Evidence-based medicine needs patient and public involvement to remain relevant: A proposal for a new curriculum / La medicina basada en la evidencia requiere la participación de la ciudadanía para mantener su relevancia: Propuesta para un nuevo plan de estudios

Introduction Public partnerships, a route to sharing expertise, networks and resources anchored in the United Nations Sustainable Development Goals, has been championed by multiple stakeholders. Objective To propose a new evidence-based medicine (EBM) curriculum for harnessing patient and public expertise to ensure that EBM teaching and learning can become more relevant and impactful. Methods A curriculum development group comprising of EBM teachers, patient and public involvement representatives, clinicians, clinical epidemiologists, public health experts and educationalists, with experience of delivering and evaluating face-to-face and online EBM courses across many countries and continents, prepared a new EBM course. Results A student-centred, problem-based and clinically integrated course for teaching and learning EBM was developed. In the spirit of shared decision-making, practitioners can learn to support patients, articulate their perspectives, recognise the need for their contribution and ensure community involvement when generating and applying evidence. With end users in mind, the application of research findings, delivery of care and EBM effectiveness in the workplace would carry increased priority. Conclusion Embracing patients as EBM collaborators can help deliver cognitive diversity and inspire different ways of thinking and working. Adopting the proposed approach in EBM education lays the foundations for a joint practitioner–patient partnership to ask, acquire, appraise and apply EBM in a more holistic context which will strengthen the EBM proposition (AU)

Introducción Las asociaciones de pacientes y ciudadanos constituyen una vía para compartir experiencias, redes y recursos siendo promovidas por los objetivos de desarrollo sostenible de la Organización de Naciones Unidas (ONU), y defendidas por todas las partes y sectores interesados. Objetivo Proponer un nuevo plan de estudios de medicina basada en la evidencia (MBE) para aprovechar la experiencia de los pacientes con el fin de garantizar de que la enseñanza y el aprendizaje de la MBE sean más relevantes e impactantes. Métodos Un grupo de expertos compuesto por profesores del área de MBE, representantes de pacientes, médicos, epidemiólogos clínicos, expertos en salud pública y pedagogos, con experiencia en la impartición y evaluación de cursos de MBE presenciales y online en el ámbito internacional, desarrolló e implementó un curso de MBE. Resultados Se desarrolló un curso centrado en el estudiante, basado en problemas y clínicamente integrado para la enseñanza y el aprendizaje de la MBE. En el espíritu de la toma de decisiones compartida, los profesionales pueden aprender a apoyar a los pacientes, a articular sus perspectivas, a reconocer la necesidad de su contribución y a garantizar la participación de la comunidad a la hora de generar y aplicar las pruebas. La aplicación de los resultados de la investigación, la prestación de cuidados y la eficacia de la MBE en el lugar de trabajo son las áreas de mayor prioridad para los asistentes. Conclusiones Adoptar a los pacientes como colaboradores de la MBE puede ayudar a proporcionar diversidad cognitiva e inspirar diferentes formas de pensar y trabajar. La adopción del enfoque propuesto en la formación en MBE sienta las bases para una colaboración conjunta entre profesionales y pacientes para preguntar, adquirir, valorar y aplicar la MBE en un contexto más holístico que reforzará la propuesta de MBE (AU)

Evidence-based medicine needs patient and public involvement to remain relevant: A proposal for a new curriculum.

INTRODUCTION: Public partnerships, a route to sharing expertise, networks and resources anchored in the United Nations Sustainable Development Goals, has been championed by multiple stakeholders. OBJECTIVE: To propose a new evidence-based medicine (EBM) curriculum for harnessing patient and public expertise to ensure that EBM teaching and learning can become more relevant and impactful. METHODS: A curriculum development group comprising of EBM teachers, patient and public involvement representatives, clinicians, clinical epidemiologists, public health experts and educationalists, with experience of delivering and evaluating face-to-face and online EBM courses across many countries and continents, prepared a new EBM course. RESULTS: A student-centred, problem-based and clinically integrated course for teaching and learning EBM was developed. In the spirit of shared decision-making, practitioners can learn to support patients, articulate their perspectives, recognise the need for their contribution and ensure community involvement when generating and applying evidence. With end users in mind, the application of research findings, delivery of care and EBM effectiveness in the workplace would carry increased priority. CONCLUSIONS: Embracing patients as EBM collaborators can help deliver cognitive diversity and inspire different ways of thinking and working. Adopting the proposed approach in EBM education lays the foundations for a joint practitioner-patient partnership to ask, acquire, appraise and apply EBM in a more holistic context which will strengthen the EBM proposition.

Screening instruments for identification of vulnerable older adults at the emergency department: a critical appraisal.

BACKGROUND: Early detection of vulnerable older adults at the emergency department (ED) and implementation of targeted interventions to prevent functional decline may lead to better patient outcomes. OBJECTIVE: To assess the level of agreement between four frequently used screening instruments: ISAR-HP, VMS, InterRAI ED Screener and APOP. METHODS: Observational prospective cohort study in patients ≥ 70 years attending Dutch ED. RESULTS: The prevalence of vulnerability ranged from 19% (APOP) to 45% (ISAR-HP). Overall there was a moderate agreement between the screening instruments (Fleiss Kappa of 0.42 (p<0.001)). CONCLUSION: Depending on the screening instrument used, either only a small percentage or almost as many as half of the presenting patients will be eligible for targeted interventions, leading to large dissimilarities in working processes, resources and costs.

Acute photosensitisation and mortality in a herd of dairy cattle in Tasmania.

CASE HISTORY: A herd of Holstein, Jersey, or Holstein-Jersey cross lactating cattle of mixed ages presented with a sudden drop in milk yield in 94/678 cows on 3 October 2014 (Day 0). The herd was located in Gretna in the Derwent Valley (Tasmania, Australia) and had been grazing dryland pasture. CLINICAL FINDINGS: On Day 0 the cows variably showed recumbency, peracute photosensitisation, inflamed coronary bands, conjunctival erythema, periauricular oedema, distress indicated by kicking at the flank, bruxism, discomfort, weight shifting, vocalisation indicating pain and depression. Blood samples collected on Day 4 from five clinically affected cows showed high activities of aspartate aminotransferase, glutamate dehydrogenase and gamma-glutamyl transferase. Morbidity, based on the number of treated cases within 72 hours of clinical onset, was estimated at 165/678 cows (24.3%). Mortality over the first 30 days was 19/678 cows (2.8%). PATHOLOGICAL FINDINGS: Necropsies of two cows on Day 4 showed marked distension of the gall bladder and extensive icterus. Necropsies of another two cows on Day 5 showed enlarged livers with severe damage and oedema of the distal abomasum. Severe ulcerative abomasal gastritis was present in both cows. Hepatic histopathology was consistent with chronic cholangiohepatitis. MYCOTOXICOLOGY: Fifty-five different mycotoxins were detected from a barley grass (Hordeum murinum) sample from the presumably contaminated pasture. Concentrations of B-trichothecenes, fumonisins, and zearalenone metabolites from this sample were remarkably high. The leaf smut, Jamesdicksonia dactylidis, that has not been previously reported in Tasmania, was identified from the sample of barley grass, but it is not known whether the smut can produce toxins. DIAGNOSIS: Probably an undescribed peracute mycotoxicosis associated with the ingestion of contaminated dryland pasture. CLINICAL RELEVANCE: A definitive diagnosis could not be reached in this case of acute photosensitisation and mortality in dairy cattle grazing possibly contaminated dryland pasture. The findings differed from both facial eczema and acute bovine liver disease, suggesting an undescribed mycotoxicosis.

High-level semi-synthetic production of the potent antimalarial artemisinin.

In 2010 there were more than 200 million cases of malaria, and at least 655,000 deaths. The World Health Organization has recommended artemisinin-based combination therapies (ACTs) for the treatment of uncomplicated malaria caused by the parasite Plasmodium falciparum. Artemisinin is a sesquiterpene endoperoxide with potent antimalarial properties, produced by the plant Artemisia annua. However, the supply of plant-derived artemisinin is unstable, resulting in shortages and price fluctuations, complicating production planning by ACT manufacturers. A stable source of affordable artemisinin is required. Here we use synthetic biology to develop strains of Saccharomyces cerevisiae (baker's yeast) for high-yielding biological production of artemisinic acid, a precursor of artemisinin. Previous attempts to produce commercially relevant concentrations of artemisinic acid were unsuccessful, allowing production of only 1.6 grams per litre of artemisinic acid. Here we demonstrate the complete biosynthetic pathway, including the discovery of a plant dehydrogenase and a second cytochrome that provide an efficient biosynthetic route to artemisinic acid, with fermentation titres of 25 grams per litre of artemisinic acid. Furthermore, we have developed a practical, efficient and scalable chemical process for the conversion of artemisinic acid to artemisinin using a chemical source of singlet oxygen, thus avoiding the need for specialized photochemical equipment. The strains and processes described here form the basis of a viable industrial process for the production of semi-synthetic artemisinin to stabilize the supply of artemisinin for derivatization into active pharmaceutical ingredients (for example, artesunate) for incorporation into ACTs. Because all intellectual property rights have been provided free of charge, this technology has the potential to increase provision of first-line antimalarial treatments to the developing world at a reduced average annual price.

Consanguinity, prematurity, birth weight and pregnancy loss: a prospective cohort study at four primary health center areas of Karnataka, India.

OBJECTIVE: To determine whether consanguinity adversely influences pregnancy outcome in South India, where consanguinity is a common means of family property retention. STUDY DESIGN: Data were collected from a prospective cohort of 647 consenting women, consecutively registered for antenatal care between 14 and 18 weeks gestation, in Belgaum district, Karnataka in 2005. Three-generation pedigree charts were drawn for consanguineous participants. χ (2)-Test and Student's t-test were used to assess categorical and continuous data, respectively, using SPSS version 14. Multivariate logistic regression adjusted for confounding variables. RESULT: Overall, 24.1% of 601 women with singleton births and outcome data were consanguineous. Demographic characteristics between study groups were similar. Non-consanguineous couples had fewer stillbirths (2.6 vs 6.9% P=0.017; adjusted P=0.050), miscarriages (1.8 vs 4.1%, P=0.097; adjusted P=0.052) and lower incidence of birth weight <2500 g (21.8 vs 29.5%, P=0.071, adjusted P=0.044). Gestation <37 weeks was 6.2% in both the groups. Adjusted for consanguinity and other potential confounders, age <20 years was protective of stillbirth (P=0.01), pregnancy loss (P=0.023) and preterm birth (P=0.013), whereas smoking (P=0.015) and poverty (P=0.003) were associated with higher rates of low birth weight. CONCLUSION: Consanguinity significantly increases pregnancy loss and birth weight <2500 g.

Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase.

A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.

Pyrazinoindolone inhibitors of MAPKAP-K2.

Optimization of pyrazinoindolone inhibitors of MAPKAP-K2 (MK2) provides a reasonable balance of cellular potency and physicochemical properties. Mechanistic studies support the inhibition of MK2 which is responsible for the sub-micromolar cellular efficacy.

Chlorhexidine vaginal and neonatal wipes in home births in Pakistan: a randomized controlled trial.

OBJECTIVE: To assess tolerance and safety of 0.6% chlorhexidine vaginal and neonatal wipes to improve perinatal outcomes in home deliveries in Pakistan and the ability of traditional birth attendants and project staff to perform a randomized trial of this intervention. METHODS: Focus groups of pregnant and nonpregnant women and in-depth interviews of traditional birth attendants explored barriers to the use of chlorhexidine wipes. Then, a study was performed of women delivering at home attended by traditional birth attendants. Consenting women were randomly assigned to receive either 0.6% chlorhexidine or saline vaginal and neonatal wipes. Women and their infants were followed up on postpartum days 7, 14, and 28. Acceptability and tolerance of vaginal and neonatal wipes, as well as maternal and neonatal outcomes, were assessed. RESULTS: The focus groups and interviews indicated that the chlorhexidine intervention would be acceptable to women and their providers. Of the 213 eligible pregnant women approached, 203 (95%) gave informed consent and were enrolled and allocated to groups. Traditional birth attendants had no difficulty administering chlorhexidine vaginal and neonatal wipes in a home setting. Of the 203 births, 103 (51%) of whom received 0.6% chlorhexidine, there were no allergic reactions, vaginal itching, burning, or requests for study termination. Follow-up at 28 days postpartum was more than 95%. Although this study was not powered to show significant differences in neonatal outcomes between treatment groups, the lower rates of some neonatal adverse clinical outcomes in the chlorhexidine group were encouraging. CONCLUSION: Use of 0.6% chlorhexidine vaginal and neonatal wipes for the prevention of neonatal infection is well-tolerated and seems safe. A trial of this intervention by traditional birth attendants in a home-delivery setting is feasible. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00121394 LEVEL OF EVIDENCE: I.

Drape estimation vs. visual assessment for estimating postpartum hemorrhage.

OBJECTIVE: To compare (1) visual estimation of postpartum blood loss with estimation using a specifically designed blood collection drape and (2) the drape estimate with a measurement of blood loss by photospectrometry. METHODS: A randomized controlled study was performed with 123 women delivered at the District Hospital, Belgaum, India. The women were randomized to visual or drape estimation of blood loss. A subsample of 10 drape estimates was compared with photospectrometry results. RESULTS: The visual estimate of blood loss was 33% less than the drape estimate. The interclass correlation of the drape estimate to photospectrometry measurement was 0.92. CONCLUSION: Drape estimation of blood loss is more accurate than visual estimation and may have particular utility in the developing world. Prompt detection of postpartum hemorrhage may reduce maternal morbidity and mortality in low-resource settings.

Comparison of effects of GnRH and prostaglandin in combination, and prostaglandin on conception rates and time to conception in dairy cows.

OBJECTIVE: To assess the effectiveness of a gonadotrophin-releasing hormone (GnRH) / prostaglandin program (GnRH-PG-GnRH, Ovsynch) on conception rates and time to conception of lactating dairy cows compared with a PG program (double prostaglandin injection). DESIGN: A randomised multi-centre cohort study was conducted with 778 cows from nine dairy herds. Cows at different stages of lactation were randomly assigned, after matching for days open at the time of treatment, to either the PG or Ovsynch program. PROCEDURE: Cows on the PG program received two intramuscular injections of prostaglandin (2 mL, Prosolvin) 11 days apart. The Ovsynch program consisted of two intramuscular injections of GnRH (1 mL, Fertagyl) 9 days apart, separated by one injection of prostaglandin 40 h before the second GnRH injection. Milk samples were taken at the time of artificial insemination and assayed for progesterone by radioimmunoassay. RESULTS: The Ovsynch program was not significantly different to PG in achieving conception, with overall conception rates of 37.6% and 41.4%, respectively, for each program. There was, however, a significant interaction between the effects of parity and treatment (P = 0.03), because conception rates were higher in older cows (parity 5 or more) on the PG program than for older cows on the Ovsynch program. There was no significant effect of treatment (P > 0.5) on time to conception after treatment, but older cows were slower to conceive (P < 0.0001). Conception rates differed (P < 0.0001) among herds. CONCLUSION: The median days to conception for both groups was 22 and mean days from treatment to conception were 36.3 +/- 3.3 and 31.6 +/- 2.7 for the Ovsynch and PG programs respectively, indicating that reproductive performance of cows was not significantly different with Ovsynch program or PG program. There appears to be a need to evaluate causes of reproductive failure in older cows.

The epidemiology of subfertility in non-seasonal calving dairy herds in the Camden region of New South Wales: description of population and incidence.

OBJECTIVE: To describe biographic, reproductive, production and disease characteristics of 965 Holstein cows from 10 non-seasonal calving dairy herds in the Camden region of New South Wales, and to describe the incidence of subfertility, that is, conception requiring > 2 inseminations, in this population. DESIGN: A retrospective epidemiologic study. METHODS: Computer records were used to determine biographic, reproductive, production and disease characteristics in all lactations that commenced between 1 July 1995 and 30 June 1996 and resulted in conception during that lactation. Differences in these characteristics among herds and between primiparous and multiparous cows were examined. The lactational incidence of subfertility for lactations commencing during the study period was determined. RESULTS: Ten herds with appropriate records and management structures entered the study. Herd size ranged from 86 to 203 lactating cows. Nutritional and reproductive management of these herds was typical of smaller pasture-based herds within the study region. Records from 1320 cows were available, of which 965 were considered suitable for descriptive analysis. Monthly variations in number of cows calving were noted, with number of lactations commenced by primiparous and multiparous cows peaking in January and October, respectively. Significant (P < 0.001) inter-herd differences for all reproductive, disease and milk production outcomes were detected for both the entire population and within primiparous and multiparous subgroups. Of 1041 cows submitted for insemination, 76 failed to conceive. The lactational incidence rate (LIR) of subfertility in all lactations was 21.1% (95% CI 19-24%). and among all cows conceiving was 22.8% (95% Cl 20-25%). The LIR of subfertility in primipara was 24.1% (95% Cl 19-28%) and varied widely between herds (10%-40%). The LIR of subfertility in multipara was 22.2% (95% Cl 20-25%) and also varied widely between herds (7%-46%). CONCLUSION: Parity and herd of origin should be considered in any further analyses of these data.

The epidemiology of subfertility in non-seasonal calving dairy herds in the Camden region of New South Wales: preliminary investigation of risk factors.

OBJECTIVE: To investigate relationships between biographic, reproductive, production and disease traits and subfertility among 965 Holstein cows from 10 non-seasonal calving dairy herds in the Camden region of New South Wales. DESIGN: A retrospective case-control study METHODS: Biographical, disease and reproductive data were collated from computerised records for cows with lactations that commenced between 1 July 1995 and 30 June 1996 and univariable and bivariable associations with subfertility were determined. RESULTS: Records from 965 cows that conceived were considered for risk factor analyses. Associations between subfertility and a number of risk factors (P < 0.3) were detected. Significant (P < 0.05) risk factors for subfertility in multiparous cows included herd of origin and, after controlling for the effect of herd, subfertility in the previous lactation, greater than 62 days dry, parity greater than five, interval between calving and first recorded heat, metritis and cystic ovarian disease. Herd of origin and, after controlling for herd effects, dystocia, metritis and percentage of milk fat plus protein at the time of first service were significant (P < 0.05) risk factors for subfertility in primiparous cows. The direction and magnitude of these associations are presented. CONCLUSION: Subfertility has a similar rate of occurrence in the herds examined to that reported overseas. Although herd of origin has a substantial effect on individual risk of subfertility, cow-level risk factors for subfertility are likely to exist. Exposures differ between primiparous and multiparous cows.

Risk factors for repeat-breeder syndrome in New South Wales dairy cows.

A retrospective case-control study involving 1041 cow lactations from 10 commercial dairy herds in Australia determined relationships between biographic, production, reproductive and disease factors and repeat-breeder syndrome (RBS) (conception to greater than two inseminations). The study population was stratified into primiparous- and multiparous-cow sub-groups and logistic regression was used. Effects of herd were examined by including this variable alternatively as a fixed and a random effect. In the primiparous-cow fixed-effect model, the risk of RBS was increased with post-calving metritis, stillbirth, and with increasing days taken to reach peak milk yield, and reduced following dystocia. An inverted U-shaped relationship with total milk-solids percentage at the time of first service was detected. In the multiparous-cow fixed-effect model, the risk of RBS was increased in cows with chronic metritis, cystic ovarian disease (COD), in cows of parity >5 and in cows that were sub-fertile in the previous lactation. Increasing days to first recorded heat (DFH) reduced risk of RBS and a non-linear relationship with average 120-day milk-protein percentage was found. When herd was fitted as a random effect, stillbirth and 120-day average milk-protein percentage were no longer significant in the primiparous and multiparous models, respectively. The study emphasises the need to control appropriately for the clustering effect of herd and supports the need to minimise periparturient disease and improve nutrient balance to achieve optimal fertility in dairy herds.

The biological activity of serum IgE changes over the course of a primary response.

Mast-cell degranulation is triggered by the bridging of Fc receptor-bound antigen-specific immunoglobulin IgE on the cell surface. In vitro experiments suggest that antibody affinity and nonspecific IgE may affect the mast-cell function, however, their importance in vivo is unclear. Investigations of the effects of these parameters on mast-cell sensitization were therefore carried out in a rat immunization model in which the IgE response is transient and peaks on days 10-15. Between these two timepoints, significant changes in the level of specific IgE were not observed, but the avidity of specific IgE increased (P < 0.05). Total serum IgE peaked on day 10 and slowly declined, with the relative proportion of specific to total IgE increasing from day 10-15 (P < 0.05). Despite similar levels of antigen-specific IgE, increasing avidity and an increased proportion of specific IgE between days 10 and 15, the biological activity of IgE in the serum peaks on day 10 and declines rapidly, dropping around seven-fold by day 15 (P < 0.001). Mechanisms that could explain this finding, such as differential expression of IgE isoforms and changes in the fine specificity of the IgE response, are discussed.

Pro-inflammatory and pro-oxidant properties of the HIV protein Tat in a microglial cell line: attenuation by 17 beta-estradiol.

Microglia are activated in humans following infection with human immunodeficiency virus (HIV), and brain inflammation is thought to be involved in neuronal injury and dysfunction during HIV infection. Numerous studies indicate a role for the HIV regulatory protein Tat in HIV-related inflammatory and neurodegenerative processes, although the specific effects of Tat on microglial activation, and the signal transduction mechanisms thereof, have not been elucidated. In the present study, we document the effects of Tat on microglial activation and characterize the signal transduction pathways responsible for Tat's pro-inflammatory effects. Application of Tat to N9 microglial cells increased multiple parameters of microglial activation, including superoxide production, phagocytosis, nitric oxide release and TNF alpha release. Tat also caused activation of both p42/p44 mitogen activated protein kinase (MAPK) and NF kappa B pathways. Inhibitor studies revealed that Tat-induced NF kappa B activation was responsible for increased nitrite release, while MAPK activation mediated superoxide release, TNF alpha release, and phagocytosis. Lastly, pre-treatment of microglial cells with physiological concentrations of 17 beta-estradiol suppressed Tat-mediated microglial activation by interfering with Tat-induced MAPK activation. Together, these data elucidate specific components of the microglial response to Tat and suggest that Tat could contribute to the neuropathology associated with HIV infection through microglial promulgation of oxidative stress.

Health for All in the Twenty-First Century, World Health Organization renewal, and equity in health: a commentary.

Health for All in the Twenty-first Century is the document presenting the global health policy adopted by the World Health Organization (WHO) in 1998, which reaffirms and updates the vision of Alma-Ata. This article provides a synopsis of the document and a commentary, concentrating on the issue of equity, which is central to WHO policy, and discussing cultural differences that underpin the notion of equity. The meaning of "equity" implies measurement, and the authors develop an approach to definitions of social strata and data issues that are used to quantify health differences. Finally, they discuss the way in which policies invoking equity are implemented into programs and present a rights-based approach as a case study of one way in which policy is being translated into action.

Nonpeptidic, monocharged, cell permeable ligands for the p56lck SH2 domain.

p56lck is a member of the src family of tyrosine kinases and plays a critical role in the signal transduction events that lead to T cell activation. Ligands for the p56lck SH2 domain have the potential to disrupt the interaction of p56lck with its substrates and derail the signaling cascade that leads to the production of cytokines such as interleukin-2. Starting from the quintuply charged (at physiological pH) phosphorylated tetrapeptide, AcpYEEI, we recently disclosed (J. Med. Chem. 1999, 42, 722 and J. Med. Chem. 1999, 42, 1757) the design of the modified dipeptide 3, which carries just two charges at physiological pH. Here we present the elaboration of 3 to the nonpeptidic, monocharged compound, 9S. This molecule displays good binding affinity for the p56lck SH2 domain (K(d) 1 microM) and good cell permeation, and this combination of properties allowed us to demonstrate clear-cut inhibitory effects on a very early event in T cell activation, namely calcium mobilization.