Background The aim of this study was to determine whether the duration of left ventricular device support (LVAD) influenced outcomes after orthotopic heart transplantation in a modern, bridge to ...transplant national cohort. Methods The United Network for Organ Sharing database, which has recently made pretransplant LVAD duration available, was queried for all adult bridge to transplant patients between January 2011 and December 2012. Three LVAD duration cohorts were generated, as follows: short (less than 90 days), intermediate (90 to 365 days), and prolonged (more than 365 days). Recipient, donor, and transplant-specific characteristics were compared among the duration cohorts. Unadjusted short-term and long-term survivals were estimated with the Kaplan-Meier method. Risk-adjusted models were also constructed to determine the independent impact of device duration on mortality. Results Of the 1,332 patients who met criteria for inclusion, 9.8% (n = 130), 54.7% (n = 729), and 35.5% (n = 473) were classified as short, intermediate, and prolonged, respectively. Although the performance status across each cohort was similar at listing ( p = 0.38), more patients in the intermediate and prolonged cohorts were considered functionally independent before orthotopic heart transplantation (32% and 37%, respectively, versus 18%; p < 0.001). Additionally, despite worse baseline renal function in the intermediate and prolonged cohorts relative to the short cohort (glomerular filtration rate, 57 and 57 versus 69, p < 0.001), there was no difference in the incidence of new onset posttransplant renal failure (7% versus 10%, 9%, p = 0.41). There was also no difference in 30-day survival (98%, 96%, 95%, p = 0.51), 6-month survival (93%, 92%, 92%, p = 0.93), or 1-year survival (91%, 89%, 89%, p = 0.78) across the cohorts. After risk adjustment, duration did not independently predict mortality at any timepoint. Conclusions In the largest, non–industry sponsored study of a modern bridge to transplant cohort, we demonstrated that duration of LVAD support before orthotopic heart transplantation does not influence posttransplant morbidity or mortality. In subanalysis, support for 90 days or more is associated with improvements in pretransplant functional performance.
Background The Blalock-Taussig shunt (BTS) was introduced 68 years ago before open repair of cyanotic congenital heart disease (CHD) was possible. The originally described technique has undergone ...many modifications but remains an integral component of the management of cyanotic CHD. We report our contemporary, single institution experience with the BTS. Study Design We performed a retrospective review of all patients treated with a BTS from June 1995 to December 2011. Results There were 730 BTS performed in 712 patients; 727 (99.6%) by interposition graft (modified). The BTS was predominantly right-sided (n = 657, 90%). Median age and weight at palliation were 8 days (range 0 days to 18.5 years) and 3.2 kg (1.5 to 51 kg). Median hospital length of stay was 16 days (range 0 to 347 days). There were 241 (33%) BTS performed as initial palliation for ultimate 2-ventricle (2V) circulation, 471 (65%) as part of staged palliation for patients with functionally univentricular lesions (1V), 6 (1%) as a part of 1.5-ventricle palliation, and 12 (1%) for Ebstein's anomaly. There were 473 (65%) BTS placed via sternotomy and the most common site of BTS was the right subclavian to right pulmonary artery (PA; n = 452, 62%). Hospital mortality was higher for BTS in 1V patients (1V 15% vs 2V 3%, p < 0.0001). Overall, 536 (73%) patients were bridged to complete repair or the second stage of 1V palliation after a median duration of 6.5 months (0 days to 15.3 years). Multivariable regression showed that sternotomy approach, use of cardiopulmonary bypass, innominate artery-PA shunt, and diagnosis of Ebstein's were risk factors for in-hospital mortality (p < 0.05). Conclusions Although the BTS remains an important component of the surgical treatment of cyanotic congenital heart disease, patients with single ventricle circulation still face significant ongoing risk of mortality.
Background A descending thoracic aorta that traverses the midline is an uncommon cause of airway compression affecting the distal trachea and proximal main bronchi. Posterior aortopexy has had ...inconsistent results. Methods A retrospective review determined that, since 2004, 5 children have undergone descending aortic translocation at Texas Children’s Hospital. The average age at the time of surgical treatment was 4.2 years, and all patients presented with recurring respiratory illness requiring hospitalization. All patients had preoperative imaging (4 patients with computed tomography scans and 1 with magnetic resonance imaging) confirming a compromised airway caused by a midline aorta, and 4 of the 5 patients had perioperative bronchoscopy. Three patients had a right-dominant double aortic arch. Descending aortic translocation was performed through a midline sternotomy with cardiopulmonary bypass and deep hypothermia. The proximal descending aorta was transected distal to the subclavian artery, brought up through the transverse sinus caudad to the tracheal carina and pulmonary artery, and anastomosed in an end-to-side fashion to the ascending aorta. Results Mean cardiopulmonary bypass was 144.8 ± 32.6 minutes, with an aortic cross-clamp time of 59 ± 40.9. Absence of perfusion to the descending thoracic aorta averaged 44.4 ± 13.7 minutes. Concomitant procedures were performed in 4 of the 5 patients. At a median follow-up of 26 months (range, 3 to 101 months), all patients had resolution of symptoms. Conclusions A midline descending aorta can cause compression of the tracheal carina and proximal bronchi, with debilitating symptoms. Translocation of the descending aorta is a reliable procedure that relieves the compression and results in long-term resolution of symptoms.
Objective Fenestration during Fontan palliation has traditionally been used to decrease surgical morbidity and mortality, particularly in high-risk cases. Potential limitations include oxygen ...desaturation, risk of paradoxic embolism, and need for late intervention. Our practice has evolved away from routine fenestration with increased extracardiac conduit use. We reviewed our experience with Fontan palliation and retrospectively assessed outcomes with decreased fenestration. Methods Between January 2002 and April 2008, 226 patients underwent primary Fontan palliation. Outcomes were assessed by hospital stay, chest drain duration, short- and long-term survivals, and late interventions. Results Anatomic subtypes were single left ventricle (n = 88, 38.9%), single right ventricle (n = 78, 34.5%), common ventricle (n = 19, 8.4%), and heterotaxy syndrome (n = 41, 18.1%). Lateral tunnel connection was created in 69 patients (30.5%); extracardiac connection was created in 157 (69.5%). Mean age and weight at surgery were 4.3 ± 3.8 years and 17.2 ± 9 kg, respectively. In 2002, 14 of 16 patients (87.5%) had fenestrated Fontan circulations, versus 2 of 32 (6.3%) in 2008. Mean hospital stay was 10.8 ± 8.8 days. Survival to discharge or 30 days was 98.7%. There were 2 (0.9%) late deaths during mean follow-up of 2.0 ± 1.7 years. Outcomes were equivalent between fenestrated and nonfenestrated procedures across anatomic subtypes. Conclusions Highly selective use of Fontan fenestration is achievable while maintaining excellent outcomes without increased surgical morbidity or mortality, irrespective of anatomic subtype. Risks of hypoxia, systemic embolism, and late instrumentation can be avoided in most cases.
Just as Koch's postulates formed the foundation of early infectious disease study, Stanley Falkow's molecular Koch's postulates define best practice in determining whether a specific gene contributes ...to virulence of a pathogen. Fundamentally, these molecular postulates state that if a gene is involved in virulence, its removal will compromise virulence. Likewise, its reintroduction should restore virulence to the mutant. These approaches are widely employed in Cryptococcus neoformans, where gene deletion via biolistic transformation is a well-established technique. However, the complementation of these mutants is less straightforward. Currently, one of three approaches will be taken: the gene is reintroduced at the original locus, the gene is reintroduced into a random site in the genome, or the mutant is not complemented at all. Depending on which approach is utilized, the mutant may be complemented but other genes are potentially disrupted in the process. To counter the drawbacks of the current approaches to complementation we have created a new tool to assist in this key step in the study of a gene's role in virulence. We have identified and characterized a small gene-free region in the C. neoformans genome dubbed the "safe haven", and constructed a plasmid vector that targets DNA constructs to this preselected site. The plasmid vector integrates with high frequency, effectively complementing a mutant strain without disrupting adjacent genes. qRT-PCR of the flanking genes on either side of the safe haven site following integration of the targeting vector revealed no changes in their expression, and no secondary phenotypes were observed in a range of phenotypic assays including an intranasal murine infection model. Combined, these data confirm that we have successfully created a much-needed molecular resource for the Cryptococcus community, enabling the reliable fulfillment of the molecular Koch's postulates.
Summary Background Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 ...trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis. Methods We assessed the retinal and visual function in 12 patients (aged 8–44 years) with RPE65 -associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1·5×1010 vector genomes), medium (4·8×1010 vector genomes), or high dose (1·5×1011 vector genomes) for up to 2 years. Findings AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with ClinicalTrials.gov , number NCT00516477. Interpretation The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain. Funding Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.
Cardiogenic shock (CS) is associated with high mortality. We report on a “Shock Team” approach of combined interdisciplinary expertise for decision making, expedited assessment, and treatment.
We ...reviewed 100 patients admitted in CS over 52 months. Patients managed under a Code Shock Team protocol (n = 64, treatment) from 2016 to 2019 were compared with standard care (n = 36, control) from 2015 to 2016. The cohort was predominantly male (78% treatment, 67% control) with a median age of 55 years (interquartile range IQR, 43-64) for treatment vs 64 years (IQR, 48-69) for control (P = 0.01). New heart failure was more common in the treatment group: 61% vs 36%, P = 0.02. Acute myocardial infarction comprised 13% of patients in CS. There were no significant differences between treatment and control in markers of clinical acuity, including median left ventricular ejection fraction (18% vs 20%), prevalence of moderate-severe right ventricular dysfunction (64% vs 56%), median peak serum lactate (5.3 vs 4.7 mmol/L), acute kidney injury (70% vs 75%), or acute liver injury (50% vs 31%). Inotropes, dialysis, and invasive ventilation were required in 92%, 33%, and 66% of patients, respectively. Temporary mechanical circulatory support was used in 45% of treatment and 28% of control patients (P = 0.08). There were no significant differences in median hospital length of stay (17.5 days), 30-day survival (71%), or survival to hospital discharge (66%). Over 240 days (IQR, 14,847) of median follow-up, survival was 67% for treatment vs 42% for control (hazard ratio, 0.53; 95% confidence interval, 0.28-0.99; P = 0.03).
A multidisciplinary Code Shock Team approach for CS is feasible and may be associated with improved long-term survival.
Le choc cardiogénique (CC) est associé à une mortalité élevée. Nous décrivons une approche où la prise de décision, l’évaluation rapide des cas et le traitement sont confiés à une « équipe de choc » interdisciplinaire.
Nous avons examiné les cas de 100 patients hospitalisés en raison d’un CC sur une période de 52 mois. Les patients pris en charge par une équipe interdisciplinaire selon un protocole d’intervention déclenché par un code-choc (n = 64, groupe traité) de 2016 à 2019 ont été comparés à des patients ayant reçu des soins courants (n = 36, groupe témoin) de 2015 à 2016. Les patients de la cohorte étaient majoritairement de sexe masculin (78 % dans le groupe traité, 67 % dans le groupe témoin) et l’âge médian était de 55 ans (intervalle interquartile IIQ : 43-64) au sein du groupe traité par rapport à 64 ans (IIQ : 48-69) au sein du groupe témoin (p = 0,01). Les nouveaux cas d’insuffisance cardiaque étaient plus fréquents dans le groupe traité : 61 % vs 36 % (p = 0,02). Les patients hospitalisés en raison d’un CC avaient subi un infarctus aigu du myocarde dans 13 % des cas. Aucune différence significative n’a été relevée entre le groupe traité et le groupe témoin au chapitre des marqueurs d’acuité clinique, y compris la fraction médiane d’éjection ventriculaire gauche (18 % vs 20 %), la prévalence d’une dysfonction modérée ou sévère du ventricule droit (64 % vs 56 %), la concentration maximale médiane de lactate sérique (5,3 vs 4,7 mmol/l), l’insuffisance rénale aiguë (70 % vs 75 %) ou l’insuffisance hépatique aiguë (50 % vs 31 %). L’administration d’inotropes, la dialyse et la ventilation effractive ont été nécessaires chez 92 %, 33 % et 66 % des patients, respectivement. Une assistance circulatoire mécanique temporaire a été utilisée chez 45 % des patients du groupe traité et 28 % des patients du groupe témoin (p = 0,08). Aucune différence significative n’a été notée en ce qui concerne la durée médiane des hospitalisations (17,5 jours), la survie à 30 jours (71 %) ou la survie à la sortie de l’hôpital (66 %). Au cours d’une période de suivi médiane de 240 jours (IIQ : 14 847), le taux de survie était de 67 % dans le groupe traité vs 42 % dans le groupe témoin (rapport des risques instantanés : 0,53; intervalle de confiance à 95 % : 0,28-0,99; p = 0,03).
Dans les cas de CC, l’intervention d’une équipe interdisciplinaire déclenchée par un code-choc est réalisable et pourrait être associée à une amélioration de la survie à long terme.
Summary Background Gene expression microarrays are being used to develop new prognostic and predictive tests for breast cancer, and might be used at the same time to confirm oestrogen-receptor status ...and ERBB2 status. Our goal was to establish a new method to assign oestrogen receptor and ERBB2-receptor status to breast carcinoma based on mRNA expression measured using Affymetrix U133A gene-expression profiling. Methods We used gene expression data of 495 breast cancer samples to assess the correlation between oestrogen receptor ( ESR1 ) and ERBB2 mRNA and clinical status of these genes (as established by immunohistochemical IHC or fluorescence in-situ hybridisation FISH, or both). Data from 195 fine-needle aspiration (FNA) samples were used to define mRNA cutoff values that assign receptor status. We assessed the accuracy of these cutoffs in two independent datasets: 123 FNA samples and 177 tissue samples (ie, resected or core-needle biopsied tissues). Profiling was done at two institutions by use of the same platform (Affymetrix U133A GeneChip). All data were uniformly normalised with dCHIP software. Findings ESR1 and ERBB2 mRNA levels correlated closely with routine measurements for receptor status in all three datasets. Spearman's correlation coefficients ranged from 0·62 to 0·77. An ESR1 mRNA cutoff value of 500 identified oestrogen-receptor-positive status with an overall accuracy of 90% (training set), 88% (first validation set), and 96% (second validation set). An ERBB2 mRNA threshold of 1150 identified ERBB2-positive status with the overall accuracy of 93% (training set), 89% (first validation set), and 90% (second validation set). Reproducibility of mRNA measurements in 34 replicate experiments was high (correlation coefficient 0·975 for ESR1 , 0·984 for ERBB2 ). Interpretation Amounts of ESR1 and ERBB2 mRNA as measured by the Affymetrix GeneChip reliably and reproducibly establish oestrogen-receptor status and ERBB2 status, respectively.
Summary Background Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations ...include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. Methods We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z -score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Findings Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10−109 for rs2282679, in GC ); 11q12 (p=2·1×10−27 for rs12785878, near DHCR7 ); and 11p15 (p=3·3×10−20 for rs10741657, near CYP2R1 ). Variants at an additional locus (20q13, CYP24A1 ) were genome-wide significant in the pooled sample (p=6·0×10−10 for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95% CI 2·20–2·78, p=2·3×10−48 ) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10−26 ) compared with those in the lowest quartile. Interpretation Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Funding Full funding sources listed at end of paper (see Acknowledgments).
Objectives This study explored the novel strategy of hypoxic preconditioning of bone marrow mesenchymal stem cells before transplantation into the infarcted heart to promote their survival and ...therapeutic potential of mesenchymal stem cell transplantation after myocardial ischemia. Methods Mesenchymal stem cells from green fluorescent protein transgenic mice were cultured under normoxic or hypoxic (0.5% oxygen for 24 hours) conditions. Expression of growth factors and anti-apoptotic genes were examined by immunoblot. Normoxic or hypoxic stem cells were intramyocardially injected into the peri-infarct region of rats 30 minutes after permanent myocaridal infarction. Death of mesenchymal stem cells was assessed in vitro and in vivo after transplantation. Angiogenesis, infarct size, and heart function were measured 6 weeks after transplantation. Results Hypoxic preconditioning increased expression of pro-survival and pro-angiogenic factors including hypoxia-inducible factor 1, angiopoietin-1, vascular endothelial growth factor and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL. Cell death of hypoxic stem cells and caspase-3 activation in these cells were significantly lower compared with that in normoxic stem cells both in vitro and in vivo. Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarctiion resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy. Conclusions Hypoxic preconditioning enhances the capacity of mesenchymal stem cells to repair infarcted myocardium, attributable to reduced cell death and apoptosis of implanted cells, increased angiogenesis/vascularization, and paracrine effects.
PDF
