Principles and recommendations for incorporating estimands into clinical study protocol templates.

Clinical study protocols are the foundation of good clinical studies. Prospective and multidisciplinary collaboration that pays attention to the design of all components of the study protocol can ensure that a clinical study will answer the research questions posed in a reliable manner that is meaningful for decision-makers and patients. The ICH E9(R1) addendum on estimands and sensitivity analysis in clinical trials provides a framework for clinical study planning to ensure alignment between study objectives, design, conduct, and analysis. The estimand or clinical question posed can be regarded as the backbone of the study and the clinical study protocol should reflect estimands accordingly. In practice, stakeholders are still learning how to embrace the estimand framework and how it impacts studies and study documents. In this paper, we anticipate that a protocol structure centred around estimands, or objectives rather than endpoints alone will prevail for all types of studies. To assist sponsors during this paradigm shift, this paper provides discussion and guidance for implementing the estimand framework in protocol templates.

Extracorporeal IgE Immunoadsorption in Allergic Asthma: Safety and Efficacy.

BACKGROUND: Prevention of IgE-binding to cellular IgE-receptors by anti-IgE (Omalizumab) is clinically effective in allergic asthma, but limited by IgE threshold-levels. To overcome this limitation, we developed a single-use IgE immunoadsorber column (IgEnio). IgEnio is based on a recombinant, IgE-specific antibody fragment and can be used for the specific extracorporeal desorption of IgE. OBJECTIVE: To study safety and efficacy of IgEnio regarding the selective depletion of IgE in a randomized, open-label, controlled pilot trial in patients with allergic asthma and to investigate if IgEnio can bind IgE-Omalizumab immune complexes. METHODS: Fifteen subjects were enrolled and randomly assigned to the treatment group (n=10) or to the control group (n=5). Immunoadsorption was done by veno-venous approach, processing the twofold calculated plasma volume during each treatment. A minimum average IgE-depletion of 50% after the last cycle in the intention-to-treat population was defined as primary endpoint. Safety of the treatment was studied as secondary endpoint. In addition, possible changes in allergen-specific sensitivity were investigated, as well as clinical effects by peak flow measurement and symptom-recording. The depletion of IgE-Omalizumab immune complexes was studied in vitro. The study was registered at clinicaltrials.gov (NCT02096237) and conducted from December 2013 to July 2014. RESULTS: IgE immunoadsorption with IgEnio selectively depleted 86.2% (±5.1% SD) of IgE until the end of the last cycle (p<0.0001). Removal of pollen allergen-specific IgE was associated with a reduction of allergen-specific basophil-sensitivity and prevented increases of allergen-specific skin-sensitivity and clinical symptoms during pollen seasons. IgEnio also depleted IgE-Omalizumab immune complexes in vitro. The therapy under investigation was safe and well-tolerated. During a total of 81 aphereses, 2 severe adverse events (SAE) were recorded, one of which, an episode of acute dyspnea, possibly was related to the treatment and resolved after administration of antihistamines and corticosteroids. CONCLUSIONS: This pilot study indicates that IgE immunoadsorption with IgEnio may be used to treat patients with pollen-induced allergic asthma. Furthermore, the treatment could render allergic patients with highly elevated IgE-levels eligible for the administration of Omalizumab and facilitate the desorption of IgE-Omalizumab complexes. This study was funded by Fresenius Medical Care Deutschland GmbH, Bad Homburg, Germany.

Cannulation technique influences arteriovenous fistula and graft survival.

Hemodialysis patient survival is dependent on the availability of a reliable vascular access. In clinical practice, procedures for vascular access cannulation vary from clinic to clinic. We investigated the impact of cannulation technique on arteriovenous fistula and graft survival. Based on an April 2009 cross-sectional survey of vascular access cannulation practices in 171 dialysis units, a cohort of patients with corresponding vascular access survival information was selected for follow-up ending March 2012. Of the 10,807 patients enrolled in the original survey, access survival data were available for 7058 patients from nine countries. Of these, 90.6% had an arteriovenous fistula and 9.4% arteriovenous graft. Access needling was by area technique for 65.8%, rope-ladder for 28.2%, and buttonhole for 6%. The most common direction of puncture was antegrade with bevel up (43.1%). A Cox regression model was applied, adjusted for within-country effects, and defining as events the need for creation of a new vascular access. Area cannulation was associated with a significantly higher risk of access failure than rope-ladder or buttonhole. Retrograde direction of the arterial needle with bevel down was also associated with an increased failure risk. Patient application of pressure during cannulation appeared more favorable for vascular access longevity than not applying pressure or using a tourniquet. The higher risk of failure associated with venous pressures under 100 or over 150 mm Hg should open a discussion on limits currently considered acceptable.

A multicentric, international matched pair analysis of body composition in peritoneal dialysis versus haemodialysis patients.

BACKGROUND: Volume status, lean and fat tissue are gaining interest as prognostic predictors in patients on dialysis. Comparative data in peritoneal dialysis (PD) versus haemodialysis (HD) patients are lacking. METHODS: In a cohort of PD (EuroBCM) and HD (Euclid database) patients, matched for country, gender, age and dialysis vintage, body composition was assessed by bioimpedance spectroscopy (BCM, Fresenius Medical Care). Time-averaged volume overload (TAVO) was defined as the mean of pre- and post-dialysis volume overload (VO), and relative (%) (TA)VO as (TA)VO/ECV. RESULTS: Four hundred and ninety-one matched pairs (55.2% males, median age 60.0 years) were included. The body mass index (BMI, PD = 26.5 ± 4.7 versus HD = 25.9 ± 4.6 kg/m(2), P = 0.18 in males and 27.4 ± 5.8 versus 27.5 ± 6.6 kg/m(2), P = 0.75 in females) and fat tissue index (males: 11.5 ± 5.3 versus 11.4 ± 5.4 kg/m(2), P = 0.90, females: 14.8 ± 6.7 versus 15.4 ± 7.2 kg/m(2), P = 0.30) were not different in PD versus HD patients, whereas the lean tissue index (LTI) was higher in PD versus HD patients (males: 14.5 ± 3.4 versus 13.7 ± 3.1 kg/m(2), P = 0.001, females: 12.6 ± 3.3 versus 11.5 ± 2.6 kg/m(2), P < 0.0001). VO/extracellular water (ECW) was not different between PD versus just before the HD treatment (males: 10.8 ± 12.1 versus 9.2 ± 10.2%, P = 0.09; females: 6.5 ± 10.8 versus 7.7 ± 9.4%, P = 0.19). The relative TAVO was higher in PD versus HD (10.8 ± 12.1% versus 3.2 ± 11.2%, and 6.5 ± 10.8% versus 1.2 ± 10.9%, both P < 0.0001). CONCLUSIONS: The LTI was impaired, and this was more in males versus females, but was better preserved on PD versus HD, whereas fat tissue index (FTI) was increased, but not different between PD and HD. Volume overload was more present in PD versus HD when TAVO, but not when predialysis volume status, was used as a reference.

Vascular access cannulation in hemodialysis patients - a survey of current practice and its relation to dialysis dose.

PURPOSE: The appropriate use of vascular access is of fundamental importance in the treatment of hemodialysis (HD) patients. This survey entailed collecting data on current practice of vascular access cannulation to assess its relation to dialysis dose. METHODS: This international, multicenter, observational, cross-sectional survey was performed in 171 dialysis centers of the European dialysis network of Fresenius Medical Care in Europe and South Africa during April 2009. Practice patterns of vascular access cannulations were documented by means of a 24-item questionnaire. Dialysis dose from the documented hemodialysis treatments was derived from the clinical database EuCliD®. RESULTS: In total, 10,807 cannulations in hemodialysis patients with either arteriovenous fistula (91%) or arteriovenous graft (9%) were documented. For the puncture, the area technique was applied most frequently using 15G and 16G needles. Blood flow rates were mostly between 300 and 400 mL/min and adjusted to the needle size used. In two-thirds of cases the arterial needle was placed first, mostly in an antegrade direction, with an average distance to the venous needle of 7.0±3.7 cm. More than two-thirds of the cannulations were performed by nurses with more than 5 years of experience in dialysis. A logistic regression model revealed a significantly higher odds ratio to attain Kt/V = 1.2 for retrograde placement of the arterial needle, and for using needles with bigger diameter. CONCLUSIONS: This survey covered a broad number of countries and centers and provides information on current practice of vascular access cannulation, their effect on dialysis dose, and serves as feedback to the dialysis centers for their quality management process.

Fluid status in peritoneal dialysis patients: the European Body Composition Monitoring (EuroBCM) study cohort.

BACKGROUND: Euvolemia is an important adequacy parameter in peritoneal dialysis (PD) patients. However, accurate tools to evaluate volume status in clinical practice and data on volume status in PD patients as compared to healthy population, and the associated factors, have not been available so far. METHODS: We used a bio-impedance spectroscopy device, the Body Composition Monitor (BCM) to assess volume status in a cross-sectional cohort of prevalent PD patients in different European countries. The results were compared to an age and gender matched healthy population. RESULTS: Only 40% out of 639 patients from 28 centres in 6 countries were normovolemic. Severe fluid overload was present in 25.2%. There was a wide scatter in the relation between blood pressure and volume status. In a multivariate analysis in the subgroup of patients from countries with unrestricted availability of all PD modalities and fluid types, older age, male gender, lower serum albumin, lower BMI, diabetes, higher systolic blood pressure, and use of at least one exchange per day with the highest hypertonic glucose were associated with higher relative tissue hydration. Neither urinary output nor ultrafiltration, PD fluid type or PD modality were retained in the model (total R² of the model = 0.57). CONCLUSIONS: The EuroBCM study demonstrates some interesting issues regarding volume status in PD. As in HD patients, hypervolemia is a frequent condition in PD patients and blood pressure can be a misleading clinical tool to evaluate volume status. To monitor fluid balance, not only fluid output but also dietary input should be considered. Close monitoring of volume status, a correct dialysis prescription adapted to the needs of the patient and dietary measures seem to be warranted to avoid hypervolemia.

Emollients in a propanol-based hand rub can significantly decrease irritant contact dermatitis.

The objective of this study is to determine the effect of emollients in a propanol-based hand rub on skin dryness and erythema. In this prospective, randomized, controlled, double-blind trial, 35 subjects participated; of them approximately half were atopic (modified Erlanger atopy score > or =8). 2 propanol-based formulations were tested in a repeated open application test, 1 contained a mixture of emollients (0.81%, w/w). 2 aliquots of 0.7 ml of each formulation were applied twice per day over 2 weeks to the cubital fossa of each subject after random assignment of the preparations. Treatment areas were assessed before each application and 3 days postfinal application by visual inspection for erythema and dryness according to a standard scale. The sum score over all assessment time-points served as primary parameter. The mean sum score for erythema and dryness was significantly lower for the hand rub with emollients (0.8 +/- 2.4) in comparison with that for the hand rub without emollients (1.5 +/- 3.5; P = 0.022; Wilcoxon signed rank test). A comparison of the atopic and non-atopic subjects revealed no significant difference for any of the products (P > 0.05; Mann-Whitney U-test). It is concluded that the addition of emollients to a propanol-based hand rub can significantly decrease irritant contact dermatitis under frequent-use conditions.

Analysis of 5' junctions of human LINE-1 and Alu retrotransposons suggests an alternative model for 5'-end attachment requiring microhomology-mediated end-joining.

Insertion of the human non-LTR retrotransposon LINE-1 (L1) into chromosomal DNA is thought to be initiated by a mechanism called target-primed reverse transcription (TPRT). This mechanism readily accounts for the attachment of the 3'-end of an L1 copy to the genomic target, but the subsequent integration steps leading to the attachment of the 5'-end to the chromosomal DNA are still cause for speculation. By applying bioinformatics to analyze the 5' junctions of recent L1 insertions in the human genome, we provide evidence that L1 uses at least two distinct mechanisms to link the 5'-end of the nascent L1 copy to its genomic target. While 5'-truncated L1 elements show a statistically significant preference for short patches of overlapping nucleotides between their target site and the point of truncation, full-length insertions display no distinct bias for such microhomologies at their 5'-ends. In a second genome-wide approach, we analyzed Alu elements to examine whether these nonautonomous retrotransposons, which are thought to be mobilized through L1 proteins, show similar characteristics. We found that Alu elements appear to be predominantly integrated via a pathway not involving overlapping nucleotides. The results indicate that a cellular nonhomologous DNA end-joining pathway may resolve intermediates from incomplete L1 retrotransposition events and thus lead to 5' truncations.

Tissue at risk is overestimated in perfusion-weighted imaging: MR imaging in acute stroke patients without vessel recanalization.

BACKGROUND AND PURPOSE: The volume of decreased cerebral blood flow (CBF) in acute stroke perfusion-weighted imaging frequently overestimates final infarct volume. We hypothesized that surviving tissue exists even in patients without recanalization and tried to determine perfusion thresholds from initial MR imaging. METHODS: Stroke MR imaging including MR angiography was carried out at days 0, 1, and 7 after stroke onset in 19 patients without recanalization at least until day 1. The following lesions were defined: L0 = diffusion restriction at day 0; LG1 = lesion growth until day 1; LG7 = lesion growth until day 7; ST7 = initially hypoperfused, but surviving tissue. These lesions were transferred on initial MR imaging within 4.7 hours and perfusion values at day 0 were determined. RESULTS: Median lesion volume L0 at day 0 was 18.2 mL and increased to 39.4 and 43.8 mL at days 1 and 7. Volume of decreased rCBF not progressing to infarction was 148.5 mL (ST7). Mean ST7 perfusion values were different from L0 and LG1, but only mean relative cerebral blood volume (rCBV) was different from LG7, discriminating survival against death of tissue. A threshold value of 0.82 CBV for death versus survival was determined with a sensitivity of 0.56 and specificity of 0.95. Carotid T occlusions showed the greatest potential of lesion growth. CONCLUSION: Even when vessel occlusion persists, hypoperfused tissue on MR imaging does not necessarily progress toward infarction. The most conclusive inferences can be drawn from CBV images. The site of arterial occlusion also determines progression to infarction.

Analysis of concerted expression of angiogenic growth factors in acute myeloid leukemia: expression of angiopoietin-2 represents an independent prognostic factor for overall survival.

PURPOSE: Bone marrow neoangiogenesis plays an important pathogenetic and possible prognostic role in acute myeloid leukemia (AML). Members of the vascular endothelial growth factor (VEGF) and angiopoietin family represent the most specific inducers of angiogenesis secreted by AML blasts. We therefore correlated expression of angiogenic factors with clinical variables. PATIENTS AND METHODS: We investigated the expression of VEGF-A, VEGF-C, angiopoietin-1 (Ang1), angiopoietin-2 (Ang2), and the receptor Tie2 by quantitative polymerase chain reaction in a cohort of 90 patients younger than 61 years with de novo AML entered into the German AML Süddeutsche Hämoblastose Gruppe Hannover 95 trial. Uni- and multivariate analyses were performed using clinical and gene expression variables. RESULTS: Univariate analysis of overall survival indicated the following variables as prognostic factors: good response on a day-15 bone marrow examination after initiation of induction chemotherapy, karyotype, and high Ang2 expression. In multivariate analysis, only bad response and log Ang2 expression remained of statistical significance, with a hazard ratio of 3.51 (95% CI, 1.91 to 6.47) and 0.75 (95% CI, 0.61 to 0.91), respectively. Subgroup analysis suggested that the prognostic impact of Ang2 expression was especially evident in cohorts with low VEGF-C and Ang1 mRNA levels. CONCLUSION: These results show that expression of Ang2 represents an independent prognostic factor in AML. Additional research into interactions of angiogenic cytokines in the pathogenesis of bone marrow angiogenesis in AML is warranted.

MR evaluation of dural ectasia in Marfan syndrome: reassessment of the established criteria in children, adolescents, and young adults.

PURPOSE: To retrospectively evaluate known criteria for assessment of dural ectasia by using magnetic resonance (MR) imaging in children, adolescents, and young adults with and those without Marfan syndrome. MATERIALS AND METHODS: Local ethics committee approval and informed consent were obtained. MR images of the lumbar spine in 28 patients with clinically proved Marfan syndrome (group A; 17 male, 11 female; age range, 4-21 years; mean, 12.1 years), seven patients with suspicion of Marfan syndrome (group B; six male, one female; age range, 6-18 years; mean, 10.4 years), and 55 patients without Marfan syndrome (group C; 26 male, 29 female; age range, 4-20 years; mean, 10.7 years) were evaluated retrospectively for dural ectasia criteria (scalloping, dural sac ratio, nerve root sleeve diameter, sagittal dural sac width at S1 greater than that at L4) and according to classifications by Ahn et al and Fattori et al. For statistical comparison of results, one-way analysis of variance with Scheffe post hoc comparisons was used, with an overall two-tailed significance at alpha = .05. RESULTS: No significant differences in scalloping and nerve root sleeve diameter were shown between groups. A significant difference was measured for dural sac ratios at L5 and S1 (F test, P = .003 and P < .001 at L5 and S1, respectively; post hoc t test for groups A vs C, P = .004 and P < .001 at L5 and S1, respectively). Significant differences were also obtained between groups A and C for sagittal dural sac width at S1 greater than that at L4 according to the calculated mean difference (for both F test and post hoc t test, P < .001 and P = .003 at S1 and L4, respectively). The Ahn et al and Fattori et al classifications were of limited value. CONCLUSION: The data suggest that only dural sac ratio at L5 and S1 and a sagittal dural sac width at S1 greater than that at L4 are statistically significant criteria for the assessment of dural ectasia in children, adolescents, and young adults.

[Tooth eruption times of permanent teeth in male and female adolescents in Niedersachsen]. / Durchbruchszeiten der bleibenden Zähne bei Jungen und Mädchen in Niedersachsen.

The aim of this study was to determine the eruption times of permanent teeth, excluding third molars, in a defined area population of a country district in Lower Saxony. The authors investigated 2495 oral findings of 664 patients (male 315, female 349) in a longitudinal study. The minimum age was 3.00 years and the maximum age 24.00 years. The dental findings were collected over a period of about 20 years (1980-2002). The oral findings per child/adolescent were assessed between one and 16 times. The eruption times of teeth in females are earlier than those for the same teeth in males. Further, the permanent dentition in females is completed earlier than in males. The tooth eruption occurs symmetrically in both jaws. The comparison of both jaws revealed a slightly advanced eruption of the lower jaw teeth for both sexes. There is a noteworthy change in the eruption sequence of the teeth. In contrast to other reports we determined that the eruption of the canine proceeds the eruption of the second premolar. We found no acceleration of the dentition when compared to other reports and confirmed the rules of tooth eruption in man. Oral examination of teeth is a simple tool to calculate tooth eruption intervals. This first investigation on a population of Lower Saxony revealed a change in the eruption sequence of permanent teeth. The findings are relevant for dental treatment planning and should be reconfirmed at certain intervals.

Preoperative staging of gastric adenocarcinoma: comparison of helical CT and endoscopic US.

PURPOSE: To compare the performance of helical computed tomography (CT) and endoscopic ultrasonography (US) in the preoperative staging of gastric cancer. MATERIALS AND METHODS: Fifty-one consecutive patients with a primary malignant gastric tumor (stage T2-T4) were preoperatively evaluated with both helical CT and endoscopic US within 3 days. Each tumor was staged according to the TNM classification system with both modalities. All patients subsequently underwent surgery. Results of CT and endoscopic US were compared with histologic staging of tumor invasion depth and regional lymph node metastasis. For comparison of CT and endoscopic US data, the marginal homogeneity test was used, and a P value of less than.05 was determined to indicate statistical significance. RESULTS: In comparison with histologic results, CT achieved correct T staging in 39 patients (76%) and correct N staging in 35 patients (70%). The corresponding results for endoscopic US achieved correct T staging in 44 patients (86%) and correct N staging in 45 patients (90%). There was no significant difference between T staging (P =.55) and N staging (P >.99). Because of challenging detection of wall layers, correct T staging was difficult for CT and endoscopic US in the differentiation of T2 and T3 lesions. CONCLUSION: Compared with endoscopic US, helical CT focused on the stomach provides valuable results regarding T and N staging in patients with gastric cancer.

Prediction of malignant middle cerebral artery infarction by early perfusion- and diffusion-weighted magnetic resonance imaging.

BACKGROUND AND PURPOSE: We tested the hypothesis that early diffusion- and perfusion-weighted MRI (DWI and PWI, respectively) allows the prediction of malignant middle cerebral artery (MCA) infarction (MMI). METHODS: Thirty-seven patients with acute MCA infarction and proximal vessel occlusion (carotid-T, MCA main stem) were studied by DWI, PWI, and MR angiography within 6 hours of symptom onset. Eleven patients developed MMI, defined by decline of consciousness and radiological signs of space-occupying brain edema. Lesion volumes were retrospectively defined as apparent diffusion coefficient <80% (ADC<80%) and time to peak >+4 seconds (TTP>+4s) compared with the unaffected hemisphere. ADC decrease within the infarct core (ADCcore) and relative ADC within the ADC<80% lesion (rADClesion) were measured. Neurological deficit at admission was assessed with the National Institutes of Health Stroke Scale (NIHSS). RESULTS: Patients with MMI showed larger ADC<80% (median, 157 versus 22 mL; P<0.001) and TTP>+4s (208 versus 125 mL; P<0.001) lesion volumes, smaller TTP/ADC mismatch ratio (1.5 versus 5.5; P<0.001), lower ADCcore values (290 versus 411 mm2/s; P<0.001), lower rADClesion (0.60 versus 0.66; P=0.001), higher frequency of carotid-T occlusion (64% versus 15%; P=0.006), and higher NIHSS score at admission (20 versus 15; P=0.001). Predictors of MMI were as follows for sensitivity and specificity, respectively: ADC<80% >82 mL, 87%, 91%; TTP>+4s >162 mL, 83%, 75%; TTP/ADC mismatch ratio <2.4, 80%, 79%; ADCcore <300 mm2/s, 83%, 85%; rADClesion <0.62, 79%, 74%; and NIHSS score at admission > or =19, 96%, 72%. CONCLUSIONS: Quantitative analysis of early DWI and PWI parameters allows the prediction of MMI and can help in the selection of patients for aggressive tissue-protective therapy.

Sensitivity and interrater agreement of CT and diffusion-weighted MR imaging in hyperacute stroke.

BACKGROUND AND PURPOSE: Previous acute stroke studies found diffusion-weighted (DW) imaging superior to CT for detection of early ischemic signs (EIS). However, these findings were confounded by a large time interval in favor of DW imaging. We compared DW images and CT scans obtained with a short time delay in patients with acute stroke to define the sensitivity and interrater agreement of both imaging techniques. METHODS: CT scans and DW images were obtained within 6 hours of symptom onset in 46 patients with acute stroke. Three neuroradiologists and three neurologists reviewed the images for EIS in five regions of the middle cerebral artery (MCA) territory and estimated the extent of EIS (< or > one-third of the MCA territory). RESULTS: The mean delay between imaging with both modalities was 24.5 minutes (range, 10-41 minutes). Forty-five of 46 patients had an ischemic stroke. EIS were seen on 33 of 45 CT scans (73% sensitivity; 95% confidence interval [CI]: 58-85%) and on 42 of 45 DW images (93% sensitivity; 94% CI: 82-99%). Interrater agreement was moderate (kappa = 0.57) for CT and excellent (kappa = 0.85) for DW imaging. CT studies had a moderate interrater agreement for estimation of EIS greater than one-third of the MCA territory (kappa = 0.40), whereas DW imaging showed good results (kappa = 0.68). Sensitivity for detection of greater than one-third of the MCA territory was equally poor (57%, 95% CI: 29-82%) for both CT and DW imaging. CONCLUSION: DW imaging helped identify EIS with higher sensitivity than that of CT. The interrater variability of the one-third rule was high for CT, and thus the clinical applicability of CT is limited. Our results support the application of stroke MR imaging for the treatment of patients with acute stroke.

Split liver transplantation and risk to the adult recipient: analysis using matched pairs.

BACKGROUND: The technique of liver splitting is an effective way of increasing the donor pool and reducing pediatric waiting list mortality. But the procedure is still not fully accepted because of concerns that it may cause complications in adult recipients. STUDY DESIGN: Fifty-nine adult recipients of primary extended right split liver transplantations (SLTs) were matched to recipients of whole liver transplantations (WLTs) according to the following criteria: 1) United Network for Organ Sharing (UNOS) status, 2) donor age, 3) recipient age, 4) total cold ischemic time, 5) indication for liver transplantation, 6) Child-Pugh class, and 7) year of transplantation. A WLT-recipient match was identified in 40 adult recipients of primary SLT. RESULTS: Fifteen percent of the recipients in our study were highly urgent cases (UNOS 1), and 85% were UNOS status 3-4. The 3- and 12-month patient survival rates after SLT and WLT were 82.5% and 77.1%, and 92.5% and 87.5%, respectively (log rank p = 0.358). The 3- and 12-month graft survival rates showed no significant difference in either group (80% and 74% in SLT and 87.5% and 77.4% in WLT [log rank p = 0.887]). The rates of primary nonfunction, primary poor function, biliary and vascular complications, intra- and postoperative blood transfusion, and intensive care stay were comparable for SLT and WLT. CONCLUSIONS: SLT, using the extended right hepatic lobe, does not notably differ from WLT with regard to initial graft function, postoperative complications, or patient and graft survival. Based on this, the liver can be considered a paired organ, and mandatory splitting of good-quality livers can be recommended.

A randomized and controlled pilot trial of beta-blockers for the treatment of recurrent syncope in patients with a positive or negative response to head-up tilt test.

The aim of this study was to assess the efficacy of lipophilic beta-blockers in preventing recurrent neurocardiogenic syncope and the value of head-up tilt test (HUT) in predicting response to therapy. The efficacy of beta-blockers in recurrent syncope is controversial. The value of HUT in predicting efficacy of therapy has not been investigated. Fifty-six patients (44+/-18 years, 36 women) with recurrent syncope (> 1 event in the last 6 months) of suspected neurocardiogenic origin were included in the study. Independent of the response to HUT, patients were randomized to receive metoprolol or propanolol at the maximal tolerated dose (28 patients, group A, 86+/-23 vs 98+/-29 mg/d) or no pharmacological therapy (28 patients, group B). The primary endpoint was the first recurrence of syncope. During the 1-year of follow-up, 20 patients of group A and 8 of group B had no recurrence. In group A, of 20 patients without recurrences 12 had a positive and 8 a negative HUT result while of 8 patients with recurrences 5 had a positive and 3 a negative response to HUT. In the group B, of 20 patients with recurrences 10 had a positive and 10 a negative HUT result while of 8 patients without recurrences 4 had a positive and 4 a negative response to HUT. In a multivariate Cox-regression analysis, medical therapy was the only independent factor for predicting recurrence of syncope (P = 0.004); HUT had no influence in this regard (P = 0.773). In conclusion, lipophilic beta-blockers appear efficacious in preventing recurrent syncope of suspected neurocardiogenic origin. The efficacy of therapy seems to be not predicted by HUT.