Search

Background: Despite the constant presence of change and innovation in health professions education (HPE), there has been relatively little theoretical modelling of such change, the experiences of change, the ideology associated with change or the unexpected consequences of change. In this paper, the authors explore theoretical approaches to the adoption of innovations in HPE as a way of mapping a broader theoretical landscape of change. Method: The authors, HPE researchers with an interest in technology adoption and systemic change, present a narrative review of the literature based on a series of thought experiments regarding how communities and individuals respond to the introduction of new ideas or methods. This research investigates the stages of innovation adoption, from the emergence and hype around new ideas to the concrete experiences of early adopters. Results: When an innovation first emerges, there is often little concrete information available to inform potential adopters, leaving it susceptible to hype, both positive and negative. This can be described using the Gartner Hype Cycle model, albeit with important caveats. Once the adoption of an innovation gets underway, early adopter user experiences can inform those that follow. This can be described using Rogers' diffusion of innovation model, again with caveats. Notably, neither model goes beyond the point of single point‐in‐time, yes/no, individual adoption. Other approaches, such as learning curve theory, are needed to track uptake and maintenance by individuals over time. Significance: This expanded theoretical base, while still somewhat instrumentalist, combined with complementary theoretical perspectives can afford opportunities to better explore reasons for variance, volunteerism and resistance to change. In summary, change is complicated and nuanced, and better models and theories are needed to understand and work meaningfully with change in HPE. To that end, the authors seek to encourage richer and more thoughtful research and scholarly thinking about change and a more nuanced approach to the pursuit of change in HPE as a whole. Innovation in #meded has regularities. In this @MedEd_Journal State of Science article, the authors openly wonder about the applicability of models such as #GartnerHypeCycle #RogersAdoption to #meded [ABSTRACT FROM AUTHOR]

Pusic, Crampton, and Eva announce the release of Medical Education's 15th annual State of the Science issue: Embracing the Future [ABSTRACT FROM AUTHOR]

The use of Artificial Intelligence (AI) in medical education has the potential to facilitate complicated tasks and improve efficiency. For example, AI could help automate assessment of written responses, or provide feedback on medical image interpretations with excellent reliability. While applications of AI in learning, instruction, and assessment are growing, further exploration is still required. There exist few conceptual or methodological guides for medical educators wishing to evaluate or engage in AI research. In this guide, we aim to: 1) describe practical considerations involved in reading and conducting studies in medical education using AI, 2) define basic terminology and 3) identify which medical education problems and data are ideally-suited for using AI. [ABSTRACT FROM AUTHOR]

This note is concerned with evaluation of location parameters for polytomous items in multiple-component measuring instruments. A point and interval estimation procedure for these parameters is outlined that is developed within the framework of latent variable modeling. The method permits educational, behavioral, biomedical, and marketing researchers to quantify important aspects of the functioning of items with ordered multiple response options, which follow the popular graded response model. The procedure is routinely and readily applicable in empirical studies using widely circulated software and is illustrated with empirical data. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. The information systems designed to support clinical care have evolved separately from those that support health professions education. This has resulted in a considerable digital divide between patient care and education, one that poorly serves practitioners and organizations, even as learning becomes ever more important to both. In this perspective, we advocate for the enhancement of existing health information systems so that they intentionally facilitate learning. We describe three well-regarded frameworks for learning that can point toward how health care information systems can best evolve to support learning. The Master Adaptive Learner model suggests ways that the individual practitioner can best organize their activities to ensure continual self-improvement. The PDSA cycle similarly proposes actions for improvement but at a health care organization's workflow level. Senge's Five Disciplines of the Learning Organization, a more general framework from the business literature, serves to further inform how disparate information and knowledge flows can be managed for continual improvement. Our main thesis holds that these types of learning frameworks should inform the design and integration of information systems serving the health professions. An underutilized mediator of educational improvement is the ubiquitous electronic health record. The authors list learning analytic opportunities, including potential modifications of learning management systems and the electronic health record, that would enhance health professions education and support the shared goal of delivering high-quality evidence-based health care. [ABSTRACT FROM AUTHOR]

Extracellular vesicles secreted from IFNγ-stimulated rat dendritic cells (referred to here as IFNγ-DC-EVs) contain miRNAs which promote myelination (including but not limited to miR-219), and preferentially enter oligodendrocytes in brain slice cultures. IFNγ-DC-EVs also increase myelination when nasally administered to naïve rats. While we can infer that these extracellular vesicles enter the CNS from functional studies, here we demonstrate biodistribution throughout the brain after nasal delivery by way of imaging studies. After nasal administration, Xenolight DiR-labelled IFNγ-DC-EVs were detected 30 minutes later throughout the brain and the cervical spinal cord. We next examined cellular uptake of IFNγ-DC-EVs by transfecting IFNγ-DC-EVs with mCherry mRNA prior to nasal administration. mCherry-positive cells were found along the rostrocaudal axis of the brain to the brainstem. These cells morphologically resembled oligodendrocytes, and indeed cell-specific co-staining for neurons, astrocytes, microglia and oligodendrocytes showed that mcherry positive cells were predominantly oligodendrocytes. This is in keeping with our prior in vitro results showing that IFNγ-DC-EVs are preferentially taken up by oligodendrocytes, and to a lesser extent, microglia. To confirm that IFNγ-DC-EVs delivered cargo to oligodendrocytes, we quantified protein levels of miR-219 mRNA targets expressed in oligodendrocyte lineage cells, and found significantly reduced expression. Finally, we compared intranasal versus intravenous delivery of Xenolight DiR-labelled IFNγ-DC-EVs. Though labelled IFNγ-DC-EVs entered the CNS via both routes, we found that nasal delivery more specifically targeted the CNS with less accumulation in the liver. Taken together, these data show that intranasal administration is an effective route for delivery of IFNγ-DC-EVs to the CNS, and provides additional support for their development as an EV-based neurotherapeutic that, for the first time, targets oligodendrocytes. [ABSTRACT FROM AUTHOR]

A procedure is outlined for point and interval estimation of location parameters associated with polytomous items, or raters assessing studied subjects or cases, which follow the rating scale model. The method is developed within the framework of latent variable modeling, and is readily applied in empirical research using popular software. The approach permits testing the goodness of fit of this widely used model, which represents a rather parsimonious item response theory model as a means of description and explanation of an analyzed data set. The procedure allows examination of important aspects of the functioning of measuring instruments with polytomous ordinal items, which may also constitute person assessments furnished by teachers, counselors, judges, raters, or clinicians. The described method is illustrated using an empirical example. [ABSTRACT FROM AUTHOR]

For assessing the skill of visual diagnosis such as radiograph interpretation, competency standards are often developed in an ad hoc method, with a poorly delineated connection to the target clinical population. Commonly used methods to assess for competency in radiograph interpretation are subjective and potentially biased due to a small sample size of cases, subjective evaluations, or include an expert-generated case-mix versus a representative sample from the clinical field. Further, while digital platforms are available to assess radiograph interpretation skill against an objective standard, they have not adopted a data-driven competency standard which informs educators and the public that a physician has achieved adequate mastery to enter practice where they will be making high-stakes clinical decisions. Operating on a purposeful sample of radiographs drawn from the clinical domain, we adapted the Ebel Method, an established standard setting method, to ascertain a defensible, clinically relevant mastery learning competency standard for the skill of radiograph interpretation as a model for deriving competency thresholds in visual diagnosis. Using a previously established digital platform, emergency physicians interpreted pediatric musculoskeletal extremity radiographs. Using one-parameter item response theory, these data were used to categorize radiographs by interpretation difficulty terciles (i.e. easy, intermediate, hard). A panel of emergency physicians, orthopedic surgeons, and plastic surgeons rated each radiograph with respect to clinical significance (low, medium, high). These data were then used to create a three-by-three matrix where radiographic diagnoses were categorized by interpretation difficulty and significance. Subsequently, a multidisciplinary panel that included medical and parent stakeholders determined acceptable accuracy for each of the nine cells. An overall competency standard was derived from the weighted sum. Finally, to examine consequences of implementing this standard, we reported on the types of diagnostic errors that may occur by adhering to the derived competency standard. To determine radiograph interpretation difficulty scores, 244 emergency physicians interpreted 1,835 pediatric musculoskeletal extremity radiographs. Analyses of these data demonstrated that the median interpretation difficulty rating of the radiographs was −1.8 logits (IQR −4.1, 3.2), with a significant difference of difficulty across body regions (p < 0.0001). Physician review classified the radiographs as 1,055 (57.8%) as low, 424 (23.1%) medium or 356 (19.1%) high clinical significance. The multidisciplinary panel suggested a range of acceptable scores between cells in the three-by-three table of 76% to 95% and the sum of equal-weighted scores resulted in an overall performance-based competency score of 85.5% accuracy. Of the 14.5% diagnostic interpretation errors that may occur at the bedside if this competency standard were implemented, 9.8% would be in radiographs of low-clinical significance, while 2.5% and 2.3% would be in radiographs of medium or high clinical significance, respectively. This study's novel integration of radiograph selection and a standard setting method could be used to empirically drive evidence-based competency standard for radiograph interpretation and can serve as a model for deriving competency thresholds for clinical tasks emphasizing visual diagnosis. [ABSTRACT FROM AUTHOR]

Objectives: To complement bedside learning of point‐of‐care ultrasound (POCUS), we developed an online learning assessment platform for the visual interpretation component of this skill. This study examined the amount and rate of skill acquisition in POCUS image interpretation in a cohort of pediatric emergency medicine (PEM) physician learners. Methods: This was a multicenter prospective cohort study. PEM physicians learned POCUS using a computer‐based image repository and learning assessment system that allowed participants to deliberately practice image interpretation of 400 images from four pediatric POCUS applications (soft tissue, lung, cardiac, and focused assessment sonography for trauma [FAST]). Participants completed at least one application (100 cases) over a 4‐week period. Results: We enrolled 172 PEM physicians (114 attendings, 65 fellows). The increase in accuracy from the initial to final 25 cases was 11.6%, 9.8%, 7.4%, and 8.6% for soft tissue, lung, cardiac, and FAST, respectively. For all applications, the average learners (50th percentile) required 0 to 45, 25 to 97, 66 to 175, and 141 to 290 cases to reach 80, 85, 90, and 95% accuracy, respectively. The least efficient (95th percentile) learners required 60 to 288, 109 to 456, 160 to 666, and 243 to 1040 cases to reach these same accuracy benchmarks. Generally, the soft tissue application required participants to complete the least number of cases to reach a given proficiency level, while the cardiac application required the most. Conclusions: Deliberate practice of pediatric POCUS image cases using an online learning and assessment platform may lead to skill improvement in POCUS image interpretation. Importantly, there was a highly variable rate of achievement across learners and applications. These data inform our understanding of POCUS image interpretation skill development and could complement bedside learning and performance assessments. [ABSTRACT FROM AUTHOR]

Background: Assessments of surgical quality should consider both surgeon and patient perspectives simultaneously. Focusing on patients undergoing major gastrointestinal cancer surgery, we sought to characterize hospitals, and their patients, on both these axes of quality.Methods: Using the American College of Surgeons' National Surgical Quality Improvement Program registry, hospitals were profiled on a risk-adjusted composite measure of death or serious morbidity (DSM) generated from patients who underwent colectomy, esophagectomy, hepatectomy, pancreatectomy, or proctectomy for cancer between January 1, 2015 and December 31, 2016. These hospitals were also profiled using the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. Highest-performing hospitals on both quality axes, and their respective patients, were compared to the lowest-performing hospitals.Results: Overall, 60,526 patients underwent their cancer operation at 530 hospitals. There were 38 highest- and 48 lowest-performing hospitals. The correlation between quality axes was poor (ρ = 0.10). Compared to the lowest-performing hospitals, the highest-performing hospitals were more often NCI-designated cancer centers (29.0% vs. 4.2%, p = 0.002) and cared for a lower proportion of Medicaid patients (0.14 vs. 0.23, p < 0.001). Patients who had their operations at the lowest- versus highest-performing hospitals were more often black (17.2% vs. 8.4%, p < 0.001), Hispanic (8.3% vs. 3.5%, p < 0.001), functionally dependent (3.8% vs. 0.9%, p < 0.001), and not admitted from home (4.4% vs. 2.4%, p < 0.001).Conclusions: Hospital performance varied when assessed by both risk-adjusted surgical outcomes and patient experiences. In this study, poor-performing hospitals appeared to be disproportionately serving disadvantaged and minority cancer patients. [ABSTRACT FROM AUTHOR]

Objectives: As residency programs transition from time‐ to performance‐based competency standards, validated tools are needed to measure performance‐based learning outcomes and studies are required to characterize the learning experience for residents. Since pediatric musculoskeletal (MSK) radiograph interpretation can be challenging for emergency medicine trainees, we introduced Web‐based pediatric MSK radiograph learning system with performance endpoints into pediatric emergency medicine (PEM) fellowships and determined the feasibility and effectiveness of implementing this intervention. Methods: This was a multicenter prospective cohort study conducted over 12 months. The course offered 2,100 pediatric MSK radiographs organized into seven body regions. PEM fellows diagnosed each case and received feedback after each interpretation. Participants completed cases until they achieved a performance benchmark of at least 80% accuracy, sensitivity, and specificity. The main outcome measure was the median number of cases completed by participants to achieve the performance benchmark. Results: Fifty PEM fellows from nine programs in the US and Canada participated. There were 301 of 350 (86%) modules started and 250 of 350 (71%) completed to the predefined performance benchmark during the study period. The median (interquartile range [IQR]) number of cases to performance benchmark per participant was 78 (60–104; min = 56, max = 1,333). Between modules, the median number of cases to achieve the performance benchmark was different for the ankle versus other modules (ankle 366 vs. other 76; difference = 290, 95% confidence interval [CI] = 245 to 335). The performance benchmark was achieved for 90.7% of participants in all modules except the ankle/foot, where 34.9% achieved this goal (difference = 55.8%, 95% CI = 45.3 to 66.3). The mean (95% CI) change in accuracy, sensitivity, and specificity from baseline to performance benchmark was +14.6% (13.4 to 15.8), +16.5% (14.8 to 18.1), and +12.6% (10.7 to 14.5), respectively. Median (IQR) time on each case was 31.0 (21.0–45.3) seconds. Conclusions: Most participants completed the modules to the performance benchmark within 1 hour and demonstrated significant skill improvement. Further, there was a large variation in the number of cases completed to achieve the performance endpoint in any given module, and this impacted the feasibility of completing specific modules. [ABSTRACT FROM AUTHOR]

The authors discuss the implications of silence with respect to how surveys about resident selection usually do not include race, ethnicity or other data that could promote the goals of equity, inclusion and diversity. [ABSTRACT FROM AUTHOR]

Environmental enrichment (EE) consists of increased physical, intellectual, and social activity, and has wide-ranging effects, including enhancing cognition, learning and memory, and motor coordination. Animal studies have demonstrated that EE improves outcome of brain trauma and neurodegenerative disorders, including demyelinating diseases like multiple sclerosis, making it a promising therapeutic option. However, the complexity of applying a robust EE paradigm makes clinical use difficult. A better understanding of the signaling involved in EE-based neuroprotection may allow for development of effective mimetics as an alternative. In prior work, we found that exosomes isolated from the serum of rats exposed to EE impact CNS myelination. Exosomes are naturally occurring nanovesicles containing mRNA, miRNA, and protein, which play important roles in cell function, disease, and immunomodulation. When applied to hippocampal slice cultures or nasally administered to naïve rats, EE-serum exosomes significantly increase myelin content, oligodendrocyte precursor (OPC) and neural stem cell levels, and reduce oxidative stress (OS). We found that rat EE exosomes were enriched in miR-219, which is necessary and sufficient for OPC differentiation into myelinating cells. Thus, peripherally produced exosomes may be a useful therapy for remyelination. Here, we aim to better characterize the impact of EE on CNS health and to determine the cellular source of nutritive exosomes found in serum. We found that exosomes isolated from various circulating immune cell types all increased slice culture myelin content, contained miR-219, and reduced OS, suggesting that EE globally alters immune function in a way that supports brain health. [ABSTRACT FROM AUTHOR]

The article presents the effects of coronavirus on health care delivery system, disrupting patient care processes, halting research activities, and affecting medical education. Topics include interrupting typical training experiences giving sharp decline in routine care and the urgent need for reassigning trainees to Covid-related activities; and defining specific competency-based criteria for graduation.

As high breast cancer survival rates are achieved nowadays, irrespective of type of surgery performed, prediction of long‐term physical, sexual, and psychosocial outcomes is very important in treatment decision‐making. Patient‐reported outcomes (PROs) can help facilitate this shared decision‐making. Given the significance of more personalized medicine and the growing trend on the application of machine learning techniques, we are striving to develop an algorithm using machine learning techniques to predict PROs in breast cancer patients treated with breast surgery. This short communication describes the bottlenecks in our attempt to predict PROs. [ABSTRACT FROM AUTHOR]

It is critical for health professionals to continue to learn and this must be supported by health professions education (HPE). Adaptive expert clinicians are not only expert in their work but have the additional capacity to learn and improve in their practices. The authors review a selective aspect of learning to become an adaptive expert: the capacity to optimally balance routine approaches that maximize efficiency with innovative ones where energy and resources are used to customize actions for novel or difficult situations. Optimal transfer of learning, and hence the design of instruction, differs depending on whether the goal is efficient or innovative practice. However, the task is necessarily further complicated when the aspiration is an adaptive expert practitioner who can fluidly balance innovation with efficiency as the situation requires. Using HPE examples at both the individual and organizational level, the authors explore the instructional implications of learning to shift from efficient to innovative expert functioning, and back. They argue that the efficiency-innovation tension is likely to endure deep into the future and therefore warrants important consideration in HPE. [ABSTRACT FROM AUTHOR]

Introduction: There is limited knowledge on pediatric chest radiograph (pCXR) interpretation skill among practicing physicians. We systematically determined baseline interpretation skill, the number of pCXR cases physicians required complete to achieve a performance benchmark, and which diagnoses posed the greatest diagnostic challenge. Methods: Physicians interpreted 434 pCXR cases via a web-based platform until they achieved a performance benchmark of 85% accuracy, sensitivity, and specificity. Interpretation difficulty scores for each case were derived by applying one-parameter item response theory to participant data. We compared interpretation difficulty scores across diagnostic categories and described the diagnoses of the 30% most difficult-to-interpret cases. Results: 240 physicians who practice in one of three geographic areas interpreted cases, yielding 56,833 pCXR case interpretations. The initial diagnostic performance (first 50 cases) of our participants demonstrated an accuracy of 68.9%, sensitivity of 69.4%, and a specificity of 68.4%. The median number of cases completed to achieve the performance benchmark was 102 (interquartile range 69, 176; min, max, 54, 431). Among the 30% most difficult-to-interpret cases, 39.2% were normal pCXR and 32.3% were cases of lobar pneumonia. Cases with a single trauma-related imaging finding, cardiac, hilar, and diaphragmatic pathologies were also among the most challenging. Discussion: At baseline, practicing physicians misdiagnosed about one-third of pCXR and there was up to an eight-fold difference between participants in number of cases completed to achieve the standardized performance benchmark. We also identified the diagnoses with the greatest potential for educational intervention. [ABSTRACT FROM AUTHOR]

Graduate medical education (GME) and Clinical Competency Committees (CCC) have been evolving to monitor trainee progression using competency-based medical education principles and outcomes, though evidence suggests CCCs fall short of this goal. Challenges include that evaluation data are often incomplete, insufficient, poorly aligned with performance, conflicting or of unknown quality, and CCCs struggle to organize, analyze, visualize, and integrate data elements across sources, collection methods, contexts, and time-periods, which makes advancement decisions difficult. Learning analytics have significant potential to improve competence committee decision making, yet their use is not yet commonplace. Learning analytics (LA) is the interpretation of multiple data sources gathered on trainees to assess academic progress, predict future performance, and identify potential issues to be addressed with feedback and individualized learning plans. What distinguishes LA from other educational approaches is systematic data collection and advanced digital interpretation and visualization to inform educational systems. These data are necessary to: 1) fully understand educational contexts and guide improvements; 2) advance proficiency among stakeholders to make ethical and accurate summative decisions; and 3) clearly communicate methods, findings, and actionable recommendations for a range of educational stakeholders. The ACGME released the third edition CCC Guidebook for Programs in 2020 and the 2021 Milestones 2.0 supplement of the Journal of Graduate Medical Education (JGME Supplement) presented important papers that describe evaluation and implementation features of effective CCCs. Principles of LA underpin national GME outcomes data and training across specialties; however, little guidance currently exists on how GME programs can use LA to improve the CCC process. Here we outline recommendations for implementing learning analytics for supporting decision making on trainee progress in two areas: 1) Data Quality and Decision Making, and 2) Educator Development. [ABSTRACT FROM AUTHOR]

The article discusses the importance of maintaining competency in medical procedures for emergency physicians. It highlights the risks associated with infrequent practice and the need for ongoing learning and training to keep up with new procedures, treatments, and diseases. The article proposes four approaches to maintaining competency, including lifelong learning, retraining for specific procedures, limiting practice in certain areas, and self-assessment and reflection. It emphasizes the responsibility of both individual physicians and the healthcare system in ensuring patient safety and effective care. [Extracted from the article]

Abstract: Dendritic cells (DCs) release exosomes with different characteristics based on stimulus. Here, we showed that DC cultures stimulated with low-level IFNγ released exosomes (IFNγ-DC-Exos) that contained microRNA species that can increase baseline myelination, reduce oxidative stress, and improve remyelination following acute lysolecithin-induced demyelination. Furthermore, nasally administered IFNγ-DC-Exos increased CNS myelination in vivo. IFNγ-DC-Exos were preferentially taken up by oligodendrocytes, suggesting that they directly impact oligodendrocytes to increase myelination. Thus, our results show great potential for use of these IFNγ-DC-Exos as a therapeutic to promote remyelination in multiple sclerosis and dysmyelinating syndromes. [Copyright &y& Elsevier]

In addition, among the 64 patients who had discontinued ruxolitinib, only 15 (23%) received ruxolitinib as front-line therapy for SR-aGVHD, again indicating a baseline high-risk population as a majority of the patients failed front-line therapy for SR-aGVHD. Treatment options have included extracorporeal photopheresis (ECP), anti-TNF- antibodies, anti-thymocyte globulin (ATG), and anti-IL-2R antibodies, amongst others.1,2 While initially effective, durable treatment responses are difficult to achieve and each therapy is frequently complicated with toxicity. Steroid-refractory acute graft- I versus i -host disease (SR-aGVHD) is a debilitating complication of allogeneic haematopoietic cell transplantation (HCT) and is associated with high mortality.1 Until recently, there has been no accepted standard-of-care treatment for SR-aGVHD. [Extracted from the article]

The detrimental effects of T-cell-secreted interferon gamma (IFNγ) on oxidative stress (OS) and demyelination in multiple sclerosis (MS) are well recognized. Recently, we demonstrated that IFNγ-mediated damage to myelin also increases susceptibility to spreading depression (SD; the likely basis of migraine with aura). However, before onset of MS, induction of physiological levels of IFNγ, like that produced by environmental enrichment (EE), protects against demyelination and OS. Accordingly, we focused on the potential for physiological levels of IFNγ to protect against SD. EE, which occurs with a moderate and phasic increase in proinflammatory cytokines, reduces migraine frequency. Thus, we applied phasic or pulsed IFNγ to brain slice cultures to emulate EE. This treatment reduced OS, increased myelin basic protein, a marker for myelin, and reduced susceptibility to SD. Building on our research on exosomes in EE-based neuroprotection, we found that IFNγ stimulation of slice cultures induced release of exosomes, likely from the microglia that produce the same protective effects as IFNγ treatment when applied to naive cultures. Finally, nasal administration of IFNγ to rats recapitulated in vitro effects, reducing OS, increasing myelin, and reducing SD. These results support phasic IFNγ signaling as a therapeutic target for prevention of SD and, by extension, migraine. [ABSTRACT FROM AUTHOR]

Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m 2 /day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m 2 for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m 2 , where most hematological toxicities occurred. [ABSTRACT FROM AUTHOR]

Context Despite calls for the improvement of self-assessment as a basis for self-directed learning, instructional designs that include reflection in practice are uncommon. Using data from a screen-based simulation for learning radiograph interpretation, we present validity evidence for a simple self-monitoring measure and examine how it can complement skill assessment. Methods Medical students learning ankle radiograph interpretation were given an online learning set of 50 cases which they were asked to classify as 'abnormal' (fractured) or 'normal' and to indicate the degree to which they felt certain about their response ( Definitely or Probably). They received immediate feedback on each case. All students subsequently completed two 20-case post-tests: an immediate post-test ( IPT), and a delayed post-test ( DPT) administered 2 weeks later. We determined the degree to which certainty ( Definitely versus Probably) correlated with accuracy of interpretation and how this relationship changed between the tests. Results Of 988 students approached, 115 completed both tests. Mean ± SD accuracy scores decreased from 59 ± 17% at the IPT to 53 ± 16% at the DPT (95% confidence interval [ CI] for the difference: −2% to −10%). Mean self-assessed certainty did not decrease (rates of Definitely: IPT, 17.6%; DPT, 19.5%; 95% CI for difference: +7.2% to −3.4%). Regression modelling showed that accuracy was positively associated with choosing Definitely over Probably (odds ratio [ OR] 1.63, 95% CI 1.27-2.09) and indicated a statistically significant interaction between test timing and certainty ( OR 0.72, 95% CI 0.52-0.99); thus, the accuracy of self-monitoring decayed over the retention interval, leaving students relatively overconfident in their abilities. Conclusions This study shows that, in medical students learning radiograph interpretation, the development of self-monitoring skills can be measured and should not be assumed to necessarily vary in the same way as the underlying clinical skill. [ABSTRACT FROM AUTHOR]

Using educational technology does not necessarily make medical education more effective. There are many different kinds of technology available to the contemporary medical teacher and what constitutes effective use may depend on the technology, the learning situation and many other factors. Web-based multimedia instruction (WBMI) provides learners with self-directed independent learning opportunities based on didactic material enhanced with multimedia features such as video and animations. WBMI may be used to replace other didactic events (e.g. lectures) or it may be provided in addition to other learning opportunities. Clinical educators looking to use WBMI need to make sure that it will meet both their learners' needs and the program's needs, and it has to align to the contexts in which it is used. The following 12 tips have been developed to help guide faculty through some of the key features of the effective use of WBMI in clinical teaching programs. These tips are based on more than a decade developing, using and appraising WBMI in support of surgical clerkship education across the USA and beyond and they are intended both to inform individual uses of WBMI in clinical training and to guide the strategic use of WBMI in clinical clerkship curricula. [ABSTRACT FROM AUTHOR]

Multiple sclerosis and migraine with aura are clinically correlated and both show imaging changes suggestive of myelin disruption. Furthermore, cortical myelin loss in the cuprizone animal model of multiple sclerosis enhances susceptibility to spreading depression, the likely underlying cause of migraine with aura. Since multiple sclerosis pathology involves inflammatory T cell lymphocyte production of interferon-gamma and a resulting increase in oxidative stress, we tested the hypothesis that spreading depression disrupts myelin through similar signaling pathways. Rat hippocampal slice cultures were initially used to explore myelin loss in spreading depression, since they contain T cells, and allow for controlled tissue microenvironment. These experiments were then translated to the in vivo condition in neocortex. Spreading depression in slice cultures induced significant loss of myelin integrity and myelin basic protein one day later, with gradual recovery by seven days. Myelin basic protein loss was abrogated by T cell depletion, neutralization of interferon-gamma, and pharmacological inhibition of neutral sphingomyelinase-2. Conversely, one day after exposure to interferon-gamma, significant reductions in spreading depression threshold, increases in oxidative stress, and reduced levels of glutathione, an endogenous neutral sphingomyelinase-2 inhibitor, emerged. Similarly, spreading depression triggered significant T cell accumulation, sphingomyelinase activation, increased oxidative stress, and reduction of gray and white matter myelin in vivo. Myelin disruption is involved in spreading depression, thereby providing pathophysiological links between multiple sclerosis and migraine with aura. Myelin disruption may promote spreading depression by enhancing aberrant excitability. Thus, preservation of myelin integrity may provide novel therapeutic targets for migraine with aura. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (GVHD) occurs in approximately 50% of patients and remains a primary driver of non-relapse and transplant-related mortality. The best treatment remains prevention with either in vivo or ex vivo T-cell depletion, with multiple strategies used worldwide based on factors such as institution preference, ability to perform graft manipulation, and ongoing clinical trials. Predicting patients at high risk for developing severe acute GVHD based on clinical and biomarker-based criteria allows for escalation or potential de-escalation of therapy. Modern therapies for treatment of the disease include JAK/STAT pathway inhibitors, which are standard of care in the second-line setting and are being investigated for upfront management of non-severe risk based on biomarkers. Salvage therapies beyond the second-line remain suboptimal. In this review, we will focus on the most clinically used GVHD prevention and treatment strategies, including the accumulating data on JAK inhibitors in both settings. [ABSTRACT FROM AUTHOR]

Patient-reported outcome measures (PROMs) are questionnaires that assess how patients feel and function. PROMs should be developed and validated using a mixed methods, multistep approach with extensive patient input to ensure that they are easy to understand, comprehensive, and relevant. PROMs that are specific to genderaffirming care (including surgery), such as the GENDER-Q, can be used to educate patients, align patients' goals and preferences with realistic expectations about the surgical procedures' purposes and outcomes, and conduct comparative effectiveness research. PROM data can contribute to evidence-based, shared decision making and just access to gender-affirming surgical care. [ABSTRACT FROM AUTHOR]

Objectives Most medical procedures have a time element. It is uncommon, however, to explicitly use chronometry, the measurement of time, in the learning of these procedures. This study considered whether instructional designs that include chronometry could improve deliberate practice and be used in meaningful formative assessments. Methods A selective review of the medical education literature was undertaken to identify how chronometry was used in a broad sampling of medical education research in the learning of medical procedures. We identified prior publications in which time measurement was used either directly as a pedagogic intervention or as an assessment method in a medical school programme. Results Our review suggests a number of desirable features of chronometry. For the individual learner, procedural time measurements can demonstrate both improving ability and increasing consistency. Chronometry can enhance instructional designs involving deliberate practice by facilitating overlearning (i.e. learning that goes beyond minimum competence), increasing the challenge level and enhancing self-regulation of learning (e.g. self-competition). Breaking down chronometric data into meaningful interval or split times might further inform instructional designs. Conclusions Chronometry has the potential to contribute to instructional designs and assessment methods in medical procedures training. However, more research is needed to elucidate its full potential and describe possible negative consequences of this widely available but underutilised educational tool. [ABSTRACT FROM AUTHOR]

Context Conducting research in real life settings (effectiveness studies) can introduce many confounding factors. Efficacy studies seek to control for researcher bias and data quality rather than considering how the efficacy of an intervention is changed by the contexts in which it is used. Relatively little is known about the impact of context on educational interventions, in particular on multimedia learning. Methods An effectiveness study to understand implementation variance of online educational modules in surgery clerkships was conducted in six US medical schools participating in an efficacy trial of different multimedia designs. Student and teacher experiences were captured through focus groups and one-to-one interviews with trial participants and their teachers. Audio-recordings of these sessions were transcribed and analysed using grounded theory techniques. Results Differences were identified in student and teacher perceptions of how the educational intervention had been implemented and how its uptake had been influenced by context-dependent factors: (i) the intervention was implemented in different ways to suit different educational contexts and this influenced how students and teachers responded to it; (ii) the ways students and teachers interacted with, and behaved around, the intervention influenced its uptake; (iii) the way the intervention was perceived by students and teachers influenced its uptake; and (iv) the medium and design of the intervention had a directing influence on its uptake. Conclusions It was observed that each institutional context formed a complex educational ecology. The intervention became interwoven with different educational ecologies so that it could no longer be considered a stable variable across the study. We suggest that researchers should conduct implementation-profiling studies in advance of any intervention-based research to account for the constructing nature of educational ecologies on their interventions and in doing so to more clearly differentiate between efficacy and effectiveness studies. [ABSTRACT FROM AUTHOR]

An important role of the paediatrician is that of a teacher -- every clinician is an educator to patients and their families. This education, however, often occurs under difficult or time-pressured learning conditions. The authors present principles derived from three basic theories of human cognition that may help to guide clinicians' instruction of parents and patients. Cognitive load theory holds that an individual's capacity to process information is finite. By controlling information flow rate, decreasing reliance on working memory and removing extraneous cognitive load, learning is improved. Dual code theory suggests that humans have separate cognitive 'channels' for text/audio information versus visual information. By constructing educational messages that take advantage of both channels simultaneously, information uptake may be improved. Multimedia theory is based on the notion that there is an optimal blend of media to accomplish a given learning objective. The authors suggest seven practical strategies that clinicians may use to improve patient education. [ABSTRACT FROM AUTHOR]

As we capture more and more data about learners, their learning, and the organization of their learning, our ability to identify emerging patterns and to extract meaning grows exponentially. The insights gained from the analyses of these large amounts of data are only helpful to the extent that they can be the basis for positive action such as knowledge discovery, improved capacity for prediction, and anomaly detection. Big Data involves the aggregation and melding of large and heterogeneous datasets while education analytics involves looking for patterns in educational practice or performance in single or aggregate datasets. Although it seems likely that the use of education analytics and Big Data techniques will have a transformative impact on health professional education, there is much yet to be done before they can become part of mainstream health professional education practice. If health professional education is to be accountable for its programs run and are developed, then health professional educators will need to be ready to deal with the complex and compelling dynamics of analytics and Big Data. This article provides an overview of these emerging techniques in the context of health professional education. [ABSTRACT FROM AUTHOR]

To identify the most effective way for medical students to interact with a browser-based learning module on the symptoms and neurological underpinnings of stroke syndromes, this study manipulated the way in which subjects interacted with a graphical model of the brain and examined the impact of functional changes on learning outcomes. It was hypothesized that behavioral interactions that were behaviorally more engaging and which required deeper consideration of the model would result in heightened cognitive interaction and better learning than those whose manipulation required less deliberate behavioral and cognitive processing. One hundred forty four students were randomly assigned to four conditions whose model controls incorporated features that required different levels of behavioral and cognitive interaction: Movie (low behavioral/low cognitive, n = 40), Slider (high behavioral/low cognitive, n = 36), Click (low behavioral/high cognitive, n = 30), and Drag (high behavioral/high cognitive, n = 38). Analysis of Covariates (ANCOVA) showed that students who received the treatments associated with lower cognitive interactivity (Movie and Slider) performed better on a transfer task than those receiving the module associated with high cognitive interactivity (Click and Drag, partial eta squared = .03). In addition, the students in the high cognitive interactivity conditions spent significantly more time on the stroke locator activity than other conditions (partial eta squared = .36). The results suggest that interaction with controls that were tightly coupled with the model and whose manipulation required deliberate consideration of the model's features may have overtaxed subjects' cognitive resources. Cognitive effort that facilitated manipulation of content, though directed at the model, may have resulted in extraneous cognitive load, impeding subjects in recognizing the deeper, global relationships in the materials. Instructional designers must, therefore, keep in mind that the way in which functional affordances are integrated with the content can shape both behavioral and cognitive processing, and has significant cognitive load implications. [Copyright &y& Elsevier]

The P. falciparum Merozoite Surface Protein 1–42 (MSP1-42) is one of the most studied malaria subunit vaccine candidates. The N-terminal fragment of MSP1-42, MSP1-33, is primarily composed of allelic sequences, and has been shown to possess T helper epitopes that influence protective antibody responses toward the C-terminal region, MSP1-19. A truncated MSP1-42 vaccine, Construct 33-I, consisting of exclusively conserved T epitope regions of MSP1-33 expressed in tandem with MSP1-19, was previously shown to be a more effective immunogen than the full-length MSP1-42 vaccine. Here, by way of reciprocal priming/boosting immunization regimens, we studied the immunogenicity of Construct 33-I in the context of recognition by immune responses induced by the full-length native MSP1-42 protein, in order to gauge the effects of pre- and post-exposures to MSP1-42 on vaccine induced responses. Judging by immune responsiveness, antibody and T cell responses, Construct 33-I was effective as the priming antigen followed by full-length MSP1-42 boosting, as well as the boosting antigen following full-length MSP1-42 priming. In particular, Construct 33-I priming elicited the broadest responsiveness in immunized animals subsequently exposed to MSP1-42. Moreover, Construct 33-I, with its conserved MSP1-33 specific T cell epitopes, was equally well recognized by homologous and heterologous allelic forms of MSP1-42. Serum antibodies raised against Construct 33-I efficiently inhibited the growth of parasites carrying the heterologous MSP1-42 allele. These results suggest that Construct 33-I maintains and/or enhances its immunogenicity in an allelic or strain transcending fashion when deployed in populations having prior or subsequent exposures to native MSP1-42s. [ABSTRACT FROM AUTHOR]

Abstract: The influence of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins on the cell death (caspase-3, TUNEL) of different ovarian cell lineages was immunohistochemically analyzed in six fetal and five adult human ovaries in order to disclose possible mechanisms of cell number control. Mild to moderate expression of Bcl-2 characterized ovarian surface epithelium, follicular cells and oocytes of 15 and 22 week human ovaries, while expression of Bax and caspase-3 gradually increased in all ovarian cell populations, except caspase-3 in the ovarian surface epithelium. Different levels of Bax and Bcl-2 proteins co-expression characterized fetal ovarian cells, while TUNEL and caspase-3 co-expression was found only in some of them. In adult ovaries, Bcl-2 was moderately and Bax strongly expressed in the surface ovarian epithelium and stroma. Bcl-2 and Bax expression in granulosa and theca interna cells varied depending on the stage of follicular atresia. Caspase-3 apoptotic cells characterized granulosa cells of adult atretic follicles. Our results indicate that intracellular levels of Bcl-2 and Bax protein might regulate the final destiny of developing germ cells. Caspase-3 dependent apoptosis seems to be the most important, but not the only cell death pathway in ovaries. In adult ovaries, caspase-dependent cell death characterized granulosa cells, but not the germ cells. [Copyright &y& Elsevier]

This study explored the novel use of iron oxide (IO) nanoparticles (<20 nm) as a vaccine delivery platform without additional adjuvants. A recombinant malaria vaccine antigen, the merozoite surface protein 1 (rMSP1), was conjugated to IO nanoparticles (rMSP1-IO). Immunizations in outbred mice with rMSP1-IO achieved 100% responsiveness with antibody titers comparable to those obtained with rMSP1 formulated with a clinically acceptable adjuvant, Montanide ISA51 (2.7×10-3 vs. 1.6×10-3; respectively). Only rMSP1- O could induce significant levels (80%) of parasite inhibitory antibodies. The rMSP1-IO was highly stable at 4°C and was amenable to lyophilization, maintaining its antigenicity, immunogenicity, and ability to induce inhibitory antibodies. Further testing in nonhuman primates, Aotus monkeys, also elicited 100% immune responsiveness and high levels of parasite inhibitory antibodies (55-100% inhibition). No apparent local or systemic toxicity was associated with IO immunizations. Murine macrophages and dendritic cells efficiently (>90%) internalized IO nanoparticles, but only the latter were significantly activated, with elevated expression/ secretion of CD86, cytokines (IL-6, TNF-α, IL1-b, IFN-γ, and IL-12), and chemokines (CXCL1, CXCL2, CCL2, CCL3, CCL4, and CXCL10). Thus, the IO nanoparticles is a novel, safe, and effective vaccine platform, with built-in adjuvancy, that is highly stable and field deployable for cost-effective vaccine delivery. [ABSTRACT FROM AUTHOR]

A significant proportion of adult breast cancer survivors experience deficits in function and restriction in participation in life roles that may remain many years after diagnosis. Function is a complex construct that takes into account the interactions between an individual, their health condition, and the social and personal context in which they live. Research to date on limitations in activities of daily living, upper extremity function, and functional capacity in breast cancer survivors illustrates the need for prospective measurement of function using measures that are sensitive to the unique issues of breast cancer survivors and the need for the development of effective rehabilitation interventions to improve function. Limitations in function have a significant impact on quality of life, but less is known about the implications on return to work and survival, as well as the impact of other comorbidities and aging on the function limitations in breast cancer survivors. This review provides a rationale for the integration of measures of function into breast cancer care to more fully appreciate the functional limitations associated with breast cancer diagnosis and treatment and to aid in the development of better rehabilitation care for breast cancer survivors. Cancer 2012;. © 2012 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Preeclampsia is a hypertensive disorder of pregnancy that affects many organs including the brain. Neurological complications occur during preeclampsia, the most serious of which is seizure known as eclampsia. Although preeclampsia can precede the eclamptic seizure, it often occurs during normal pregnancy, suggesting that processes associated with normal pregnancy can promote neuronal excitability. Here we investigated whether circulating inflammatory mediators that are elevated late in gestation when seizure also occurs are hyperexcitable to neuronal tissue. Evoked field potentials were measured in hippocampal slices in which control horse serum that slices are normally grown in, was replaced with serum from nonpregnant or late-pregnant Wistar rats for 48h. We found that serum from pregnant, but not nonpregnant rats, caused hyperexcitability to hippocampal neurons and seizure activity that was abrogated by inhibition of tumor necrosis factor alpha (TNFα) signaling. Additionally, application of TNFα mimicked this increased excitability. Pregnant serum also caused morphological changes in microglia characteristic of activation, and increased TNFα mRNA expression that was not seen with exposure to nonpregnant serum. However, TNFα protein was not found to be elevated in pregnant serum itself, suggesting that other circulating factors during pregnancy caused activation of hippocampal slice cells to produce a TNFα-mediated increase in neuronal excitability. Lastly, although pregnant serum caused neuroinflammation and hyperexcitability of hippocampal slices, it did not increase blood–brain barrier permeability, nor were pregnant rats from which the serum was taken undergoing seizure. Thus, the BBB has an important role in protecting the brain from circulating neuroinflammatory mediators that are hyperexcitable to the brain during pregnancy. These studies provide novel insight into the underlying cause of eclampsia without elevated blood pressure and the protective role of the BBB that prevents exposure of the brain to hyperexcitable factors. [Copyright &y& Elsevier]

Medical Education 2012: 46: 289-298 Objectives Using a large image bank, we systematically examined how the use of different ratios of abnormal to normal cases affects trainee learning. Methods This was a prospective, double-blind, randomised, three-arm education trial conducted in six academic training programmes for emergency medicine and paediatric residents in post-licensure years 2-5. We developed a paediatric ankle trauma radiograph case bank. From this bank, we constructed three different 50-case training sets, which varied in their proportions of abnormal cases (30%, 50%, 70%). Levels of difficulty and diagnoses were similar across sets. We randomly assigned residents to complete one of the training sets. Users classified each case as normal or abnormal, specifying the locations of any abnormalities. They received immediate feedback. All participants completed the same 20-case post-test in which 40% of cases were abnormal. We determined participant sensitivity, specificity, likelihood ratio and signal detection parameters. Results A total of 100 residents completed the study. The groups did not differ in accuracy on the post-test (p = 0.20). However, they showed considerable variation in their sensitivity-specificity trade-off. The group that received a training set with a high proportion of abnormal cases achieved the best sensitivity (0.69, standard deviation [SD] = 0.24), whereas the groups that received training sets with medium and low proportions of abnormal cases demonstrated sensitivities of 0.63 (SD = 0.21) and 0.51 (SD = 0.24), respectively (p < 0.01). Conversely, the group with a low proportion of abnormal cases demonstrated the best specificity (0.83, SD = 0.10) compared with the groups with medium (0.70, SD = 0.15) and high (0.66, SD = 0.17) proportions of abnormal cases (p < 0.001). The group with a low proportion of abnormal cases had the highest false negative rate and missed fractures one-third more often than the groups that trained on higher proportions of abnormal cases. Conclusions Manipulating the ratio of abnormal to normal cases in learning banks can have important educational implications. [ABSTRACT FROM AUTHOR]

Abstract: In this proof-of-concept study we report the use of <15nm, water soluble, inorganic nanoparticles as a vaccine delivery system for a blood stage malaria vaccine. The recombinant malarial antigen, Merozoite Surface Protein 1 (rMSP1) of Plasmodium falciparum served as the model vaccine. The rMSP1 was covalently conjugated to polymer-coated quantum dot CdSe/ZnS nanoparticles (QDs) via surface carboxyl groups, forming rMSP1-QDs. Anti-MSP1 antibody responses induced by rMSP1-QDs were found to have 2–3log higher titers than those obtained with rMSP1 administered with the conventional adjuvants, Montanide ISA51 and CFA. Moreover, the immune responsiveness and the induction of parasite inhibitory antibodies were significantly superior in mice injected with rMSP1-QDs. The rMSP1-QDs delivered via intra-peritoneal (i.p.), intra-muscular (i.m.), and subcutaneous (s.c.) routes were equally efficacious. The high level of immunogenicity exhibited by the rMSP1-QDs was achieved without further addition of other adjuvant components. Bone marrow derived dendritic cells were shown to efficiently take up the nanoparticles leading to their activation and the expression/secretion of key cytokines, suggesting that this may be a mode of action for the enhanced immunogenicity. This study provides promising results for the use of water soluble, inorganic nanoparticles (<15nm) as potent vehicles/platforms to enhance the immunogenicity of polypeptide antigens in adjuvant-free immunizations. [Copyright &y& Elsevier]

The C-terminal 42 kDa fragments of the P. falciparum Merozoite Surface Protein 1, MSP1-42 is a leading malaria vaccine candidate. MSP1-33, the N-terminal processed fragment of MSP1-42, is rich in T cell epitopes and it is hypothesized that they enhance antibody response toward MSP1-19. Here, we gave in vivo evidence that T cell epitope regions of MSP1-33 provide functional help in inducing anti-MSP1-19 antibodies. Eleven truncated MSP1-33 segments were expressed in tandem with MSP1-19, and immunogenicity was evaluated in Swiss Webster mice and New Zealand White rabbits. Analyses of anti-MSP1- 19 antibody responses revealed striking differences in these segments' helper function despite that they all possess T cell epitopes. Only a few fragments induced a generalized response (100%) in outbred mice. These were comparable to or surpassed the responses observed with the full length MSP1-42. In rabbits, only a subset of truncated antigens induced potent parasite growth inhibitory antibodies. Notably, two constructs were more efficacious than MSP1-42, with one containing only conserved T cell epitopes. Moreover, another T cell epitope region induced high titers of non-inhibitory antibodies and they interfered with the inhibitory activities of anti-MSP1-42 antibodies. In mice, this region also induced a skewed TH2 cellular response. This is the first demonstration that T cell epitope regions of MSP1-33 positively or negatively influenced antibody responses. Differential recognition of these regions by humans may play critical roles in vaccine induced and/or natural immunity to MSP1-42. This study provides the rational basis to re-engineer more efficacious MSP1- 42 vaccines by selective inclusion and exclusion of MSP1-33 specific T cell epitopes. [ABSTRACT FROM AUTHOR]

Summary: Historically, the ribosome has been viewed as a complex ribozyme with constitutive rather than regulatory capacity in mRNA translation. Here we identify mutations of the Ribosomal Protein L38 (Rpl38) gene in mice exhibiting surprising tissue-specific patterning defects, including pronounced homeotic transformations of the axial skeleton. In Rpl38 mutant embryos, global protein synthesis is unchanged; however the translation of a select subset of Homeobox mRNAs is perturbed. Our data reveal that RPL38 facilitates 80S complex formation on these mRNAs as a regulatory component of the ribosome to confer transcript-specific translational control. We further show that Rpl38 expression is markedly enriched in regions of the embryo where loss-of-function phenotypes occur. Unexpectedly, a ribosomal protein (RP) expression screen reveals dynamic regulation of individual RPs within the vertebrate embryo. Collectively, these findings suggest that RP activity may be highly regulated to impart a new layer of specificity in the control of gene expression and mammalian development. PaperClip: Display Omitted [ABSTRACT FROM AUTHOR]

Background: In cosmetic and reconstructive breast surgery, measurement of patient-reported outcomes has become increasingly important to research efforts and clinical care. We aimed to describe how breast conditions and breast surgery impact on patient satisfaction and quality of life. Methods: We conducted qualitative, in-depth interviews with 48 women who had undergone either breast reduction (n = 15), breast augmentation (n = 12), or breast reconstruction (n = 21) surgery in order to begin to build a theoretical understanding of patient satisfaction and quality of life in breast surgery patients. Interviews were audio-taped, transcribed verbatim and analyzed thematically. Results: The patient interviews revealed that breast conditions and breast surgery impact women in the following six main areas: satisfaction with breasts; satisfaction with overall outcome; psychosocial well-being; sexual well-being; physical well-being; and satisfaction with the process of care. We used these six themes to form the basis of a conceptual framework of patient satisfaction and quality of life in women who undergo breast surgery. Conclusion: Our conceptual framework establishes the main issues of concern for breast surgery patients. This new framework can be used to help develop local guidelines for future clinical assessment, management and measurement, establish the validity of the current management strategies, and develop evidence-based guidance for the development of new patient reported outcome measures for future outcomes research. [ABSTRACT FROM AUTHOR]

The Myc oncogene regulates the expression of several components of the protein synthetic machinery, including ribosomal proteins, initiation factors of translation, RNA polymerase III and ribosomal DNA. Whether and how increasing the cellular protein synthesis capacity affects the multistep process leading to cancer remains to be addressed. Here we use ribosomal protein heterozygote mice as a genetic tool to restore increased protein synthesis in Eμ-Myc/+ transgenic mice to normal levels, and show that the oncogenic potential of Myc in this context is suppressed. Our findings demonstrate that the ability of Myc to increase protein synthesis directly augments cell size and is sufficient to accelerate cell cycle progression independently of known cell cycle targets transcriptionally regulated by Myc. In addition, when protein synthesis is restored to normal levels, Myc-overexpressing precancerous cells are more efficiently eliminated by programmed cell death. Our findings reveal a new mechanism that links increases in general protein synthesis rates downstream of an oncogenic signal to a specific molecular impairment in the modality of translation initiation used to regulate the expression of selective messenger RNAs. We show that an aberrant increase in cap-dependent translation downstream of Myc hyperactivation specifically impairs the translational switch to internal ribosomal entry site (IRES)-dependent translation that is required for accurate mitotic progression. Failure of this translational switch results in reduced mitotic-specific expression of the endogenous IRES-dependent form of Cdk11 (also known as Cdc2l and PITSLRE), which leads to cytokinesis defects and is associated with increased centrosome numbers and genome instability in Eμ-Myc/+ mice. When accurate translational control is re-established in Eμ-Myc/+ mice, genome instability is suppressed. Our findings demonstrate how perturbations in translational control provide a highly... [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this article was to examine historic institutional autologous stem cell mobilization practices and evaluate factors influencing mobilization failure and kinetics. In this retrospective study we analyzed clinical records of 1834 patients who underwent stem cell mobilization for autologous transplantation from November 1995 to October 2006 at the Washington University in St. Louis. Successful mobilization was defined as collection of ≥2 × 106 CD34+ cells/kg. From 1834 consecutive patients, 1040 met our inclusion criteria (502 non-Hodgkin''s lymphoma [NHL], 137 Hodgkin''s lymphoma, and 401 multiple myeloma [MM]). A total of 976 patients received granulocyte colony-stimulating factor (G-CSF) and 64 received G-CSF plus chemotherapy (G/C) for the initial mobilization. Although the median CD34+ cell yield was higher in G/C group than in G-CSF alone group, the failure rates were similar: 18.8% and 18.6%, respectively. Overall, 53% of patients collected ≥2 × 106 CD34+ cells/kg during the first apheresis with either mobilization regimen. Regardless of mobilization regimen used, MM patients had the highest total CD34+ cell yield and required less aphereses to collect ≥2 × 106 CD34+ cells/kg. Mobilized, preapheresis, peripheral blood CD34+ count correlated with first day apheresis yield (r = .877, P < .001) and 20 cells/μL was the minimum threshold needed for a successful day 1 collection. For the remobilization analysis we included patients from the whole database. A total of 269 of 1834 patients underwent remobilization using G/C, G-CSF, and/or GM-CSF, and G-CSF plus plerixafor. Only 23% of remobilized patients achieved ≥2 × 106 CD34+ cells/kg and 29.7% failed to pool sufficient number of stem cells from both collections. Patients receiving G-CSF plus plerixafor had lowest failure rates, P = .03. NHL patients remobilized with G-CSF who waited ≥25 days before remobilization had lower CD34+ cell yield than those who waited ≤16 days, P = .023. Current mobilization regimens are associated with a substantial failure rate irrespective of underlying disease. Patients who fail initial mobilization are more likely to fail remobilization. These findings suggest that there is a need for more effective first-line mobilization agents. [Copyright &y& Elsevier]

Skull-base tumor resection and reconstruction produce a major physiologic and anatomic impact on the patient. At our institution, the use of vascularized, free-tissue transfer has replaced pedicled flaps as the preferred modality for reconstructing complex cranial base defects involving resection of dura, brain, or multiple major structures adjacent to skull base, including the orbit, palate, mandible, skin, and other structures. The goals of reconstruction are to: (1) support the brain and orbit; (2) separate the CNS from the aerodigestive tract; (3) provide lining for the nasal cavity; (4) re-establish the nasal and oropharyngeal cavities; (5) provide volume to decrease dead space; and (6) restore the three-dimensional appearance of the face and head with bone and soft tissues. Surgical management requires a multidisciplinary effort with collaborating neurosurgical, head and neck, and plastic surgical teams. Successful reconstruction of skull base defects is predicated upon a careful appreciation of the specific region. Defects may be classified based on their anatomic location and loss of volume, support, and skin cover. Free flaps provide reliable, well-vascularized soft tissue to seal the dura, obliterate dead space, cover exposed cranial bone, and provide cutaneous coverage for skin or mucosa. [ABSTRACT FROM AUTHOR]

Aim: To determine the effect of implementing a clinical pathway, using evidence-based clinical practice guidelines, for the emergency care of children and adolescents with asthma. Methods: A prospective, before-after, controlled trial was conducted, which included patients aged 1-18 years who had acute exacerbations of asthma treated in a tertiary care paediatric emergency department. Data were collected for identical 2-month seasonal periods before and after implementation of the clinical pathway to determine hospitalisation rate and other outcomes. For 2 weeks after emergency visits, the rate at which patients returned to emergency care for worsening asthma was evaluated. A multidisciplinary panel, using national guidelines and a systematic review, developed the pathway. Results: 267 patients were studied. The rate of hospitalisation was significantly lower in the post- implementation group (10/74; 13.5%) than in the pre-implementation control group (53/193; 27.5%; p=0.02; number needed to treat 7.1). All reduction in hospitalisation occurred in children with moderate to severe asthma exacerbation. After implementation of the clinical pathway, the rate of administration of oral corticosteroids to patients with moderate or severe exacerbations increased from 71% to 92% (p = 0.01), and significantly more patients received 32-agonists in the first hour (p = 0.02). No significant change in relapse to acute care occurred within 2 weeks (p=0.19). Conclusions: An evidence-based clinical pathway for children and adolescents with moderate to severe exacerbations of acute asthma markedly decreases their rate of hospitalisation without increased return to emergency care. [ABSTRACT FROM AUTHOR]