Background
A significant proportion of kidneys procured for transplantation are discarded because of concerns about their suitability. In this study ex vivo normothermic perfusion (EVNP) was used as ...a quality assessment device before renal transplantation.
Methods
Seventy‐four human kidneys deemed unsuitable for transplantation following retrieval underwent 60 min of EVNP with an oxygenated red cell‐based solution at 36°C. Receiver operating characteristic (ROC) curves were used to identify thresholds of renal blood flow and urine output. These thresholds and a grading of macroscopic appearance were incorporated into an EVNP assessment score (highest quality, 1; lowest, 5). This was applied to a series of 36 kidneys transplanted after EVNP.
Results
In the discarded kidney series, 60 (81 per cent) scored 1–4 and 14 (19 per cent) scored 5. Although none of these kidneys was transplanted, those with a score from 1 to 4 were considered suitable for transplantation. In the 36 transplanted kidneys, the score ranged between 1 and 3 (score 1, 17; score 2, 11; score 3, 8). All of these kidneys were transplanted without any complications or primary non‐function. The delayed graft function rate was 6 per cent (1 of 17) in kidneys scoring 1, 0 per cent (0 of 11) in those scoring 2 and 38 per cent (3 of 8) in those scoring 3 (P = 0·024). The mean(s.d.) estimated glomerular filtration rate at 12 months was 51(16), 63(15) and 38(21) ml in kidneys scoring 1, 2 and 3 respectively (P = 0·015).
Conclusion
EVNP combined with a simple scoring system is an innovative technology for pretransplant assessment of kidney quality and acceptability for transplantation. This study suggests that a high percentage of retrieved kidneys are being discarded unnecessarily.
Maximizes kidney use
Vascular endothelial cells (ECs) play a central role in the pathophysiology of many diseases. The use of targeted nanoparticles (NPs) to deliver therapeutics to ECs could dramatically improve ...efficacy by providing elevated and sustained intracellular drug levels. However, achieving sufficient levels of NP targeting in human settings remains elusive. Here, we overcome this barrier by engineering a monobody adapter that presents antibodies on the NP surface in a manner that fully preserves their antigen-binding function. This system improves targeting efficacy in cultured ECs under flow by >1000-fold over conventional antibody immobilization using amine coupling and enables robust delivery of NPs to the ECs of human kidneys undergoing ex vivo perfusion, a clinical setting used for organ transplant. Our monobody adapter also enables a simple plug-and-play capacity that facilitates the evaluation of a diverse array of targeted NPs. This technology has the potential to simplify and possibly accelerate both the development and clinical translation of EC-targeted nanomedicines.
High-entropy alloys are multicomponent solid solutions in which various elements with different chemistries and sizes occupy the same crystallographic lattice sites. Thus, none of the atoms perfectly ...fit the lattice site, giving rise to considerable local lattice distortions and atomic-level stresses. These characteristics can be beneficial for performance under radiation and in a high-temperature environment, making them attractive candidates as nuclear materials. We discuss electronic origin of the atomic-level stresses based upon first-principles calculations using a density functional theory approach.
A role for type A Clostridium perfringens in acute hemorrhagic and necrotizing gastroenteritis in dogs and in necrotizing enterocolitis of neonatal foals has long been suspected but incompletely ...characterized. The supernatants of an isolate made from a dog and from a foal that died from these diseases were both found to be highly cytotoxic for an equine ovarian (EO) cell line. Partial genome sequencing of the canine isolate revealed three novel putative toxin genes encoding proteins related to the pore-forming Leukocidin/Hemolysin Superfamily; these were designated netE, netF, and netG. netE and netF were located on one large conjugative plasmid, and netG was located with a cpe enterotoxin gene on a second large conjugative plasmid. Mutation and complementation showed that only netF was associated with the cytotoxicity. Although netE and netG were not associated with cytotoxicity, immunoblotting with specific antisera showed these proteins to be expressed in vitro. There was a highly significant association between the presence of netF with type A strains isolated from cases of canine acute hemorrhagic gastroenteritis and foal necrotizing enterocolitis. netE and netF were found in all cytotoxic isolates, as was cpe, but netG was less consistently present. Pulsed-field gel electrophoresis showed that netF-positive isolates belonged to a clonal population; some canine and equine netF-positive isolates were genetically indistinguishable. Equine antisera to recombinant Net proteins showed that only antiserum to rNetF had high supernatant cytotoxin neutralizing activity. The identifica-tion of this novel necrotizing toxin is an important advance in understanding the virulence of type A C. perfringens in specific enteric disease of animals.
To evaluate a universal obesity prevention intervention, which commenced at infant age 4-6 months, using outcome data assessed 6 months after completion of the first of two intervention modules and 9 ...months from baseline.
Randomised controlled trial of a community-based early feeding intervention.
Six hundred and ninety-eight first-time mothers (mean age 30±5 years) with healthy term infants (51% male) aged 4.3±1.0 months at baseline. Mothers and infants were randomly allocated to self-directed access to usual care or to attend two group education modules, each delivered over 3 months, that provided anticipatory guidance on early feeding practices. Outcome data reported here were assessed at infant age 13.7±1.3 months. Anthropometrics were expressed as z-scores (WHO reference). Rapid weight gain was defined as change in weight-for-age z-score (WAZ) of >+0.67. Maternal feeding practices were assessed via self-administered questionnaire.
There were no differences according to group allocation on key maternal and infant characteristics. At follow-up (n=598 (86%)), the control group infants had higher BMI-for-age z-score (BMIZ) (0.42±0.85 vs 0.23±0.93, P=0.009) and were more likely to show rapid weight gain from baseline to follow-up (odds ratio (OR)=1.5, confidence interval (CI) 95%=1.1-2.1, P=0.014). Mothers in the control group were more likely to report using non-responsive feeding practices that fail to respond to infant satiety cues such as encouraging eating by using food as a reward (15% vs 4%, P=0.001) or using games (67% vs 29%, P<0.001).
These results provide early evidence that anticipatory guidance targeting the 'when, what and how' of solid feeding can be effective in changing maternal feeding practices and, at least in the short term, reducing anthropometric indicators of childhood obesity risk. Analyses of outcomes at later ages are required to determine if these promising effects can be sustained.
A short period of ex vivo normothermic perfusion (EVNP) immediately before transplantation can revive the kidney and reduce the effects of cold ischemic (CI) injury. Herein, we report a clinical case ...of EVNP carried out at an intermediate period of the preservation interval. The kidney was retrieved from a 63‐year‐old extended criteria donor. After 10 h 29 min of CI the kidney underwent EVNP with 1 unit of compatible packed red blood cells mixed with a priming solution at 35.0°C while the recipient was being prepared for surgery. The mean renal blood flow was 93.6 mL/min/100 g and the kidney produced 60 mL of urine. Shortly after the start of surgery the first intended recipient became unfit for transplantation. After 60 min EVNP the kidney was flushed with cold preservation solution and re‐packed in ice. The second period of CI was 5 h and 21 min. The kidney was transplanted without any complications into a 54‐year‐old predialysis patient. The recipient had immediate graft function with serum creatinine levels falling from 315 to 105 µmol/L by day 7. This is the first report of an intermediate period of EVNP in clinical renal transplantation. This case demonstrates the feasibility and safety of the technique.
This case describes the practicality of an intermediate period of ex vivo normothermic kidney perfusion.
Many kidneys are rejected for transplantation due to inadequate in situ perfusion during organ retrieval because of the risk of additional ischaemic injury and microvasculature thrombosis. This study ...describes the use of ex vivo normothermic perfusion (EVNP) for the resuscitation and assessment of human kidneys that were discarded after inadequate in situ perfusion.
Twenty-two human kidneys were retrieved but then deemed unsuitable for transplantation, primarily due to inadequate in situ perfusion. After a period of static cold storage, kidneys were perfused for 60 min with an oxygenated red cell based solution at 36 °C.
Nineteen out of 22 kidneys (86 %) were from DCD donors. During EVNP, kidneys were assessed and scored based on their macroscopic appearance, measures of renal blood flow and urine production. Kidneys were scored from 1 indicating the least injury to 5, indicating the worst. Twelve kidneys had an EVNP score of 1-2, 7 scored 3-4 and 3 kidneys scored 5. The EVNP score 5 kidneys had a low level of tubular function compared to the score 1-4 kidneys. Their perfusion parameters did not improve during EVNP and they were considered non-transplantable. There was no association between the histological evaluation and EVNP parameters.
EVNP restores function ex vivo and enables an assessment of kidneys that have been declined for transplantation due to inadequate in situ perfusion.
In interpreting attention-deficit/hyperactivity disorder (ADHD) symptoms, categorical and dimensional approaches are commonly used. Both employ binary symptom counts which give equal weighting, with ...little attention to the combinations and relative contributions of individual symptoms. Alternatively, symptoms can be viewed as an interacting network, revealing the complex relationship between symptoms. Using a novel network modelling approach, this study explores the relationships between the 18 symptoms in the Diagnostic Statistical Manual (DSM-5) criteria and whether network measures are useful in predicting outcomes. Participants were from a community cohort, the Children's Attention Project. DSM ADHD symptoms were recorded in a face-to-face structured parent interview for 146 medication naïve children with ADHD and 209 controls (aged 6-8 years). Analyses indicated that not all symptoms are equal. Frequencies of endorsement and configurations of symptoms varied, with certain symptoms playing a more important role within the ADHD symptom network. In total, 116,220 combinations of symptoms within a diagnosis of ADHD were identified, with 92% demonstrating a unique symptom configuration. Symptom association networks highlighted the relative importance of hyperactive/impulsive symptoms in the symptom network. In particular, the 'motoric'-type symptoms as well as interrupts as a marker of impulsivity in the hyperactive domain, as well as loses things and does not follow instructions in the inattentive domain, had high measures of centrality. Centrality-measure weighted symptom counts showed significant association with clinical but not cognitive outcomes, however the relationships were not significantly stronger than symptom count alone. The finding may help to explain heterogeneity in the ADHD phenotype.
Objective We sought to compare the different mortality risks between delivery and expectant management in women with gestational diabetes mellitus (GDM). Study Design This is a retrospective cohort ...study that included singleton pregnancies of women diagnosed with GDM delivering at 36-42 weeks' gestational age in California from 1997 through 2006. A composite mortality rate was developed to estimate the risk of expectant management at each gestational age incorporating the stillbirth risk during the week of continuing pregnancy plus the infant mortality risk at the gestational age 1 week hence. Results In women with GDM, the risk of expectant management is lower than the risk of delivery at 36 weeks (17.4 vs 19.3/10,000), but at 39 weeks, the risk of expectant management exceeds that of delivery (relative risk, 1.8; 95% confidence interval, 1.2–2.6). Conclusion In women with GDM, infant mortality rates at 39 weeks are lower than the overall mortality risk of expectant management for 1 week; absolute risks of stillbirth and infant death are low.
Shiga toxin-producing Escherichia coli (STEC) O157:H7 (O157) is a foodborne pathogen causing human disease ranging from hemorrhagic colitis and hemolytic uremic syndrome to kidney failure, while ...remaining harmless to cattle, its primary reservoir. The severity of the human disease associated mainly with Shiga toxin production and a global emergence of antibiotic resistant STEC highlights the need for effective non-antibiotic, pre-harvest strategies to reduce O157 in cattle, the principal source of human infection. Towards this goal three synthetic antimicrobial peptides (AMPs): human granulysin (hGRNL), bovine NK-lysin (bNK2A), and porcine NK-lysin (pNKL), were tested in vitro against O157 isolates. As expected, circular dichroism spectroscopy findings were consistent with a predominantly alpha-helical conformation for all three AMPs in an environment mimicking bacterial outer surface or liposaccharides. The minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations of hGRNL (200 muM), bNK2A (12.5 muM against strain 86-24 and 25 muM against EDL933), and pNKL (6.25 muM) were determined using the Clinical and Laboratory Standards Institute broth microdilution method in Müeller-Hinton broth (cation-adjusted). The bNK2A and pNKL AMPs did not induce Shiga toxin expression in O157 at MIC, as there was a significant decrease or no change in toxin expression following 4- or 20 h incubation with the AMPs; bNK2A p <0.0001 (4 h) and p = 0.4831 (20 h); pNKL p <0.0001 (4 h) and p = 0.0001 (20 h). Propidium iodide uptake assay revealed faster O157 membrane damage or killing kinetics with bNK2A and pNKL compared to hGRNL. Nonetheless, transmission electron microscopy demonstrated that all three AMPs mediated damage to O157 membranes. In contrast, the three AMPs showed minimal cytotoxicity (<2%) against cattle red blood cells at tested concentrations (0.39-50 muM). Overall, our results demonstrate the potential for bNK2A and pNKL to be further developed into novel non-antibiotic agents to reduce O157 shedding in cattle.
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