Chronic Pancreas Allograft Rejection Followed by Successful HLA-Incompatible Islet Alloautotransplantation:A Novel Strategy?

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this “islet alloautotransplantation” consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.</p

Chronic Pancreas Allograft Rejection Followed by Successful HLA-Incompatible Islet Alloautotransplantation:A Novel Strategy?

The purpose of pancreas or islet transplantation is to restore glycemic control in order to mitigate diabetes-related complications and prevent severe hypoglycemia. Complications from chronic pancreas allograft rejection may lead to transplantectomy, even when the endocrine function remains preserved. We present first evidence of a successful HLA incompatible islet re-transplantation with islets isolated from a rejecting pancreas allograft after simultaneous kidney pancreas transplantation. The pancreas allograft was removed because of progressively painful pancreatic panniculitis from clinically uncontrolled chronic rejection. The endocrine function was preserved. Induction treatment for this “islet alloautotransplantation” consisted of plasmapheresis, IVIg and alemtuzumab. At 1 year, the patient retained islet graft function with good glycemic control and absence of severe hypoglycemia, despite persistent low-grade HLA donor-specific antibodies. His panniculitis had resolved completely. In our point of view, islet alloautotransplantation derived from a chronically rejecting pancreas allograft is a potential option to salvage (partial) islet function, despite preformed donor-specific antibodies, in order to maintain stable glycemic control. Thereby it protects against severe hypoglycemia, and it potentially mitigates kidney graft dysfunction and other diabetes-related complications in patients with continued need for immunosuppression and who are otherwise difficult to retransplant.</p

Cost impact of procalcitonin-guided decision making on duration of antibiotic therapy for suspected early-onset sepsis in neonates

Abstract Backgrounds The large, international, randomized controlled NeoPInS trial showed that procalcitonin (PCT)-guided decision making was superior to standard care in reducing the duration of antibiotic therapy and hospitalization in neonates suspected of early-onset sepsis (EOS), without increased adverse events. This study aimed to perform a cost-minimization study of the NeoPInS trial, comparing health care costs of standard care and PCT-guided decision making based on the NeoPInS algorithm, and to analyze subgroups based on country, risk category and gestational age. Methods Data from the NeoPInS trial in neonates born after 34 weeks of gestational age with suspected EOS in the first 72 h of life requiring antibiotic therapy were used. We performed a cost-minimization study of health care costs, comparing standard care to PCT-guided decision making. Results In total, 1489 neonates were included in the study, of which 754 were treated according to PCT-guided decision making and 735 received standard care. Mean health care costs of PCT-guided decision making were not significantly different from costs of standard care (€3649 vs. €3616). Considering subgroups, we found a significant reduction in health care costs of PCT-guided decision making for risk category ‘infection unlikely’ and for gestational age ≥ 37 weeks in the Netherlands, Switzerland and the Czech Republic, and for gestational age < 37 weeks in the Czech Republic. Conclusions Health care costs of PCT-guided decision making of term and late-preterm neonates with suspected EOS are not significantly different from costs of standard care. Significant cost reduction was found for risk category ‘infection unlikely,’ and is affected by both the price of PCT-testing and (prolonged) hospitalization due to SAEs

Machine learning used to compare the diagnostic accuracy of risk factors, clinical signs and biomarkers and to develop a new prediction model for neonatal early-onset sepsis

Background: Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs. Study Design: Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier. Results: One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random. Conclusions: Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics

C-Reactive Protein, Procalcitonin, and White Blood Count to Rule Out Neonatal Early-onset Sepsis Within 36 Hours: A Secondary Analysis of the Neonatal Procalcitonin Intervention Study.

BACKGROUND: Neonatal early-onset sepsis (EOS) is one of the main causes of global neonatal mortality and morbidity, and initiation of early antibiotic treatment is key. However, antibiotics may be harmful. METHODS: We performed a secondary analysis of results from the Neonatal Procalcitonin Intervention Study, a prospective, multicenter, randomized, controlled intervention study. The primary outcome was the diagnostic accuracy of serial measurements of C-reactive protein (CRP), procalcitonin (PCT), and white blood count (WBC) within different time windows to rule out culture-positive EOS (proven sepsis). RESULTS: We analyzed 1678 neonates with 10 899 biomarker measurements (4654 CRP, 2047 PCT, and 4198 WBC) obtained within the first 48 hours after the start of antibiotic therapy due to suspected EOS. The areas under the curve (AUC) comparing no sepsis vs proven sepsis for maximum values of CRP, PCT, and WBC within 36 hours were 0.986, 0.921, and 0.360, respectively. The AUCs for CRP and PCT increased with extended time frames up to 36 hours, but there was no further difference between start to 36 hours vs start to 48 hours. Cutoff values at 16 mg/L for CRP and 2.8 ng/L for PCT provided a sensitivity of 100% for discriminating no sepsis vs proven sepsis. CONCLUSIONS: Normal serial CRP and PCT measurements within 36 hours after the start of empiric antibiotic therapy can exclude the presence of neonatal EOS with a high probability. The negative predictive values of CRP and PCT do not increase after 36 hours

Influenza virus hemagglutinin contains a cholesterol consensus motif required for efficient intracellular transport and lipid raft integration

Das Hämagglutinin (HA) der Influenzaviren wird während der Assemblierung in Cholesterin- und Sphingolipid-reiche Domänen (Rafts) der Plasmamembran rekrutiert. Vorangehende Studien konnten mittels Fluoreszenzresonanzenergietransfer eine Raft-Integration nachweisen, die von zwei Raft-Zielsignalen abhängig war; zum einen von drei S-acylierten Cysteinen in der zytoplasmatischen Domäne und zum anderen von hydrophoben Aminosäuren (VIL) am Beginn der Transmembrandomäne (TMD). Zudem zeigte sich ein möglicher Einfluss des VIL-Motives auf den intrazellulären Proteintransport. Um diese Annahme zu bestätigen, wurden HA Mutanten in Zellen exprimiert und ihre Ankunft im medialen und trans-Golgi verfolgt. In dieser Arbeit konnte eine Beteiligung des VIL-Motives am Transport bestätigt werden, jedoch nicht der S-Acylierungen. Zudem wurde eine generelle Abhängigkeit des Transportes von der Sphingolipidsynthese beobachtet. Da sowohl die Cholesterinsynthese als auch die Sphingolipidsynthese für den Transport von HA benötigt werden, habe ich die Hypothese aufgestellt, dass das VIL-Motiv in der Lage sein könnte, mit Raft Lipiden zu interagieren. Ein Sequenzvergleich ergab, dass kein Sphingolipid-Bindemotiv vorhanden ist, jedoch ein potenzielles Cholesterin-Consensus-Motiv (CCM, W/Y-I/V/L-K/R). Dieses Motiv wurde nur in der Sequenz von Gruppe 1 jedoch nicht Gruppe 2 HAs gefunden und umfasst das Leucin des VIL Motives. Tatsächlich ist die Mutation des Leucins aber nicht des vorangehenden Isoleucins für den verzögerten Transport verantwortlich. Untersuchungen weiter Einzel- und Mehrfachmutanten konnten eine Abhängigkeit des intrazellulären Transportes von einer möglichen Cholesterinbindung verifizieren. Zudem konnte auch ein zunehmender Effekt auf die Kinetiken vom medialen Golgi zum TGN beobachtet werden, welcher auch die Oberflächenexpression negativ beeinflusste. FLIM-FRET Analysen zeigten zusätzlich eine reduzierte Raft Assoziation der CCMMutanten mit Rafts an der Plasmamembran. Daher kann man spekulieren, dass HA mit Cholesterin interagiert, wodurch sein intrazellulärer Transport durch den Golgi und die Assoziation mit Rafts gewährleistet wird.During assembly the hemagglutinin (HA) of influenza viruses is recruited to cholesterol- and sphingolipid rich domains of the plasma membrane (lipid rafts). Preceding studies using fluorescence resonance energy transfer showed that lipid-raft integration is dependent on two raft-targeting signals, three S-acylated cysteines located in the cytoplasmic tail and hydrophobic amino acids (VIL) in the part of the transmembrane region (TMR). Furthermore, they gave rise to the assumption that at least the VIL motif might also be important for the intracellular transport of the protein along the exocytic pathway. To verify this assumption, HA mutants were transiently expressed in cells and their arrival in the medial and trans-Golgi compartment was quantified. The observation regarding the involvement of the VIL motif, but not the S-acylation, was verified and a general dependency of HA´s transport on sphingolipid synthesis was detected. Since both cholesterol and sphingolipid synthesis are needed for the transport of HA, I hypothesized that the VIL motif might be able to interact with raft lipids. Sequence alignment revealed no sphingolipid-binding motif, but a putative cholesterol consensus motif (CCM, W/Y-I/V/L-K/R). This CCM is found only in the sequence of group 1 but not group 2 HAs and includes the leucine of the VIL motif. Indeed, mutation of the leucine, but not of the preceding isoleucine is responsible for the delayed transport. Investigation of further single and multiple mutations in the CCM verified a dependency of HA´s intracellular transport on the putative cholesterol-binding motif. Additionally the effect on the kinetics increased from the medial Golgi to the TGN also negatively effecting surface expression. Analysis by FLIM-FRET furthermore displayed a reduced association of HA with mutations in the CCM with lipid rafts at the plasma membrane. Therefore, it is speculated that HA associates with cholesterol, an interaction that facilitates its intracellular transport through the Golgi and association with lipid rafts at the plasma membrane

Toll-like receptor signalling on Tregs: to suppress or not to suppress?

To balance self-tolerance and immunity against pathogens or tumours, the immune system depends on both activation mechanisms and down-regulatory mechanisms. Immunologists have long been focusing on activation mechanisms, and a major breakthrough was the identification of the Toll-like receptor (TLR) family of proteins. TLRs recognize conserved molecular patterns present on pathogens, including bacteria, viruses, fungi and protozoa. Pathogen recognition via TLRs activates the innate as well as the adaptive immune response. The discovery of a suppressive T-cell subset that constitutively expresses the interleukin (IL)-2 receptor α-chain (CD25) has boosted efforts to investigate the negative regulation of immune responses. It is now well appreciated that these regulatory T cells (Tregs) play a pivotal role in controlling immune function. Interestingly, recent studies revealed that TLR2 signalling affects Treg expansion and function. This review will focus on the presence and influence of different TLRs on T lymphocytes, including Tregs, and their role in cancer

Towards Adaptive Social Comparison for Education

Informing students about their progress in comparison to their peers has been widely used in educational research as a strong motivational factor, effective gamification technique and means for adaptive guidance to learning material. A typical social comparison interface helps students weight their individual levels against the average levels of other students. However, such uniform approach may not be effective for every category of students and every learning situation. Underachieving students might find the displayed social goal impossible, while overachieving students might decide that the learning goal has been attained and stop investing time and efforts. An alternative approach is an adaptive social comparison strategy that chooses different levels of the social goal for different categories of students. This paper presents one of the first steps towards developing such a strategy