The Joint Center for Structural Genomics high-throughput structural biology pipeline has delivered more than 1000 structures to the community over the past ten years and has made a significant contribution to the overall goal of the NIH Protein Structure Initiative (PSI) of expanding structural coverage of the protein universe. The Joint Center for Structural Genomics high-throughput structural biology pipeline has delivered more than 1000 structures to the community over the past ten years. The JCSG has made a significant contribution to the overall goal of the NIH Protein Structure Initiative (PSI) of expanding structural coverage of the protein universe, as well as making substantial inroads into structural coverage of an entire organism. Targets are processed through an extensive combination of bioinformatics and biophysical analyses to efficiently characterize and optimize each target prior to selection for structure determination. The pipeline uses parallel processing methods at almost every step in the process and can adapt to a wide range of protein targets from bacterial to human. The construction, expansion and optimization of the JCSG gene-to-structure pipeline over the years have resulted in many technological and methodological advances and developments. The vast number of targets and the enormous amounts of associated data processed through the multiple stages of the experimental pipeline required the development of variety of valuable resources that, wherever feasible, have been converted to free-access web-based tools and applications. Combined with genetic manipulation and engineering to facilitate heavy-atom integration into the target of interest, these developments greatly increased the range of proteins accessible to X-ray and NMR structure determination. Major technological improvements in X-ray crystallography have significantly increased the resolution, speed and quality of data collection and structure determination. These developments included improved crystallization screening methods that enhanced our ability to obtain and optimize protein crystals, cryocooling techniques to obtain better quality data from single crystals and increased brightness, stability, availability and ‘user-friendliness’ of synchrotron and other X-ray sources. Together, these advances greatly enhanced the quality of data collection and extended it to smaller and smaller crystals. In parallel, advances in the ‘dry lab’, such as continued development and improvement of crystallographic and bioinformatics software packages, have increased the speed, reliability and quality of structure determination. Although it was clear that significant progress was being made in structural biology, it still paled in comparison to the escalating numbers of new protein sequences that were being generated by the worldwide DNA-sequencing efforts, such as the human genome project.The landscape of structural biology has changed dramatically during the past decade. At the turn of this century, technological advances broadened the application of structural biology to a much larger audience by increasing the number and the complexity of specific biological problems that could be addressed. This evolution in molecular biology, which resulted from major improvements in cloning, protein expression in heterologous systems, such as 2.et al., 2001http://www.nigms.nih.gov/Initiatives/PSI/) played a decisive role in embracing this new challenge in a timely way. The main scientific goal put forth by the PSI was to determine atomic level structures of most proteins readily obtainable from knowledge of their corresponding DNA sequences. Thus, structural biologists were enabled to broaden their focus from studying biological molecules one at a time and to a wider exploration of the rapidly expanding protein-sequence universe, thereby addressing questions on a genome scale. This new view of structural biology was, therefore, called structural genomics and added new perspectives and directions to the field  protein-structure determination coincided with the dawn of the genomic era in biology. The enormous success of DNA-sequencing technology, followed by the development of other HT technologies, allowed biology to extend its molecular perspective to the level of entire organisms. These breakthroughs prompted global efforts into serious consideration of the feasibility of HT protein-structure determination, which included the establishment of pilot projects in the USA, Europe and Asia . The PSI-2 centers embraced the concept of broad structural coverage of protein-sequence space and vigorously pursued this goal by judicious and highly coordinated target selection that focused on selecting protein sequences that represented large families with little or no structural coverage and then leveraging the resulting experimental structures by homology modeling to cover other memebers of the protein family . The lessons gleaned from these efforts then enabled the assembly of high-throughput structural biology pipelines that developed into the Large-Scale Production (LSP) Centers in PSI-2 .During this period, the four LSP Centers expended the majority (70%) of their effort on these PSI Network targets. However, a significant effort (30%) was also committed to targets nominated by the broader research community and to specific biological/biomedical themes selected by each Center. As a result, the LSP Centers expanded and tailored their experimental and computational platforms to tackle a wide diversity of protein types and classes using a multitude of approaches, technologies and tools. They thereby identified a number of bottlenecks in the HT process for which solutions were achieved, thus opening new routes for solving the structures of many targets that had previously presented seemingly insurmountable obstacles. The six Specialized Centers in PSI-2 also continued the PSI tradition of developing innovative methods, approaches and technologies for protein production and structure determination of macromolecules and complexes that are considered to be highly challenging by the scientific community. The PSI Materials Repository (PSI-MR) and the PSI/Nature Structural Genomics Knowledgebase (PSI-SGKB), now called PSI-SBKB in PSI:Biology were established in the latter half of PSI-2 in order to gather the valuable products of the PSI Centers and make them available to the general scientific community, and two Modeling Centers were formed to complete the PSI Network . The majority of the targets for structure determination will be defined through consortium partnership proposals that are vetted by peer review through the NIH grant system and via an open on-going community nomination process administered through the PSI-SBKB. Additional targets will be defined through the individual biological and biomedical theme projects of the LSP centers.The PSI is now entering its third phase as PSI:Biology, where investigators will apply this new paradigm of high-throughput structure determination to study a broad range of challenging biological and biomedical problems (3.3.1.http://www.jcsg.org) was initiated in 1999 while the concepts of HT structural biology (HTSB) and structural genomics centers were still being formulated. At that time, most tasks associated with structure determination were highly labor-intensive, costly and could not be scaled to a genomic level without a substantial influx of resources and funding. The JCSG was established in 2000 as one of nine pilot centers under the auspices of the NIGMS PSI to evaluate the feasibility of assembling HT pipelines for protein-structure determination. The primary mission of the JCSG was to establish a robust and scalable HT structural biology pipeline and to assess its capability as a foundation for establishing production centers in PSI-2. The design, assembly and implementation of the JCSG pipeline was based on three scientific cores, each specializing in specific components of the gene-to-structure process: the BioInformatics Core , the Crystallomics Core  and the Structure Determination Core . The assembly of these pipelines came from developing integrated and innovative technologies, methods and robotic platforms to circumvent bottlenecks in traditional structural biology. Our pipeline concept used a multi-tiered target-processing strategy that efficiently incorporated the multiple steps from target selection to structure deposition  stands as a unique accomplishment of the JCSG in PSI-1. The wide diversity of TM targets processed through the pipeline established success rates for individual steps in the process and enabled us to more reliably predict the outcome for each stage , with the most pertinent information exported to TargetDB (http://targetdb.pdb.org). Finally, information on all experimental protocols is deposited in PepcDB (http://pepcdb.pdb.org), and TOPSAN  as defined by a less than 30% sequence identity of the JCSG structure to any other structure in the PDB at the time of deposition. The structures deposited range from bacterial to human proteins, although the vast majority are of bacterial origin, since these were the ones on which the pipeline was assembled and tested. The large numbers of targets and the enormous amounts of associated data collected and processed through the multiple stages of our experimental pipeline have resulted in the development of innovative methods and tools at critical stages in our gene-to-structure pipeline. These resources, where feasible, have been converted to free-access web-based tools and applications that include XtalPred  and Ligand Search . In particular, the JCSG maintains a crystallographic data-set repository that contains all files from all stages of the structure-solution process, including a full set of diffraction images for each of our deposited structures, enabling complete reconstruction of the data processing (http://www.jcsg.org/datasets-info.shtml). The repository has been used by numerous prominent crystallographic software developers to assist in testing new algorithms . The repository currently has 72 registered users, many of whom are students or postdocs who are keen to have access to data sets to advance their knowledge of X-ray crystallography. The repository is freely available to the scientific community and will be maintained and extended in PSI:Biology. We understand that such resources are of high value to the general scientific community and we welcome any feedback and comments on how to improve their utility.This special JCSG issue of et al., 2008As we move forward, the goal is to continue to push the limits of what can be accomplished in structural biology and to ensure that the methods, technologies and automation that have been and are being developed are transferable to individual laboratories (Gräslund


Cancer is a leading cause of death worldwide: it accounted for 7.9 million deaths  in 2007. Tobacco use is the single most important risk factor for cancer, especially lung cancer. Lung cancer accounts for 1.4 million deaths per year, making it the number one cancer killer in both men and women worldwide.In 2002 lung and bronchial cancer were the third leading cause of death in men and the tenth leading cause of death in women in Saudi Arabia. Since 19Recent European studies have shown that variations in lung cancer care can negatively impact survival in a population. These stThere is an ever-expanding body of knowledge in medicine. It is difficult, if not impossible, for the individual practicing physician to master this body of knowledge by himself or herself. Cancer guidelines assist the physician in assimilating and evaluating the evidence for the current best practice in the care of the lung cancer patient and in implementing it in their clinical practice.The process involved in guideline development has steadily advanced and now embraces more rigorous evidence standards, multidisciplinary participation, and a patient-centered approach. These advances have been incorporated into these lung cancer management guidelines.While the American College of Chest Physician, National Comprehensive Cancer Center, and other lung cancer guidelines exist, regional guidelines better take into account the region-specific epidemiology, the available technologies , and the therapeutic options available in the region. Regional guidelines also take into consideration the financial and resource limitations and the social values of the society in which the guidelines are implemented.The lung cancer guidelines that appear as a supplement to this issue of the journal were developed by internationally trained physicians from various medical and surgical disciplines working in the field of thoracic oncology at leading medical institutions in the Kingdom of Saudi Arabia. The committee members also represent the Saudi Oncology Society and the Saudi Thoracic Society.The evidence in these guidelines is rated at three levels. EL-1 (highest level) evidence involves data from phase 3 randomized trials or meta-analyses. EL-2 (intermediate-level) evidence is based on good phase 2 trials or phase 3 trials with limitations. EL-3 (low-level) evidence is based on retrospective or observational data and/or expert opinion. This easy-to-follow grading system allows the reader to accurately assess the applicability of the guideline in individual patients.This evidence-based guideline is a comprehensive overview and covers the epidemiology, radiographic workup, pathology specimen handling and reporting, staging (including discussion of the changes coming with the seventh edition of the staging system), initial evaluation, surgical management, radiation therapy, and systemic therapy for lung cancer patients.The lung cancer management guidelines are stage specific and easy to follow and incorporate the current state of the art in the treatment of lung cancer patients. The guidelines are supported by well-written and well-researched manuscripts.The lung cancer management guidelines are also concise and practical and, at two pages, could easily be posted in areas of care to facilitate their implementation and assure best practices. These lung cancer guidelines will result in further improvements in the treatment and outcomes of lung cancer patients in the Kingdom of Saudi Arabia.


Evidence based medicine (EBM) is considered an integral part of medical training, but integration of teaching various EBM steps in everyday clinical practice is uncommon. Currently EBM is predominantly taught through theoretical courses, workshops and e-learning. However, clinical teachers lack confidence in teaching EBM in workplace and are often unsure of the existing opportunities for teaching EBM in the clinical setting. There is a need for continuing professional development (CPD) courses that train clinical trainers to teach EBM through on-the-job training by demonstration of applied EBM real time in clinical practice. We developed such a course to encourage clinically relevant teaching of EBM in post-graduate education in various clinical environments.We devised an e-learning course targeting trainers with EBM knowledge to impart educational methods needed to teach application of EBM teaching in commonly used clinical settings. The curriculum development group comprised experienced EBM teachers, clinical epidemiologists, clinicians and educationalists from institutions in seven European countries. The e-learning sessions were designed to allow participants (teachers) to undertake the course in the workplace during short breaks within clinical activities. An independent European steering committee provided input into the process.The curriculum defined specific learning objectives for teaching EBM by exploiting educational opportunities in six different clinical settings. The e-modules incorporated video clips that demonstrate practical and effective methods of EBM teaching in everyday clinical practice. The course encouraged focussed teaching activities embedded within a trainer's personal learning plan and documentation in a CPD portfolio for reflection.This curriculum will help senior clinicians to identify and make the best use of available opportunities in everyday practice in clinical situations to teach various steps of EBM and demonstrate their applicability to clinical practice. Once fully implemented, the ultimate outcome of this pilot project will be a European qualification in teaching EBM, which will be used by doctors, hospitals, professional bodies responsible for postgraduate qualifications and continuing medical education. Evidence-based medicine (EBM) is considered to be the most ethical way to practice medicine as it integrates research into clinical practice. It has evolved into a powerful tool for well informed decision-making within the clinician's daily practice. The challenge is to teach it practically in a clinical setting -4. Unleslearners of EBM . Ou. Ou13]. Teaching opportunities during clinical encounters were taught through two modules focussing on ward rounds and outpatient clinics . These tOpportunities to teach EBM during clinical meetings were covered in three modules using Journal club, Morbidity and Mortality meetings, and Audit presentations ,20,21. TClinical assessment of trainees are ideal opportunities for the teacher to provide formative or summative assessment of EBM competence and for giving feedback on their performance ,22. Thes, USB or CD-ROM. In addition to the above methods, we aim to provide access through video podcasts and social websites like Face book. Furthermore it will enable busy clinicians to access the course both inside and outside the hospital, target a wider audience and promote dissemination. The e-modules integrate a combination of teaching methods  for the trainer to learn integration of EBM teaching in clinical practice by working through the modules in a setting and time of their choice. To our knowledge at the moment such a curriculum aimed at this target population does not exist. By showing the teaching opportunities in various clinical settings encountered by any healthcare professional in day-to-day practice, it is highly Relevant (R) to this group of individuals. The curriculum is Individualised (I) with flexibility to apply the principles of teaching in various clinical settings, medical disciplines and countries. Where possible every effort has been made to ensure that the variations in healthcare system across the EU countries are taken into account during the curriculum development. At the end of modules, there is the prospect of Self-assessment (S) of the participants to evaluate their knowledge and competency in teaching EBM. The assessment tools have been developed and validated and has been piloted in the partner countries. Use of short segments of slides combined with video clip recordings of the actual EBM teaching in various clinical set up is aimed at arousing the Interest (I) of the learner. By highlighting the differences in clinical practice, teaching techniques, available resources and educational culture we have attempted to Speculate (S) on difficult and controversial areas of the course. The entire e-curriculum is devised in such a way that the learning process is Systematic (S) with specific aims, learning objectives, content and summary for each module.The e-curriculum for trainers satisfies the CRISIS criteria for successful CPD . It is dThe use of the curriculum may be limited by the differences in clinical settings, EBM knowledge, resources and attitudes in various institutions and countries. The examples provided in the modules are limited to articles on therapy. With increasing use of the modules in various countries will help in further development with necessary adaptations as required.The goal of this project is to help clinical trainers identify opportunities to teach trainees integration of EBM, provide them with tips to perform this in various clinical settings and to rCurrently in this project we have covered ways to teach EBM in six clinical settings. Furthermore to complement our previous project on EBM curriculum, we have provided examples using systematic reviews of therapy. We are translating the course in six languages. In the future, we plan to increase the number of modules to cover other clinical settings not currently included, provide examples using diagnostic and prognostic studies and make the curriculum relevant to healthcare professionals other than doctors.The EU EBM Training the Trainers curriculum will help senior clinicians to identify and make the best use of available opportunities in everyday practice in clinical situations to teach various steps of EBM and demonstrate their applicability to clinical practice. Complete application of this pilot project aimed at teachers of EBM will be a European qualification in teaching EBM, which will be used by senior doctors, hospitals and professional bodies responsible for postgraduate qualifications and continuing medical education. The EU EBM Training the Trainers project will lead the way in bringing about teaching EBM closer to everyday clinical practice with the prospect of improving patient care.The authors declare that they have no competing interests.ST, KSK and TNA drafted the first version of the manuscript. GZ developed the website. RK, BWM, KO, KS, JW, AK, SW, BM, GB, HG and ARH revised the manuscript and approved final submission for publication. All authors are members of the EU-EBM and were involved in the design, development and implementation of the course described.To provide guidance on practical and effective methods to teach clinically integrated evidence based medicine (EBM) in various clinical settingsSenior health professionals in a clinical setting with responsibility for teaching and training.Upon completion of the course participants should be confidently able to identify and use learning opportunities in a clinical setting to provide on-the-job training to trainees by- exposing knowledge gaps in the trainees that leads to construction of structured question- seeking information from trainees on how they will track the best evidence to answer the question- developing confidence in number crunching to interpret the results- effectively using various clinical opportunities to teach critical appraisal of literature- demonstrating how clinical judgement is used to determine the extent to which research evidence can be applied for individual patient care- enabling trainees to present and discuss in formal clinical meetings by applying the steps of EBMParticipants to pursue independent study by using the following e-learning modules to obtain CPD or continuing medical education (CME) creditsE-learning modules with demonstration videos• Module 1: Ward Rounds• Module 2: Journal Club• Module 3: Clinical assessment• Module 4: Outpatients Clinic• Module 5: Formal Clinical Meeting• Module 6: AuditQuestionnaire and log of teaching activities in a personal learning planThe pre-publication history for this paper can be accessed here:


In established cases of multicentricity, the histopathology has to be properly reviewed and the patient has to be followed up for a longer time with serial whole body assessment to pick up any subsquent lesions. The treatment of the local disease does not differ from a standard GCT.Multicentric giant cell tumour (GCT) is extremely rare; no case has been previously reported where two lesions occurred in the same foot at different sites. We report a case involving the calcaneus and subsequently the 3 Giant cell tumor (GCT) of bone is a benign aggressive tumor with features of frequent local recurrences and potential for metastasis and malignant transformation.2413A 22-year-old female patient presented in March 2001 with complaints of pain and swelling in the right heel of six months duration. Physical examination revealed a tender, medially prominent bony hard swelling in the hind foot, appearing to arise from the calcaneum. Radiographs showed an expansile osteolytic lesion in the body of the calcaneum with intact articular surface and thinned out surrounding cortex . A CT scFollow-up was uneventful for 18 months; she then started complaining of pain in the same (right) forefoot at the base of the third toe. Examination revealed swelling and tenderness around the base of the third toe; X-rays showed an osteolytic lesion in the proximal phalanx of the third toe . Serum bGCT of the foot in itself is a rare occurrence.et al[16103612MCGCT, when compared to solitary GCT, is encountered more frequently in the short bones of the hand and feet; nevertheless the knee is still the most common site.3610et al in theirl16103612.MCGCT tends to involve the younger population compared to solitary GCT, with mean age reported between 20-24 years.610210124de novo multi-focal formation. Synchronous tumors are lesions arising from different locations and are discovered within a short period of time or simultaneously.[1116616610et al in their review of literature opined that most of the MCGCTs are synchronous, occurring within a poorly defined time of the initial tumor presentation.Controversy regarding pathogenesis of MCGCT exists to date. Various mechanisms101215 ha1012aneously.111617 Meusly.1116–21 The iy.1116616 Most of Since MCGCT occurs in less than 1% of GCT, regular screening of GCT patients for multicentricity may not be cost-effective.7 Half-yeThe present case is presented for its rarity, as GCT in the foot is unusual in the first place, while MCGCT isolated to the foot has never been reported. It is hoped that the level of awareness of the average orthopedic surgeon would be increased by this report.


The review presents pediatric adverse drug events from a historical perspective and focuses on selected safety issues associated with off-label use of medications for the psychiatric treatment of youth. Clinical monitoring procedures for major psychotropic drug classes are reviewed. Prior studies suggest that systematic treatment monitoring is warranted so as to both minimize risk of unexpected adverse events and exposures to ineffective treatments. Clinical trials to establish the efficacy and safety of drugs currently being used off-label in the pediatric population are needed. In the meantime, clinicians should consider the existing evidence-base for these drugs and institute close clinical monitoring. Most medications are approved for marketing based on favorable benefit to risk assessments from clinical trial data in adults. Pediatric medical practice has been primarily off-label, i.e., permissible even though the drug was not specified for this age group, or indication in the product label approved by the Food and Drug Administration (FDA) . Off-labA Medline search since 1990 and a review of clinical textbooks in Pediatrics , PharmacOff-label pediatric drug use has been based primarily on extrapolation of efficacy, dosing, administration and side effect profiles from adult studies. For treatments specific to youth, particularly to the neonate, the evidence is most often based on anecdote, case reports or open studies of clinical experience. Yet, the history of pediatric pharmacology is rich with examples illustrating that newly marketed drugs off-label for youth may have incomplete adverse event profiles that require widespread community utilization in such populations before uncommon or rare serious adverse events are known . This drThe use of oxygen therapy to improve breathing for babies in incubators was a widely accepted treatment as far back as the 1930s. In the 1940s, increases in dosage and length of exposure of oxygen were gradually accepted without safety research. The incidence of retrolental fibroplasia suddenly increased, followed by considerable debate in the literature over the suggestion that prematurity itself was responsible for the condition. Epidemiological data suggested that the increase in retrolental fibroplasia's adverse event rates following oxygen use varied by locale and practice . Yet it The late '40s saw the introduction of chloramphenicol, an important new antibiotic with the promise of effectiveness in serious infections not controlled by available drugs. Within a decade, however, increased use resulted in the development of 'grey baby' syndrome in many of the infants so treated. This devastating and lethal illness of neonates, occurred due to inadequate enzymes to metabolize the drug to the glucuronide salt and then on insufficient renal filtration rate for excretion .Recently marketed products also pose safety concerns for children. For example, propofol, a sedative-hypnotic, was marketed in 1989 in the U.S. and used for pre-anesthesia induction. Trial data in children from 1988 showed it had a 9% mortality rate in critically ill patients with upper respiratory tract infections compared with 4% for standard sedatives, but causality was not established . Since tPediatric drug safety issues might be viewed narrowly as simply the consequence of immature enzyme systems in the neonate. But the history of pharmacology proves this assumption wrong – elementary school age children can also be at increased risk of adverse events  and can Phenobarbital was introduced as an antiepileptic more than 90 years ago. Currently, its long-term use in children and adolescents is rarely justified because it is now known to increase the risk of adverse cognitive and behavioral events . These ePromethazine is a phenothiazine type antihistamine used in over-the-counter cough and cold products for the treatment of allergic symptoms. FDA's recent Public Health Advisory recommends avoiding use in children less than 2 years of age because of reports of serious and potentially life-threatening respiratory depression . This reboth pediatricians and child psychiatrists  follow appropriate standards of practice; 3) the absence of objective markers of emotional and behavioral conditions which can limit solid decision-making on the use of psychotropic medications; and 4) the need for close clinical monitoring and the engagement of parents and caregivers in such activities. The recent actions of the FDA and other regulatory bodies regarding antidepressant medication use in children make this need all the more salient.This brief historical review of serious pitfalls in pediatric drug safety suggests the need for reassessing and updating the level of confidence required for prescribed drug use in children. This is true for general medical conditions, but is particularly true for the treatment of emotional and behavioral disorders. The reasons behind this specific emphasis include: 1) the rapid, expanded use of many drugs for psychotherapeutic purposes, both singly and in combination ,26; 2) tThe use of pemoline illustrates the challenges of drug safety for youth. While early evidence of hepatotoxicity in adults was recognized, the relatively low use in children meant that a long (unexamined) safety experience would accrue before a more definitive risk was recognized. After 21 years of modest usage in the treatment of attention-deficit/hyperactivity disorder (ADHD), liver toxicity including fatalities in youth were significantly associated . WarningThe psychotropic treatment of youth has expanded substantially since 1990, a relatively short time period from a population-based safety perspective . In addiChanges in anticonvulsant pediatric usage in the past decade are largely attributed to their increased use for psychotherapeutic purposes, specifically as mood stabilizers . FortunaTable all 3 classes of antidepressants, namely SSRIs, tricyclic antidepressants (TCAs) and Other antidepressants [Of the SSRIs, only fluoxetine has been shown to be effective for the treatment of depression in children and adolescents ,38. Howeressants .Other adverse events are more common with antidepressants and may be useful in identifying who is at risk for suicidal thoughts or attempts. For example, activation was highlighted in the Hammad meta-analysis in association with suicidal ideation or behavior . UnfortuThe growing use of concomitant psychotropics in U.S. children ,48 raiseMost European country health care systems are substantially different than that of the U.S. European health insurance and access to care is usually available for nearly everyone either in state run systems or by state regulated health insurance companies. Despite this high standard for provision of care, many aspects of drug treatment safety are still neglected. Collecting safety information from health insurance data and networks to monitor and report adverse events could be easily regulated and implemented on a national level but still these initiatives rely on the activities of different insurance companies as shown in a recent report of the Gmünder Ersatzkasse, a statutory insurance company in Germany .At the European Union level, The European Agency for the Evaluation of Medicinal Products (EMEA) is responsible for the implementation of the European Risk Management Strategy (ERMS) . This stAt the country level, in German adult psychiatry a therapeutic drug monitoring network (TDM) was established -54. SuppIn cases of inpatient treatment with psychotropic drugs, the German insurance companies pay for therapeutic drug monitoring as a measure of quality assurance in the field of pediatric psychopharmacology. In the Future the TDM model might be extended to large U.S practices using simplified validated adverse drug event monitoring. For example, in The Child and Adolescent Psychiatry Trials Network (CAPTN), the practice-based research network in child psychiatry, the pilot study of Pediatric Adverse Events Rating Scale (PAERS)  could beAt the most global level, the World Health Organization (WHO) promotes an international drug monitoring program which started operating in 1968. Currently, 86 countries participate in that program. Reported cases are forwarded from national pharmacovigilance centers to the WHO collaborating center for international drug monitoring in Uppsala Sweden. The case reports are stored in the Adverse Drug Reaction (ADR) database of the WHO which is the most comprehensive source of international ADR information. This time-honored system notwithstanding, there are significant challenges to improve the probability of finding serious and rare events in youth and to rule out long-term adverse effects on development. The encouraging signs of renewed efforts in the European Union collaborations are further aided by the advent of powerful computing systems and suggest that psychopharmacologic drug safety in children is progressing.before introducing psychotropic medications, whether utilized for labeled or off-label uses [A comprehensive assessment of health status (rating of symptoms and impairment) should be conducted bel uses . A comprThe rationale for drug class-specific monitoring includes the following:® is substantial with as much as half of U.S. stimulant use in youth now representing exposure to amphetamine salts rather than to methylphenidate. Consequently, recent concerns about cardiac risks from FDA analysis of MedWatch data sparked controversy [• Amphetamines. The growth in use of amphetamines since the marketing of Adderalltroversy  and Canatroversy . Until ttroversy .• Alpha-Agonists. Clonidine and guanfacine were approved for adult treatment of hypertension. Since 1987, these drugs have been used off-label in pediatrics for the treatment of ADHD, to reduce stimulant rebound and induce sleep. Baseline evidence of cardiovascular health status is useful to permit adverse symptoms following drug initiation to be linked to the medication  and to a∘ Divalproex and Valproic Acid. Valproate treatment initiated in women before the age of 20 had significantly increased risk of polycystic ovaries . In addi∘ Lamotrigine has been reported to have a higher risk of rash in children than adults . Trial d∘ SSRI suicidality  was noted in an average of 4% of of children and adolescents treated with antidepressants in clinical trials reviewed by regulatory agencies ; other p∘ TCA Dose-dependent cardiac conduction delays; asystole in high dose .∘ Bupropion. The risk of dose-dependent seizures may suggest use of an alternative antidepressant to treat youth with a history of seizure disorder or bulimia.• Atypical Antipsychotics. Relatively greater weight gain develops in youth than in adults  so that • Lithium has a narrow therapeutic range which emphasizes the importance of educating parents and youth as to the need for adequate hydration and risks of exposure to situations where excessive sweating may occur , or if the child experiences significant diarrhea, in order to avoid toxicity. Baseline and repeat assessment of thyroid function as well as kidney function during use is recommended . Laborat∘ Desmopressin. Recently, an FDA alert warned of severe hyponatremia and seizures in children treated with intranasal formulations of desmopressin (DDAVP) for primary nocturnal enuresis. The nasal product is no longer indicated for primary nocturnal enuresis and oral formulations should not be used during acute illnesses which may lead to fluid and/or electrolyte imbalance .After initiating drug therapy, safety assessments at regular intervals are useful to observe the ongoing impact of medication use Table . Column School performance and social development are measures of the effectiveness of treatment on overall functioning, and the patient's or parent's report of adherence is vital to this assessment and may in part reflect the level of satisfaction. When cognitive or emotional symptoms show a lack of improvement or deterioration, an assessment of the temporal pattern of drug usage, dosage change and potential drug-drug interactions can assist in establishing whether behavioral toxicity, i.e. iatrogenic psychiatric symptoms, is a likely explanation. This could lead to the need for discontinuation of the psychotropic medication responsible for behavioral adverse events.This selective review of pediatric medical and psychiatric drug usage illustrates the role of clinical monitoring as a routine aspect of post-marketing surveillance. Distinctions between off-label and labeled indications indicate that the majority of pediatric psychotropic use is off-label and supports close monitoring to assure adequate safety. Until all drugs are properly studied in the populations for which they are being used, it will be necessary for practitioners to prescribe off-label drugs. Additionally, it is sometimes necessary to utilize products that have uncertain efficacy and unresolved safety questions, even when such issues raise serious ethical and clinical considerations. The particular medical circumstances will dictate what clinical criteria and monitoring are most appropriate. An adequate diagnostic assessment and the establishment of sound baseline data are always mandatory. In addition, particular attention must be paid to the ethical considerations generated by clinical decisions to use off-label treatments, particularly where the evidence of efficacy is weak or anecdotal, and safety signals are unresolved. We believe the 1979 Belmont Report on ethical guidelines for the protection of human subjects of biomedical and behavioral research with its associated principles could provide an ethical framework for off-label usage in children in clinical practice . ExaminiThis historical review presented examples of serious pediatric drug safety problems in the post-marketing phase of utilization and identified off-label psychiatric use. As a broad survey of pediatric psychiatric pharmacotherapy, it provides evidence to support changes in the way we monitor newly approved or off-label drugs for emotional and behavioral conditions in youth. Since there is less certainty about the outcome of these medications in children and adolescents (particularly in concomitant drug regimens), close clinical monitoring is critical to detect adverse physical and mental changes as well as to ascertain if there is ongoing reduction of symptoms and improved functioning. This approach would minimize ineffective treatments that expose youth to drugs of uncertain or unknown risks.JMZ, ATD, CJK, and LLG contributed to the conception and design; JMZ, ATD, DJS, CJK, JMF were involved in drafting, revising and interpreting the review. All authors read and approved the version to be published.


We describe a case of rare complication of typhoid fever in a seven-year-old child and review the literature with regard to other rare causes of bleeding per rectum. Dieulafoy's lesion is an uncommon but important cause of recurrent gastrointestinal bleeding. Dieulafoy's lesion located extragastrically is rare. We report a case of typhoid ulcer with Dieulafoy's lesion of the ileum causing severe life-threatening bleeding and discuss the management of this extremely uncommon entity.As a complication of typhoid fever, a seven-year-old Kurdish girl from Northern Iraq developed massive fresh bleeding per rectum. During colonoscopy and laparotomy, she was discovered to have multiple bleeding ulcers within the Dieulafoy's lesion in the terminal ileum and ileocecal region.Although there is no practical way of predicting the occurrence of such rare complications, we emphasize in this case report the wide array of pathologies that can result from typhoid fever. Salmonella enterica, including S. enterica serotype Typhi (S. typhi) and serotype Paratyphi (S. paratyphi). Enteric fever is a faecal-oral transmissible disease and thus occurs in an environment with overcrowding, poor sanitation and untreated water . MUlcerations generally occur in the terminal ileum, cecum and the ascending colon, and rarely in the left side of the colon . DieulafHistologically, a thick-walled arterial vessel is seen. This is larger than the surrounding submucosal vessels and runs below the muscularis mucosae. A similar appearance has been reported throughout the gastrointestinal tract. Although the pathogenesis is unclear, the lesion is believed to be congenital in origin. Endoscopic diagnosis of extragastric Dieulafoy's lesion can be difficult because of its small size and obscure location. Increased awareness and careful and early endoscopic evaluation following the bleeding episode are the key to accurate diagnosis . In a laExtragastric DLs are uncommon. In a review of over 100 cases of DLs, Veldhuyzen found no lesion of the duodenum . SimilarThe duodenum was the most common location 18%) of extragastric DLs, followed by the colon (10%), jejunum (2%) and the esophagus (2%) % of extr.The endoscopic criteria proposed to define DL are: 1) active arterial spurting or micropulsatile streaming from a minute mucosal defect or through normal surrounding mucosa; 2) visualization of a protruding vessel with or without active bleeding within a minute mucosal defect or through normal surrounding mucosa; and 3) fresh, densely adherent clot with a narrow point of attachment to a minute mucosal defect or to normal appearing mucosa .Meanwhile, several surgical options are used in the management of patients with lower intestinal bleeding: 1) emergency limited segmental resection for a known bleeding source in continued severe bleeding ; 2) elective segmental resection for a known bleeding source such as adenocarcinoma of the colon or for rebleeding from a known lesion such as a colon diverticulum; 3) emergency segmental colon resection for an unknown bleeding source ; and 4) emergency total abdominal colectomy with ileorectal anastomosis  for an unknown bleeding location.Several criteria have been used to recommend surgery for patients with acute lower intestinal bleeding. Transfusion requirements of >4 units during 24 hours and before 10 units overall have been used as indicators for surgical intervention. These data support the importance of pursuing an aggressive approach to pre-operative localization of the bleeding source.Written informed consent was obtained from the parents/guardian of our patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.The authors declare that they have no competing interests.RFE collected, analyzed and interpreted our patient's data, and assisted in the endoscopy and performed the surgery of our patient. HH performed the endoscopy and assisted in interpreting our patient's data. TSB performed the histological examination of the surgical specimen and assisted in interpreting our patient's data. ATR assisted in the operation and in analyzing our patient's data. KMA received our patient and assisted in collecting our patient's data. All authors read and approved the final manuscript.


Most cases of caudal regression are sporadic or associated with gestational/maternal diabetes. The condition is thought to be part of a spectrum including imperforate anus, sacral agenesis and sirenomelia. Infants of diabetic mothers have two to three times the average incidence of congenital anomalies.We report on a 7-year-old boy from non-consanguineous family in Austria was born with features of caudal regression syndrome. A constellation of malformation complex such as caudal regression syndrome and anorectal malformation complex were evident at birth. Of great interest was the abnormal articulation between the pelvis and the remaining abnormal spine. Spinal-pelvic instability, dislocation of the hip, and knee-flexion contracture associated with popliteal webbing were the major orthopaedic abnormalities.We showed that an offspring of a diabetic mother was at significant risk of developing caudal regression syndrome. Our present patient demonstrated type1 of Welch and Aterman classification. There was total sacral agenesis associated with subtotal lumbar agenesis. The lowest vertebrae were resting above an iliac amphiathrosis. We strongly encourage primary care providers to discuss the consequences of maternal diabetes mellitus as part of routine anticipatory guidance for antenatal/prenatal management. Careful diabetic control in the preconceptional period and the first eight weeks of pregnancy may lower the chances of congenital anomalies. Caudal regression syndrome and caudal dysgenesis syndrome are broad terms that refer to a heterogenous constellation of congenital caudal anomalies affecting the caudal spine and spinal cord, the hindgut, the urogenital system, and the lower limbs. About 15–25% of mothers of children with caudal regression syndrome have insulin-dependant diabetes mellitus [The boy was referred to the orthopaedic department at the age of 3 years fig . A loop Caudal regression syndrome was first proposed by Duhamel , based oIt has been known that diabetes-antedating pregnancy can have severe adverse effects on fetal and neonatal outcomes. As early as in the 1940s, it was recognized that women who developed diabetes years after pregnancy had experienced abnormally high fetal and neonatal mortality. The basic pathognomonic features in our current patient were total sacral and partial lumbar spine agenesis in connection with maternal diabetes mellitus. Prenatal diagnosis by ultrasound is possible at 22 weeks of gestation, seen as sudden interruption of the spine due to absence of vertebrae and a frog-like position of the lower limbs. In a recent case report, CRS was diagnosed antenatally after detection of a large nuchal translucency, although the diagnosis was not confirmed until 16 weeks CRS: Caudal regression syndrome; HLXB9 gene: homeobox gene.Written informed consent was obtained from the parents for the purpose of publication of the manuscript and figures of their child. A copy of the written consent is available for review by the editor-in-Chief of this journal.The authors declare that they have no competing interests.All of the authors were involved in the clinico-radiographic assessment and finalising the paper. All authors have red and approved the final version of the paper.


Little is known about the impact of implementing nursing-oriented best practice guidelines on the delivery of patient care in either hospital or community settings.A naturalistic study with a prospective, before and after design documented the implementation of six newly developed nursing best practice guidelines , foot complications in diabetes, smoking cessation and venous leg ulcers). Eleven health care organisations were selected for a one-year project. At each site, clinical resource nurses (CRNs) worked with managers and a multidisciplinary steering committee to conduct an environmental scan and develop an action plan of activities . Process and patient outcomes were assessed by chart audit . Outcomes were also assessed for four of six topics by in-hospital/home interviews  and follow-up telephone interviews . Interviews were conducted with 83/95 (87%) CRN's, nurses and administrators to describe recommendations selected, strategies used and participants' perceived facilitators and barriers to guideline implementation.While statistically significant improvements in 5% to 83% of indicators were observed in each organization, more than 80% of indicators for breastfeeding, DDD and smoking cessation did not change. Statistically significant improvements were found in > 50% of indicators for asthma (52%), diabetes foot care (83%) and venous leg ulcers (60%). Organizations with > 50% improvements reported two unique implementation strategies which included hands-on skill practice sessions for nurses and the development of new patient education materials. Key facilitators for all organizations included education sessions as well as support from champions and managers while key barriers were lack of time, workload pressure and staff resistance.Implementation of nursing best practice guidelines can result in improved practice and patient outcomes across diverse settings yet many indicators remained unchanged. Mobilization of the nursing workforce to actively implement guidelines and to monitor the delivery of their care is important so that patients may learn about and receive recommended healthcare. The gap between research evidence and clinical practice is one of the most persistent problems in the provision of quality health care. Approximately 30 to 40% of patients do not receive health care according to current scientific evidence and some patients receive unnecessary or harmful care ,2. In prOne might question whether or not discipline-specific guidelines are required. We take the position that while health care is delivered to patients from a multidisciplinary perspective, the responsibilities of each team member need to be informed by the best available research evidence and some of this evidence is discipline-specific. The nursing profession represents a large proportion of health care providers and a potential workforce to address gaps in the provision of recommended health care.The effectiveness of guideline implementation in nursing and allied health professions has received relatively little research attention. A Cochrane review summarized the results of 18 intervention studies of which 13 included physicians and nurses, and only 4 specifically targeted nurses . The autIn contrast, there is a considerable body of physician-oriented and multi-disciplinary research with 235 studies reviewed by Grimshaw and colleagues (2004) of the effectiveness and costs of guideline development, dissemination and implementation strategies . PhysiciIn nursing, there are few empirical studies about the quality of care and it is crucial to examine the interrelationships between evidence-based nursing care processes and outcomes . A stateIn summary, there is a very limited evidence base for either the design of nursing guideline implementation interventions or for measuring the process and outcome of nursing care. An opportunity arose with the production of new nursing guidelines for a naturalistic study that examined implementation of various guidelines across settings to provide insights which are often absent from other studies where the protocol is tightly prescribed, only one guideline is implemented and it is implemented across homogeneous settings. The context for the study is described below.For the past seven years, the Registered Nurses' Association of Ontario (RNAO) in Canada has been leading the development and implementation of nursing best practice guidelines funded by the provincial government. Priority topics are selected using focus groups, surveys and an open web-based invitation to nurses. An expert panel is convened for each topic with representatives from different health care sectors , and responsibilities . Guidelines undergo extensive review by multidisciplinary stakeholders. Further details about the methodology for guideline development are described elsewhere ,14. To dWe report on the real-time implementation of six guidelines during 2002–2004: asthma, breastfeeding, delirium-dementia-depression (DDD), foot complications in diabetes, smoking cessation and venous leg ulcers . SpecifiA one-year prospective before and after implementation project was conducted with three months allotted for the baseline data collection, six months for implementation and three months for the follow-up data collection. The one-year time-frame was determined by the requirements of the government contract funding. The approach used was to evaluate guideline implementation as it naturally occurred in clinical settings. Ethics approval was received from the University of Ottawa Health and Social Sciences Ethics Review Board and from participating organizations. Following a call for proposals and a peer review process, eleven health care organisations were selected to implement one of the six guidelines. Organizations selected included four acute care teaching hospitals, two community hospitals, one chronic care hospital, one mental health teaching hospital, two home visiting nursing agencies and one regional public health unit. Sites began implementation of four topics in 2002  and two topics in 2003 .Each site committed in-kind resources including at least 10% of an administrator's time and paid educational time for nurses. Project funding supported the release of one full-time equivalent clinical resource nurse (CRN) for a year which included the implementation as well as the pre-implementation and post-implementation data collection. Some organizations elected to allocate this funding to more than one CRN as described in Table Initial workshops coordinated by the RNAO were held with three to five key stakeholders from each site . Leaders from each guideline development panel gave structured presentations about the guideline recommendations with the supporting research evidence. A Toolkit ,18 with At each organization, a multidisciplinary steering committee reviewed the Toolkit and planned the implementation of the selected guideline in their setting. As recommended in the Toolkit, an environmental assessment of barriers and facilitators was undertaken, stakeholders were identified and specific implementation strategies were identified in a written action plan. Paid education sessions range 2–9 hours) were provided by the CRNs for nurses and other health care providers. These sessions were interactive, incorporated problem solving, case studies and skill practice sessions. Table –9 hours In order to select key outcomes, a rapid three-way consultation occurred with the leader of the specific guideline development panel, decision-makers from each implementation site and a member of the research team. Criteria guiding final selection of outcomes included: outcomes with the strongest research evidence, outcomes feasible to measure in a short time frame, and outcomes relevant to priorities at participating organizations. Chart abstraction forms were adapted from tools used in previous research when available -27 and aConsecutive patient charts that met the inclusion/exclusion criteria were audited pre- and post-implementation. In addition, for one topic (asthma), patient techniques for use of medication inhaler device were observed . In fourPatient eligibility criteria were defined for each guideline Table . Our goaThe data collection process was supervised centrally by an experienced Project Manager who frequently communicated with the CRNs to maintain the quality of data collection. The CRNs extracted pilot data from five to 10 charts at each organization to develop an effective system for obtaining charts and to assess the feasibility of coding categories. Part-time data collectors were then trained and supervised by the CRN locally to conduct the chart audits. The Project Manager reviewed data from all sites on an ongoing basis and contacted local CRNs about missing data or inconsistencies.Descriptive statistics and bivariate statistics  were used to describe characteristics of the sample, and to compare before and after measures of clinical outcomes within study sites. Fisher's exact test was used when expected frequencies were small.Semi-structured interview schedules were developed by the co-investigators and administered to all CRNs, administrators and selected staff nurses immediately after the implementation. The staff nurses (2–3 per unit) were identified by the CRN to include those who had a favourable as well as those who had a less favourable experience with the guideline implementation.Questions were designed to elicit information about the strategies used as well as the perceived factors that facilitated or provided barriers to guideline implementation. In addition, CRNs were interviewed at the mid-point of implementation to describe priority recommendations selected for implementation and reasons why some recommendations were not selected. Examples of these interview schedules as well as our approach used to conduct and analyze interview data are provided in an available monograph .The Project Manager and trained interviewers conducted the interviews which were audio-taped with the consent of each respondent. Analysis of the interviews was conducted using QSR-N5. Interviews were initially coded by one individual using a coding guide. Content analysis was conducted looking for prominent themes and patterns across respondents for each guideline .Completion rates for chart audits were greater than 95% for all eligible cases. Response rates varied for initial and follow-up patient interviews, as displayed in Table As described in Table Overall, with respect to chart audit data, there were statistically significant improvements in nearly half of the indicators . It is interesting to note that improvements were found in items related to: patient assessment/risk classification 37%; patient education 29%; medication and treatments 14%; symptom monitoring 9%; supportive care 6%; and other 6%. Statistically significant improvements were also found in pre- and post-observation scores of asthma patients' correct use of an inhaler device (p =.014). With respect to patient interview data, it is notable that statistically significant improvements were found in all seven indicators for diabetes foot care as reported in Table No statistically significant differences were found > 80% of the indicators for three guidelines . In addition, two statistically significant negative results were found for two of these guidelines. Specifically, fewer mothers were exclusively breastfeeding their infants in hospital  and fewer mental health patients reported that they had tried to quit smoking post-guideline implementation .The concordance of nursing practices with indicators measured varied considerably post-implementation. The lowest level was 17.4% for the provision of smoking cessation advice to smokers in a mental health organization and the highest level was 96.2% for the patients in the chronic care hospital and the clients receiving community-based nursing services for the care of their venous leg ulcers Table .Even in the three guidelines with statistically significant improvements in > 50% of indicators, there were still substantial gaps in the provision of evidence-based recommendations at post-intervention as follows: Only 23.9% of hospital patients with asthma had an action plan at discharge; only 60.5% of hospital and community-based patients with diabetes had a documented assessment of risk factors for foot ulcers; and only 45.7% of patients with venous leg ulcers from long-term care and a community-based nursing service received a Doppler Assessment of Ankle BrachialPressure Index  with a range of 75%–100% per guideline. The proportion of recommendations implemented varied by guideline topic from 43% (e.g. 3/7) to 100% (e.g. 7/7). A very brief synopsis of the content of recommendations is described in Table these are very expensive and would require too much personnel time and it is felt not possible at this time". Also, the recommendation to conduct an in-person follow-up and assessment if a mother and baby were discharged within 48 hours of birth was not implemented due to perceived lack of available public health nurses. Controversy arose about the recommendation for exclusive breastfeeding for the first six months of life from the hospital nutrition/dietetic staff. According to the CRN, these nutritionists followed other national guidelines recommending exclusive breastfeeding for only four months.The prenatal components which included a comprehensive assessment to facilitate a breastfeeding plan and small informal group education classes were not implemented because ""We felt that it was something that we did not have a lot of control over, some clients live in rooming houses and boarding houses and collective group settings."The CRN reported that three recommendations were not implemented: provide intensive smoking cessation interventions, implement interventions with pregnant women and encourage smokers and non-smokers to have smoke-free homes. Reasons for non-implementation included lack of time for nurses to do intensive smoking cessation counselling and the availability of experts at a nicotine dependence clinic within the organization. The pregnant women population was not applicable to the participating mental health organization. With respect to the quest for smoke-free homes of patients/clients, the CRN stated these are second wave treatment option, so the first part of our process has really been trying to educate the nurses around the guidelines, care and so that sort of comes after the initial care."Of the 56 recommendations, 52 were implemented. Recommendations not implemented related to secondary treatment options including venous surgery, electrical stimulation, hyperbaric oxygen, and therapeutic ultrasound. The CRN explained that "Participants' perceptions  of the most important facilitators were remarkably similar across implementation sites, with the most common including the education sessions, support from champions such as the CRN, APNs, and physicians, organizational and administrative support , and involvement of multiple stakeholders Table . Partici"Although considerable time was spent conducting a stakeholder analysis, the committee recognized that as changes occurred, more work was required in analyzing, revising and engaging stakeholders."Participant perceptions of the most important barriers to implementation included some common barriers across all topics and sites such as workload and time pressures, competing demands, staff resistance and lack of buy-in, lack of support from other organizational levels, and organizational change. Other barriers were specific to the implementation sites, such as short patient stays, lack of support from physicians, and lack of changed documentation Table . A need After the one-year implementation of newly developed nursing-oriented guidelines, a substantial proportion of patients were not receiving recommended nursing care. While our results reveal that some statistically significant positive improvements were found for all guideline topics, more than 80% of the indicators for breastfeeding, DDD and smoking cessation did not change from pre-implementation to post-implementation. However, there were statistically significant improvements in more than half of the indicators for the asthma, diabetes foot care and venous leg ulcer guidelines. These improvements are notable given the relatively short time frame of one-year for project completion.Overall, this situation is consistent with findings of other studies of guideline implementation and assessment of the quality of care -3,6,8. PRecent studies of nursing practice including subsequent work of our own suggest that it is possible to obtain data in a reliable and valid way -33. ElecThe implementation strategies used in this study reflect those generally classified as multi-faceted interventions by Grimshaw and colleagues . We obseThe second unique implementation element used with the three guidelines with substantial practice changes was the development of patient education toolkits and brochures. The CRN for the asthma guideline suggested that the new patient information tool provided an opportunity to reinforce previous teaching provided to nurses. The CRN for diabetes foot care reported that patients appreciated the education suggesting a positive feedback process from clients may have encouraged implementation of the guideline. It is noteworthy that all seven process and outcome indicators from the patient interviews increased significantly from pre to post-implementation for the topic of diabetes foot care.For other guideline topics, positive feedback from patient education was less likely in part due to the nature of the guideline topic and in part due to the application in the selected clinical context. While the diabetes guideline was directly applicable to the day-to-day care in the medical hospital in-patient units and the ongoing care of home visiting nurses, the smoking cessation guideline required a considerable shift in the norms at the participating mental health facility where previously, cigarettes had been provided as a positive reward for good patient behaviour. With respect to the breastfeeding guideline, the post-partum nurses did not receive feedback about the impact of their hospital-based teaching because public health nurses assumed care once the mother and infant were discharged from the hospital. The public health nurses did not receive feedback about long-term breast-feeding outcomes because their teaching was concentrated in the early post-partum period. The uptake of guidelines such as breastfeeding or smoking cessation with a preventive focus appears to be slower, a finding that is consistent with Rogers contention that preventive innovations have a particularly slow rate of adoption because individuals have difficulties perceiving the relative advantage and the consequences are distant in the future .Management support was reported as an important facilitator for all guideline implementations except for breastfeeding. We report in this study and in previous evaluations of RNAO guidelines , that onWith respect to process and patient outcomes, we found that none of the organizations had existing patient care databases with sufficient detail or data about nursing process of care to be used in the evaluation of these RNAO guidelines. Thus, we endeavoured to rapidly adapt existing published tools and develop new tools  to measure the processes of nursing care that are meaningful and actionable by nursing managers and senior administrators. These data collection tools were assessed for content validity and applicability and are available on the web with the RNAO Cycle 3 guidelines  and may An environmental scan of facilitators and barriers as recommended in the implementation Toolkit ,18 was cA note of caution is required about the evaluation of recommendations that are sensitive to patient preferences and nurses' values. As one report advises , performLack of time and workload considerations were reported as barriers across all guideline implementation initiatives. Cost considerations such as staffing for increased workload due to new procedures recommended in guidelines are critical for decision-makers , yet fewOrganizations in this evaluation study volunteered to participate and are therefore a self-selected group. Their volunteer status may have stimulated guideline recommendation uptake and we note that these organizations may reflect the early adopters and innovation champions . Indeed A unique opportunity to study the process and impact of six newly developed nursing guidelines in hospital and community settings existed. We report a real-world implementation project that provides data about promising implementation strategies.Specifically, these strategies include the opportunity to practice skills in interactive educational sessions for nurses, the development and use of patient educations tools, and the importance of managerial leadership for nurses' use of research-based guidelines. The lessons learned in this evaluation project may be helpful in planning future guideline implementations and in planning future research.With funding from the Canadian Health Services Research Foundation, the Canadian Institutes of Health Research and the Canadian Nurses Foundation, we are currently conducting follow-up studies to examine the long-term impact of nursing guideline implementation on clinical and process outcomes. This follows from the comments of CRNs and managers who observed that it takes longer than the six months allocated to the intervention to make clinical changes. In addition, our longitudinal study examines the predictors of sustained implementation of guideline recommendations .nursing are essential elements in high quality health care.In Canada, there is a strong public and political agenda to continuously strive towards high quality health care. The 10-year action plan to strengthen health care includes a priority to share best practices and provide information to make progress transparent to citizens . The nurnursing best practice guidelines and the most effective strategies to implement such guidelines. We found that a multi-faceted intervention for the implementation of nursing guidelines about asthma, breastfeeding, delirium-dementia-depression, reducing foot complications in diabetes, smoking cessation and venous leg ulcers can result in some improvement in practice and patient outcomes across diverse healthcare settings yet many outcomes remained unchanged. Promising elements for future initiatives are identified including interactive education with skill practice sessions, attention to patient education, involvement of managerial leadership and electronic gathering and dissemination systems offering both real-time feedback and access to guidelines.Clinical practice guidelines have the potential to improve the quality of care received by patients and thereby improve patient outcomes. Yet there is a lack of evidence about the impact of All authors declare that they have no competing interests. Tazim Virani was contracted by the RNAO to lead the overall initiative and work in collaboration with the other authors in pilot testing and evaluating the best practice guidelines.BD and NE were Co-Principal Investigators and conceived and designed the evaluation of this project. TV led the implementation strategies, reviewed the action plans of the Clinical Resource Nurses and was involved in providing input in draft measures and protocols. BD, NE, JP designed data collection measures and protocols. All authors contributed to the interpretation of data and the preparation of this manuscript.We acknowledge project funding from the Government of Ontario. Dr. Edwards holds a Nursing Chair funded by the Canadian Health Services Research Foundation, the Canadian Institutes of Health Research and the Government of Ontario. Dr. Davies held a Career Scientist award funded by the Ontario Ministry of Health and Long-Term Care at the time of this study. Dr. Ploeg held an Investigator Award from the Canadian Institutes of Health Research and St. Joseph's Health Care, Hamilton, Ontario. Tazim Virani holds a doctoral fellowship funded by the Ontario Ministry of Health and Long-term Care and awarded by the RNAO. The views expressed in this publication are those of the authors and not those of the RNAO or the Government of Ontario.The pre-publication history for this paper can be accessed here:


We find a 7-fold increase in mechanical power when antagonist muscles act synergistically compared to individually at a frequency higher than the load natural frequency. These observed behaviors are interpreted in the context of resonance tuning and the engineering notion of impedance matching. These findings suggest that the central nervous system can adopt strategies to harness inherent muscle impedance in relation to external loads to attain favorable mechanical energetics.Integrative approaches to studying the coupled dynamics of skeletal muscles with their loads while under neural control have focused largely on questions pertaining to the postural and dynamical stability of animals and humans. Prior studies have focused on how the central nervous system actively modulates muscle mechanical impedance to generate and stabilize motion and posture. However, the question of whether muscle impedance properties can be neurally modulated to create favorable mechanical energetics, particularly in the context of periodic tasks, remains open. Through muscle stiffness tuning, we hypothesize that a pair of antagonist muscles acting against a common load may produce significantly more power synergistically than individually when impedance matching conditions are met between muscle and load. Since neurally modulated muscle stiffness contributes to the coupled muscle-load stiffness, we further anticipate that power-optimal oscillation frequencies will occur at frequencies greater than the natural frequency of the load. These hypotheses were evaluated computationally by applying optimal control methods to a bilinear muscle model, and also evaluated through  Movement in organisms is a result of the interplay between biomechanics, neural control, and the influence of external environmental loads. Understanding the interaction between these factors is important not only for scientific reasons but also for engineering robotic systems and prostheses that strive to match biological performance. Muscle mechanical impedance is key in defining the mechanical interaction between muscles and their loads. It is well known that neural activation modulates muscle impedance, particularly stiffness, and that such modulation can be used advantageously to stabilize the posture and motion in organisms. Here, we show computationally and experimentally that stiffness modulation can also be used to enhance the capability of muscle to generate mechanical power, which is key in determining how fast animals can run, fly, swim, or jump. When muscles are activated optimally in relation to their external loads, they can create resonance conditions at optimal frequencies that significantly enhance their mechanical energetics by up to 7-fold. These findings can be interpreted in the context of the engineering notions of impedance matching and resonance tuning, which are commonly used as guiding principles in the design of diverse power optimal systems, such as communication circuits and robotic systems. The capability of skeletal muscles to deliver mechanical power is key in determining the neuromechanical performance envelope of organisms. How fast and how far animals run, fly, swim, or jump is clearly limited by the mechanical power delivered by the muscle-tendon units to skeletal and environmental loads. Therefore, estimating the mechanical energetics of muscles  has been of interest in diverse fields such as organismal biomechanics, biomimetic robotics and prosthetics Many factors influence the neuromechanical performance of organisms, including i) the dynamics and mechanical properties of muscle actuators, ii) skeletal mechanics, iii) neural control and iv) influence of loads external to the organism. Integrative approaches have been proposed to capture the interaction of all, or subsets of these factors. For example, the connection between muscle impedance (particularly stiffness) and neural control has been studied in depth with respect to postural and dynamic stability In the context of muscle energetics, most investigations focused on experimentally measuring the power output of individual muscles at a range of frequencies, phases and electrical stimulation parameters, and finding maximal power generating capability of muscles under prescribed motion trajectories. However, the role of muscle-load interaction on output energetics has not been formalized. The central premise of this work is that the mechanical energetics of a muscle-actuated system cannot be determined in a meaningful manner without considering the coupling of muscle properties, load dynamics and neural activation. By considering this coupling explicitly, we arrive at phenomena that cannot be captured using standard workloop testing methodologies, including the opportunity to harness muscle-load interaction in an energetically advantageous manner.in vitroin vivoIn vitro measurements relied almost invariably on the workloop technique in vivo conditions because motion profiles are imposed on single isolated muscles with no muscle-load interactions In vivo measurements, on the other hand, capture all of the above effects in principle, but lack the experimental flexibility of varying load conditions in an unambiguous manner.Muscle energetics have been characterized under dynamic conditions, both Capturing the effect of muscle-load interaction on muscle energetics is critical. This interaction can be captured by considering the impedance of the muscles in relation to the impedance of the load. When a group of muscles acts on a common load, as exemplified by an antagonist pair acting on a common load, each muscle forms part of the load borne by the other muscles in its group. Because muscle impedance is activation dependent, neural control can be used to modulate the effective load observed by each muscle by modulating the impedance of the opposing muscles, thereby offering the opportunity to create favorable impedance conditions that maximize power transfer to the external environmental load. This is akin to the notion of impedance matching in engineering systems, where the driving source and the load are “matched” to provide optimal power transfer. In the context of neuromuscular control, impedance matching can enable groups of muscles to work synergistically to provide significantly higher energetics than the sum of individual muscles.in vitro measurements of workloop energetics of electrically-stimulated, frog muscle acting against emulated mass-spring-damper loads.Consequently, in this investigation we studied the influence of muscle-load interaction on muscle workloop energetics both computationally and experimentally. We set up a model problem consisting of a mass-spring-damper system actuated by either a single muscle , or a paTo investigate the role of muscle-load interaction and muscle impedance on output energetics, a mathematical model of the problem was developed. This model formed the basis for the ensuing optimization of workloop energetics. We modeled the case of We assumed the excitation-contraction dynamics had temporal responses that were of the same time scale as that of the oscillatory periods, and consequently cannot be neglected. These dynamics capture the rise and fall of muscle force in time as inputs are applied. They were captured by second order processes with real poles that model calcium diffusion dynamics. We assumed the following model:We assumed that the contractile force exerted by muscle In this model, muscle force Since the contractile force of each muscle was described with respect to its local coordinates, we used the following transformation:The net muscle force excites the mass-spring-damper system and the resulting response is characterized by:From Equations (1), (2), (3), (4), and (5) the dynamics of the interconnected system are written as:The model of Equation (6) was treated as the basis for our analysis. Since our objective is to analyze optimal muscle workloop energetics, we maximize the average power transfer from the muscles to the load integrated over one periodic cycle. The instantaneous power delivered to the load is given by To derive necessary conditions for the optimal solution of Problem (7), we applied the Pontryagin Minimum Principle Augment the cost function with multipliers for each of the constraints.Define the Lagrangian and Hamiltonian scalar functions.Write the equations governing the dynamics of the optimal multipliers.Define the necessary conditions for optimal control.Solve the resulting 2-point boundary value problem for the optimal state trajectory and the associated multipliers.Details of this derivation, and the numerical methods employed therein are described as follows. The integrand of the Lagrangian cost function bang-bang control solution, and is an expected outcome in such power-optimal (or maximum acceleration) problems The optimal control In summary, the first order necessary conditions for power-optimal solutions are given by:Equations (8) and (9) define a two-point boundary value problem (2-point BVP) that is subject to the cyclic boundary conditions (11) and (12) and control constraints (10). This 2-point BVP was solved to give the optimal state trajectory .Experimental investigations played a key verification role in this work in measuring muscle workloop energetics under the conditions illustrated in Plantaris longus muscles harvested from adult male Rana pipiens (leopard frogs). These muscles were chosen primarily for ease of dissection of two contralateral muscles from the same frog, and because their extremal points provide natural mechanical interfaces to the experimental apparatus . Experiments were performed on single muscle configurations as well as configurations of muscle pairs acting antagonistically as shown in Explanted muscle experiments were conducted on  muscles , experimBipolar electrical stimulation was delivered to the muscles via hook electrodes that were in contact with the sciatic nerve. Since the efficacy of electrical stimulation depends on the contact resistance of the nerve and the electrode , the voltage of the simulation trains was gradually increased at the beginning of each muscle until full recruitment was observed (as determined by saturation in the amplitudes of isometric twitch force profiles). Stimulation was provided in waveforms repeating at the desired oscillation frequency of the mechanical system. During the active segments of the waveform, the muscles were stimulated with a pulse train at 200 Hz to ensure full recruitment, and a pulsewidth of 100 To evaluate the hypotheses, we measured workloop energetics of single muscles and muscle pairs acting against emulated mass-spring-damper system. To evaluate Hypothesis 1, we compared the power output of a single muscle acting on the mass-spring-damper system at three frequencies: i) To evaluate Hypothesis 2, we compared the sum of the powers generated by each muscle individually to the power generated by two muscles working together on the same load. Here, measurement sets consisted of In both sets of experiments, the setting of the natural frequency of the load (2–4 Hz) was comparable to frog jumping frequencies ) was solved for various values of the time horizon To investigate Hypothesis 1 computationally, successive optimizations similar to those of To investigate Hypothesis 2 computationally, we compared the power output of the optimal solutions of the single-muscle case against the optimal solutions of the case of a muscle pair in In the experimental measurements above, the absolute power value of the muscles, normalized by muscle mass, ranged between 17 [W/kg] and 81 [W/kg] at the optimal conditions.The role of active and passive muscle impedance, particularly stiffness properties, has been studied intensively in the neuromechanics and motor control literature from the perspective of stability of posture and movement. The main focus of this work is to extend this literature to include the study of muscle mechanical energetics, particularly in the context of periodic motions. We focused on the representative problem of driving a mass-spring-damper by either a single muscle or a pair of antagonist muscles. This setup can be considered as an idealization of a single degree-of-freedom joint.One consequence of explicitly accounting for muscle-load interaction is the increase in the optimal stimulation frequency of the coupled system relative to the natural frequency of the uncoupled load. This is captured by Taken to the limit of zero load stiffness, we conjecture that this feature potentially enables creating resonance conditions out of non-resonant loads. The biomechanics of natural loads in many biological systems are non-resonating. Consider, as an example, the motion of a swimming fish. The external restoring force on a fish's body is negligible, therefore the sideways bending dynamics can be considered non-resonant. In the presence of muscle activation, however, significant activation modulate stiffness is added to the system, which can be tuned to the desired oscillatory frequency of the undulating motion. The importance of body bending stiffness in relation to the undulating frequency and speed of swimming fish has been reported in Another consequence of the coupling between muscle impedance and load dynamics pertains to energetic synergies that are observed in systems driven by multiple muscle systems. When multiple muscles act jointly on a common load, each muscle contributes to the effective load observed by the other muscles acting on that load. This contribution can be strongly modulated by the neural input to the muscles.Taking the simplest case of two antagonist muscles acting in parallel on a common load, shown in , and as Our findings may be interpreted in the context of the engineering notion of impedance matching. In engineering systems, impedance matching plays an essential role when it is desired to maximize power transfer between two dynamical systems. When a power source is connected in series with a load , maximal power transfer occurs when the internal impedance of the source is equal to the complex conjugate of the load impedance The impedance of a linear mass-spring-damper load  Left: an isometric twitch used to estimate activation states. Right: estimated activation states based on the normalized twitch profile.Identification of the bilinear model for muscle contractile force. (A) To explore contractile response over a wide range of muscle velocities and positions, oscillatory motions were imposed on the muscles (shown as circles in the position-velocity space). Each circle represents a particular oscillation, with larger circles representing larger amplitudes. Electrical stimulation is triggered at the points indicated by the red asterisks. These were repeated for oscillations at various frequencies, ranging from 1–6 Hz. (B) Typical force trajectories showing modulation of contractile force (as the muscle undergoes oscillations). Experimental measurements shown in black on left, bilinear model estimates shown in blue on right. Red astersisks indicated electrical stimulation trigger points. (C) Contribution of individual model terms to the overall model fit. The bar labeled “All” shows model prediction when all terms from the generalized impedance model (Equation 13) are included. The bar labeled “Bilinear” includes only the bilinear terms (Equation 3). All terms except for the (2.38 MB TIF)Click here for additional data file.Text S1Supporting material text.(0.19 MB PDF)Click here for additional data file.