines could be minimized by establishing a P&T Committee to develop formularies and add additional players in decision making processes  with theThe influence of pharmaceutical marketing is a heavily scrutinized topic around the world because of its impact on patient care. Influence of pharmaceutical companies on medicine selection and other procurement-related behaviours evident in Nepal is in contrast with Basel Statement 17 , which dFurthermore, undeclared conflicts of interest observed in Nepalese hospital pharmacies suggest that there is room to decrease influence and bias. The WHO actually suggests establishing guidelines for declaration of conflict of interest by people involved in the decision-making processes in order to minimize corruption, favoritism or influence, and to increase transparency in procurement processes . In lineInterestingly, many participants did not seem to consider safety issues whilst procuring. Although most procurement officers aimed to procure registered medicines to ensure quality, a few reported procurement of unregistered medicines through unauthorised supply chains, especially from India, one of the leading countries for counterfeit and substandard medicine production . ProcureAlthough a minority took the extra step of checking analysis certificates and performing analytical testing, trusting doctors’ prescriptions and the reputation of pharmaceutical companies in an environment of incentive-based selection and aggressive pharmaceutical marketing may not assure quality of medicine.Procurement officers could utilize the model and guide of quality assurance system developed by the WHO  or the UIn an attempt to combat counterfeiting globally, the WHO has developed a toolkit named “BE AWARE”  in collaThe majority of hospital pharmacies reportedly managed medicine shortages through spontaneous workarounds, such as searching for alternatives, emergency purchasing, and borrowing from other hospital pharmacies. Some even stockpiled or tried to acquire prior knowledge about anticipated shortages, to help overcome shortages in epidemics or seasonal demands. These measures were in line with some guidelines recommended by ASHP , but posNepal recently endured disastrous earthquakes in April and May 2015 causing major medicines shortages, which was reported to be a crucial issue of concern in the massive aftermath of the tragedy . In suchThe findings of this study indicated that procurement guidelines of the Basel Statements are currently implemented to a certain extent in hospital pharmacies of Nepal. This study also found some significant factors that influenced procurement practices in Nepal such as hospital pharmacy ownership, pharmaceutical companies’ influences, authority of doctors, and lack of regulatory enforcement. Moreover, purchase of unregistered medicines from unauthorised supply chain reported in the study showed possibility of health threats by counterfeit and substandard medicines. Absence of strategic contingency plans during shortage was also a major concern especially as Nepal could be heavily reliant on other countries for essential and lifesaving medicines in emergency situations such earthquakes, flooding, other natural disasters or health epidemics. Adoption and regulation of national and international policies is recommended for improving accessibility of high-quality, evidence-based and affordable medicines as well as preparedness for health emergencies during natural disasters and health epidemics. Enforcement of such regulations might be challenging both in terms of patient access and to actual enforcing–however, by highlighting findings of this study, we believe we can contribute to the general debate on access to medicines and challenges faced in Nepal.This study successfully examined the medicine procurement practices of Nepal and has proposed evidence-based recommendations to improve current medicine procurement practices in Nepal. Although this qualitative study did not cover all hospitals of Nepal and thus may not be completely generalizable, major hospitals from most regions of Nepal were included and therefore provided meaningful insight into medicine procurement practices in Nepal. This study involved interviews with hospital pharmacists and procurement officers, however perspectives of policy makers, national regulatory authorities and hospital administrators could have provided in-depth and first-hand perspectives about the practical challenges in the adoption, regulation and implementation of guidelines. Further studies are recommended to include the perspectives of such key stakeholders.Social desirability bias can also be common in this kind of research. To address potential bias, the ground researcher reassured all participants of anonymity and confidentiality. Nonetheless, we cannot guarantee that the data was completely void of social bias.S1 AppendixInterview guide.(DOC)Click here for additional data file.


An overwhelming response followed my inaugural article in Frontiers in Pediatric Critical Care in 2015, which focused on hypoxic ischemic injury in the developing brain , and neoTo address these concerns, we gathered a team of neonatal and pediatric CCPR experts from across the globe and proposed a research topic on neonatal and pediatric CCPR. The topic received a robust response from across the world and we received original research articles and review articles from neonatal and pediatric resuscitation experts.Alahmari et al in our research topic tested the hypothesis that neuropathology associated with in utero inflammation is exacerbated by inappropriate delivery room ventilation in preterm lambs (TM) with four other available devices used for stabilization in the delivery room. The study showed that routinely used newborn resuscitators delivered excess tidal volume, whereas the Next StepTM under delivered in the low compliant test lung  rate and compression to ventilation (C:V) ratio during delivery room resuscitation , 6. DespOn one hand, the investigators are looking at post-partum measures such as placental transfusion to improve outcomes of neonatal asphyxia  and on tCurrent guidelines recommend monitoring of vital signs which do not include monitoring of the brain, the most vulnerable organ especially to hypoxia during transition immediately after birth. Doppler sonography allows non-invasive monitoring of the perfusion in different regions of the brain. However, this method is limited since it does not allow continuous monitoring, it is difficult during transition after birth and it is prone to motion artifacts, especially in infants . In the Dix et al in their review paper discuss about the importance of cerebral oxygenation monitoring in the first 3 days of life, particularly during neonatal resuscitation and beyond resuscitation  in EEG amplitude. A sustained change in the EEG signals a risk of impending brain injury. EEG activity should recover immediately following restoration of oxygen delivery to the brain, if EEG activity does not return immediately post-resuscitation or activity is severely disrupted, this indicates that the infant is at risk of hypoxic-ischemic brain injury. Dr. Finn and co-authors describe the rationale for using delivery room EEG, explored the current evidence on feasibility of delivery room EEG monitoring and the role of DR EEG monitoring on neurologic outcome. Though delivery room EEG is feasible, it is challenging to apply within minutes after delivery. The EEG pattern correlates with cerebral oxygen saturation and oxygen extraction and therefore it provides useful information about neonates' status during transition after delivery. This could potentially identify neonates who might benefit from early cooling within first 3 h of delivery. Prospective, randomized controlled studies are needed to support the authors' statements on use of EEG in delivery room, especially to determine early (<3 h after delivery) vs. late (3–6 h after delivery) cooling.In summary, the field of cerebro-cardiopulmonary resuscitation is evolving significantly but many questions still remain unanswered. There is a growing interest in monitoring of cerebral function through non-invasive modalities such as NIRS and understanding the effects of interventions such as placental transfusion, ventilation and use of epinephrine during neonatal resuscitation. Multi-center, prospective, randomized controlled trials focused on multi-modality monitoring of brain function and goal-directed interventions will potentially help us bridge the knowledge gaps.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Increasing access to fresh produce in small retail venues could improve the diet of people in underserved communities. However, small retailers face barriers to stocking fresh produce. In 2014, an innovative distribution program, Community Markets Purchasing Real and Affordable Foods (COMPRA), was launched in Los Angeles with the aim of making it more convenient and profitable for small retailers to stock fresh produce. Our case study describes the key processes and lessons learned in the first 2 years of implementing COMPRA. Considerable investments in staff capacity and infrastructure were needed to launch COMPRA. Early successes included significant week-to-week increases in the volume of produce distributed. Leveraging partnerships, maintaining a flexible operational and funding structure, and broadly addressing store owners’ needs contributed to initial gains. We describe key challenges and next steps to scaling the program. Lessons learned from implementing COMPRA could inform other jurisdictions considering supply-side approaches to increase access to healthy food. Although a diet high in fruits and vegetables is a key component of a healthy lifestyle, most Americans do not meet dietary recommendations for consumption of fresh produce. The lowest consumption rates are in low-income communities . One facAugmenting food distribution systems to work more favorably for small retailers may reduce obstacles they face in stocking fresh produce, especially when paired with complementary strategies that build store owners’ capacity to operate a successful produce business. Although several communities have tested and established these types of healthy food distribution programs ,4, the eCommunity Markets Purchasing Real and Affordable Foods (COMPRA) is a healthy food distribution program that was started as a joint venture of the Los Angeles Food Policy Council (LAFPC), Leadership for Urban Renewal Network (LURN) and Asian Pacific Islander Forward Movement (APIFM). COMPRA provides 2 key benefits to participating retailers: distribution services and technical assistance. COMPRA provides these services in parallel to affect a number of primary program outputs and expected outcomes for both store owners and community members .First, COMPRA provides distribution services designed to meet the needs of small retailers — a sector that was previously left out of the produce distribution market in Los Angeles. Distribution services are intended to remove the logistical barriers store owners face to offering fresh produce, by coordinating all aspects of weekly ordering and product delivery and by making every effort possible to secure products at wholesale prices without minimum order requirements . These services may reduce required staff time, up-front monetary investment, and the risk of waste associated with stocking fresh produce, providing an opportunity for store owners to experiment with different varieties and quantities of fruits and vegetables until they find the right product mix for their customers.Second, COMPRA provides a suite of technical assistance services, including one-on-one training using a structured curriculum progression, targeted funding, and resource linkage and navigation. This comprehensive approach, tailored to each store owner’s needs, time, and the demands of running her or his business, is intended to build capacity in 5 areas: 1) human capital (knowledge and skills around selling fresh produce), 2) technical capital , 3) built capital , 4) economic capital (connection to financing institutions), and 5) social capital (connections to supportive networks and institutions including neighborhood agencies and city departments). By following a community empowerment model , a learning community convened by LAFPC to build the capacity of independently owned small retailers to offer healthier produce options. These discussions identified a pressing need for a distribution system that could provide a convenient and profitable way for small retailers to source fresh produce.COMPRA was launched as a pilot in late 2014, delivering produce to 7 stores. Each organization on the operating team contributed unique resources that were critical to getting the program off the ground; for instance, APIFM provided a delivery van and LAFPC leveraged existing partnerships with retailers through HNMN to begin recruitment. Working through existing partner networks, the team secured a large supplier willing to provide products at cost and accommodate small-volume orders. The 7 members of the initial group were recruited by using a combined snowball and convenience sampling approach in which participants were identified through existing networks  and asked to provide referrals to other potentially interested retailers. Personnel resources, contributed on an in-kind basis by LAFPC and LURN, represented the other primary up-front investment. Significant staff time and expertise were needed to outreach to small retailers; process orders; pick up, sort, and deliver produce; and provide technical assistance to member stores . To refine and scale up the program following the pilot phase, it became clear that additional staffing  and equipment  were needed. To acquire these resources and to fully support operations, COMPRA secured a diverse combination of funding streams by summer 2015, blending local and national government and foundation resources. With this additional operational capacity, recruitment expanded beyond the original group of members. Stores were identified (by using the same approach as in the pilot phase) and recruited in designated “Promise Zones” in Los Angeles  — high-poverty, predominantly racial/ethnic and linguistic minority neighborhoods with a high burden of chronic disease ,7. TableCOMPRA’s first 2 years of operation were characterized by steady growth and progress. The program experienced several key operational successes during this time, including standardizing order-taking and management processes, adjusting technical assistance services to better meet store owners’ needs, and developing safety and standard operating procedures. Membership in COMPRA increased in parallel with the evolving operations; by January 2017 the program was delivering to 27 active members (up from 7 when pilot deliveries began in late 2014).Preliminary program evaluation, conducted in partnership with the Los Angeles County Department of Public Health (LACDPH), used sales data to examine trends in the volume of produce distributed by COMPRA over a one-year period (August 2015–August 2016). In addition, the evaluation team collected comparison price data, by abstraction of publicly available wholesale market prices and local grocery store audits, to understand how prices available through COMPRA compared with those of store owners’ previous vendors. Results (available elsewhere ) demonstEarly program successes demonstrate the potential for public health practitioners to leverage social enterprise models to create changes in the availability of fresh produce in small retail settings. Key challenges in implementing COMPRA included lack of institutional knowledge of the produce distribution sector, the complex nature of the produce business, the need for large up-front investments in equipment and infrastructure, difficulty obtaining the right type of funding, working with small retail store owners, and low consumer demand for fresh produce . COMPRA' Moving forward, COMPRA administrators are committed to making the program a profitable, self-sustaining social enterprise while still providing participating stores with high-quality products at affordable prices. COMPRA has identified, and is currently testing, 5 priority strategies to help achieve this goal. Where feasible, administrators have developed targets for each strategy through a forecasting process that takes into account profit margins, projected growth in membership and sales, and food industry trends:Connect directly with farmers or growers. Despite establishing a strong partnership with a large national produce distributor, COMPRA is exploring the possibility of sourcing directly from a network of local farmers and producers to lower costs while maintaining quality. Sourcing from an estimated 5 to 10 farmers could provide the optimal balance between any potential cost savings associated with a shorter distribution chain and the added complexity of sourcing from multiple, small-scale producers. Alternatively, partnering with a distributor of local products, a growers’ association, or a comparable agency could also provide an efficient mechanism to tap into local markets.Streamline labor. As the program matures, the COMPRA staff is designing and implementing better management systems to reduce the amount of labor required to operate the program. For example, COMPRA has implemented a custom ordering system that aims to reduce the time needed to take and track orders by 20%. In addition, administrators are developing new and potentially more efficient technical assistance elements, such as small group trainings hosted at participating stores and training delivery drivers to provide preliminary technical assistance. Greater operational efficiency could allow administrators to spend less time on day-to-day logistics and to invest capacity instead in growth activities, including business development and strategic member recruitment. Simultaneously, administrators have established tracking systems to more systematically examine the impact of program changes  on operations costs and program outcomes .Diversify product offerings. To help increase overall profit margins, COMPRA will begin to distribute higher-margin, more shelf-stable products, including healthy packaged snacks and prepared foods. COMPRA has begun developing this new product line through real-time testing and close consultation with store owners to determine a product mix that is both profitable and appealing to community members. While the exact product catalog is being refined, it is estimated that shifting toward 30% non-produce items could provide a sufficient cushion to account for the less stable profits associated with produce sales. Because determining which packaged and prepared foods count as “healthy” is more complex than with fresh produce, COMPRA is working closely with subject-matter experts at LACDPH to define nutrition standards for their product lines. A key next step will be to develop materials that help communicate technical nutrition criteria to participating store owners  and identifying vendors to provide a consistent supply of products matching these criteria.Target high-volume stores: To generate more revenue and increase sales efficiency, COMPRA is moving to a more strategic recruitment model, with the goal of having at least 50% of the member base ordering in the weekly $45 to $50 range. Engaging stores that order at high volumes but require minimal technical assistance can further optimize revenue. Meeting or exceeding these recruitment goals could subsidize the costs of providing services to less-revenue–generating members, keeping them engaged, so as to gradually increase their motivation and ability to offer fresh produce.Invest in marketing: Developing a professional, long-term marketing structure to support operations at participating stores could help address low consumer demand for healthy products. This type of marketing effort will likely require significant and regular investment. COMPRA is in the early, exploratory phases of identifying, in consultation with business experts, a marketing model most likely to be both effective and sustainable. However, broad and complementary systems and policy changes are likely needed to significantly increase community demand for and consumption of fresh produce  and achieve sustainability is a key next step to advance healthy food distribution programs locally. As national interest grows in developing similar supply chain approaches to improve access to healthy foods, the lessons learned from COMPRA’s implementation in Los Angeles provide a practice-based example that can inform planning in other jurisdictions.