Histologic and Molecular Patterns in Responders and Non-responders With Chronic-Active Antibody-Mediated Rejection in Kidney Transplants

Introduction There is no proven therapy for chronic-active antibody-mediated rejection (caABMR), the major cause of late kidney allograft failure. Histological and molecular patterns associated with possible therapy responsiveness are not known. Methods Based on rigorous selection criteria this single center, retrospective study identified 16 out of 1027 consecutive kidney transplant biopsies taken between 2008 and 2016 with pure, unquestionable caABMR, without other pathologic features. The change in estimated GFR pre- and post-biopsy/treatment were utilized to differentiate subjects into responders and non-responders. Gene sets reflecting active immune processes of caABMR were defined a priori, including endothelial, inflammatory, cellular, interferon gamma (IFNg) and calcineurin inhibitor (CNI) related-genes based on the literature. Transcript measurements were performed in RNA extracted from stored, formalin-fixed, paraffin-embedded (FFPE) samples using NanoString™ technology. Histology and gene expression patterns of responders and non-responders were compared. Results A reductionist approach applying very tight criteria to identify caABMR and treatment response excluded the vast majority of clinical ABMR cases. Only 16 out of 139 cases with a written diagnosis of chronic rejection fulfilled the caABMR criteria. Histological associations with therapy response included a lower peritubular capillaritis score (p = 0.028) along with less glomerulitis. In contrast, no single gene discriminated responders from non-responders. Activated genes associated with NK cells and endothelial cells suggested lack of treatment response. Conclusion In caABMR active microvascular injury, in particular peritubular capillaritis, differentiates treatment responders from non-responders. Transcriptome changes in NK cell and endothelial cell associated genes may further help to identify treatment response. Future prospective studies will be needed which include more subjects, who receive standardized treatment protocols to identify biomarkers for treatment response. Clinical Trial Registration [ClinicalTrials.gov], identifier [NCT03430414]

Kann die 18F-FDG-PET/CT-Untersuchung die Panendoskopie zur Detektion von synchronen Zweitkarzinomen ersetzen?

Ziel der Arbeit war es, die Wertigkeit der 18F-FDG-PET/ CT-Untersuchung bezüglich synchroner Zweitkarzinome im Vergleich mit der Panendoskopie beim initialen Staging zu untersuchen. 311 Patienten wurden mit beiden Untersuchungsmethoden abgeklärt. Als Referenz galt die zytologische, histologische und/oder klinische oder radiologische Untersuchung. Die Prävalenz für synchrone Zweitkarzinome betrug mit der Panendoskopie 4,5%, während die Prävalenz mittels PET/ CT-Untersuchung 6,1% betrug. Die Sensitivität für die Panendoskopie betrug 74%, die Spezifität 99,7%, der positiv prädiktive Wert 93% und der negativ prädiktive Wert 98%. Die Sensitivität für die PET/CT-Untersuchung betrug 100%, die Spezifität 95,7% der positiv prädiktive Wert 59% und der negativ prädiktive Wert 100%. Die PET/CT-Untersuchung scheint der Panendoskopie überlegen zu sein. Bei bezüglich synchroner Zweitkarzinome unauffälligem PET/CT kann die Panendoskopie auf die Endoskopie und Beurteilung des Primärtumors beschränkt werden kann. Aufgrund der hohen Kosten und der grossen Anzahl falsch positiver Resultate, welche durch das PET/CT generiert werden, empfehlen wir die Durchführung dieser Untersuchung nur bei fortgeschrittenen Tumoren mit der Frage nach Fernmetastasen. Die Panendoskopie bleibt weiterhin der Goldstandar

Potential benefits of laparoscopic repair of duodenal atresia: Insights from a retrospective comparative study

Introduction: Congenital duodenal obstruction (CDO) repair can be performed open or laparoscopically. We aimed to determine the potential benefit of laparoscopic repair regarding tolerance of enteral feeding, postoperative pain, hospital stay, and complication rate. Materials and Methods: In a single-center retrospective cohort study, we compared neonates with isolated CDO operated open versus laparoscopically from 2010 to 2019. No transanastomotic tubes were used, and anastomoses were created in a side-to-side fashion in all cases. An early feeding policy is applied for all cases operated at our institution. Statistical comparison was performed using the Mann–Whitney's test or Fisher's exact test where appropriate. Results Forty-one patients analyzed were similar regarding body weight, gestational age, and proportion of patients with trisomy 21. Median follow-up was 21 months. Four (20%) out of 20 laparoscopic procedures started laparoscopically were converted to open. Comparing the 21 open with the 16 laparoscopically completed patients, median anesthetic duration was shorter by 18% in the open versus laparoscopic completed group (218 vs. 179 minutes, respectively; p = 0.025). Median postoperative time to full enteral feeds was shorter by 4 days in the first group (7 vs. 11 days, respectively; p = 0.028). In accordance, the median duration of parenteral nutrition (PN) was less than half in the laparoscopic completed compared with the open group (5 vs. 11.5 days, respectively; p = 0.031). Postoperative opioids were required for only half the duration in the laparoscopically completed group compared with open (2 vs. 4 days, respectively; p = 0.026). Outcomes such as length of stay, the occurrence of strictures or adhesions requiring reintervention, or line sepsis were similar in both groups. Conclusion: Patients undergoing laparoscopic CDO repair at our institution benefited from shorter time to full enteral feeds, and reduced the need for PN as well as postoperative pain medication

Solar heat gains through train windows: a non-negligible contribution to the energy balance

The sector of transportation accounts for about one third of the total energy consumption in Switzerland. A monitoring campaign of the energy consumption of a regional train revealed the critical energy-consuming systems. Heating, cooling and ventilation were identified as major consumers. Windows are a source of non-controlled heat transfer. In summer, it may result in overheating leading to larger cooling loads while in winter, it is an important source of thermal losses. Selective double glazing and solar protection coatings can reduce these effects. Angular-dependent optical properties of a selective double glazing have been measured, and the solar heat gain coefficient (g value) was determined. An estimation of the solar gains received by a panoramic waggon was performed using the monitored solar irradiation and the measured properties of the glazing. These data were compared to the heating and cooling energy consumption monitored in this waggon. Solar gains were found to be in the same order of magnitude that the heating energy during some sunny days. They were also compared to the estimated thermal losses through the glazing and the entire envelope. These results show that the solar gains play a non-negligible role in the energy balance of the waggon. Furthermore, thermal simulations were performed to evaluate the solar gains in different conditions. It showed that 7 to 13% of energy can be saved using the glazing adapted to the climatic conditions. In addition, improving the thermal insulation of the train envelope or equipping the train with an efficient heat recovery system can lead to significant energy savings

Transcutaneous treatment with vetdrop(®) sustains the adjacent cartilage in a microfracturing joint defect model in sheep

The significance of the adjacent cartilage in cartilage defect healing is not yet completely understood. Furthermore, it is unknown if the adjacent cartilage can somehow be influenced into responding after cartilage damage. The present study was undertaken to investigate whether the adjacent cartilage can be better sustained after microfracturing in a cartilage defect model in the stifle joint of sheep using a transcutaneous treatment concept (Vetdrop(®)). Carprofen and chito-oligosaccharids were added either as single components or as a mixture to a vehicle suspension consisting of a herbal carrier oil in a water-in-oil phase. This mixture was administered onto the skin with the aid of a specific applicator during 6 weeks in 28 sheep, allocated into 6 different groups, that underwent microfracturing surgery either on the left or the right medial femoral condyle. Two groups served as control and were either treated intravenously or sham treated with oxygen only. Sheep were sacrificed and their medial condyle histologically evaluated qualitatively and semi-quantitatively according to 4 different scoring systems (Mankin, ICRS, Little and O'Driscoll). The adjacent cartilage of animals of group 4 treated transcutaneously with vehicle, chito-oligosaccharids and carprofen had better histological scores compared to all the other groups (Mankin 3.3±0.8, ICRS 15.7±0.7, Little 9.0±1.4). Complete defect filling was absent from the transcutaneous treatment groups. The experiment suggests that the adjacent cartilage is susceptible to treatment and that the combination of vehicle, chitooligosaccharids and carprofen may sustain the adjacent cartilage during the recovery period

Sub-100 nm-scale Aluminum Nanowires by Stencil Lithography: Fabrication and Characterization

We present the fabrication process and electrical characterization of sub-100 nm scale Al nanowires (NWs) fabricated by stencil lithography (SL). We use a stencil with sub- 100 nm wide nanoslits patterned by focused ion beam (FIB) milling. The stencil is aligned and clamped onto a substrate containing predefined electrical contacts. Then a 60 nm-thick layer of Aluminum (Al) is deposited through the stencil producing NWs with lengths of ~1, 2 and 5 μm and widths down to 65 nm. The NWs show an ohmic behavior with values varying from 30 Ω up to 300 Ω, depending on the dimensions of the structures. We have extracted a resistivity for the Al NWs of ~10 x 10-8 Ωm. We also show that stencils can be cleaned and reused, proving that SL is a cost-efficient and scalable manufacturing method for the direct fabrication of metallic NWs on a full wafer scale

Predicting Kindergarteners' End-Of-Year Spelling Ability Based On Their Reading, Alphabetic, Vocabulary, And Phonological Awareness Skills, As Well As Prior Literacy Experiences

This study examined the role of home literacy, parental education, and demographic factors in addition to conventional literacy skills at the beginning and end of kindergarten in predicting end-of-kindergarten spelling achievement. The study involved 9 schools and 29 classrooms serving an economically and ethnically diverse population (N = 288). Students spelled three types of words: sight words, decodable real words, and decodable pseudowords; spellings were scored to allow partial credit for invented spelling. Results from a three-step hierarchical regression indicated the variables accounted for 66% of the variance in spelling scores, with the single strongest spring predictor being a 1-minute letter-sound fluency test. Implications for instruction and for identifying students at risk for spelling and reading difficulties are discussed

Entanglement of single-photons and chiral phonons in atomically thin WSe2_2

Quantum entanglement is a fundamental phenomenon which, on the one hand, reveals deep connections between quantum mechanics, gravity and the space-time; on the other hand, has practical applications as a key resource in quantum information processing. While it is routinely achieved in photon-atom ensembles, entanglement involving the solid-state or macroscopic objects remains challenging albeit promising for both fundamental physics and technological applications. Here, we report entanglement between collective, chiral vibrations in two-dimensional (2D) WSe$_2$ host --- chiral phonons (CPs) --- and single-photons emitted from quantum dots (QDs) present in it. CPs which carry angular momentum were recently observed in WSe$_2$ and are a distinguishing feature of the underlying honeycomb lattice. The entanglement results from a "which-way" scattering process, involving an optical excitation in a QD and doubly-degenerate CPs, which takes place via two indistinguishable paths. Our unveiling of entanglement involving a macroscopic, collective excitation together with strong interaction between CPs and QDs in 2D materials opens up ways for phonon-driven entanglement of QDs and engineering chiral or non-reciprocal interactions at the single-photon level

Coronary optical frequency domain imaging (OFDI) for in vivo evaluation of stent healing: comparison with light and electron microscopy

Aims Coronary late stent thrombosis, a rare but devastating complication, remains an important concern in particular with the increasing use of drug-eluting stents. Notably, pathological studies have indicated that the proportion of uncovered coronary stent struts represents the best morphometric predictor of late stent thrombosis. Intracoronary optical frequency domain imaging (OFDI), a novel second-generation optical coherence tomography (OCT)-derived imaging method, may allow rapid imaging for the detection of coronary stent strut coverage with a markedly higher precision when compared with intravascular ultrasound, due to a microscopic resolution (axial ∼10-20 µm), and at a substantially increased speed of image acquisition when compared with first-generation time-domain OCT. However, a histological validation of coronary OFDI for the evaluation of stent strut coverage in vivo is urgently needed. Hence, the present study was designed to evaluate the capacity of coronary OFDI by electron (SEM) and light microscopy (LM) analysis to detect and evaluate stent strut coverage in a porcine model. Methods and results Twenty stents were implanted into 10 pigs and coronary OFDI was performed after 1, 3, 10, 14, and 28 days. Neointimal thickness as detected by OFDI correlated closely with neointimal thickness as measured by LM (r = 0.90, P < 0.01). The comparison of stent strut coverage as detected by OFDI and SEM analysis revealed an excellent agreement (r = 0.96, P < 0.01). In particular, stents completely covered by OFDI analysis were also completely covered by SEM analysis. All incompletely covered stents by OFDI were also incompletely covered by SEM. Analyses of fibrin-covered stent struts suggested that these may rarely be detected as uncovered stent struts by OFDI. Importantly, optical density measurements revealed a significant difference between fibrin- and neointima-covered coronary stent struts [0.395 (0.35-0.43) vs. 0.53 (0.47-0.57); P < 0.001], suggesting that differences in optical density provide information on the type of stent strut coverage. The sensitivity and specificity for detection of fibrin vs. neointimal coverage was evaluated using receiver-operating characteristic analysis. Conclusion The present study demonstrates that OFDI is a highly promising tool for accurate evaluation of coronary stent strut coverage, as supported by a high agreement between OFDI and light and electron microscopic analysis. Furthermore, our data indicate that optical density measurements can provide additional information with respect to the type of stent strut coverage, i.e. fibrin vs. neointimal coverage. Therefore, coronary OFDI analysis will provide important information on the biocompatibility of coronary stent

Organometallic iridium(III) anticancer complexes with new mechanisms of action: NCI-60 screening, mitochondrial targeting, and apoptosis

Platinum complexes related to cisplatin, cis-[PtCl2(NH3)2], are successful anticancer drugs; however, other transition metal complexes offer potential for combating cisplatin resistance, decreasing side effects, and widening the spectrum of activity. Organometallic half-sandwich iridium (IrIII) complexes [Ir(Cpx)(XY)Cl]+/0 (Cpx = biphenyltetramethylcyclopentadienyl and XY = phenanthroline (1), bipyridine (2), or phenylpyridine (3)) all hydrolyze rapidly, forming monofunctional G adducts on DNA with additional intercalation of the phenyl substituents on the Cpx ring. In comparison, highly potent complex 4 (Cpx = phenyltetramethylcyclopentadienyl and XY = N,N-dimethylphenylazopyridine) does not hydrolyze. All show higher potency toward A2780 human ovarian cancer cells compared to cisplatin, with 1, 3, and 4 also demonstrating higher potency in the National Cancer Institute (NCI) NCI-60 cell-line screen. Use of the NCI COMPARE algorithm (which predicts mechanisms of action (MoAs) for emerging anticancer compounds by correlating NCI-60 patterns of sensitivity) shows that the MoA of these IrIII complexes has no correlation to cisplatin (or oxaliplatin), with 3 and 4 emerging as particularly novel compounds. Those findings by COMPARE were experimentally probed by transmission electron microscopy (TEM) of A2780 cells exposed to 1, showing mitochondrial swelling and activation of apoptosis after 24 h. Significant changes in mitochondrial membrane polarization were detected by flow cytometry, and the potency of the complexes was enhanced ca. 5× by co-administration with a low concentration (5 μM) of the γ-glutamyl cysteine synthetase inhibitor L-buthionine sulfoximine (L-BSO). These studies reveal potential polypharmacology of organometallic IrIII complexes, with MoA and cell selectivity governed by structural changes in the chelating ligands