A randomized phase II trial of tacrolimus,mycophenolate mofetil and sirolimus after non-myeloablative unrelated donor transplantation

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m² fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 – tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 – tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 – tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).     

Systemic Effects of Intracoronary Nitroglycerin during Coronary Angiography in Children after Heart Transplantation

Coronary spasm during coronary angiography for vasculopathy in children can be prevented by the intracoronary administration of nitroglycerin. We reviewed the anesthesia and catheterization reports and charts for pediatric transplant recipients who underwent angiography from 2005 through 2010. Correlation analysis was used to study the relation of post-injection systolic blood pressure (SBP) to nitroglycerin dose. Forty-one angiographic evaluations were performed on 25 patients (13 male and 12 female). Mean age was 9.9 ± 3.2 years (range, 3.3–16.1 yr). The mean total dose of nitroglycerin was 2.93 ± 1.60 µg/kg (range, 1–8 µg/kg).There was a significant drop between the baseline SBP (mean, 106 ± 21.6 mmHg) and the lowest mean SBP before nitroglycerin administration (78 ± 13.2, P <0.0001, paired t test). There was no significant additional change in SBP (mean after nitroglycerin administration, 80.7 ± 13.1 mmHg; P = 0.2). There was a significant drop in lowest heart rate between baseline (109 ± 16.5 beats/min) and before nitroglycerin administration (89 ± 14.3 beats/min; P <0.0001, paired t test). There was no significant additional change in heart rate (mean heart rate after nitroglycerin, 84 ± 17.7 beats/min; P = 0.09). There were 2 interventions for SBP before nitroglycerin and 2 after nitroglycerin. One child experienced a transient ST-T–segment change during angiography after nitroglycerin. In the highest dose range, the additional decrease in SBP was 7.2 mmHg (P=0.03). Routine intracoronary nitroglycerin administration in this dose range produced no significant changes in SBP or heart rate in children.Key words: Child, coronary angiography, coronary vasospasm/etiology, dose-response relationship, drug, heart transplantation/adverse effects, hemodynamics/drug effects, nitroglycerin/administration & dosage/therapeutic use, postoperative complications/therapy, retrospective studies, vasodilation/drug effectsAllograft coronary disease in children occurs with increasing frequency after transplantation, as a function of time. In a multicenter study,¹ the incidence of coronary artery disease in children 5 years post-transplant was 17% of all recipients. Coronary angiography remains the gold standard in the detection of vasculopathy in heart-transplant recipients.² Coronary artery spasm can complicate selective coronary angiography and result in myocardial ischemia. Coronary spasm can simulate the angiographic appearance of graft vasculopathy and cause diagnostic confusion.³ The spasm can arise from manipulation of the arterial wall by the catheter or from intraluminal injection of contrast material. In cardiac transplant recipients, coronary artery spasm has been reported in as many as 4.9% of coronary angiograms.³In adults, intracoronary nitroglycerin is routinely administered during coronary angiography to prevent coronary artery spasm.⁴ In children, however, safety and dosage guidelines for intracoronary nitroglycerin have not yet been firmly established. A dose of 3 µg/kg can be extrapolated by weight from the established adult dose of 200 µg; this dose was used in a study of children after the arterial switch operation and was shown to produce coronary vasodilation—with a small reduction in systolic blood pressure (SBP) and no noteworthy change in heart rate—in a control group of patients.^5,6We previously reported a case of coronary artery spasm during routine coronary angiographic monitoring in a 9-year-old boy who had undergone heart transplantation as an infant.⁷ After left main coronary artery injection of contrast material, the patient''s left anterior descending and left circumflex coronary arteries appeared to be diffusely narrow, and he developed marked ST-segment elevation, hypotension, and ventricular tachycardia. After cardiopulmonary resuscitation, he recovered uneventfully and displayed normal systolic function. Coronary angiography one month later, with the administration of intracoronary nitroglycerin before the injection of contrast material, revealed normal coronary artery diameter and was accomplished without complication.Since 2005, intracoronary nitroglycerin has routinely been used in pediatric transplant patients during biennial selective coronary angiographic monitoring at our institution. The purpose of the study is to report our experience with the routine use of intracoronary nitroglycerin for coronary angiography in children: its effects on blood pressure, on heart rate, and on the occurrence of arrhythmia and ST-segment elevation.     

Protocols,practices, and needs for investigating sudden unexpected infant deaths

Understanding case identification practices, protocols, and training needs of medical examiners and coroners (MEC) may inform efforts to improve cause-of-death certification. We surveyed a U.S.-representative sample of MECs and described investigation practices and protocols used in certifying sudden unexpected infant deaths (SUID). We also identified MEC training and resource needs. Of the 377 respondents, use of the SUID Investigation Reporting Form or an equivalent was 89% for large, 87% for medium, and 52% for small jurisdictions. Routine completion of infant medical history, witness interviews, autopsy, photos or videos, and family social history for infant death investigations was ≥80%, but routine scene re-creation with a doll was 30% in small, 64% in medium, and 59% in large offices. Seventy percent of MECs reported infant death investigation training needs. Increased training and use of standardized practices may improve SUID cause-of-death certification, allowing us to better understand SUID.     

A systematic review of health service interventions to improve linkage with or retention in HIV care

The importance of early linkage to and continuing retention in HIV care is increasingly recognised, particularly in light of the implications poor linkage and retention rates have for the effectiveness of HIV treatment as prevention strategies. The purpose of this systematic review was to examine the effectiveness of healthcare interventions in improving patient linkage to or retention in HIV care. We systematically searched PubMed (MEDLINE and PubMed-only citations) and EMBASE databases for articles reporting the original results of randomised controlled trials, and used a standard data collection form to extract information on study characteristics and outcome data. Five articles met the inclusion criteria, of which two articles focused on linkage to care and three on retention in care. The methodological quality, both of internal and external validity, of most of the trials was suboptimal. Wide variation in the interventions and outcome measures meant synthesis of the results using meta-analysis was not appropriate. This review shows evidence that interventions based on supporting patient self-management improves linkage to, and possibly retention in, care. Interventions aimed at delivery service design may also be effective, although evidence in this review was limited. It is vital that interventions are developed to improve patient engagement in HIV care. The dearth of research identified by this review highlights the need for well-designed trials of interventions in this area in the future.     

From knowledge to action: participant stories of a population health intervention to reduce gender violence and HIV in three southern African countries

This paper describes implementation research of an intervention in a complex HIV prevention randomised trial in southern Africa. Researchers collected stories of change attributed by 106 community members to an audio-drama edutainment intervention in 41 sites in Botswana, Namibia and Swaziland. The team analysed themes in the stories following a behaviour change model of conscious knowledge, attitudes, subjective norms, intention to change, agency, discussion and action (CASCADA). Storytellers attributed positive changes to the intervention in the areas of gender violence, multiple sexual partners, transactional and intergenerational sex and condom use. Their stories illustrate each of the steps in the CASCADA behaviour change model. As well as supporting an enabling environment for other interventions in the trial, the audio-drama also helped some participants to make personal changes. Collecting and discussing the stories were encouraging for the trial fieldworkers. Documenting the experiences of participants and framing the analysis of stories in an explicit behaviour change model allowed us to reflect on potential mechanisms and pathways through which the intervention impacts on individuals and communities. It helped in the design of the quantitative instruments to measure intermediate outcomes of the trial.     

Smoldering multiple myeloma: present position and potential promises

Since smoldering multiple myeloma (SMM) was first described over three decades ago based on a case series of six patients, its definition and our understanding of the entity have evolved considerably. The risk of progression to symptomatic myeloma (MM) varies greatly among individuals diagnosed with myeloma precursor disease. Epidemiologic, molecular, flow cytometric and radiological techniques have demonstrated that this transformation to MM from precursor states is not sudden but rather a continuous overlapping series of events with evidence of end‐organ damage that could manifest in the earliest stages of disease. Contemporary antimyeloma therapies can yield rapid, deep, and durable responses with manageable toxicities, and molecular‐cell‐based measures are now available to rule out minimal residual disease. With this information, clinical studies with correlative measures can now be developed to test the fundamental hypothesis that intervention in early myeloma may provide a measurable clinical benefit to patients by either delaying progression or eradicating plasma cell clones.