Rank‐based principal stratum sensitivity analyses

We describe rank‐based approaches to assess principal stratification treatment effects in studies where the outcome of interest is only well‐defined in a subgroup selected after randomization. Our methods are sensitivity analyses, in that estimands are identified by fixing a parameter and then we investigate the sensitivity of results by varying this parameter over a range of plausible values. We present three rank‐based test statistics and compare their performance through simulations, and provide recommendations. We also study three different bootstrap approaches for determining levels of significance. Finally, we apply our methods to two studies: an HIV vaccine trial and a prostate cancer prevention trial. Copyright © 2013 John Wiley & Sons, Ltd.     

Double blind comparison of omeprazole (40 mg od) versus cimetidine (400 mg qd) in the treatment of symptomatic erosive reflux oesophagitis, assessed endoscopically, histologically and by 24 h pH monitoring.

This double blind, double dummy study compares the rate of healing of erosive reflux oesophagitis, assessed endoscopically, with four and eight weeks treatment using omeprazole or cimetidine, and the effect of four and eight weeks treatment of reflux oesophagitis with omeprazole or cimetidine on reflux symptoms, microscopic healing, and in a subgroup of patients, oesophageal pH measurements. Omeprazole 40 mg once daily achieves (i) greater and more rapid symptom relief, (ii) more rapid and sustained endoscopic and histological healing, and (iii) greater reduction of oesophageal acid exposure than cimetidine 400 mg four times daily.     

Reversal of granulocyte adherence to nylon fibers using local anesthetic agents: possible application to filtration leukapheresis

The effects of the cationic anesthetic agents tetracaine and lidocaine on granulocyte function, morphology, and adherence to nylon fibers were studied in an attempt to improve current methods of granulocyte collection by filtration leukapheresis (FL). When dissolved in acid- citrate-dextrose (ACD) plasma, these drugs significantly increased granulocyte elution from the fibers in a dose-related fashion. Granulocytes exposed to tetracaine and lidocaine remained more than 95% viable, retained normal bactericidal capacity after the drugs were washed from the cells, and had preserved membrane integrity, as evidenced by the normal ultrastructural appearance of tetracaine- exposed cells and an absence of leakage of lysozyme or lactic dehydrogenase. Granulocytes eluted with the anesthetic agents were rounded in shape with a reduction in the number of filopodial cytoplasmic projections and a relative absence of cytoplasmic vacuolization when compared to granulocytes eluted with ACD plasma alone. Dose-related inhibition of phagocytosis and adherence, which was largely reversible after washing the granulocytes, was noted. Greater than 95% of the lidocaine could be removed from the eluate with a single centrifugation and resuspension, indicating that granulocytes prepared by FL with anesthetic-enhanced elution could be potentially transfusable.     

Effects on upper airway collapsibility of presence of a pharyngeal catheter

Catheters that traverse the pharynx are often in place during clinical or research evaluations of upper airway function. The purpose of this study was to determine whether the presence of such catheters affects measures of upper airway collapsibility itself. To do so, pharyngeal critical closing pressure (Pcrit) and resistance upstream of the site of collapse Rus) were assessed in 24 propofol‐anaesthetized subjects (14 men) with and without a multi‐sensor oesophageal catheter (external diameter 2.7 mm) in place. Anaesthetic depth and posture were maintained constant throughout each study. Six subjects had polysomnography(PSG)‐defined obstructive sleep apnea (OSA) and 18 either did not have or were at low risk of OSA. Airway patency was maintained with positive airway pressure. At intervals, pressure was reduced by varying amounts to induce varying degrees of inspiratory flow limitation. The slope of the pressure flow relationship for flow‐limited breaths defined Rus. Pcrit was similar with the catheter in and out (?1.5 ± 5.4 cmH₂O and ?2.1 ± 5.6 cmH₂O, respectively, P = 0.14, n = 24). This remained the case both for those with PSG‐defined OSA (3.9 ± 2.2 cmH₂O and 2.6 ± 1.4 cmH₂O, n = 6) and those at low risk/without OSA (?3.3 ± 4.9 cmH₂O and ‐3.7 ± 5.6 cmH₂O, respectively, n = 18). Rus was similar with the catheter in and out (20.0 ± 12.3 cmH₂O mL^?1 s^?1 and 16.8 ± 10.1 cmH₂O mL^?1 s^?1, P = 0.22, n = 24). In conclusion, the presence of a small catheter traversing the pharynx had no significant effect on upper airway collapsibility in these anaesthestized subjects, providing reassurance that such measures can be made reliably in their presence.     

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in second remission - long-term follow-up

From 1984 to 1996, 31 consecutive children without sibling donors, aged 5-19 years (median 8) with acute lymphoblastic leukaemia (ALL) in second complete remission (CR), received unpurged autologous bone marrow transplantation (ABMT) after melphalan and single fraction total body irradiation (TBI). ABMT was performed using fresh unmanipulated marrow harvested after standard reinduction and consolidation therapy 2-11 months (median 5) after relapse. With a median survival of 2.9 years the probability of survival for all patients in continuing second CR was 45.1% (95% CI, 24%-62%) after 5 years. Regimen-related and non-leukaemia mortality was 7% (95% CI, 2%-26%). The longest time to second relapse from ABMT was 3.1 years. Pituitary and gonadal dysfunction requiring hormonal replacement therapy occurred in the majority of long-term survivors. Twelve patients developed cataracts. ABMT with melphalan/single fraction TBI has proved an effective anti-leukaemia treatment with low regimen-related mortality but significant long-term morbidity. The current approach of allogeneic BMT from an unrelated donor when no sibling donor is available, following conditioning with cyclophosphamide/ fractionated TBI has resulted in a reduced relapse rate and improved short-term overall survival in the treatment of relapsed childhood ALL. However, long-term results are awaited.     

Endothelium-dependent inhibition of ergonovine-induced contraction is impaired in porcine coronary arteries with regenerated endothelium

The inhibitory effects of the endothelium against ergonovine-induced contraction were examined in isolated porcine coronary arteries under normal conditions and after endothelial regeneration. Endothelium-dependent responses were examined in vitro in normal Yorkshire pigs (n = 16) and in pigs that had undergone balloon endothelium removal of the left anterior descending coronary artery (LAD) 4 weeks before the study (n = 10). The presence of a complete endothelial lining was confirmed histologically. In rings from normal arteries contracted with prostaglandin F2 alpha in the presence of indomethacin and ketanserin (a 5-HT2-serotonergic blocker), ergonovine caused endothelium-dependent relaxations. They were attenuated by rauwolscine (an alpha 2-adrenergic blocker), inhibited by methiothepin (a combined 5-HT1- and 5-HT2-serotonergic blocker) or by pertussis toxin (an inhibitor of several G proteins) and abolished by oxyhemoglobin (a selective inactivator of endothelium-derived relaxing factor). In quiescent rings from normal arteries, ergonovine caused contractions that were inhibited by the presence of the endothelium; this endothelium-dependent inhibition was abolished by oxyhemoglobin. The direct contractions were not affected by prazosin (an alpha 1-adrenergic blocker), rauwolscine, 6-hydroxydopamine (an agent causing chemical sympathetectomy), or diphenhydramine (an H1-histaminergic blocker) but were inhibited by ketanserin. In rings with regenerated endothelium contracted with prostaglandin F2 alpha, the endothelium-dependent relaxations to ergonovine were reduced significantly and were not inhibited by pertussis toxin. In quiescent rings with regenerated endothelium, the endothelium-dependent inhibition of ergonovine-induced contraction was less.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rapid isolation of low density lipoprotein (LDL) subfractions from plasma by density gradient ultracentrifugation

High resolution density gradient ultracentrifugation (DGUC) and non-denaturing gradient gel electrophoresis (GGE) indicate that low density lipoprotein (LDL) in both normal and hyperlipidaemic subjects is composed of overlapping particle populations. A new centrifugation procedure has been developed which permits the separation of LDL subspecies directly from plasma within 24 h. The profiles obtained were analogous to those seen on gradient gel electrophoresis. LDL was divided into 3 fractions. The plasma concentration of LDL-I seen in young females was twice that in men (85.6 +/- 28.8 vs. 42.3 +/- 25.7 mg/dl, P less than 0.005). LDL-II was not significantly different in any group while LDL-III was specifically elevated in coronary artery disease (CAD) patients (207.1 +/- 92.6 mg/dl in CAD vs. 87.4 +/- 79.6 mg/dl in normal men, P less than 0.05). The presence of small, dense LDL detected either by density gradient centrifugation or gel electrophoresis was associated with raised triglyceride (TG) and low high density lipoprotein (HDL) cholesterol and may be a risk marker for coronary artery disease.     

Obstructive sleep apnoea and nocturnal gastroesophageal reflux are common in lung transplant patients

Background and objective: Gastroesophageal reflux (GOR) has been implicated in the pathogenesis of bronchiolitis obliterans syndrome (BOS), possibly due to pulmonary aspiration of refluxed acid. Risk of aspiration of gastric contents is increased during sleep due to decreased oesophageal clearance mechanisms and may be further increased by the presence of OSA. This study investigated the relationship between nocturnal GOR, OSA and BOS in a group of lung transplant patients. Methods: Fourteen lung transplant patients underwent overnight polysomnography with simultaneous dual oesophageal pH monitoring. Results: Patients had an FEV₁ of 84 ± 15% of their best post-transplant FEV₁. Six of the 14 patients were in various stages of BOS. The average proportion of time spent overnight with a pH of <4 was 1.7 ± 3.1%. Increased GOR was evident in 8/14 patients during the postprandial period and/or overnight in the distal and/or proximal oesophagus. All patients had OSA (AHI >5 events per hour). There were no relationships between severity of OSA or GOR and severity of BOS. Conclusion: Both nocturnal GOR and OSA were common in this group of patients but their occurrences were not related. Neither was there any relationship between the presence of nocturnal GOR or OSA and severity of BOS.     

Severe cytopenias associated with the sequential use of busulphan and interferon-alpha in chronic myeloid leukaemia

We describe four patients who developed severe thrombocytopenia which progressed to aplasia after the use of α-interferon in maintenance therapy of chronic phase CML after busulphan induction. On reviewing over 400 patients in the MRC CML III trial we found that there is a risk of cytopenia developing after busulphan therapy and a lesser risk of cytopenias developing after α-interferon therapy. If the therapies are given in a sequential fashion the risk of cytopenia developing appears to be additive, may be pronounced, and may lead to clinically significant problems. Hydroxyurea alone does not lead to sustained cytopenia. Care should be taken to ensure that counts are stable after the use of busulphan before starting α-interferon as maintenance therapy.