Immunosuppression, eotaxin and the diagnostic changes in eosinophils that precede early acute heart allograft rejection.

Peripheral blood eosinophil counts (EOS) are undetectable in 40% blood samples sent for routine haematology at Papworth Hospital during the first 3 months after heart transplantation (HTx). Increases in EOS usually precede the development of allograft rejection by a median of 4 days. We compared the effects of cyclosporin (dose and total blood concentration), prednisolone (dose and both total and unbound plasma concentrations) and azathioprine, as well as plasma concentrations of the CCR-3 chemokines, eotaxin and RANTES, on changes in EOS in 47 consecutive HTx recipients, with a median follow-up of 90 (IQR 85-95) days. Multivariate analysis confirmed the independent association between both prednisolone dose (P<0.0001) and eotaxin (P<0.0001) and changes in EOS. The plasma eotaxin concentration was, in turn, most closely associated with the cyclosporin dose (P<0.001) and plasma prednisolone concentration (P=0.022). The blood cyclosporin concentration (P=0.028), EOS (P=0.012) and prednisolone dose (P=0.015) were all independently associated with the risk of treated acute rejection. When prednisolone pharmacokinetic parameters were substituted for the prednisolone dose in this multivariate model, only the pharmacokinetic parameter retained a significant association with the risk of rejection. Changes in EOS preceding cardiac allograft rejection are directly associated with plasma eotaxin concentrations and indirectly with prednisolone dosage. Cyclosporin may also indirectly influence these changes by inhibiting eotaxin production. EOS, prednisolone dose and blood cyclosporin concentrations were independently associated with the risk of acute rejection. The total and unbound fractions of prednisolone in plasma appear to be even more closely related to rejection but are difficult to measure. Monitoring EOS, as a surrogate measure of prednisolone immunosuppression, may be more cost-effective for controlling rejection than conventional cyclosporin monitoring in the first 6 weeks after HTx

Application of intervention mapping to develop and evaluate a pharmaceutical discharge letter to improve information transfer between hospital and community pharmacists

Background: Insufficient information transfer is a major barrier in the transition from hospital to home. This study describes the systematic development and evaluation of an intervention to improve medication information transfer between hospital and community pharmacists. Objective: To develop and evaluate an intervention to improve the medication information transfer between hospital and community pharmacists based on patients', community and hospital pharmacists’ needs. Methods: The intervention development and evaluation was guided by the six-step Intervention Mapping (IM) approach: (1) needs assessment to identify determinants of the problem, with a scoping review and focus groups with patients and healthcare providers, (2) formulation of intervention objectives with an expert group, (3) inventory of communication models to design the intervention, (4) using literature review and qualitative research with pharmacists and patients to develop the intervention (5) pilot-testing of the intervention in two hospitals, and (6) a qualitative evaluation of the intervention as part of a multicenter before-after study with hospital and community pharmacists. Results: Barriers in the information transfer are mainly time and content related. The intervention was designed to target a complete, accurate and timely medication information transfer between hospital and community pharmacists. A pharmaceutical discharge letter was developed to improve medication information transfer. Hospital and community pharmacists were positive about the usability, content, and comprehensiveness of the pharmaceutical discharge letter, which gave community pharmacists sufficient knowledge about in-hospital medication changes. However, hospital pharmacists reported that it was time-consuming to draft the discharge letter and not always feasible to send it on time. The intervention showed that pharmacists are positive about the usability, content and comprehensiveness. Conclusion: This study developed an intervention systematically to improve medication information transfer, consisting of a discharge letter to be used by hospital and community pharmacists supporting continuity of care

Biological efficacy of low versus medium dose aspirin after coronary surgery: results from a randomized trial [NCT00262275]

BACKGROUND: The beneficial effect of aspirin after coronary surgery is established; however, a recent study reported the inability of low doses (100 mg) to inhibit postoperative platelet function. We conducted a double-blind randomised trial to establish the efficacy of low dose aspirin and to compare it against medium dose aspirin. METHODS: Patients undergoing coronary surgery were invited to participate and consenting patients were randomised to 100 mg or 325 mg of aspirin daily for 5 days. Our primary outcome was the difference in platelet aggregation (day 5 – baseline) using 1 μg/ml of collagen. Secondary outcomes were differences in EC50 of collagen, ADP and epinephrine (assessed using the technique of Born). RESULTS: From September 2002 to April 2004, 72 patients were randomised; 3 patients discontinued, leaving 35 and 34 in the low and medium dose aspirin arms respectively. The mean aggregation (using 1.1 μg/ml of collagen) was reduced in both the medium and low dose aspirin arms by 37% and 36% respectively. The baseline adjusted difference (low – medium) was 6% (95% CI -3 to 14; p = 0.19). The directions of the results for the differences in EC50 (low – medium) were consistent for collagen, ADP and epinephrine at -0.07 (-0.53 to 0.40), -0.08 (-0.28 to 0.11) and -4.41 (-10.56 to 1.72) respectively, but none were statistically significant. CONCLUSION: Contrary to recent findings, low dose aspirin is effective and medium dose aspirin did not prove superior for inhibiting platelet aggregation after coronary surgery

Bayesian interim analysis for prospective randomized studies:reanalysis of the acute myeloid leukemia HOVON 132 clinical trial

Randomized controlled trials (RCTs) are the gold standard to establish the benefit-risk ratio of novel drugs. However, the evaluation of mature results often takes many years. We hypothesized that the addition of Bayesian inference methods at interim analysis time points might accelerate and enforce the knowledge that such trials may generate. In order to test that hypothesis, we retrospectively applied a Bayesian approach to the HOVON 132 trial, in which 800 newly diagnosed AML patients aged 18 to 65 years were randomly assigned to a “7 + 3” induction with or without lenalidomide. Five years after the first patient was recruited, the trial was negative for its primary endpoint with no difference in event-free survival (EFS) between experimental and control groups (hazard ratio [HR] 0.99, p = 0.96) in the final conventional analysis. We retrospectively simulated interim analyses after the inclusion of 150, 300, 450, and 600 patients using a Bayesian methodology to detect early lack of efficacy signals. The HR for EFS comparing the lenalidomide arm with the control treatment arm was 1.21 (95% CI 0.81–1.69), 1.05 (95% CI 0.86–1.30), 1.00 (95% CI 0.84–1.19), and 1.02 (95% CI 0.87–1.19) at interim analysis 1, 2, 3 and 4, respectively. Complete remission rates were lower in the lenalidomide arm, and early deaths more frequent. A Bayesian approach identified that the probability of a clinically relevant benefit for EFS (HR &lt; 0.76, as assumed in the statistical analysis plan) was very low at the first interim analysis (1.2%, 0.6%, 0.4%, and 0.1%, respectively). Similar observations were made for low probabilities of any benefit regarding CR. Therefore, Bayesian analysis significantly adds to conventional methods applied for interim analysis and may thereby accelerate the performance and completion of phase III trials.</p

A comparative analysis of host responses to avian influenza infection in ducks and chickens highlights a role for the interferon-induced transmembrane proteins in viral resistance

Chickens are susceptible to infection with a limited number of Influenza A viruses and are a potential source of a human influenza pandemic. In particular, H5 and H7 haemagglutinin subtypes can evolve from low to highly pathogenic strains in gallinaceous poultry. Ducks on the other hand are a natural reservoir for these viruses and are able to withstand most avian influenza strains. Results: Transcriptomic sequencing of lung and ileum tissue samples from birds infected with high (H5N1) and low (H5N2) pathogenic influenza viruses has allowed us to compare the early host response to these infections in both these species. Chickens (but not ducks) lack the intracellular receptor for viral ssRNA, RIG-I and the gene for an important RIG-I binding protein, RNF135. These differences in gene content partly explain the differences in host responses to low pathogenic and highly pathogenic avian influenza virus in chicken and ducks. We reveal very different patterns of expression of members of the interferon-induced transmembrane protein (IFITM) gene family in ducks and chickens. In ducks, IFITM1, 2 and 3 are strongly up regulated in response to highly pathogenic avian influenza, where little response is seen in chickens. Clustering of gene expression profiles suggests IFITM1 and 2 have an anti-viral response and IFITM3 may restrict avian influenza virus through cell membrane fusion. We also show, through molecular phylogenetic analyses, that avian IFITM1 and IFITM3 genes have been subject to both episodic and pervasive positive selection at specific codons. In particular, avian IFITM1 showed evidence of positive selection in the duck lineage at sites known to restrict influenza virus infection. Conclusions: Taken together these results support a model where the IFITM123 protein family and RIG-I all play a crucial role in the tolerance of ducks to highly pathogenic and low pathogenic strains of avian influenza viruses when compared to the chicken

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Saphenous vein bypass graft occlusion : signalling pathways and apoptosis

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The Unequal Neighborhood: Hardship and Privilege in Northwest Detroit

After decades of depopulation, deindustrialization, and disinvestment, the City of Detroit filed for Chapter IX bankruptcy in 2013. National media that once fueled the city’s notoriety as “Murder Capital” began to describe Detroit as place to be. This dissertation shows a changing Detroit from the vantage point of Brightmoor, a poor majority black depopulated neighborhood on the city’s edge. In the last decade, white newcomers had moved in next door to Detroiters. These so-called urban farmers bought houses from five hundred dollars and started gardens, farms, and parks on vacant lots. Drawing on three years of ethnographic fieldwork while I lived and became a homeowner in Brightmoor, this dissertation answers three questions: what life was like in a depopulated poor urban neighborhood, what attracted white middle-class newcomers to move to such a place, and how residents coped with new inequalities in their neighborhood. In my dissertation chapters, I show how Brightmoor residents differently related to almost valueless real estate, to neighborhood stigma, nature and vacant lots, street violence, and national politics. I show how many longtime residents were forced to treat their homes as disposable assets and lost their houses to tax foreclosures. White newcomers, by contrast, turned the constraints of this market into a lifestyle. As middle-class individuals without middle-class careers, they found their vocation and sense of fulfillment amidst Brightmoor’s vacancies. I also show how longtimers and newcomers differently acted on nature returning in the wake of depopulation, and how they navigated public life in distinct styles based on perceptions of neighborhood violence. Finally, I analyze how a national upswing in populist politics, with President Trump’s election, shifted interactions between white and black longtimers. Overall, this dissertation highlights how experienced places, that is, different ways of experiencing the neighborhood, shaped how residents lived in Brightmoor. I argue that to understand unequal cities today, we have to not only look at inequalities between places, but also attend to how past and present inequalities structure residents’ unequal experiences within neighborhoods. In my conclusion, I offer policy recommendations for how we can better help depopulated poor urban neighborhoods and their residents

The Unequal Neighborhood: Hardship and Privilege in Northwest Detroit

After decades of depopulation, deindustrialization, and disinvestment, the City of Detroit filed for Chapter IX bankruptcy in 2013. National media that once fueled the city’s notoriety as “Murder Capital” began to describe Detroit as place to be. This dissertation shows a changing Detroit from the vantage point of Brightmoor, a poor majority black depopulated neighborhood on the city’s edge. In the last decade, white newcomers had moved in next door to Detroiters. These so-called urban farmers bought houses from five hundred dollars and started gardens, farms, and parks on vacant lots. Drawing on three years of ethnographic fieldwork while I lived and became a homeowner in Brightmoor, this dissertation answers three questions: what life was like in a depopulated poor urban neighborhood, what attracted white middle-class newcomers to move to such a place, and how residents coped with new inequalities in their neighborhood. In my dissertation chapters, I show how Brightmoor residents differently related to almost valueless real estate, to neighborhood stigma, nature and vacant lots, street violence, and national politics. I show how many longtime residents were forced to treat their homes as disposable assets and lost their houses to tax foreclosures. White newcomers, by contrast, turned the constraints of this market into a lifestyle. As middle-class individuals without middle-class careers, they found their vocation and sense of fulfillment amidst Brightmoor’s vacancies. I also show how longtimers and newcomers differently acted on nature returning in the wake of depopulation, and how they navigated public life in distinct styles based on perceptions of neighborhood violence. Finally, I analyze how a national upswing in populist politics, with President Trump’s election, shifted interactions between white and black longtimers. Overall, this dissertation highlights how experienced places, that is, different ways of experiencing the neighborhood, shaped how residents lived in Brightmoor. I argue that to understand unequal cities today, we have to not only look at inequalities between places, but also attend to how past and present inequalities structure residents’ unequal experiences within neighborhoods. In my conclusion, I offer policy recommendations for how we can better help depopulated poor urban neighborhoods and their residents