Broader Geographic Sharing of Pediatric Donor Lungs Improves Pediatric Access to Transplant.

US pediatric transplant candidates have limited access to lung transplant due to the small number of donors within current geographic boundaries, leading to assertions that the current lung allocation system does not adequately serve pediatric patients. We hypothesized that broader geographic sharing of pediatric (adolescent, 12-17 years; child, <12 years) donor lungs would increase pediatric candidate access to transplant. We used the thoracic simulated allocation model to simulate broader geographic sharing. Simulation 1 used current allocation rules. Simulation 2 offered adolescent donor lungs across a wider geographic area to adolescents. Simulation 3 offered child donor lungs across a wider geographic area to adolescents. Simulation 4 combined simulations 2 and 3. Simulation 5 prioritized adolescent donor lungs to children across a wider geographic area. Simulation 4 resulted in 461 adolescent transplants per 100 patient-years on the waiting list (range 417-542), compared with 206 (range 180-228) under current rules. Simulation 5 resulted in 388 adolescent transplants per 100 patient-years on the waiting list (range 348-418) and likely increased transplant rates for children. Adult transplant rates, waitlist mortality, and 1-year posttransplant mortality were not adversely affected. Broader geographic sharing of pediatric donor lungs may increase pediatric candidate access to lung transplant.

OPTN/SRTR 2013 Annual Data Report: lung.

Lungs are allocated to adult and adolescent transplant candidates (aged ⩾ 12 years) on the basis of age, geography, blood type compatibility, and the lung allocation score (LAS), which reflects risk of waitlist mortality and probability of posttransplant survival. In 2013, the most adult candidates, 2394, of any year were added to the list. Overall median waiting time for candidates listed in 2013 was 4.0 months. The preferred procedure remained bilateral lung transplant, representing approximately 70% of lung transplants in 2013. Measures of short-term and longterm survival have plateaued since the implementation of the LAS in 2005. The number of new child candidates (aged 0-11 years) added to the lung transplant waiting list increased to 39 in 2013. A total of 28 lung transplants were performed in child recipients, 3 for ages younger than 1 year, 9 for ages 1 to 5 years, and 16 for ages 6 to 11 years. The diagnosis of pulmonary hypertension was associated with higher survival rates than cystic fibrosis or other diagnosis (pulmonary fibrosis, bronchiolitis obliterans, bronchopulmonary dysplasia). For child candidates, infection was the leading cause of death in year 1 posttransplant and graft failure in years 2 to 5.

The equitable allocation of deceased donor lungs for transplant in children in the United States.

On June 5, 2013, a US Federal Court ordered a temporary restraining order to allow two children within the court's jurisdiction to be registered on the adolescent lung transplant waiting list. On June 10, 2013, the Organ Procurement and Transplantation Network's Executive Committee altered lung allocation policy to offer candidates aged younger than 12 years greater access to adult lungs at the discretion of the national Lung Review Board. The Scientific Registry of Transplant Recipients reviewed trends over time in deceased donor lung transplant waitlist mortality and transplant rates, comparing children and adults. Mortality rates of candidates active on the waiting list have been higher for children aged 0-5 years, but have not differed for children aged 6-11 years compared with adolescents aged 12-17 years or adults aged 18 years or older. Transplant rates among active waitlist candidates have been comparable across all age groups. Thus, there is little evidence that the allocation system led to differences in waitlist mortality or transplant rates for children compared with adults. However, these comparisons are difficult to interpret given that current policies likely led to unaccounted differences in the severity of illness at the time of listing.

OPTN/SRTR 2012 Annual Data Report: lung.

Lung transplants are increasingly used as treatment for end-stage lung diseases not amenable to other medical and surgical therapies. Lungs are allocated to adult and adolescent transplant candidates on the basis of age, geography, blood type compatibility, and the Lung Allocation Score, which reflects risk of wait-list mortality and probability of posttransplant survival. The overall median waiting time in 2012 was 4 months, and 65.3% of candidates underwent transplant within 1 year of listing; however, this proportion varied greatly by donation service area. Unadjusted median survival of lung transplant recipients was 5.3 years in 2012, and median survival conditional on living for 1 year posttransplant was 6.7 years. Among pediatric lung candidates in 2012, 32.1% were wait-listed for less than 1 year, 17.9% for 1 to less than 2 years, 16.7% for 2 to less than 4 years, and 33.3% for 4 or more years. Both graft and patient survival have continued to improve; survival rates for recipients aged 6-11 years are better than for younger recipients. Compared with recipients of other solid organ transplants, lung transplant recipients experienced the highest rates of rehospitalization for transplant complications: 43.7 per 100 patients in year 1 and 36.0 in year 2.

Hospital-based antimicrobial stewardship in Denmark, Greenland and the Faroe Islands - current landscape and barriers.

OBJECTIVES: To describe the current organization and implementation of formalized, multi-disciplinary hospital-based antimicrobial stewardship (AMS) structures in Denmark, the Faroe Islands and Greenland. METHODS: A structured electronic questionnaire was sent to all trainees and specialists in clinical microbiology (N=207) and infectious diseases (N=260), as well as clinical pharmacists (N=20) and paediatricians (N=10) with expertise in infectious diseases. The survey had 30 multiple-choice, rating-scale, and open-ended questions based on an international consensus checklist for hospital AMS, adapted to a Danish context. RESULTS: Overall, 145 individual responses representing 20 hospitals were received. Nine hospitals (45%) reported a formal AMS strategy, eight (40%) a formal organizational multi-disciplinary structure and a multi-disciplinary AMS team, and six (30%) a designated professional as a leader of the AMS team. A majority of hospitals reported access to updated guidelines (80%) and regularly monitored and reported the quantity of antibiotics prescribed (70% and 65%, respectively). Only one hospital (5%) reported a dedicated, sustainable and sufficient AMS budget, three hospitals (15%) audited courses of therapy for specific agents/clinical conditions and four hospitals (20%) had a document clearly defining roles, procedures of collaboration and responsibilities for AMS. A total of 42% of all individual respondents had received formal AMS training. Main barriers were a lack of financial resources (52%), a lack of mandate from the hospital management (30%) and AMS not being a priority (18%). CONCLUSIONS: Core elements important for multi-disciplinary hospital-based AMS can be strengthened in Danish hospitals. Funding, clear mandates, prioritization from the hospital management and the implementation of multi-disciplinary AMS structures may help close the identified gaps.

OPTN/SRTR 2011 Annual Data Report: lung.

Lungs are allocated in part based on the Lung Allocation Score (LAS), which considers risk of death without transplant and posttransplant. Wait-list additions have been increasing steadily after an initial decline following LAS implementation. In 2011, the largest number of adult candidates were added to the waiting list in a single year since 1998; donation and transplant rates have been unable to keep pace with wait-list additions. Candidates aged 65 years or older have been added faster than candidates in other age groups. After an initial decline following LAS implementation, wait-list mortality increased to 15.7 per 100 wait-list years in 2011. Short- and long-term graft survival improved in 2011; 10-year graft failure fell to an all-time low. Since 1998, the number of new pediatric (aged 0-11 years) candidates added yearly to the waiting list has declined. In 2011, 19 pediatric lung transplants were performed, a transplant rate of 34.7 per 100 wait-list years. The percentage of patients hospitalized before transplant has not changed. Both graft and patient survival have continued to improve over the past decade. Posttransplant complications for pediatric lung transplant recipients, similar to complications for adult recipients, include hypertension, renal dysfunction, diabetes, bronchiolitis obliterans syndrome, and malignancy.

Lung and heart allocation in the United States.

Lung and heart allocation in the United States has evolved over the past 20-30 years to better serve transplant candidates and improve organ utilization. The current lung allocation policy, based on the Lung Allocation Score, attempts to take into account risk of death on the waiting list and chance of survival posttransplant. This policy is flexible and can be adjusted to improve the predictive ability of the score. Similarly, in response to the changing clinical phenotype of heart transplant candidates, heart allocation policies have evolved to a multitiered algorithm that attempts to prioritize organs to the most infirm, a designation that fluctuates with trends in therapy. The Organ Procurement and Transplantation Network and its committees have been responsive, as demonstrated by recent modifications to pediatric heart allocation and mechanical circulatory support policies and by ongoing efforts to ensure that heart allocation policies are equitable and current. Here we examine the development of US lung and heart allocation policy, evaluate the application of the current policy on clinical practice and explore future directions for lung and heart allocation.

Post-transplant lymphoproliferative disorders in lung transplant recipients: 20-yr experience at the University of Minnesota.

Post-transplant lymphoproliferative disorders (PTLD) are potentially fatal complications of solid organ transplantation. The natural history of PTLD varies considerably among the different types of organs transplanted. While lung transplant recipients are highly susceptible to PTLD, there are only a few small studies that detail PTLD in this setting. We undertook this study to better describe the characteristics and treatment response in PTLD after lung transplantation. We conducted a retrospective chart review of lung and heart/lung-transplant recipients between 1985 and 2008. A total of 32 cases (5%) of PTLD were identified in 639 patients. The median interval after transplantation to the diagnosis was 40 (3-242) months. Eight patients (25%) were diagnosed within one yr of transplantation and had PTLD predominantly within the thorax and allograft. Twenty-four patients (75%) were diagnosed more than one yr after transplantation and their tumors mainly affected the gastrointestinal tract. Monomorphic PTLD, diffuse large B-cell lymphoma, was diagnosed in 91%. Treatment of PTLD varied according to stage and clinical circumstances. Twenty-four patients (75%) have died. The median overall survival was 10 (0-108) months. PTLD after lung transplantation remains a challenge as a result of its frequency, complexity and disappointing outcome.

Differentiation between right tubo-ovarian abscess and appendicitis using CT--a diagnostic challenge.

AIM: To determine CT features that can potentially differentiate right tubo-ovarian abscess (TOA) from acute appendicitis (AA; including abscess formation). MATERIALS AND METHODS: The abdominal computed tomography (CT) images of 48 patients with right-sided TOA (average age 39.3 ± 9.8 years) and 80 patients (average age 53.5 ± 19.9 years) with AA (24 with peri-appendicular abscess) were retrospectively evaluated. Two experienced radiologists evaluated 12 CT signs (including enlarged, thickened wall ovary, appendix diameter and wall thickness, peri-appendicular fluid collection, adjacent bowel wall thickening, fat stranding, free fluid, and extraluminal gas) in consensus to categorize the studies as either TOA or AA. The diagnosis and the frequency of each of the signs were correlated with the surgical and clinical outcome. RESULTS: Reviewers classified 92% cases correctly (TOA=85%, AA=96.3%), 3% incorrectly (TOA=6.3%, AA=1.3%); 5% were equivocal (TOA=8.3%, AA=2.5%). In the peri-appendicular abscess group reviewers were correct in 100%. Frequent findings in the TOA group were an abnormal ovary (87.5%), peri-ovarian fat stranding (58.3%), and recto-sigmoid wall thickening (37.5%). An abnormal appendix was observed in 2% of TOA patients. Frequent findings in the AA group were a thickened wall (32.5%) and distended (80%) appendix. Recto-sigmoid wall thickening was less frequent in AA (12.5%). The appendix was not identified in 45.8% of the TOA patients compared to 15% AA. CONCLUSIONS: In the presence of a right lower quadrant inflammatory mass, peri-ovarian fat stranding, thickened recto-sigmoid wall, and a normal appearing caecum, in young patients favour the diagnosis of TOA. An unidentified appendix does not contribute to the differentiation between TOA and peri-appendicular abscess.

Sealed rupture of abdominal aortic aneurysms: CT features in 6 patients and a review of the literature.

PURPOSE: To assess the CT features of sealed rupture of abdominal aortic aneurysm. PATIENTS AND METHODS: We reviewed the CT scans of six index cases obtained over a 3 year period with a sealed rupture of an abdominal aortic aneurysm and those reported in the literature over a 21 year period. CT scans were reviewed for aneurysm size, the presence of a draped aorta and adjacent vertebral erosion. A group of consecutive patients with non-ruptured abdominal aortic aneurysm, referred for endovascular aneurysm repair during the same 3 year period constituted the control group. RESULTS: In the study group of 31 patients the mean size of the aneurysm was 6.24 +/- 2.01 cm, compared to 6.01 +/- 0.99 cm in the control group, without statistically significant difference (t = 0.75, df = 97, P = 0.46). A draped aorta was detected in all patients with a sealed rupture. Vertebral erosion was present in all our six, but mentioned in only 14 of the cases reported. CONCLUSION: A sealed rupture of an abdominal aortic aneurysm can occur in relatively small aneurysms. A draped aorta and adjacent vertebral erosion are characteristic CT signs of such a rupture.

Superconductivity in a uranium containing high entropy alloy.

High entropy alloys (HEA) are an unusual class of materials where mixtures of elements are stochastically arrayed on a simple crystalline lattice. These systems exhibit remarkable functionality, often along several distinct axes: e.g., the examples [TaNb]1-x(TiZrHf)x are high strength and damage resistant refractory metals that also exhibit superconductivity with large upper critical fields. Here we report the discovery of an f-electron containing HEA, [TaNb]0.31(TiUHf)0.69, which is the first to include an actinide ion. Similar to the Zr-analogue, this material crystallizes in a body-centered cubic lattice with the lattice constant a = 3.41(1) Å and exhibits phonon mediated superconductivity with a transition temperatures Tc ≈ 3.2 K and upper critical fields Hc2 ≈ 6.4 T. These results expand this class of materials to include actinide elements, shows that superconductivity is robust in this sub-group, and opens the path towards leveraging HEAs as functional waste forms for a variety of radioisotopes.

The B cell antigen receptor complex: association of Ig-alpha and Ig-beta with distinct cytoplasmic effectors.

The B cell antigen receptor complex is a hetero-oligomeric structure composed of antigen binding, membrane immunoglobulin, and transducer-transporter substructures. The transducer-transporter substructure is composed of disulfide-linked dimers of immunoglobulin (Ig)-alpha and Ig-beta/gamma subunits that are products of the mb-1(alpha) and B29 (beta/gamma) genes. Although the receptor complex associates with Src family kinases that are activated after receptor ligation, the site of interaction of these and other cytoplasmic effector molecules with receptor subunits is unknown. The cytoplasmic tails of Ig-alpha and Ig-beta chains were found to associate with distinct sets of effector molecules. The Ig-alpha chain cytoplasmic domain bound to the Src family kinases Lyn and Fyn, phosphatidylinositol-3 kinase (PI-3 kinase), and an unidentified 38-kilodalton phosphoprotein; the cytoplasmic tail of Ig-beta bound PI-3 kinase and unidentified 40- and 42-kilodalton phosphoproteins. Binding activity was found to occur within a 26-amino acid sequence of Ig-alpha and Ig-beta that contains a motif [(Asp or Glu)-(any amino acid)7-(Asp or Glu)-Tyr-(any amino acid)3-Leu-(any amino acid)7-Tyr-(any amino acid)2-(Leu or Ile)] previously implicated in signal transduction via other receptors including the Fc epsilon receptor I and the T cell antigen receptor. These findings indicate that the subunits act independently to activate distinct second messenger pathways.

Heterogeneity of cerebral capillary flow in man and its consequences for estimation of blood-brain barrier permeability.

Blood-brain barrier permeability studies made in man using the indicator dilution method revealed that the extraction of the test substance increases during the upslope of the venous (outflow) dilution curve. The present study aimed to obviate the possibility that this could result from intravascular phenomena, such as interlaminar diffusion (the result of differences in molecular size) and erythrocyte carriage. Several reference substances were employed for the determination of the extraction in order that careful correction could be made for differences in intravascular behavior of the test and reference substance. The test substances studied were D-glucose, L-phenylalanine, water, propranolol, and benzodiazepines, representing both carrier-transported and lipophilic substances. In-diethylenetriamine pentaacetic acid, Na+, Cl-, L-glucose, and L-lysine were employed as reference substances. For all the substances tested, and after correction for intravascular phenomena, the extractions were found to increase during the initial part of the dilution curve. This increasing extraction can be ascribed to heterogeneity of the cerebral circulation; the higher extraction corresponds to longer contact with the blood-brain barrier and indicates a longer transit time. Signs of heterogeneity were also present when blood flow was elevated above normal. Any influence that heterogeneity might have on the mean extraction value can be minimized by using an appropriate calculation of the extraction of the test substance.

Insulin increases glucose transfer across the blood-brain barrier in man.

The influence of insulin on unidirectional flux of glucose across the blood-brain barrier and on net uptake of glucose by the brain was investigated in seven fasting patients. The unidirectional extraction, E, of [14C]D-glucose was determined using 36Cl- as an intravascular reference, by the indicator dilution method. 0.4 U insulin/kg body wt was infused intravenously over 30 min while blood glucose was maintained constant by glucose infusion. Six determinations were made in each patient, two before, two during insulin infusion, and two after. In connection with each blood-brain barrier study, arterial and cerebral venous samples were taken for measurement of glucose, oxygen, insulin, K+, and phosphate. Cerebral blood flow (CBF) was measured in each patient. The main finding was an increased extraction of glucose from 14 to 21% and a highly significant increase in unidirectional flux (CBF X unidirectional extraction X arterial glucose concentration) from 0.46 to 0.66 mumol/g X min during insulin infusion (plasma insulin approximately 1,500 microU/ml). The net brain uptake of glucose (CBF X arterio-venous difference for glucose) as unaltered during the investigation period of 45 min, which is too short a time for insulin to penetrate the barrier. It follows that the backflux of glucose from the brain was increased during insulin application. The effect of insulin might be a speeding up of the glucose carrier in analogy to heart muscle.

Acute lung injury. Pathogenesis of intraalveolar fibrosis.

In patients dying with acute lung injury, interstitial mesenchymal cells migrate into the airspace where they replicate and deposit connective tissue. We therefore hypothesized that peptides capable of promoting mesenchymal cell migration and replication would be present in the alveolar airspace. To examine this hypothesis, patients with severe acute diffuse lung injury (n = 26) underwent bronchoalveolar lavage. Acutely ill patients without lung injury served as controls (n = 12). Recovered effluent was examined for mesenchymal cell growth-promoting and migration-promoting activity. Lavage cell supernates from both patients and controls were devoid of bioactivity. However, substantial growth-promoting and migration-promoting activity was present in lavage fluid from nearly every patient, whereas little or none was present in fluid from controls. Characterization of the bioactivity indicated a significant proportion consisted of three peptides related to PDGF: (a) a 14-kD peptide that shared with PDGF several biophysical, biochemical, receptor-binding, and antigenic properties; (b) a 29-kD peptide that appeared identical to PDGF of platelet origin; and (c) a 38-kD peptide that was biophysically and antigenically similar to PDGF. These data indicate that peptide moieties are present in the airspace of patients after acute lung injury that can signal mesenchymal cell migration and replication.

Receptor editing and commitment in B lymphocytes.

B cells that fail to pass a developmental checkpoint, either as immature or mature B cells, can be rescued by creating a new B cell antigen receptor through nested secondary immunoglobulin gene rearrangements, a process termed receptor editing. Tolerance-mediated receptor editing occurs in self-reactive immature bone marrow B cells, while peripheral receptor editing probably occurs in low-affinity B cells competing for antigen and for survival signals within the germinal center response.

Congenital anomalies of the spleen.

Various congenital anomalies may affect the spleen, starting with common anomalies, such as an accessory spleen, up to rare conditions such as a wandering spleen and polysplenia. Most of these anatomic variants have no clinical significance; they need, however, to be recognized by the radiologist as such. Awareness of these variants is important for the radiologist to interpret the findings correctly and avoid mistaking them for a clinically significant abnormality. In this review we illustrate the spectrum of congenital anomalies of the spleen and stress pitfalls and possible complications resulting from these anomalies.

Minimally invasive management of urolithiasis.

The management of urolithiasis has radically changed over the last two decades. Open surgery has been almost completely replaced by minimally invasive procedures, mainly extracorporeal shock wave lithotripsy (ESWL) and ureteroscopy (URS). Although these treatment modalities have been proven to be very safe and effective, serious complications can occur. Prompt diagnosis is often essential and may even be lifesaving. Radiologists play an important role in this setting, since many of these complications can be readily diagnosed by imaging. Awareness of the wide spectrum of complications may be crucial in interpreting imaging studies of patients who have undergone one of these procedures. This article reviews the contemporary management of ureteric stones with ESWL and URS and illustrates the radiological findings of complications of these procedures.

B-cell-receptor-dependent positive and negative selection in immature B cells.

This review touches on only a small part of the complex biology of B cells, but serves to illustrate the point that the antigen receptor is the most important of many cell-surface receptors affecting cell-fate decisions. Receptor expression is necessary, but not sufficient, for cell survival. It is also essential that a B cell's antigen-receptor specificity be appropriate for its environment. The need to balance reactivity with self tolerance has resulted in an intricate feedback control (affected by both the recombinase and cell survival) that regulates independent selection events at the level of the receptor and the cell.