DNA-PKcs as an upstream mediator of OCT4-induced MYC activation in small cell lung cancer.

Small cell lung cancer (SCLC) is a neuroendocrine tumor noted for the rapid development of both metastases and resistance to chemotherapy. High mutation burden, ubiquitous loss of TP53 and RB1, and a mutually exclusive amplification of MYC gene family members contribute to genomic instability and make the development of new targeted agents a challenge. Previously, we reported a novel OCT4-induced MYC transcriptional activation pathway involving c-MYC, pOCT4S111, and MAPKAPK2 in progressive neuroblastoma, also a neuroendocrine tumor. Using tumor microarray analysis of clinical samples and preclinical models, we now report a correlation in expression between these proteins in SCLC. In correlating c-MYC protein expression with genomic amplification, we determined that some SCLC cell lines exhibited high c-MYC without genomic amplification, implying amplification-independent MYC activation. We then confirmed direct interaction between OCT4 and DNA-PKcs and identified specific OCT4 and DNA-PKcs binding sites. Knock-down of both POU5F1 (encoding OCT4) and PRKDC (encoding DNA-PKcs) resulted in decreased c-MYC expression. Further, we confirmed binding of OCT4 to the promoter/enhancer region of MYC. Together, these data establish the presence of a DNA-PKcs/OCT4/c-MYC pathway in SCLCs. We then disruptively targeted this pathway and demonstrated anticancer activity in SCLC cell lines and xenografts using both DNA-PKcs inhibitors and a protein-protein interaction inhibitor of DNA-PKcs and OCT4. In conclusion, we demonstrate here that DNA-PKcs can mediate high c-MYC expression in SCLCs, and that this pathway may represent a new therapeutic target for SCLCs with high c-MYC expression.

In vitro growth inhibitory effect of selected 18ß-glycyrrhetinic acid esters on Theileriaannulata.

Glycyrrhetinic acid (GA) is one of the important Pentacyclic Triterpenoids (PT) found in the roots of licorice. This study aimed to evaluate the in vitro growth inhibitory effect of 18ß-GA (18ß-Glycyrrhetinic acid) and C-30 esters against Theileria annulata, the causative agent of Tropical Bovine Theileriosis. C-30 esters of 18ß-GA were synthesized and their structures were elucidated using spectroscopy. The pharmacodynamic properties of 18ß-GA and its C-30 esters were predicted using DataWarrior and Swiss ADME tools. Cattle isolates of T. annulata schizont-infected bovine lymphoblastoid cells were cultured using standard conditions and the growth inhibitory effect of GA and its esters were evaluated using MTT assay. The isopropyl ester of 18ß-GA (GI50- 1.638 µM; R2- 0.818) showed improved anti-theileriosis efficacy than other 18ß-GA derivatives. The propyl (GI50 - 5.549 µM), ethyl (GI50 - 5.638 µM), and benzyl (GI50 - 7.431 µM) esters also showed considerable inhibitory effect. The GI50 value for 18ß-GA was recorded as 6.829 µM. This study throws light on the usefulness of 18ß-GA and its esters for the treatment of Tropical Bovine Theileriosis.

Plasma chemokines as immune biomarkers for diagnosis of pediatric tuberculosis.

BACKGROUND: Diagnosing tuberculosis (TB) in children is challenging due to paucibacillary disease, and lack of ability for microbiologic confirmation. Hence, we measured the plasma chemokines as biomarkers for diagnosis of pediatric tuberculosis. METHODS: We conducted a prospective case control study using children with confirmed, unconfirmed and unlikely TB. Multiplex assay was performed to examine the plasma CC and CXC levels of chemokines. RESULTS: Baseline levels of CCL1, CCL3, CXCL1, CXCL2 and CXCL10 were significantly higher in active TB (confirmed TB and unconfirmed TB) in comparison to unlikely TB children. Receiver operating characteristics curve analysis revealed that CCL1, CXCL1 and CXCL10 could act as biomarkers distinguishing confirmed or unconfirmed TB from unlikely TB with the sensitivity and specificity of more than 80%. In addition, combiROC exhibited more than 90% sensitivity and specificity in distinguishing confirmed and unconfirmed TB from unlikely TB. Finally, classification and regression tree models also offered more than 90% sensitivity and specificity for CCL1 with a cutoff value of 28 pg/ml, which clearly classify active TB from unlikely TB. The levels of CCL1, CXCL1, CXCL2 and CXCL10 exhibited a significant reduction following anti-TB treatment. CONCLUSION: Thus, a baseline chemokine signature of CCL1/CXCL1/CXCL10 could serve as an accurate biomarker for the diagnosis of pediatric tuberculosis.

Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.

Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.

Ultrafast Electron Transfer Kinetics of Graphene Grown by Chemical Vapor Deposition.

High electrochemical reactivity is required for various energy and sensing applications of graphene grown by chemical vapor deposition (CVD). Herein, we report that heterogeneous electron transfer can be remarkably fast at CVD-grown graphene electrodes that are fabricated without using the conventional poly(methyl methacrylate) (PMMA) for graphene transfer from a growth substrate. We use nanogap voltammetry based on scanning electrochemical microscopy to obtain very high standard rate constants k(0) ≥25 cm s(-1) for ferrocenemethanol oxidation at polystyrene-supported graphene. The rate constants are at least 2-3 orders of magnitude higher than those at PMMA-transferred graphene, which demonstrates an anomalously weak dependence of electron-transfer rates on the potential. Slow kinetics at PMMA-transferred graphene is attributed to the presence of residual PMMA. This unprecedentedly high reactivity of PMMA-free CVD-grown graphene electrodes is fundamentally and practically important.

Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families.

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

The Matchmaker Exchange: a platform for rare disease gene discovery.

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for "the needle in a haystack" to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease-specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can "match" these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

Facilitating collaboration in rare genetic disorders through effective matchmaking in DECIPHER.

DECIPHER (https://decipher.sanger.ac.uk) is a web-based platform for secure deposition, analysis, and sharing of plausibly pathogenic genomic variants from well-phenotyped patients suffering from genetic disorders. DECIPHER aids clinical interpretation of these rare sequence and copy-number variants by providing tools for variant analysis and identification of other patients exhibiting similar genotype-phenotype characteristics. DECIPHER also provides mechanisms to encourage collaboration among a global community of clinical centers and researchers, as well as exchange of information between clinicians and researchers within a consortium, to accelerate discovery and diagnosis. DECIPHER has contributed to matchmaking efforts by enabling the global clinical genetics community to identify many previously undiagnosed syndromes and new disease genes, and has facilitated the publication of over 700 peer-reviewed scientific publications since 2004. At the time of writing, DECIPHER contains anonymized data from ∼250 registered centers on more than 51,500 patients (∼18000 patients with consent for data sharing and ∼25000 anonymized records shared privately). In this paper, we describe salient features of the platform, with special emphasis on the tools and processes that aid interpretation, sharing, and effective matchmaking with other data held in the database and that make DECIPHER an invaluable clinical and research resource.

Hierarchical graphene/metal grid structures for stable, flexible transparent conductors.

We report an experimental study on the fabrication and characterization of hierarchical graphene/metal grid structures for transparent conductors. The hierarchical structure allows for uniform and local current conductivity due to the graphene and exhibits low sheet resistance because the microscale silver grid serves as a conductive backbone. Our samples demonstrate 94% diffusive transmission with a sheet resistance of 0.6 Ω/sq and a direct current to optical conductivity ratio σdc/σop of 8900. The sheet resistance of the hierarchical structure may be improved by over 3 orders of magnitude and with little decrease in transmission compared with graphene. Furthermore, the graphene protects the silver grid from thermal oxidation and better maintains the sheet resistance of the structure at elevated temperature. The graphene also strengthens the adhesion of the metal grid with the substrate such that the structure is more resilient under repeated bending.

Reversibility of brainstem evoked response audiometry abnormalities at 3 months in term newborns with hyperbilirubinemia.

BACKGROUND: High bilirubin level is toxic to developing brain and auditory system but the current debate surrounds the toxicity of bilirubin in healthy term infants. METHODS: Longitudinal observational study to find BERA abnormalities in term newborns with isolated hyperbilirubinemia of 20 mg/dL and more and to follow up babies at 3 months to find out about the reversibility in BERA abnormalities noted at birth. RESULTS: BERA abnormalities were present in 17.64% of babies with isolated hyperbilirubinemia at discharge. There was a reversibility of BERA abnormalities in 61.61% during follow up. CONCLUSIONS: BERA abnormalities are reversible in term neonates with hyperbilirubinemia.

Enhanced room-temperature corrosion of copper in the presence of graphene.

This paper reports the enhancement of long-term oxidation of copper at room temperature by a graphene coating. Previous studies showed that graphene is an effective anticorrosion barrier against short-term thermal and electrochemical oxidation of metals. Here, we show that a graphene coating can, on the contrary, accelerate long-term oxidation of an underlying copper substrate in ambient atmosphere at room temperature. After 6 months of exposure in air, both Raman spectroscopy and energy-dispersive X-ray spectroscopy indicated that graphene-coated copper foil had a higher degree of oxidation than uncoated foil, although X-ray photoelectron spectroscopy showed that the surface concentration of Cu(2+) was higher for the uncoated sample. In addition, we observed that the oxidation of graphene-coated copper foil was not homogeneous and occurred within micrometer-sized domains. The corrosion enhancement effect of graphene was attributed to its ability to promote electrochemical corrosion of copper.

DECIPHER: web-based, community resource for clinical interpretation of rare variants in developmental disorders.

Patients with developmental disorders often harbour sub-microscopic deletions or duplications that lead to a disruption of normal gene expression or perturbation in the copy number of dosage-sensitive genes. Clinical interpretation for such patients in isolation is hindered by the rarity and novelty of such disorders. The DECIPHER project (https://decipher.sanger.ac.uk) was established in 2004 as an accessible online repository of genomic and associated phenotypic data with the primary goal of aiding the clinical interpretation of rare copy-number variants (CNVs). DECIPHER integrates information from a variety of bioinformatics resources and uses visualization tools to identify potential disease genes within a CNV. A two-tier access system permits clinicians and clinical scientists to maintain confidential linked anonymous records of phenotypes and CNVs for their patients that, with informed consent, can subsequently be shared with the wider clinical genetics and research communities. Advances in next-generation sequencing technologies are making it practical and affordable to sequence the whole exome/genome of patients who display features suggestive of a genetic disorder. This approach enables the identification of smaller intragenic mutations including single-nucleotide variants that are not accessible even with high-resolution genomic array analysis. This article briefly summarizes the current status and achievements of the DECIPHER project and looks ahead to the opportunities and challenges of jointly analysing structural and sequence variation in the human genome.

Motorist actions at a crosswalk with an in-pavement flashing light system.

OBJECTIVE: An in-pavement flashing light system is used at crosswalks to alert motorists and pedestrians of possible conflicts and to influence their behavior to enhance safety. The relative behaviors of the drivers and the pedestrians affect safety. An evaluation of motorist behavior at a pedestrian crosswalk with an in-pavement flashing light system is presented in this manuscript. METHODS: Field observations provide the basis to evaluate motorist behavior at a crosswalk with an in-pavement flashing light system. Outcomes of pedestrian and motorists actions were observed to quantify measures of effectiveness (MOEs) such as yielding behavior of motorists, vehicle speeds, and yielding distance from the crosswalk. A before-and-after study design was used. The before condition was prior to the activation of the in-pavement flashing light system and the after condition was after the activation of the in-pavement flashing light system. The study was conducted on a relatively low-volume roadway located in the Henderson, Nevada. The significance of the differences in the MOEs between the 2 study periods was evaluated using statistical analysis tools such as a one-tailed test for proportions and the Welch-Satterthwaite t-test. RESULTS: The results show that the installation of the in-pavement flashing light system increased the yielding behavior of motorists significantly (P < 0.001). The vehicular speeds decreased when pedestrians were waiting at the curb to cross and when they were crossing (P < 0.001). Motorists yielded to pedestrians on an average about 3 m (∼10 feet) upstream from the yield markings and the yielding distances were consistent in both directions. CONCLUSION: The in-pavement flashing light system is seen to be effective to improve motorists' yielding behavior and the speeds of vehicles were also observed to decrease in the presence of pedestrians.

Comparison of the diagnostic capability of the Heidelberg Retina Tomographs 2 and 3 for glaucoma in the Indian population.

PURPOSE: To compare the diagnostic capability of the Heidelberg Retina Tomograph (HRT) 2 and 3 (Heidelberg Engineering, GmBH, Dossenheim, Germany) for glaucoma in an Indian population. DESIGN: Evaluation of a diagnostic technology. PARTICIPANTS: Ninety-eight glaucoma subjects and 79 normal controls. METHODS: All participants underwent imaging with HRT2. Heidelberg Retina Tomograph 2 examinations were exported to HRT3 software. The stereometric parameters of HRT2 and HRT3 were compared. The diagnostic capability of Moorfields Regression Analysis (MRA) in the HRT2, HRT3 with and without ethnicity correction, and Glaucoma Probability Score (GPS) of HRT3 were compared. Analysis was done with the borderline results of MRA and GPS considered as normal to derive the most specific criteria and as abnormal to derive the least specific criteria. MAIN OUTCOME MEASURES: Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). RESULTS: On standard automated perimetry (SAP), the mean deviation (mean+/-standard deviation) of the glaucoma and normal groups were -7.3+/-6.7 dB and -0.4+/-1.1 dB, respectively (P<0.001). The AUC for the individual stereometric parameters of HRT2 were similar to that of HRT3. The sensitivity and specificity (most specific criteria) were 56.1% and 96.2%, respectively, for MRA of HRT2 and 56.1% and 91.1%, respectively, for MRA of HRT3. The sensitivity and specificity (least specific criteria) were 88.8% and 88.6%, respectively, for MRA of HRT2 and 70.4% and 81%, respectively, for MRA of HRT3. By using the Indian specific normative database of HRT3, the sensitivity and specificity were 37.8% and 97.5%, respectively, for the most specific criteria, and 55.1% and 89.9%, respectively, for the least specific criteria. Sensitivity and specificity of GPS were 86.7% and 68.3%, respectively, for the most specific criteria, and 93.9% and 39.2%, respectively, for the least specific criteria. CONCLUSIONS: In this cohort, the diagnostic capability of HRT2 MRA was similar to that of HRT3 MRA; ethnicity correction did not improve results; GPS was more sensitive but less specific than MRA in diagnosing glaucoma.

Clinical measurement and categorization of optic disc in glaucoma patients.

BACKGROUND: Assessment of optic disc size is an important component of optic nerve head examination. Agreement between different methods of disc size measurements is not very good. PURPOSE: To assess the agreement between the disc size assessed by Heidelberg retina tomograph (HRT) and stereobiomicroscopy with a 90 diopter (D) lens. To report the clinical (measured by biomicroscopy) disc diameters of small, average and large optic discs categorized by HRT disc areas. SETTING AND DESIGN: Observational study of subjects examined in the glaucoma clinic of a tertiary eye institute. MATERIALS AND METHODS: Seventy-five eyes of 75 glaucoma subjects were studied. Disc diameter was measured using stereobiomicroscopy and HRT. The agreement between the two sets of measurements was assessed by intraclass correlation coefficient (ICC). Discs were classified into small (<1.6 mm(2)), average (1.6-2.6 mm(2)) and large (>2.6 mm(2)) depending on cutoffs provided by the manufacturers of HRT. The means (95% CI) of the corresponding vertical disc diameter in these groups were assessed. STATISTICAL ANALYSIS: ICC, Bland and Altman plots. RESULTS: ICC for measurements of clinical and HRT horizontal disc diameter was 0.518 and for vertical disc diameter measurement was 0.487. The mean difference between the clinical and HRT measurements as analyzed by the Bland and Altman plot was 0.17 (95% CI, 0.13- 0.47) for horizontal and 0.22 (95% CI, 0.11- 0.54) for vertical disc diameter. Of the 75 eyes, 3 eyes had small discs, 54 average and 18 large discs. The mean clinical vertical disc diameter for small discs was 1.55 mm (95% CI, 1.2-1.7), for average discs was 1.91 mm (95% CI, 1.87-1.96) and for large discs was 2.15 mm (95% CI, 2.03-2.27). CONCLUSION: The agreement between clinical and HRT disc diameter measurements is moderate. Disc diameter measurement on stereobiomicroscopy can be used to categorize discs into small, average and large discs.

Data deposition and annotation at the worldwide protein data bank.

The Protein Data Bank (PDB) is the repository for three-dimensional structures of biological macromolecules, determined by experimental methods. The data in the archive is free and easily available via the Internet from any of the worldwide centers managing this global archive. These data are used by scientists, researchers, bioinformatics specialists, educators, students, and general audiences to understand biological phenomenon at a molecular level. Analysis of this structural data also inspires and facilitates new discoveries in science. This chapter describes the tools and methods currently used for deposition, processing, and release of data in the PDB. References to future enhancements are also included.

Data deposition and annotation at the worldwide protein data bank.

The Protein Data Bank (PDB) is the repository for the three-dimensional structures of biological macromolecules, determined by experimental methods. The data in the archive are free and easily available via the Internet from any of the worldwide centers managing this global archive. These data are used by scientists, researchers, bioinformatics specialists, educators, students, and lay audiences to understand biological phenomena at a molecular level. Analysis of these structural data also inspires and facilitates new discoveries in science. This chapter describes the tools and methods currently used for deposition, processing, and release of data in the PDB. References to future enhancements are also included.

Does the method of lung preservation influence outcome after transplantation? An analysis of 681 consecutive procedures.

OBJECTIVE: Despite 50 years of lung preservation research, the optimal preservation technique is undefined. Using data from a national cohort, we investigated outcomes with different preservation methods after adult lung transplantation. METHODS: Early (30-day), late (30-day to 3-year), and overall (3-year) mortalities, adjusted for differences in donor and recipient characteristics, were compared by using Cox regression. Intensive care unit length of stay and the number of rejection episodes were secondary outcomes. RESULTS: Six hundred eighty-one eligible lung transplantations between July 1995 and June 2003 were preserved with Euro-Collins solution (n = 284), blood albumin (n = 139), core cooling (n = 107), or low potassium dextran solution (n = 151). There was significantly increased use of low potassium dextran solution over time (P < .001). Unadjusted 3-year survival was similar across the groups (P = .72), with the highest 3-year survival in the low potassium dextran group (62%; 95% confidence interval, 51%-72%) and the lowest in the blood albumin group (49%; 95% confidence interval, 39%-58%). Risk-adjusted early (P = .70), late (P = .27), and overall (P = .72) survival was similar across the groups and was not affected by ischemic time. Freedom from death caused by primary graft dysfunction was again highest in the low potassium dextran group (95%; 95% confidence interval, 90%-98%) and lowest in the blood albumin group (91%; 95% confidence interval, 85%-95%). There was no difference in intensive care unit length of stay. An increased incidence of rejection was apparent with increasing ischemic time (P = .067). CONCLUSION: The methods of lung preservation in current use do not seem to affect early or midterm survival after transplantation, but increasing ischemic time might predispose to increased rejection.

Donor cause of death and mid-term survival in lung transplantation.

BACKGROUND: The influence of donor cause of death (DCD) on survival after lung transplantation (LTx) is uncertain. This was investigated using data from a national prospective cohort study of adult single and bilateral LTx undertaken between July 1995 and June 2002. METHODS: DCD was categorized a priori into vascular and tumor (V), traumatic (T), hypoxic brain damage (H) and infective (I) causes. All T donor deaths were the result of blunt trauma. Risk factors for early (30 days), late (30 days to 5 years) and overall (5 years) mortality were identified using Cox regression analysis. RESULTS: Of 580 eligible transplants, DCDs were classified as V (n = 372), T (n = 153), H (n = 38) and I (n = 17). V donors were older (median 42 years) than the others (medians < 27 years) (p < 0.001). T donors were more likely to be of male gender (p < 0.001). Two hundred fifty-nine patients died within 5 years of surgery. The median follow-up time of survivors was 37 months. Unadjusted 5-year Kaplan-Meier survival rates did not vary with DCD (p = 0.6). Cox analysis identified donor age group, recipient diagnosis, pre-operative recipient ventilation, donor-recipient size mismatch, donor-recipient blood group variance, cytomegalovirus (CMV) mismatch and recipient creatinine clearance as predictors of mortality. After adjustment for these risk factors, DCD was not identified as a predictor of early (p = 0.2), late (p = 0.5) or overall mortality (p = 0.4) in LTx recipients. CONCLUSION: We found that DCD did not affect mid-term survival after LTx.

Outcome of heart-lung and bilateral sequential lung transplantation for cystic fibrosis: a UK national study.

Cystic fibrosis (CF) patients requiring transplantation for respiratory failure may undergo either heart-lung (HLT) or bilateral sequential lung (BSLT) transplantation. The choice of operation varies between surgeons, centres and countries. The current authors investigated whether operation type influenced outcome in adult CF patients transplanted in the UK between July 1995 and June 2002. Propensity scores for receipt of BSLT versus HLT were derived using logistic regression. Cox regression was used to compare survival. In total, 88 BSLTs and 93 HLTs were identified. Patient characteristics were similar overall, but HLT recipients were more likely to be on long-term oxygen therapy and to have had prior resuscitation. There were 72 deaths (29 BSLT and 43 HLT) within 4 yrs. There was a trend towards higher unadjusted survival following BSLT, but, after adjustment, no difference was found (hazard ratio = 0.77; 95% confidence interval 0.29-2.06). Time to the first rejection episode and infection rates were also similar. A total of 82% of hearts from HLT recipients were used as domino heart transplants. In conclusion, after adjusting for comorbidity, donor factors and ischaemia time, it was found that heart-lung and bilateral sequential lung transplantation achieved a similar outcome. The use of domino heart transplantation ameliorated the impact of heart-lung transplantation on total organ availability.