Malaria Liver Stage Susceptibility Locus Identified on Mouse Chromosome 17 by Congenic Mapping

Host genetic variants are known to confer resistance to Plasmodium blood stage infection and to control malaria severity both in humans and mice. This work describes the genetic mapping of a locus for resistance to liver stage parasite in the mouse. First, we show that decreased susceptibility to the liver stage of Plasmodium berghei in the BALB/c mouse strain is attributable to intra-hepatic factors and impacts on the initial phase of blood stage infection. We used QTL mapping techniques to identify a locus controlling this susceptibility phenotype (LOD score 4.2) on mouse chromosome 17 (belr1 locus). Furthermore, analysis of congenic mouse strains delimited the belr1 locus boundaries distally to the H2 region. Quantification of parasites in the liver of infected congenic mice strongly suggested that the belr1 locus represents a genetic factor controlling the expansion of P. berghei in the hepatic tissue. The mapping of belr1 locus raises the hypothesis that host gene variation is able to control the progression of Plasmodium liver stage infection and opens the possibility that the human genomic region orthologue to belr1 may contain genes that confer resistance to the human malaria liver stage

Contribution of Recipient-Derived Cells in Allograft Neointima Formation and the Response to Stent Implantation

Allograft coronary disease is the dominant cause of increased risk of death after cardiac transplantation. While the percutaneous insertion of stents is the most efficacious revascularization strategy for allograft coronary disease there is a high incidence of stent renarrowing. We developed a novel rabbit model of sex-mismatched allograft vascular disease as well as the response to stent implantation. In situ hybridization for the Y-chromosome was employed to detect male cells in the neointima of stented allograft, and the population of recipient derived neointimal cells was measured by quantitative polymerase chain reaction and characterized by immunohistochemistry. To demonstrate the participation of circulatory derived cells in stent neointima formation we infused ex vivo labeled peripheral blood mononuclear cells into native rabbit carotid arteries immediately after stenting. Fourteen days after stenting the neointima area was 58% greater in the stented vs. non-stented allograft segments (p = 0.02). Male cells were detected in the neointima of stented female-to-male allografts. Recipient-derived cells constituted 72.1±5.7% and 81.5±4.2% of neointimal cell population in the non-stented and stented segments, respectively and the corresponding proliferation rates were only 2.7±0.5% and 2.3±0.2%. Some of the recipient-derived neointimal cells were of endothelial lineage. The ex vivo tagged cells constituted 9.0±0.4% of the cells per high power field in the stent neointima 14 days after stenting. These experiments provide important quantitative data regarding the degree to which host-derived blood-borne cells contribute to neointima formation in allograft vasculopathy and the early response to stent implantation

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

Background: Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications. The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas. Methods/design. Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma 3 cm, located between 115 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane i

Pijn op de borst : Veilige diagnose met de HEART-score

Doel Het meten van het effect van het gebruik van de HEART-score op patiëntuitkomsten en zorggebruik. Opzet ‘Stepped wedge’, cluster-gerandomiseerde trial. Methode In 9 Nederlandse ziekenhuizen includeerden we patiënten die zich in de periode juli 2013- augustus 2014 met pijn op de borst meldden op de Spoedeisende Hulp (SEH). Alle ziekenhuizen begonnen met een controleperiode en elke 6 weken stapte 1 willekeurig gekozen ziekenhuis over op de interventieperiode, de zogenoemde ‘HEART-care’. Tijdens HEART-care rekenden artsen de HEART-score van de patiënt uit om het verdere beleid te bepalen. Om de veiligheid van deze toepassing te evalueren, was er een non-inferiority-limiet van 3% absolute toename van cardiale gebeurtenissen binnen 6 weken na bezoek aan de SEH. Andere uitkomstmaten waren zorggebruik, kwaliteit van leven en kosteneffectiviteit (trialregistratie: ClinicalTrials.gov 80-82310-97-12154). Resultaten We includeerden 3648 patiënten (1827 in de controleperiode en 1821 in de interventieperiode). De incidentie van cardiale gebeurtenissen binnen 6 weken was in de interventieperiode 1,3% lager dan tijdens de controleperiode (bovenste limiet 95%-BI: 2,1%; de non-inferiority-limiet van 3% werd niet overschreden). Bij patiënten met een lage HEART-score was de incidentie van cardiale gebeurtenissen 2,0% (95%-BI: 1,2-3,3). We vonden geen significante verschillen in vroeg ontslag vanaf de SEH, heropnames, herhaalde bezoeken aan de SEH, poliklinische bezoeken of bezoeken aan de huisarts. Conclusie Het gebruik van de HEART-score voor de beoordeling van patiënten met pijn op de borst op de SEH is veilig, maar het effect op zorggebruik was gering, mogelijk door terughoudendheid van artsen om het voorgestelde beleid te volgen

Pijn op de borst: Veilige diagnose met de HEART-score

Doel: Het meten van het effect van het gebruik van de HEART-score op patiëntuitkomsten en zorggebruik. Opzet: ‘Stepped wedge’, cluster-gerandomiseerde trial. Methode: In 9 Nederlandse ziekenhuizen includeerden we patiënten die zich in de periode juli 2013- augustus 2014 met pijn op de borst meldden op de Spoedeisende Hulp (SEH). Alle ziekenhuizen begonnen met een controleperiode en elke 6 weken stapte 1 willekeurig gekozen ziekenhuis over op de interventieperiode, de zogenoemde ‘HEART-care’. Tijdens HEART-care rekenden artsen de HEART-score van de patiënt uit om het verdere beleid te bepalen. Om de veiligheid van deze toepassing te evalueren, was er een non-inferiority-limiet van 3% absolute toename van cardiale gebeurtenissen binnen 6 weken na bezoek aan de SEH. Andere uitkomstmaten waren zorggebruik, kwaliteit van leven en kosteneffectiviteit (trialregistratie: ClinicalTrials.gov 80-82310-97-12154). Resultaten: We includeerden 3648 patiënten (1827 in de controleperiode en 1821 in de interventieperiode). De incidentie van cardiale gebeurtenissen binnen 6 weken was in de interventieperiode 1,3% lager dan tijdens de controleperiode (bovenste limiet 95%-BI: 2,1%; de non-inferiority-limiet van 3% werd niet overschreden). Bij patiënten met een lage HEART-score was de incidentie van cardiale gebeurtenissen 2,0% (95%-BI: 1,2-3,3). We vonden geen significante verschillen in vroeg ontslag vanaf de SEH, heropnames, herhaalde bezoeken aan de SEH, poliklinische bezoeken of bezoeken aan de huisarts. Conclusie: Het gebruik van de HEART-score voor de beoordeling van patiënten met pijn op de borst op de SEH is veilig, maar het effect op zorggebruik was gering, mogelijk door terughoudendheid van artsen om het voorgestelde beleid te volgen

The impact of the HEART risk score in the early assessment of patients with acute chest pain: Design of a stepped wedge, cluster randomised trial

Background: Chest pain remains a diagnostic challenge: physicians do not want to miss an acute coronary syndrome (ACS), but, they also wish to avoid unnecessary additional diagnostic procedures. In approximately 75% of the patients presenting with chest pain at the emergency department (ED) there is no underlying cardiac cause. Therefore, diagnostic strategies focus on identifying patients in whom an ACS can be safely ruled out based on findings from history, physical examination and early cardiac marker measurement. The HEART score, a clinical prediction rule, was developed to provide the clinician with a simple, early and reliable predictor of cardiac risk. We set out to quantify the impact of the use of the HEART score in daily practice on patient outcomes and costs. Methods/Design: We designed a prospective, multi-centre, stepped wedge, cluster randomised trial. Our aim is to include a total of 6600 unselected chest pain patients presenting at the ED in 10 Dutch hospitals during an 11-month period. All clusters (i.e. hospitals) start with a period of 'usual care' and are randomised in their timing when to switch to 'intervention care'. The latter involves the calculation of the HEART score in each patient to guide clinical decision; notably reassurance and discharge of patients with low scores and intensive monitoring and early intervention in patients with high HEART scores. Primary outcome is occurrence of major adverse cardiac events (MACE), including acute myocardial infarction, revascularisation or death within 6 weeks after presentation. Secondary outcomes include occurrence of MACE in low-risk patients, quality of life, use of health care resources and costs. Discussion: Stepped wedge designs are increasingly used to evaluate the real-life effectiveness of non-pharmacological interventions because of the following potential advantages: (a) each hospital has both a usual care and an intervention period, therefore, outcomes can be compared within and across hospitals; (b) each hospital will have an intervention period which enhances participation in case of a promising intervention; (c) all hospitals generate data about potential implementation problems. This large impact trial will generate evidence whether the anticipated benefits (in terms of safety and cost-effectiveness) of using the HEART score will indeed be achieved in real-life clinical practice. Trial registration: ClinicalTrials.gov 80-82310-97-12154

Pijn op de borst : Veilige diagnose met de HEART-score

Doel Het meten van het effect van het gebruik van de HEART-score op patiëntuitkomsten en zorggebruik. Opzet ‘Stepped wedge’, cluster-gerandomiseerde trial. Methode In 9 Nederlandse ziekenhuizen includeerden we patiënten die zich in de periode juli 2013- augustus 2014 met pijn op de borst meldden op de Spoedeisende Hulp (SEH). Alle ziekenhuizen begonnen met een controleperiode en elke 6 weken stapte 1 willekeurig gekozen ziekenhuis over op de interventieperiode, de zogenoemde ‘HEART-care’. Tijdens HEART-care rekenden artsen de HEART-score van de patiënt uit om het verdere beleid te bepalen. Om de veiligheid van deze toepassing te evalueren, was er een non-inferiority-limiet van 3% absolute toename van cardiale gebeurtenissen binnen 6 weken na bezoek aan de SEH. Andere uitkomstmaten waren zorggebruik, kwaliteit van leven en kosteneffectiviteit (trialregistratie: ClinicalTrials.gov 80-82310-97-12154). Resultaten We includeerden 3648 patiënten (1827 in de controleperiode en 1821 in de interventieperiode). De incidentie van cardiale gebeurtenissen binnen 6 weken was in de interventieperiode 1,3% lager dan tijdens de controleperiode (bovenste limiet 95%-BI: 2,1%; de non-inferiority-limiet van 3% werd niet overschreden). Bij patiënten met een lage HEART-score was de incidentie van cardiale gebeurtenissen 2,0% (95%-BI: 1,2-3,3). We vonden geen significante verschillen in vroeg ontslag vanaf de SEH, heropnames, herhaalde bezoeken aan de SEH, poliklinische bezoeken of bezoeken aan de huisarts. Conclusie Het gebruik van de HEART-score voor de beoordeling van patiënten met pijn op de borst op de SEH is veilig, maar het effect op zorggebruik was gering, mogelijk door terughoudendheid van artsen om het voorgestelde beleid te volgen

Decision analytic modeling was useful to assess the impact of a prediction model on health outcomes before a randomized trial

OBJECTIVE: To demonstrate how decision analytic models (DAMs) can be used to quantify impact of using a (diagnostic or prognostic) prediction model in clinical practice and provide general guidance on how to perform such assessments. STUDY DESIGN AND SETTING: A DAM was developed to assess the impact of using the HEART score for predicting major adverse cardiac events (MACE). Impact on patient health outcomes and health care costs was assessed in scenarios by varying compliance with and informed deviation (ID) (using additional clinical knowledge) from HEART score management recommendations. Probabilistic sensitivity analysis was used to assess estimated impact robustness. RESULTS: Impact of using the HEART score on health outcomes and health care costs was influenced by an interplay of compliance with and ID from HEART score management recommendations. Compliance of 50% (with 0% ID) resulted in increased missed MACE and costs compared with usual care. Any compliance combined with at least 50% ID reduced both costs and missed MACE. Other scenarios yielded a reduction in missed MACE at higher costs. CONCLUSION: Decision analytic modeling is a useful approach to assess impact of using a prediction model in practice on health outcomes and health care costs. This approach is recommended before conducting an impact trial to improve its design and conduct

Effect of using the HEART score in patients with chest pain in the emergency department: A Stepped-wedge, cluster randomized trial

Background: The HEART (History, Electrocardiogram, Age, Risk factors, and initial Troponin) score is an easy-to-apply instrument to stratify patients with chest pain according to their short-term risk for major adverse cardiac events (MACEs), but its effect on daily practice is unknown. Objective: To measure the effect of use of the HEART score on patient outcomes and use of health care resources. Design: Stepped-wedge, cluster randomized trial. (Clinical Trials.gov: NCT01756846) Setting: Emergency departments in 9 Dutch hospitals. Patients: Unselected patients with chest pain presenting at emergency departments in 2013 and 2014. Intervention: All hospitals started with usual care. Every 6 weeks, 1 hospital was randomly assigned to switch to "HEART care," during which physicians calculated the HEART score to guide patient management. Measurements: For safety, a noninferiority margin of a 3.0% absolute increase in MACEs within 6 weeks was set. Other outcomes included use of health care resources, quality of life, and cost-effectiveness. Results: A total of 3648 patients were included (1827 receiving usual care and 1821 receiving HEART care). Six-week incidence of MACEs during HEART care was 1.3% lower than during usual care (upper limit of the 1-sided 95% CI, 2.1% [within the noninferiority margin of 3.0%]). In low-risk patients, incidence of MACEs was 2.0% (95% CI, 1.2% to 3.3%). No statistically significant differences in early discharge, readmissions, recurrent emergency department visits, outpatient visits, or visits to general practitioners were observed. Limitation: Physicians were hesitant to refrain from admission and diagnostic tests in patients classified as low risk by the HEART score. Conclusion: Using the HEART score during initial assessment of patients with chest pain is safe, but the effect on health care resources is limited, possibly due to nonadherence to management recommendations

Transanal endoscopic microsurgery versus endoscopic mucosal resection for large rectal adenomas (TREND-study)

Abstract Background Recent non-randomized studies suggest that extended endoscopic mucosal resection (EMR) is equally effective in removing large rectal adenomas as transanal endoscopic microsurgery (TEM). If equally effective, EMR might be a more cost-effective approach as this strategy does not require expensive equipment, general anesthesia and hospital admission. Furthermore, EMR appears to be associated with fewer complications. The aim of this study is to compare the cost-effectiveness and cost-utility of TEM and EMR for the resection of large rectal adenomas. Methods/design Multicenter randomized trial among 15 hospitals in the Netherlands. Patients with a rectal adenoma ≥ 3 cm, located between 1–15 cm ab ano, will be randomized to a TEM- or EMR-treatment strategy. For TEM, patients will be treated under general anesthesia, adenomas will be dissected en-bloc by a full-thickness excision, and patients will be admitted to the hospital. For EMR, no or conscious sedation is used, lesions will be resected through the submucosal plane in a piecemeal fashion, and patients will be discharged from the hospital. Residual adenoma that is visible during the first surveillance endoscopy at 3 months will be removed endoscopically in both treatment strategies and is considered as part of the primary treatment. Primary outcome measure is the proportion of patients with recurrence after 3 months. Secondary outcome measures are: 2) number of days not spent in hospital from initial treatment until 2 years afterwards; 3) major and minor morbidity; 4) disease specific and general quality of life; 5) anorectal function; 6) health care utilization and costs. A cost-effectiveness and cost-utility analysis of EMR against TEM for large rectal adenomas will be performed from a societal perspective with respectively the costs per recurrence free patient and the cost per quality adjusted life year as outcome measures. Based on comparable recurrence rates for TEM and EMR of 3.3% and considering an upper-limit of 10% for EMR to be non-inferior (beta-error 0.2 and one-sided alpha-error 0.05), 89 patients are needed per group. Discussion The TREND study is the first randomized trial evaluating whether TEM or EMR is more cost-effective for the treatment of large rectal adenomas. Trial registration number (trialregister.nl) NTR1422</p