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Introduction: Novel treatment strategies by taking advantage of the host anti-tumor immunity, known as immunotherapy, have been under development in the treatment of patients with colorectal cancer (CRC). The fact that the privilege of these promising remedies is limited to relatively few patients has led to the efforts to discover novel immune checkpoints, among which CD73 has gained considerable interest as a potential therapeutic target. CD73, also known as ecto-5’-nucleotidase (NT5E), is one of the key enzymes catalyzing the conversion of extracellular ATP into adenosine, which in turn exerts potent immune suppressive effects by activating adenosine receptors, thus favoring tumor immune escape. CD73 is increased in human CRCs and high CD73 is correlated to poor prognosis, while targeting CD73 has been proved effective in restoring anti-tumor immune response and controlling tumor progression in mouse tumor models. Nevertheless, the expression of CD73 on various cell types in CRCs is still unknown and needs further investigation. Methods: We acquired tumor and adjacent normal tissues from eligible CRC patients. The samples were subjected to enzymatic digestion to acquire cell suspensions, which were stained with antibody cocktail for cell membrane proteins identifying specific cell types of interest and CD73, followed by multiparameter flow cytometric analyses. The absolute cell number, cell percentage in the parental cell population, and CD73 mean fluorescence intensity (MFI) were calculated for all the cells of interest. Besides, histology sections were performed on the CRC tissues and anti-CD73 monoclonal antibody was used for immunohistochemistry (IHC) staining. In addition, the tumor-infiltrating lymphocytes and CD73 expression were correlated to the clinicopathological parameters including tumor location, T stage, tumor differentiation grading, neoadjuvant therapy, and treatment response following neoadjuvant therapy. Results: We demonstrated that CD73 was increased in CRC tumors comparing to adjacent normal tissues, as shown by the increased CD73+ absolute cell number, CD73+ cell percentage, and CD73 MFI, as well as the enhanced CD73 IHC staining. We found that the elevation of CD73 in CRC tumors might be attributable to the EpCAM+ epithelial/adenocarcinoma cells, as indicated by the higher proportion of EpCAM+ cells expressing CD73 and higher CD73 MFI on EpCAM+ cell population in CRC tumors. Nevertheless, we revealed that CD73 on CD45+ tumor-infiltrating leukocytes was decreased in CRC tumors, as indicated by the lower proportion of CD45+ leukocytes expressing CD73 and lower CD73 MFI on CD45+ cell population in CRC tumors; although the leukocyte infiltration was enhanced in the tumors. When looking into the tumor-infiltrating lymphocytes, we found that both the CD3+ T and CD20+ B lymphocytes were increasingly infiltrated in the CRC tumors as shown by their raised cell numbers. Besides, we observed higher CD3+ T lymphocyte but lower CD20+ B lymphocyte percentages within CD45+ leukocyte population in CRC tumors. Concerning the expression of CD73 on the tumor-infiltrating lymphocytes, we found less proportion of both T and B lymphocytes expressed CD73 in CRC tumors; the CD73 MFI on CD20+ B lymphocytes was also decreased in CRC tumors but on CD3+ T lymphocytes it was similar between tumor and normal tissues. When correlating the tumor-infiltrating lymphocytes and CD73 expression to clinicopathological parameters, we found that T and B cells seemed to be increasingly infiltrated in right colon and rectal cancers, while B cells seemed to be suppressed by neoadjuvant therapy. In addition, the expression of CD73 on tumor-infiltrating lymphocytes seemed to be influenced by tumor location, differentiation grading, and neoadjuvant therapy. Conclusion: We demonstrated that CD73 was increased in CRC tumors as compared to adjacent normal tissues, which might be contributable to EpCAM+ epithelial/adenocarcinoma cells. Nevertheless, CD73 was decreased in tumor-infiltrating leukocytes, including T and B lymphocytes, although these immune cells were increasingly infiltrated in the tumor microenvironment. Future studies investigating the CD73 expression pattern on distinct T and B cell subtypes are needed. Einleitung: In den letzten Jahren gewinnt die Immuntherapie in der Behandlung bösartiger Tumore immer mehr an Bedeutung. Hierbei wird das Immunsystem gezielt unterstützt oder aktiviert, um eine antitumorale Immunantwort zu generieren. Diese Behandlungsform kommt auch bei Patienten mit Kolorektalem Karzinom (KRK) immer mehr zum Einsatz, jedoch profitieren aktuell nur wenige Patienten von der neuartigen Behandlung, daher ist es notwendig neue Immun-Checkpoints zu erforschen. Hierbei könnte CD73 als neues therapeutisches Ziel dienen. Dieser Marker, auch bekannt als Ecto-5´Nucleotidase (NT5E), ist eines der Schlüsselenzyme, die die Umwandlung von extrazellulärem ATP in Adenosin katalysieren, welches wiederum immunsupprimierend durch die Aktivierung von Adenosinrezeptoren wirkt und somit das Tumorwachstum begünstigt. Im KRK ist CD73 vermehrt exprimiert und auch mit einer schlechteren Prognose assoziiert. Im Maustumormodell konnte gezeigt werden, dass eine Applikation von einem CD73-Antikörper die antitumorale Immunantwort verbessert und dies auch zu einer Tumorprogression führt. Dennoch ist die CD73-Expression auf den verschiedenen Zelltypen im KRK weitgehendst unbekannt und bedarf weiterer Untersuchungen. Methoden: Es wurde Tumorgewebe und angrenzendes normal erscheinendes Gewebe des Kolons von Patienten untersucht, die sich aufgrund eines KRKs einer Operation unterzogen haben. Die Einwilligung der Patienten wurde im Vorfeld eingeholt. Die Gewebeproben wurden enzymatisch verdaut, um eine Zellsuspension zu erhalten. Anschließend erfolgte eine Zugabe verschiedener Antikörper, um unterschiedliche Oberflächenmarker, unter Anderem CD73, mithilfe von Durchflusszytometrie (FACS) zu identifizieren. Dabei wurden die absolute Zellzahl, der prozentuale Anteil der Zellen in der Gesamtpopulation und die mittlere CD73 Fluoreszenzintensität (MFI) ermittelt. Desweiterem wurde immunhistochemische Analysen von Tumorgewebe mit einem anti-CD73 mononuklearem Antikörper durchgeführt. Darüber hinaus wurden die Tumor-infiltrierende Lymphozyten und die CD73-Expression mit den klinisch-pathologischen Parametern verglichen, einschließlich Tumorlokalisation, dem T-Stadium, der Tumordifferenzierung, der neoadjuvanten Therapie und dem Behandlungsansprechen nach der adjuvanten Therapie. Ergebnisse: Man konnte im Tumorgewebe des KRKs eine erhöhte CD73 Expression feststellen, verglichen mit dem gesunden Kolongewebe. Sowohl die absolute CD73+ Zellzahl, als auch der erhöhte CD73+ Zellanteil, die CD73 Fluoreszenzintensität und die verstärkte immunhistochemische Anfärbung sind beweisend dafür. Die erhöhte Expression ist vermutlich auf EpCAM+ Zellen des Epithel-/Adenokarzinoms zurückzuführen, da ein großer Teil der EpCAM+ Zellen CD73 exprimiert und die auch die CD73 Fluoreszenzintensität auf EpCAM+ Zellen erhöht war. Dennoch zeigt sich, dass CD73 auf CD45+ tumorinfiltrierenden Leukozyten im KRK vermindert exprimiert wird, obwohl die Infiltration von Leukozyten in das tumoröse Gewebe erhöht war. Bei der näheren Untersuchung dieser Zellen stellte sich heraus, dass sowohl die CD3+ T- als auch die CD20+ B-Lymphozyten vermehrt infiltrierten. Außerdem beobachteten wir einen höheren Anteil an CD3+ T-Lymphozyten, aber einen verringerten Anteil an CD20+ B-Lymphozyten innerhalb der CD45+ Leukozyten Population im KRK. Bezüglich der Expression von CD73 auf den Tumor-infiltrierenden Lymphozyten wurde ein geringerer Anteil an T- und B-Lymphozyten festgestellt. Auch die CD73 Fluoreszenzintensität auf CD20+ B-Lymphozyten war im KRK verringert, bei der CD3+ T-Lymphozyten jedoch war sie zwischen Tumor- und Normalgewebe ähnlich. Bei der Korrelation der Tumor-infiltrierenden Lymphozyten und der CD73-Expression mit klinisch-pathologischen Parametern wurde festgestellt, dass T- und B-Lymphozyten vermehrt infiltrieren bei Befall des rechten Kolons und des Rektums, währenddessen B-Lymphozyten durch eine neoadjuvante Therapie unterdrückt zu werden scheinen. Darüber hinaus wird die CD73-Expression auf Tumor-infiltrierenden Lymphozyten durch die Tumorlokalisation, Tumordifferenzierung und neoadjuvanter Therapie beeinflusst. Schlussfolgerung: Wir konnten zeigen, dass CD73 im KRK im Vergleich zu gesundem Kolongewebe erhöht war, wohlmöglich aufgrund der EpCAM+ Zellen des Epithel-/Adenokarzinoms. Dennoch war CD73 in Tumor-infiltrierenden Leukozyten, einschließlich T- und B-Lymphozyten, verringert, trotz der erhöhten Präsenz von Immunzellen im tumorösen Gewebe. Weitere Studien zur Untersuchung der CD73-Expression auf verschiedenen T- und B-Zell-Subtypen sind erforderlich.

Der Erfolg einer Versorgung mit dentalen Implantaten hängt von der Osseointegration in den Kieferknochen ab. Die Osseointegration kann durch pathologische Prozesse, die den Knochenstoffwechsel beeinflussen, beeinträchtigt werden. Hierzu gehören eine Therapie mit Bisphosphonaten, eine Erkrankung mit Diabetes mellitus oder Osteoporose, und eine stattgehabte Radiotherapie. Um den Einfluss dieser Kompromittierungen zu erfassen wurde eine systematische Literaturrecherche durchgeführt, die die Osseointegration von Implantaten unter kompromittierten Wundverhältnissen im Tiermodell untersucht. The success of dental implants depends upon their osseointegration. Pathological processes like bisphosphonate therapy, Diabetes mellitus, osteoporosis or radiotherapy can negatively influence bone turnover and hinder implant osseointegration. This review aimed to assess the impact of the aforementioned conditions on osseointegration as reported in animal studies.

Physical examination (PE) has always been a corner stone of medical practice. The recent advances in imaging and fading of doctors’ ability in performing it, however, raised doubts on PE usefulness. Point-of-care ultrasonography (POCUS) is gaining ground in medicine with the detection of free fluids being one of its main applications. To estimate physicians’ confidence and use of PE and POCUS for the detection of abdominal or pleural free fluid, we conducted a cross-sectional survey. In all, 246 internal and emergency medicine physicians answered to the survey (197 in-hospital physicians and 49 general practitioners; response rate 28.5%). Almost all declared to perform PE in case of suspected ascites or pleural effusion (88% and 90%, respectively). The highest rates of confidence were observed in conventional PE signs (91% for diminished breath sounds, 80% for dullness to thorax percussion, and 66% for abdominal flank dullness). For the remaining signs, rates of confidence were less than 53%. Physicians with > 15 years of experience and POCUS-naïve doctors reported higher confidence in PE. Most of emergency and almost half of internal medicine physicians (78% and 44%, respectively) attended a structured POCUS course. POCUS use was higher among trained physicians for both ascites (84% vs 50%,p p

1. Zusammenfassung 1.1 Hintergrund und Ziele Das Plattenepithelkarzinom der Mundhöhle, sowie dessen chirurgische Behandlung, kann zu schwerwiegenden morphologischen und funktionellen Einschränkungen führen. Die zu erwartende Lebensqualität hängt dabei von vielfältigen Faktoren ab und betrifft maßgeblich alltägliche Abläufe wie Essen, Schlucken und Sprechen. Als Mittel der sozialen Interaktion, besitzt die Sprachverständlichkeit einen hohen Stellenwert für betroffene Tumorpatienten. Die unterschiedlichen Auswirkungen der Spracheinschränkungen hängen von diversen Faktoren der Tumorentwicklung und Tumorbehandlung ab. Der Fokus dieser Studie liegt auf dem Einfluss der Unterkieferkontinuitätsresektion und der daraus resultierenden Rekonstruktion auf die Sprachverständlichkeit, am Beispiel des mikrovaskulären Scapula-Transplantats, über einen longitudinalen Beobachtungszeitraum von 30 Monaten. Somit sollen Langzeitfolgen dargestellt werden, um eine Prognose für Patienten aufzeigen zu können. 1.2 Material und Methoden In einer prospektiven Langzeituntersuchung über 30 Monate wurden 51 Patienten mit dem Befund der Unterkieferkontinuitätsunterbrechung, in Folge der Tumorresektion und anschließender Defektrekonstruktion, mittels eines Scapula-Transplantats versorgt. Dabei wurden zu definierten Zeitpunkten Sprachaufnahmen erstellt, mit derer die Sprachverständlichkeit im Verlauf dargestellt wurde. Hinsichtlich verschiedener Kriterien, wie T-Stadium, Volumen und dem Vorhandensein einer adjuvanten Radiatio wurden diese Daten ausgewertet. Das Patientenkollektiv bestand aus 11 Frauen und 40 Männern, mit einem Altersdurchschnitt von 59 Jahren. Es waren alle Tumorstadien repräsentiert. Die Sprachdatenerhebung erfolgte durch ein automatisches, benutzer- unabhängiges Spracherkennungssystem (PEAKS) und wurde anschließend anhand der gegebenen Kriterien statistisch analysiert. Zur Gegenüberstellung der Daten diente eine Kontrollkohorte von Personen ohne Spracheinschränkung. 1.3 Ergebnisse und Beobachtungen Zu Beginn der Messaufzeichnung (präoperativ) wurde bei 51 Personen die Sprachverständlichkeit aufgenommen. Im weiteren Verlauf der Messzeitpunkte nahm die Anzahl der jeweiligen sprachlich erfassten Patienten ab. Der Gesamtverlauf aller Patienten zeigte bereits vor der Tumorresektion eine signifikant niedrigere (p= 0,007) Sprachverständlichkeit (Word Recognition Rate, WR) als die Kontrollgruppe. Im zeitlichen Verlauf kam es zu einem starken Abfallen der Kurve, welche innerhalb der weiteren Messpunkte wieder stieg. Weder zum höchsten Punkt der WR, zum Zeitpunkt 18 Monate, noch zum Ende der Sprachaufzeichnung wurde der Ausgangwert erreicht. Die Sprachverständlichkeit war zu jedem Zeitpunkt signifikant schlechter als der Ausgangswert und als der Kontrollwert. Für die gewählten Einzelkriterien (T-Stadium, Volumen, Radiatio) zeigten sich vereinzelt signifikante Unterschiede zwischen den Untergruppen. Zum Ende der Aufnahmezeit von 30 Monaten zeigte, bis auf eine Ausnahme (T3-Verlauf), kein Einzelgraph signifikante Unterschiede zu den Graphen verglichener Kriterien. Der Gesamtverlauf aller Patienten zeigte einen repräsentativen Verlauf für alle Einzelkriterien, vereinzelte Ausnahmen waren durch eine geringe Anzahl der jeweiligen Messwerte gekennzeichnet. 1.4 Schlussfolgerungen Bei Tumoren, die in Folge der Tumorresektion eine Unterkieferkontinuitätsdurchtrennung vorweisen, ist bereits präoperativ eine verminderte Sprachverständlichkeit zu erkennen, die sich im Verlauf der postoperativen Nachsorge nicht wieder auf den Ausgangswert erholt. Diese Erkenntnis lässt vermuten, dass die Kontinuitätsunterbrechung als ein dominanter Haupteinflussfaktor gesehen werden kann, der den Krankheitsverlauf und somit die Sprachverständlichkeit maßgeblich beeinflusst. Es gilt, durch weitere Untersuchungen mit einer größeren Kohorte und anhand weiterer Rekonstruktionstechniken, die gewonnenen Aussagen wissenschaftlich evident darzustellen.

To investigate trabeculopuncture (TP) for predicting the outcome of ab interno trabeculectomy (AIT). Ex vivo porcine anterior segments were perfused and sequentially underwent two procedures, TP and AIT. We concluded that a 10% reduction in IOP after TP can be used to predict the success (>20% IOP decrease) of AIT in porcine eyes. As porcine eyes share many similarities with human eyes, our findings may have implications on the validity of this test as a predictor for surgical outcomes of AITs in humans., Wir untersuchten die Trabekulopunktion (TP) zur Vorhersage des Erfolgs einer Ab Interno Trabekulektomie (AIT) an einem ex vivo Schweineaugen-Perfusionsmodell. Die Schweineaugen wurden nacheinander zwei Verfahren (TP und AIT) unterzogen. Wir kamen zu dem Schluss, dass eine 10-prozentige Senkung des Augeninnendrucks nach der TP zur Vorhersage des Erfolgs (>20-prozentige Senkung des Augeninnendrucks) einer AIT in Schweineaugen verwendet werden kann. Schweineaugen weisen viele Ähnlichkeiten mit menschlichen Augen auf. Die Implementation eines solchen Tests zur Vorhersage des chirurgischen Erfolgs einer AIT beim Menschen wäre von hoher klinischer Relevanz.

In 90% of pancreatic ductal adenocarcinoma cases, genetic alteration of the protooncogene Kras has occurred, leading to uncontrolled proliferation of cancerous cells. Targeting Kras has proven to be difficult and the battle against pancreatic cancer is ongoing. A promising approach to combat cancer was the discovery of the clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (Cas) system, which can be used to genetically modify cells. To assess the potential of a CRISPR/CRISPR-associated protein 9 (Cas9) method to eliminate Kras mutations in cells, we aimed to knock-out the c.35G>A (p.G12D) Kras mutation. Therefore, three cell lines with a heterozygous Kras mutation (the human cell lines SUIT-2 and Panc-1 and the cell line TB32047 from a KPC mouse model) were used. After transfection, puromycin selection and single-cell cloning, proteins from two negative controls and five to seven clones were isolated to verify the knock-out and to analyze changes in key signal transduction proteins. Western blots showed a specific knock-out in the KrasG12D protein, but wildtype Kras was expressed by all of the cells. Signal transduction analysis (for Erk, Akt, Stat3, AMPK , and c-myc) revealed expression levels similar to the wildtype. The results described herein indicate that knocking-out the KrasG12D mutation by CRISPR/Cas9 is possible. Additionally, under regular growth conditions, the knock-out clones resembled wildtype cells. Das Pankreaskarzinom (PaCa) ist die vierthäufigste Krebstodesursache in Deutschland. Die Überlebenschancen nach Diagnosestellung sind sehr gering, was sich in der negativen 5-Jahres-Überlebensrate von nur circa 9% widerspiegelt. Es ist bekannt, dass in rund 90% der PaCa-Fälle eine Mutation im Protoonkogen KRAS nachweisbar ist. Als zentrales Element in verschiedenen Signalwegen ist KRAS in der Regulation von Zellproliferation, -differenzierung und -überleben involviert. Eine aktivierende Mutation kann zur kontinuierlichen Transmission eines Wachstumssignals und damit zur Tumorentstehung führen. Mit dem CRISPR/Cas9-System, welches die Modifikation von Genen ermöglicht, wurde analysiert, ob ein Knock-out von mutiertem KRAS durchführbar ist. Zur Durchführung des CRISPR/Cas9 vermittelten Knock-outs und zur Überprüfung der Rolle von mutiertem KRAS im Pankreaskarzinom wurden zwei humane Zelllinien (Panc-1 und SUIT-2) und eine Zelllinie aus dem Mausmodell (TB32047) verwendet. Alle drei Zelllinien enthalten die heterozygote KRASG12D-Mutation (c.35G>A). Nach Transfektion, Puromycin Selektion und Einzelzell-Klonierung wurden Western Blots durchgeführt, um den Knock-out zu bestätigen. Zur weiteren Überprüfung des Knock-outs im Bereich von KRASG12D wurde die DNA aller Klone sequenziert. Auf Grund der Expressionsveränderungen der Signaltransduktionsproteine der veränderten TB32047 Zellen wurde die Genexpression dieser Klone mittels RNA-Sequenzierung untersucht. Mit Hilfe der DNA Sequenzierung konnten Insertions- und Deletionsmutationen in der KRASG12D-Sequenz festgestellt werden. Mittels Western Blot war keine Expression von KRASG12D nachweisbar. Daher ist von erfolgreichen Knock-outs in allen drei getesteten Zelllinien auszugehen. Normales KRAS wurde dennoch von allen Klonen exprimiert. Die Untersuchung der Signaltransduktionsproteine (Erk, Akt, Stat3, AMPKa, c-myc) zeigte eine heterogene Expression dieser Proteine. Das CRISPR/Cas-System eignet sich zur erfolgreichen Durchführung von Knock-Outs. Insbesondere in diesem Versuch zeigt sich keine Apoptose oder Wachstumsstopp.

Introduction / Background Clinical radiostereometric analysis (RSA) is routinely conducted with a set-up of two paired X-ray tubes. One set-up of two purpose-built RSA tubes is associated with huge investment costs. Another set-up of a combination of one ceiling-mounted tube and additional portable X-ray tube could be quite time-consuming. Thus, the application of a single programmable robotic Roentgen tube with a time difference of just a few seconds for image acquisition could be a time-saving, space-efficient and less expensive alternative. The purposes of this thesis are (1) to evaluate accuracy of such a special RSA set-up in a phantom study and (2) to simulate patient motion for the influence on acquisition of paired radiostereometric images. Materials and Methods Radiographs were acquired by means of the conventional RSA set-up as forms of both simultaneous and non-simultaneous exposures. A customized phantom within two implants was designed to imitate the clinical scenario for assessing the effects of patient motion on acquisition of paired radiostereometric images. The values of mean (±standard deviation, SD), accuracy and precision of measured implant migration were calculated for comparison. Crossing line distance (CLD) of bone markers, difference (DIF) of implant contours, mean error (ME) of rigid body matching, condition number (CN), migration and maximum total point motion (MTPM) were compared to each motion in each RSA scene. The paired t-test was used, and p values below 0.05 were considered significant. Results There were no statistically significant differences between the conventional RSA set-up and the special set-up on accuracy of migration measurements in phantom experiments. In the simulation study of patient motion, the levels of permitted translation motion along the medial, superior and anterior axes and rotation around the superior axis in model-based RSA were less than 8 mm (p = 0.021), 1 mm (p < 0.001), 3 mm (p = 0.021) and 5 degrees (p = 0.003), respectively. Whereas in marker-based RSA, they were generally higher than 10 mm, less than 1 mm (p < 0.001) and 4 mm (p = 0.007) and higher than 10 degrees, respectively. As the phantom motion increased, the values of calculated migration enlarged. Discussion / Conclusion The use of the single robotic X-ray tube is feasible in comparison with conventional RSA in phantom experiments. Model-based RSA within motion artifacts is more robust than marker-based RSA in terms of analyzing the RSA scenes. Activated markers, CLD and DIF are sensitive to detect RSA-related motion artifacts, along with matched markers, ME and CN. But, MTPM is better than above-mentioned parameters. Specific patient motion can lead to detectably RSA-related motion artifacts. RSA within patient motion (over 1 mm) or RSA within motion artifacts is not the golden standard method any more. Motion artifacts are able to cause the inaccuracy of academic conclusion. Clinical studies should make 100% simultaneous or electronically synchronous acquisition of paired radiostereometric images in order to avoid RSA-related motion artifacts. Hintergrund und Ziele Die klinische radiostereometrische Analyse (RSA) wird routinemäßig mit einem Aufbau von zwei gepaarten Röntgenröhren durchgeführt. Ein Aufbau von zwei speziell angefertigten RSA-Röhren ist mit enormen Investitionskosten verbunden. Ein weiterer Aufbau einer Kombination aus einer an der Decke montierten Röhre und einer zusätzlichen tragbaren Röntgenröhre kann sehr zeitaufwändig sein. Die Anwendung einer einzelnen programmierbaren Roboterröntgenröhre mit einem Zeitunterschied von nur wenigen Sekunden für die Bildaufnahme könnte daher eine zeitsparende, platzsparende und kostengünstigere Alternative sein. Ziel dieser Arbeit ist es, (1) die Genauigkeit eines solchen speziellen RSA-Aufbaus in einer Phantomstudie zu bewerten und (2) die Bewegung des Patienten für den Einfluss auf die Erfassung gepaarter radiostereometrischer Bilder zu simulieren. Methoden Röntgenaufnahmen wurden mittels des herkömmlichen RSA- Aufbaus als Formen sowohl simultaner als auch nicht simultaner Expositionen aufgenommen. Ein angepasstes Phantom innerhalb von zwei Implantaten wurde entwickelt, um das klinische Szenario zur Bewertung der Auswirkungen der Patientenbewegung auf die Erfassung gepaarter radiostereometrischer Bilder nachzuahmen. Zum Vergleich wurden die Mittelwerte (± Standardabweichung, SD), Genauigkeit und Präzision der gemessenen Implantatmigration berechnet. Der Kreuzungslinienabstand (CLD) der Knochenmarker, die Differenz (DIF) der Implantatkonturen, der mittlere Fehler (ME) der Starrkörperanpassung, die Zustandsnummer (CN), die Migration und die maximale Gesamtpunktbewegung (MTPM) wurden jeweils mit jeder Bewegung verglichen RSA- Szene. Der gepaarte t- Test wurde verwendet und p- Werte unter 0,05 wurden als signifikant angesehen. Ergebnisse und Beobachtungen Es gab keine statistisch signifikanten Unterschiede zwischen dem konventionellen RSA-Aufbau und dem speziellen Aufbau zur Genauigkeit von Migrationsmessungen in Phantomexperimenten. In der Simulationsstudie zur Patientenbewegung betrugen die zulässigen Translationsbewegungen entlang der medialen, oberen und vorderen Achse sowie die Rotation um die obere Achse bei modellbasiertem RSA weniger als 8 mm (p = 0,021), 1 mm (p

Afin d’assister le prescripteur dans la rationalisation de la prescription gériatrique et la limitation de la polymédication, qui est un facteur de morbidité et de mortalité majeur chez la personne âgée, de nombreux outils d’aide à la revue de la qualité de la prescription ont été développés durant ces 30 dernières années. Parmi eux, le Stopp-Start permet d’identifier les traitements potentiellement inappropriés, mais également les omissions de traitement, et est adapté à tous les contextes de soin. Une étude prospective en grappes en contrôle croisé, comparant deux interventions (Stopp-Start versus observation), indique que l’usage hebdomadaire du Stopp-Start en gériatrie hospitalière aigue pourrait permettre de diminuer la survenue et la sévérité des effets indésirables médicamenteux durant la période d’hospitalisation dans le premier groupe étudié. Toutefois, un certain nombre de limitations méthodologiques, que nous discutons dans ce travail, nuance la portée de ces résultats.

Die Therapieentscheidung beim HCC richtet sich derzeit nach den BCLC-Kriterien. Die effektivste Therapieoption, eine Resektion, wird allerdings nur in den frühen Stadien empfohlen. Um postoperative Komplikationen zu vermeiden, benötigt es unter anderem eine effiziente präoperative Leberfunktionsevaluation zur Auswahl der Resektionskandidaten. Frühere Studien konnten zeigen, dass der LiMAx-Test hierfür geeignet ist. Da aber Daten zu HCC-Patienten noch fehlen, war das Ziel dieser Studie zu untersuchen, ob der LiMAx-Test die präoperative Evaluation von HCC-Patienten erleichtert und so die postoperative Morbidität und Mortalität insbesondere für Patienten mit Leberzirrhose gesenkt werden kann. Insgesamt erhielten 92 HCC Patienten zur Therapieevaluation eine LiMAx-Messung und wurden in eine Gruppe mit Zirrhose (LZ-Gruppe) und eine ohne (NL-Gruppe) eingeteilt und miteinander verglichen. Jeder Fall wurde in einer Tumorkonferenz besprochen und anhand der erhobenen Leberfunktionsparameter entschieden. 46 Patienten erhielten eine Resektion, 46 wurden abgelehnt, 17 aufgrund zu schlechter LiMAx-Ergebnisse. Die LiMAx-Werte der Resezierten waren mit 388 vs. 322µg/kg/h höher als die der abgelehnten Patienten (p=0,004). Zudem waren sie ein unabhängiger Risikofaktor für eine Leberzirrhose und Prädiktoren für eine unzureichende Leberfunktionsreserve. Ein unterer Grenzwert von 221µg/kg/h wurde ermittelt, bei welchem auch bei Zirrhosepatienten eine Resektion noch sicher durchgeführt werden kann. Generell gab es in der LZ-Gruppe nicht mehr postoperative Komplikationen als in der NL-Gruppe. Eine Vorhersage zur Entwicklung eines postoperativen Leberversagens durch den LiMAx-Test konnte in unserer Studie nicht gezeigt werden. Präoperativ eingesetzt, ermöglicht der LiMAx-Test somit eine effektive und sichere Evaluation von HCC Patienten, die von einer Resektion profitieren, mit niedriger postoperativer Morbiditäts- und Mortalitätsrate, sowohl bei Patienten mit oder ohne Leberzirrhose., The treatment decision in HCC is currently based on the BCLC criteria. However, the most effective therapeutic option, resection, is recommended only in the early stages. To avoid postoperative complications, it requires, among other things, an efficient preoperative liver function evaluation to select resection candidates. Previous studies have shown that the LiMAx test is suitable for this purpose. However, since data on HCC patients are still lacking, the aim of this study was to investigate whether the LiMAx test can facilitate the preoperative evaluation of HCC patients and thus reduce postoperative morbidity and mortality, especially for patients with liver cirrhosis. A total of 92 HCC patients received LiMAx measurement for treatment evaluation and were divided into a group with cirrhosis (LZ group) and one without (NL group) and afterwards compared. Each case was discussed in a tumor conference and a decision was made based on the liver function parameters obtained. 46 patients received resection, 46 were rejected, and 17 because of too poor LiMAx results. The LiMAx values of the resected patients were higher than those of the rejected patients, 388 vs. 322µg/kg/h (p=0.004). Moreover, they were an independent risk factor for liver cirrhosis and predictors of inadequate liver functional reserve. A lower limit of 221µg/kg/h was identified at which resection can still be safely performed even in cirrhotic patients. In general, there were no more postoperative complications in the LZ group than in the NL group. A prediction of the development of postoperative liver failure by the LiMAx test could not be shown in our study. Thus, used preoperatively, the LiMAx test allows an effective and safe evaluation of HCC patients who benefit from resection, with low postoperative morbidity and mortality rates, both in patients with or without liver cirrhosis.

Zusammenfassung Hintergrund und Ziele Bei dem oralen Plattenepithelkarzinom - engl. oral squamous cell Carcinoma (OSCC) – handelt es sich um eine weltweit häufig auftretende Erkrankung. Das OSCC macht mehr als 90 % aller Malignome der Mundhöhle aus und geht in späten Stadien mit einer schlechten Lebenserwartungsprognose einher. Studien belegen, dass die Tumorimmunologie für die Tumorentwicklung von Bedeutung ist und dass die Makrophagenpolarisierung für den Krankheitsverlauf wichtige prognostische Hinweise liefert. So kann auf der Basis des vorhandenen Patientenkollektivs die Frage formuliert werden: Lässt die Makrophagenpolarisierung in regionären Lymphknoten Rückschlüsse auf den klinischen Verlauf bei frühen (T1/T2, N0, R0  5 mm, keine adjuvante Therapie, G1/G2), nicht metastasierten oralen Plattenepithel-karzinomen zu? Des Weiteren wird die Frage untersucht, inwieweit sich die absolute Makrophageninfiltration von günstigeren (T1, G1 ohne Rezidiv) zu ungünstigeren (T2, G2, mit Rezidiv) klinischen Fällen verändert. Material und Methoden In dieser Studie wird das Patientenkollektiv in zwei Gruppen aufgeteilt: Kein Rezidiv innerhalb von zwei Jahren nach initialer Tumorresektion (günstiger Verlauf) und mit Rezidiv innerhalb von zwei Jahren (ungünstiger Verlauf). 17 Patienten erfüllen die Einschlusskriterien für diese retrospektive Auswertung (T1/T2, N0, R0  5 mm, keine adjuvante Therapie, G1/G2). Von den Lymphknotenpräparaten der Patienten wird ein Tissue Microarray (TMA) erstellt. Im Anschluss wird eine immunhistochemische Analyse der Makrophagenmarker CD11c, CD68, CD163 und MRC1 in den Lymphknotenkompartimenten Sinus, Perisinus und Gesamtgewebe durchgeführt. Für die Auswertung wird das Tool SPSS 22 für Mac OS (IBM inc. New York, USA) eingesetzt; dabei wird ein p-Wert von ≤ 0,05 als signifikant angesehen und mithilfe der Varianzanalyse mittels ANOVA bestimmt. Ergebnisse Die absolute Makrophageninfiltration in Lymphknotenproben liegt bei den Makrophagenmarkern CD68, CD163 und MRC1 in T1 Fällen in allen Kompartimenten höher als in T2 Fällen. In CD11c positiv markierten Zellen liegt die Makrophagenanzahl im Perisinus und Gesamtgewebe der Lymphknoten in T2 Fällen höher als in T1 Tumoren. In den Lymphknotenproben von T1 und T2 Fällen finden sich signifikante p-Werte im Sinus von CD68, im Perisinus von CD163 und im Sinus von MRC1. Bei diesen vier Makrophagenmarkern ist die absolute Makrophageninfiltration in Lymphknotenproben bei einem günstigeren klinischen Verlauf (ohne Rezidiv) höher als im ungünstigeren Fall (mit Rezidiv). Signifikante p-Werte in den Lymphknotenproben von Patienten mit Rezidiv und ohne Rezidiv finden sich im Sinus und Gesamtgewebe von CD163 sowie im Sinus und Perisinus von MRC1. Des Weiteren liegt die absolute Makrophageninfiltration in Lymphknotenproben - abhängig vom Grading - bei den Markern CD68, CD163 und MRC1 in den Lymphknoten von G1-Karzinomen höher als in den G2-Fällen, einzig die Makrophagenanzahl von CD11c positiven Zellen liegt im Sinus in G1-Fällen niedriger als in G2-Fällen. In den Lymphknotenproben von G1- und G2-Fällen findet sich lediglich im Sinus von CD11c ein signifikanter p-Wert. Schlussfolgerung Die Ergebnisse zeigen eine erhöhte Infiltration an M2 polarisierten Makrophagen im regionären Lymphknoten bei Patienten ohne Rezidiv und günstigerer Ausgangslage (T1- und G2-Fälle). Ursächlich für diese Ergebnisse könnten die strengen Auswahlkriterien bzw. die Limitationen der TMA-Methodik bei der Untersuchung von Lymphknoten sein. Zu prüfen wäre deshalb, inwieweit die Beschränkungen auf die günstigsten Parameter (T1/T2, G1/G2, N0, R0  5 mm, kein Rezidiv innerhalb von zwei Jahren), die Größe des Patientenkollektivs und die TMA-Methode für eine qualitativ aussagekräftige Analyse reichen. Weitere, komplexer angelegte Studien könnten die vorliegenden Ergebnisse verifizieren bzw. falsifizieren.

Sekundäre Rekonstruktionen der Orbita sind anspruchsvolle Eingriffe (Bittermann et al. 2014). Es wird eine Vielzahl von Methoden und Materialien diskutiert (Aldekhayel et al. 2014, Dubois et al. 2015b). Individuell gefertigte Implantate besitzen die beste Passgenauigkeit und müssen somit weniger oft repositioniert werden (Baumann et al. 2015). Dadurch verkürzt sich die Operationszeit (Baumann et al. 2015). Materialtechnisch geht der Trend hin zu alloplastischen Materialien (Aldekhayel et al. 2014). Am häufigsten verwendet wird Titan (Aldekhayel et al. 2014). Ein weiteres vielversprechendes Material ist die Glaskeramik Bioverit, welche bis jetzt kaum bei Rekonstruktionen der Orbitae verwendet wird (Beleites et al. 2001, Koscielny und Beleites 2002). Im Bereich der craniomaxillofazialen Rekonstruktionen hat Bioverit bereits gute Ergebnisse gezeigt (Beleites et al. 2001, Nkenke et al. 2011, Siebert et al. 2006). Ein wichtiges Kriterium für den Erfolg eines Eingriffes ist zudem die von Patienten beschriebene Zufriedenheit (Baino 2011, Hartwig et al. 2019). Nach aktuellem Kenntnisstand der Autoren gibt es bisher keine Studie, die patientenberichtete Ergebnisse mithilfe eines Fragebogens nach sekundären Rekonstruktionen der Orbitae ermittelt hat (Hartwig et al. 2019). Das Ziel dieser Studie war herauszufinden, ob sekundäre Rekonstruktionen mit individuell gefertigten Keramikimplantaten einen Zugewinn an Lebensqualität für den Patienten darstellen. Im Verlauf von 11 Jahren (10/2006 – 11/2017) wurden in der Mund-Kiefer- und Gesichtschirurgischen Klinik des Universitätsklinikums Erlangen-Nürnberg 14 Patienten mit einem individuellen CAD/CAM (computer-aided-designing/computer-aided-machining = computergestützte Konstruktion und computergestützte Fertigung) gefertigten Keramikimplantat versorgt. Die Studie besteht aus drei verschiedenen Abschnitten. Im ersten Abschnitt wurden augenärztliche Untersuchungen, durchgeführt durch die Augenklinik des Universitätsklinikums, ausgewertet. Die klinischen Parameter von Visus, Innenaugendruck und der Hertel Exophthalmometrie wurden prä- und postoperativ miteinander verglichen. Im zweiten Abschnitt wurde mithilfe des Programms syngo.via (Siemens, Erlangen, Deutschland) die dreidimensionale Bildgebung (CT oder DVT) genutzt um die Volumina der Orbitae prä- und postoperativ zu bestimmen und zu vergleichen. Der dritte Abschnitt der Studie war ein eigens hierfür konzipierter Fragebogen für die Patienten, der QoL-SOR/PSI. Der Fragebogen bezieht sich auf die Veränderungen für den Patienten durch die sekundäre Rekonstruktion. Themen des Fragebogens sind Doppelbilder, die Sehstärke, das Gesichtsfeld, Einschränkungen im Alltag und ästhetische Beeinträchtigungen. Anhand von numerischen Skalen können Patienten jeweils die Intensität bewerten. Die Auswertungen der augenärztlichen Untersuchungen ergaben keine funktionellen Einschränkungen für die Patienten. Alle Parameter waren präoperativ sowie postoperativ im Normbereich. Die volumetrischen Vermessungen ergaben eine signifikante Reduktion des Volumens der betroffenen Orbitae von präoperativ (33,94 3,24 cm3) zu postoperativ (30,67 2,07 cm3). Postoperativ war das Volumen der betroffenen Orbitae (30,67 2,07 cm3) kleiner als das der nicht betroffenen (31,38 2,80 cm3). Die Auswertungen der Patientenfragebögen ergaben keine Einschränkungen im funktionellen Bereich. Im Bereich der Einschränkungen im Alltag und ästhetischen Beeinträchtigungen gaben die Patienten an, präoperativ deutliche Einschränkungen gehabt zu haben. Nach der Rekonstruktion gaben die Patienten deutliche Verbesserungen an. Sekundäre Rekonstruktionen mit individuellen CAD/CAM gefertigten Implantaten stellen eine sichere und reproduzierbare Behandlung dar. Die Ergebnisse sind vorhersehbar und nicht nur im Bereich der funktionellen Aspekte zufriedenstellend, sondern auch aus Sicht der Patienten. The aim of this study was to determine whether patients benefit from a secondary reconstruction since it carries the risks of no improvement or worsening of their current situation. Patients treated with individual computer-aided-design/computer-aided-manufacturing (CAD/CAM) ceramic implants were reviewed. To ascertain changes throughout the secondary reconstruction, the study investigators reviewed ophthalmological examinations, took volumetric measurements of the orbits and asked the patients for evaluation of their situation before and after the reconstruction. Points addressed were double vision, visual acuity, field of vision, limitations in daily life and aesthetic considerations. A total of 14 patients were reviewed and 11 answered the questionnaire. Ophthalmological exami- nations showed that the physical integrity of the eye was maintained. Volumetric measurements pre- opeatively (33.94 ± 3.24 cm3) and postoperatively (30.67 ± 2.07 cm3) showed that a statistically significant overcorrection of orbital volume leads to good functional and aesthetic outcomes. Patients’ subjective opinions were that they greatly benefitted, especially concerning limitations in daily life, which improved by 4.4 ± 2.8 points out of 10 possible points, and aesthetics, with an improvement of 5.9 ± 1.78 points. Based on these findings, we conclude that secondary reconstructions contribute to improvement of the patients’ quality of life and therefore should be considered as an option to improve patients’ condition.

Immediate results of crural angioplasty for critical limb ischemia Zusammenfassung- Sofortergebnisse der kruralen Angioplastie bei kritischer Extremitätenischämie

Knowledge is power and we believe in a philosophy where all have free access to knowledge. We live in a rapidly evolving environment, where access to resources is paramount to keep the pace with scientific innovation. Social Media (SoMe) and digital learning tools provide a unique opportunity to reach an unlimited audience. The value of SoMe has been emphasised during the current pandemic.

Zusammenfassung Hintergrund Seit 2015 erfolgt in Europa mithilfe des EUROCRINE®-Registers eine systematische Dokumentation endokrin-chirurgischer Operationen. Ziel dieser ersten Auswertung war eine Darstellung der Versorgungsrealität für Nebenniereneingriffe in einem homogenen Versorgungsumfeld, entsprechend des deutschsprachigen Raums – bzw. des Präsenzgebiets der Chirurgischen Arbeitsgemeinschaft Endokrinologie (CAEK) der Deutschen Gesellschaft für Allgemein- und Viszeralchirurgie (DGAV) – einschließlich einer Analyse der Adhärenz zu geltenden Therapieempfehlungen. Methodik Es erfolgte eine deskriptive Analyse der präoperativen Diagnostik, der angewandten Operationstechniken sowie der zugrunde liegenden histologischen Entitäten der zwischen den Jahren 2015 und 2019 über EUROCRINE® in Deutschland, Österreich und der Schweiz dokumentierten Nebennierenoperationen. Ergebnisse In den insgesamt 21 teilnehmenden Kliniken des deutschsprachigen EUROCRINE®-Gebiets wurden 658 Operationen an Nebennieren durchgeführt. In 90 % erfolgten unilaterale, in 3 % bilaterale Adrenalektomien und in 7 % andere Resektionsverfahren. Die in 41 % der Operationen dokumentierte histologische Hauptdiagnose war das adrenokortikale Adenom. In 15 % lagen maligne Befunde zugrunde (einschließlich 6 % Nebennierenrindenkarzinome (ACC) und 8 % Nebennierenmetastasen). 23 % der Operationen erfolgten bei Phäochromozytomen. Diese wurden zu 82 % minimal-invasiv operiert, Nebennierenrindenkarzinome lediglich zu 28 % und Nebennierenmetastasen zu 66 %. Schlussfolgerung Überraschenderweise wurden nach Nebennierenadenomen und Phäochromozytomen an dritthäufigster Stelle Nebennierenmetastasen unterschiedlicher Primärtumoren reseziert. 28 % der ACC waren für minimal-invasive Techniken vorgesehen, wobei 20 % dieser Fälle eine Konversion zur offenen Operation erforderten. Die aktuelle Analyse deckte Diskrepanzen zwischen Versorgungsrealität und Leitlinienempfehlungen auf, aus denen sich zahlreiche Fragestellungen ergeben, welche nun in ein überarbeitetes EUROCRINE®-Modul zur Dokumentation von Nebennierenoperationen einfließen werden.

Objective To stratify major hepatectomies (MajHs) according to their outcomes. Summary of background data MajHs are associated with non-negligible operative risks, but they include a wide range of procedures. Detailed depiction of the outcomes of different MajHs is the basis for a new classification of liver resections. Methods We retrospectively considered patients that underwent hepatectomy in 17 high-volume centers. Patients with an associated digestive/biliary resection were excluded. We analyzed open MajHs in non-cirrhotic patients. MajHs were classified according to the Brisbane nomenclature. Right hepatectomies (RHs) were reference standards. Outcomes were adjusted for potential confounders, including indication, liver function, preoperative portal vein embolization, and enrolling center. Results We analyzed a series of 2212 patients. In comparison with RH, left hepatectomy had lower mortality [0.6% vs 2.2%, odds ratio (OR) = 0.25], severe morbidity (11.7% vs 14.4%, OR = 0.62), and liver failure rates (2.1% vs 11.6%, OR = 0.16). Left hepatectomy+Sg1 and mesohepatectomy+/-Sg1 had outcomes similar to RH, except for higher bile leak rate (31.3% and 13.5% vs 6.7%, OR = 4.36 and OR = 2.29). RH + Sg1 had slightly worse outcomes than RH. Right and left trisectionectomies had higher mortality (5.0% and 7.3% vs 2.2%, OR = 2.07 and OR = 2.71) and liver failure rates than RH (19.0% and 22.0% vs 11.6%, OR = 2.03 and OR = 2.21). Left trisectionectomy had even higher severe morbidity (25.6% vs 14.4%, OR = 2.07) and bile leak rates (14.6% vs 6.7%, OR = 2.31). Conclusions The term "major hepatectomy" includes resections having heterogeneous outcome. Different MajHs can be stratified according to their mortality, severe morbidity, liver failure, and bile leak rates.

To evaluate the value of synthetic magnetic resonance imaging (MRI) and T2 mapping in distinguishing between different types of fillers in soft tissues. Ex vivo fillers of buttock soft tissues (silicone, collagen, and different types of hyaluronic acid) were scanned using a synthetic MRI sequence at 1.5 and 3 T and an optimized T2 mapping sequence to measure the T2 relaxation times of the fillers ex vivo. Three patients addressed to assess complications with buttock fillers underwent MRI with the standard morphological sequences and an additional synthetic MRI sequence; T2 mapping was not performed for the patients. Two patients had silicone fillers, whereas the exact filler composition for the third patient was unknown. Measurements of T1 and T2 relaxation times of ex vivo fillers at 1.5 and 3 T using synthetic MRI showed that the silicone, collagen, and hyaluronic acid had distinct relaxation time characteristics. In vivo, the synthetic MRI correctly identified silicone in the two patients with known silicone fillers, showing low T1 and T2 values, whereas in the third patient with an unknown filler type, the synthetic MRI suggested a collagen filler, with intermediate relaxation time values. Quantitative sequences have the potential to differentiate between filler types in a noninvasive fashion.

Aim To provide dynamic guidance from a rigorous and up-to-date consensus on the safe implementation and application of transanal total mesorectal excision (TaTME) from an international panel of expert surgeons and educationalists supported by 14 international surgical societies. Method An adapted Delphi method and focus group discussion approach was implemented for this consensus process, with expert advice from a guidelines methodologist. Statements were generated focusing on three main topics relating to the safe implementation of TaTME: (1) indications, (2) quality and outcome measures, (3) training and implementation of TaTME. Results Five rounds of the Delphi consensus process were completed over a 13-month period. A total of 56 surgeons experienced in TaTME and surgical education participated in this project. By Delphi round four, 80.0% or greater agreement was reached for all statements except for two, which were further reviewed during a fifth round. More complex cases that are likely to benefit from TaTME were identified, with the recommendation that they should be referred to TaTME expert centres. The most agreed upon definition of expert centres is outlined. Conclusion We have provided a current framework of best practice related to implementation of TaTME. The statements are not indefinite and will continue to be 'dynamic' and updated as new evidence emerges.

From birth, children may need to take medication for acute or chronic diseases. Antibiotics, anti-asthmatic drugs, antihistamines, analgesics, gastrointestinal drugs and attention-deficit/hyperacti...

Liver transplantation (LT) offers excellent long-term outcome for certain patients with hepatocellular carcinoma (HCC), with a push to not simply rely on tumor size and number. Selection criteria should also consider tumor biology (including alpha-fetoprotein), probability of waitlist and post-LT survival (ie, transplant benefit), organ availability, and waitlist composition. These criteria may be expanded for live donor LT (LDLT) compared to deceased donor LT though this should not adversely affect the double equipoise in LDLT, namely ensuring both acceptable recipient outcomes and donor safety. HCC patients with compensated liver disease and minimal tumor burden have low urgency for LT, especially after local-regional therapy with complete response, and do not appear to derive the same benefit from LT as other waitlist candidates. These guidelines were developed to assist in selecting appropriate HCC patients for both deceased donor LT and LDLT.

BACKGROUND: Metastatic duodenopancreatic neuro-endocrine tumors (dpNETs) are the most important disease-related cause of death in patients with multiple endocrine neoplasia type 1 (MEN1). Nonfunctioning pNETs (NF-pNETs) are highly prevalent in MEN1 and clinically heterogeneous. Therefore, management is controversial. Data on prognostic factors for risk stratification is limited. This systematic review aims to establish the current state of evidence regarding prognostic factors in MEN1-related NF-pNETs. METHODS: We systematically searched four databases for studies assessing prognostic value of any factor on NF-pNET progression, development of distant metastases, and/or overall survival. In- and exclusion, critical appraisal and data-extraction were performed independently by two authors according to pre-defined criteria. RESULTS: Thirteen studies (370 unique patients) were included. Prognostic factors investigated were tumor size, timing of surgical resection, WHO grade, methylation, p27/p18 expression by immunohistochemistry (IHC), ARX/PDX1 IHC and alternative lengthening of telomeres. Results were complemented with evidence from studies in MEN1-related pNET for which data could not be separately extracted for NF-pNET and data from sporadic NF-pNET. CONCLUSION: The most important prognostic factors used in clinical decision making in MEN1-related NF-pNETs are tumor size and grade. NF-pNETs

Patients with moderate to severe acute respiratory distress syndrome (ARDS) benefit from prone positioning. Although the accuracy of esophageal pressure (Pes) to estimate regional pleural pressure (Ppl) has previously been assessed in the supine position, such data are not available in the prone position in ARDS. In six anesthetized, paralyzed, and mechanically ventilated female pigs, we measured Pes and Ppl into dorsal and ventral parts of the right pleural cavity. Airway pressure (Paw) and flow were measured at the airway opening. Severe ARDS [arterial partial pressure of oxygen ([Formula: see text])/fraction of inspired oxygen ([Formula: see text]) < 100 mmHg at positive end-expiratory pressure (PEEP) of 5 cmH2O] was induced by surfactant depletion. In supine and prone positions assigned in a random order, PEEP was set to 20, 15, 10, and 5 cmH2O and static end-expiratory chest wall pressures were measured from Pes (PEEPtot,es) and dorsal (PEEPtot,PplD) and ventral (PEEPtot,PplV) Ppl. The magnitude of the difference between PEEPtot,es and PEEPtot,PplD was similar in each position [-3.6 cmH2O in supine vs. -3.8 cmH2O in prone at PEEP 20 cmH2O (PEEP 20)]. The difference between PEEPtot,es and PEEPtot,PplV became narrower in the prone position (-8.3 cmH2O supine vs. -3.0 cmH2O prone at PEEP 20). PEEPtot,PplV was overestimated by Pes in the prone position at higher pressures. The median (1st-3rd quartiles) dorsal-to-ventral Ppl gradient was 4.4 (2.4-6.8) cmH2O in the supine position and -1.5 (-3.5 to +1.1) cmH2O in the prone position (P < 0.0001) and marginally influenced by PEEP (P = 0.058). Prone position narrowed end-expiratory dorsal-to-ventral Ppl vertical gradient, likely because of a more even distribution of mechanical forces over the chest wall.NEW & NOTEWORTHY In a porcine model of acute respiratory distress syndrome, we found that static end-expiratory esophageal pressure did not change significantly in prone position compared with supine position at any positive end-expiratory pressure (PEEP) tested between 5 and 20 cmH2O. Prone position was associated with an increased ventral pleural pressure and reduced end-expiratory dorsal-to-ventral pleural pressure (Ppl) vertical gradient, likely due to a more even distribution of mechanical forces over the chest wall.

This case report describes a full-thickness frostbite complication following cryolipolysis for subcutaneous fat reduction performed in a non-medical esthetic clinic. The deep and large abdominal wound (15 × 12 cm) required hospitalization and multiple surgical debridement before a two-step direct closure. Even though cryolipolysis is considered as a non-invasive and safe technique to reduce local adiposity, it could present some side-effects and complications. Health-care professionals should be aware of these risks and inform their patients about its potential sequelae.

Respiratory epithelial orbital cysts (REOC) are rare benign lesions that may be either congenital or acquired. Congenital REOC develop from embryological epithelial rests and are known as choristomas, whereas acquired forms develop from the sequestration of respiratory epithelium from adjacent paranasal sinuses following trauma and/or fracture repair procedures. The final diagnosis can be difficult because congenital and acquired REOC and mucoceles share the same features histologically. The involvement of the paranasal sinuses, which is the landmark of mucoceles, does not occur with REOC. Moreover, the intracranial extension, which is known for mucoceles, has never been reported for REOC. Respiratory epithelial orbital cysts warrant prompt radical surgical resection given that these lesions may lead to a progressive intracranial progression and/or recurrent infection with a potential for meningitis or cerebral abscess. The authors report a unique case of a patient with an intraorbital posttraumatic respiratory epithelial orbital cyst associated with intracranial involvement.

BACKGROUND Capnoperitoneum during laparoscopy leads to cranial shift of the diaphragm, loss in lung volume, and risk of impaired gas exchange. Infants are susceptible to these changes and bedside assessment of lung volume during laparoscopy might assist with optimizing the ventilation. Thus, the primary aim was to investigate the monitoring value of a continuous end-expiratory lung volume (EELV) assessment method based on CO2 dynamics ( EELVCO2 ) in a pediatric capnoperitoneum model by evaluating the correlation and trending ability against helium washout (EELVHe ). METHODS Intra-abdominal pressure (IAP) was randomly varied between 0, 6, and 12 mm Hg with CO2 insufflation, while positive end-expiratory pressure (PEEP) levels of 3, 6, and 9 cm H2 O were randomly applied in eight anesthetized and mechanically ventilated chinchilla rabbits. Concomitant EELVCO2 and EELVHe and lung clearance index (LCI) were obtained under each experimental condition. RESULTS Significant correlations were found between EELVCO2 and EELVHe before capnoperitoneum (r = .85, P

Early detection of local complications (venipuncture complications, nerve lesions, infections, arthritis, and tenosynovitis, tendon adhesions and re-tears, complications related to orthopaedic hardware) after hand surgery is required for prompt treatment. Ultrasound has proven to be a valuable imaging modality for detecting and assessing a variety of disorders of the wrist and hand. The purpose of this pictorial essay is to present a wide range of complications after wrist and hand surgery assessed by ultrasound.

AIM To explore how patients with cerebral palsy (CP) perceive their gait and evaluate associations between subjective gait perception and: objective gait parameters, endurance, pain, and fatigue. METHOD Sixty-two patients (21 females and 41 males; mean [SD] age 20y [5y 1mo], range 15-29y) performed a clinical gait analysis. Self-selected walking speed, Gait Profile Score, and Gait Variable Score were calculated. Subjective gait perception was assessed with a visual analogue scale using the question: 'On a scale from 0 (worst) to 10 (optimal), how would you describe your walking today?'. A 6-minute walk test (6MWT) measured endurance; the 36-Item Short Form Health Survey (SF-36) evaluated quality of life. T-tests, Pearson correlations, and univariate and multiple linear regression models were used to compare and find associations between the data. RESULTS Overall mean (SD) subjective gait perception was 7.5 (1.8) and was significantly higher for patients in Gross Motor Function Classification System (GMFCS) level I (7.9 [1.5]) than for patients in GMFCS levels II and III (5.9 [2.0]). Positive correlations were found between subjective gait perception and gait scores, walking speed, 6MWT distance, and SF-36 score. Only walking speed was a significant predictor of subjective gait perception. INTERPRETATION Subjective gait perception was influenced by GMFCS level and linked partially with the walking speed. The gait quality did not explain subjective gait perception. It is important to combine subjective and objective gait scores to develop personalized therapeutic goals. WHAT THIS PAPER ADDS Subjective gait perception is influenced by the physical impairment levels of patients with cerebral palsy. Subjective gait perception and objective gait scores are associated. Walking speed is the only predictor of gait perception.

Due to the shortage of multi-organ donors, human pancreatic islet transplantation has now been extended to islets originating from obese subjects. In this study, our aim is to compare the respective sensitivity of human islets from lean vs obese donors to chronic high glucose or high palmitate.Human islets were isolated from pancreases harvested from brain-dead multi-organ donors. Islets were cultured during 72 hours in the presence of moderate (16.7 mmol/L) or high (28 mmoL/L) glucose concentrations, or glucose (5.6 mmoL/L) and palmitate (0.4 mmoL/L), before measurement of their response to glucose.We first observed a greater insulin response in islets from obese donors under both basal and high-glucose conditions, confirming their hyperresponsiveness to glucose. When islets from obese donors were cultured in the presence of moderate or high glucose concentrations, insulin response to glucose remained unchanged or was slightly reduced, as opposed to that observed in lean subjects. Moreover, culturing islets from obese donors with high palmitate also induced less reduction in insulin response to glucose than in lean subjects. This partial protection of obese islets is associated with less induction of inducible nitric oxide synthase in islets, together with a greater expression of the transcription factor forkhead box O1 (FOXO1).Our data suggest that in addition to an increased sensitivity to glucose, islets from obese subjects can be considered as more resistant to glucose and fatty acid excursions and are thus valuable candidates for transplantation.背景: 由于缺乏多器官供体, 人胰岛移植目前已衍生到肥胖者来源的胰岛移植。在这项研究中, 我们旨在比较瘦人和肥胖者的胰岛对慢性高糖或棕榈酸盐的敏感性。 方法: 从脑死亡的多器官捐赠者的胰腺中分离胰岛。胰岛在中等浓度(16.7 mmol/L)或高浓度(28 mmol/L)葡萄糖培养基中, 或是葡萄糖(5.6 mmol/L)和棕榈酸盐(0.4 mmol/L)存在下培养72h, 然后测定其对葡萄糖的反应。 结果: 我们首先观察到肥胖捐赠者的胰岛在基础和高糖条件下都有更大的胰岛素反应, 证实了其对葡萄糖的高反应性。但当来自肥胖捐赠者的胰岛在中高浓度葡萄糖存在的情况下继续培养时, 胰岛对葡萄糖的反应则保持不变或略有降低, 这与在瘦的捐赠者中观察到的相反。此外, 用高棕榈酸培养后的肥胖捐赠者胰岛也比瘦捐献者的对于葡萄糖的胰岛素反应减少得少。这种对肥胖者胰岛的部分保护作用, 与较少诱导一氧化氮合成酶有关, 以及转录因子FOXO1的较高表达相关。 结论: 我们的结果表明, 除了对葡萄糖的敏感性增加外, 肥胖者的胰岛可以被认为对葡萄糖和脂肪酸剧增更有抵抗力, 因此是有价值的移植候选者。.

Background: Dermatoporosis is defined as a chronic cutaneous fragility and insufficiency syndrome. It results from chronological aging, long-term and unprotected sun exposure, genetic factors, or the chronic use of topical and systemic corticosteroids. There is currently a lack of noninvasive tools for the evaluation and quantification of dermatoporosis. Objectives: The aim of this study was to define the dermal-epidermal modifications which characterize dermatoporosis using noninvasive methods such as in vivo reflectance confocal microscopy (RCM) and ultrasound (US). Subjects and Methods: Seventeen patients with stage I dermatoporosis and 14 healthy volunteers were included in the study. The posterior surface of the right forearm was analyzed in all subjects, and stellate pseudoscars and senile purpura in patients with dermatoporosis were analyzed when possible. We used a commercially available reflectance confocal microscope and measured different histometric parameters (thickness of the epidermis and its different layers, cellular architecture, aspect of the dermal-epidermal junction and the dermis). We also used a commercially available US skin system to define the dermal-epidermal thickness (DET) in all subjects. Results: The DET measured with the US skin system was significantly different between the two groups: mean value 1.19 mm (volunteers group) versus 0.81 mm (patient group). The significant differences measured with RCM were (1) epidermal thickness, (2) number of dermal papillae, and (3) thickness of solar elastosis. Stellate pseudoscars are also characterized by a modified dermis, with a linear organization of the collagen bundles. Conclusion: US and in vivo RCM are useful tools for the diagnosis of dermatoporosis. Dermal-epidermal atrophy, reduction of dermal papillae/area, and the thickness of dermal elastosis seem to be the major histometric parameters which characterize dermatoporosis.

Intraportal islet transplantation is plagued by an acute destruction of transplanted islets. Amongst the first responders, NK cells and macrophages harbour an activating receptor, NKG2D, recognizing ligands expressed by stressed cells. We aimed to determine whether islet NKG2D ligand expression increases with culture time, and to analyse the impact of antibody-induced NKG2D blockade in islet transplantation. NKG2D-ligand expression was analysed in rat and human islets. Syngeneic marginal mass intraportal islet transplantations were performed in rats: control group, recipients transplanted with NKG2D-recombinant-treated islets (recombinant group), and recipients treated with a mouse anti-rat anti-NKG2D antibody and transplanted with recombinant-treated islets (antibody-recombinant group). Islets demonstrated increased gene expression of NKG2D ligands with culture time. Blockade of NKG2D on NK cells decreased in vitro cytotoxicity against islets. Recipients from the control and recombinant groups showed similar metabolic results; conversely, treatment with the antibody resulted in lower diabetes reversal. The antibody depleted circulating and liver NK cells in recipients, who displayed increased macrophage infiltration of recipient origin around the transplanted islets. In vitro blockade of NKG2D ligands had no impact on early graft function. Systemic treatment of recipients with an anti-NKG2D antibody was deleterious to the islet graft, possibly through an antibody-dependent cell-mediated cytotoxicity reaction.

Gait assessments in standardized settings, as part of the clinical follow-up of children with cerebral palsy (CP), may not represent gait in daily life. This study aimed at comparing gait characteristics in laboratory and real life settings on the basis of multiple parameters in children with CP and with typical development (TD). Fifteen children with CP and 14 with TD wore 5 inertial sensors (chest, thighs and shanks) during in-laboratory gait assessments and during 3 days of daily life. Sixteen parameters belonging to 8 distinct domains were computed from the angular velocities and/or accelerations. Each parameter measured in the laboratory was compared to the same parameter measured in daily life for walking bouts defined by a travelled distance similar to the laboratory, using Wilcoxon paired tests and Spearman’s correlations. Most gait characteristics differed between both environments in both groups. Numerous high correlations were found between laboratory and daily life gait parameters for the CP group, whereas fewer correlations were found in the TD group. These results demonstrated that children with CP perform better in clinical settings. Such quantitative evidence may enhance clinicians’ understanding of the gap between capacity and performance in children with CP and improve their decision-making.

BACKGROUND Busulfan (Bu) is one of the conditioning regimen components for pediatric hematopoietic stem cell transplantation. Bu therapeutic drug monitoring (TDM) is essential for a successful treatment outcome and toxicity evasion. Dried blood spot (DBS) sampling is a rapid and simple method for Bu TDM, compared with conventional plasma sampling. This study evaluated the feasibility of using the DBS method for Bu TDM. The hematocrit (Hct) and conditioning day were also examined for their impact on the DBS method's performance. METHODS Venous blood collected from 6 healthy volunteers was diluted, using their plasma into 4 samples of varying Hct values. Each sample was spiked with Bu calibrators (300, 600, and 1400 ng/mL), prepared using DBS and dried plasma spot (DPS) sampling and analyzed using a validated liquid-chromatography tandem-mass spectrometry method. Clinical blood samples (n = 153) from pediatric patients (n = 15) treated with Bu (mainly from doses 1, 2, 5, and 9) were used to prepare paired volumetric DBS and DPS samples. A Bland-Altman plot and Deming regression were used to define the agreement between the paired DBS and DPS measurements. Passing-Bablok regression analyses investigated the effects of Hct and conditioning day on the linearity between both methods. RESULTS In vitro analyses showed good agreement between DBS and DPS measurements, with a mean difference of -5.4% and a 95% confidence interval on the limits of agreement of -15.3% to 4.6%. Clinical samples showed good correlation (Pearson correlation coefficient = 0.96; slope = 1.00) between the DBS and DPS methods. The DBS method met the clinical acceptance limits for clinical samples, with a bias

Background The burden and timeline of posttransplant infections are not comprehensively documented in the current era of immunosuppression and prophylaxis. Methods In this prospective study nested within the Swiss Transplant Cohort Study (STCS), all clinically relevant infections were identified by transplant–infectious diseases physicians in persons receiving solid organ transplant (SOT) between May 2008 and December 2014 with ≥12 months of follow-up. Results Among 3541 SOT recipients, 2761 (1612 kidney, 577 liver, 286 lung, 213 heart, and 73 kidney-pancreas) had ≥12 months of follow-up; 1520 patients (55%) suffered 3520 infections during the first year posttransplantation. Burden and timelines of clinically relevant infections differed between transplantations. Bacteria were responsible for 2202 infections (63%) prevailing throughout the year, with a predominance of Enterobacteriaceae (54%) as urinary pathogens in heart, lung, and kidney transplant recipients, and as digestive tract pathogens in liver transplant recipients. Enterococcus spp (20%) occurred as urinary tract pathogens in kidney transplant recipients and as digestive tract pathogens in liver transplant recipients, and Pseudomonas aeruginosa (9%) in lung transplant recipients. Among 1039 viral infections, herpesviruses predominated (51%) in kidney, liver, and heart transplant recipients. Among 263 fungal infections, Candida spp (60%) prevailed as digestive tract pathogens in liver transplant recipients. Opportunistic pathogens, including Aspergillus fumigatus (1.4%) and cytomegalovirus (6%), were rare, scattering over 12 months across all SOT recipients. Conclusions In the current era of immunosuppression and prophylaxis, SOT recipients experience a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria., Data on burden and timeline of infections following solid organ transplantation are currently lacking. This Swiss nationwide cohort study found a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria.

L'utilisation depuis 50 ans d'antidépresseurs ayant à la fois une action sérotoninergique et noradrénergique comme première ligne pour la prise en charge de douleurs neuropathiques ou de syndromes douloureux chroniques est basée sur les deux raisons suivantes : d'une part, un mécanisme d'action antalgique plausible et indépendant de l'effet thymique, d'autre part, des données d'effi-cacité chez l'humain et l'animal. Leur prescription doit s'inscrire dans une approche multimodale de la douleur. La dose nécessaire pour atteindre l'effet antalgique, qui survient en moyenne dans les 4 semaines après l'introduction du traitement, est parfois moins importante que celle qui permet d'obtenir l'effet antidépresseur. Le choix de la molécule se fera en fonction du profil d'effets indé-sirables et d'autres bénéfices secondaires éventuels attendus.

Over the past two decades since the introduction of the Milan criteria, the field of transplant oncology has undergone a rapid development with a rising proportion of liver transplantations being performed for oncological indications. For many patients with liver tumours, transplantation represents the only chance for cure. However, many challenges remain, such as the adequate patient selection, management of post-transplant recurrence and refinement of neoadjuvant treatment protocols. This review provides an overview of the current state of the art of liver transplantation for oncological indications such as hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastasis and metastatic neuroendocrine tumours. We also summarize the ongoing research and explore future trends. Clinical trials are currently studying new diagnostic modalities, innovative pharmacological treatments, novel surgical techniques, downstaging regimens and new indications for liver transplantation. These emerging results will continue to shape the field of transplant oncology and provide us with the necessary tools to better select, treat and follow patients with liver tumours qualifying for liver transplantation.

STUDY DESIGN A cross-sectional comparative study. OBJECTIVE The present study aimed to investigate the relationship between the FR phenomenon asymmetry of lumbar muscles and trunk lateral range of motion (ROM) asymmetry in nonspecific chronic low back pain (NSCLBP) patients. SUMMARY OF BACKGROUND DATA Imbalance in trunk muscle activation between right and left sides can induce pain by loading the spine incorrectly, especially in patients with NSCLBP. A previous study reported a greater asymmetry in the FR phenomenon of the erector spinae in NSCLBP patients than in asymptomatic participants (APs). Imbalance of muscle properties, such as trunk ROM, has been suggested as a possible cause of this observed asymmetry. METHODS Twenty-eight NSCLBP patients and 22 AP performed 3 standing maximal trunk flexions. Surface electromyography was recorded bilaterally for erector spinae longissimus and lumbar multifidus. A FR ratio was calculated for each muscle. The fingertip-to-thigh test was performed to assess trunk lateral ROM. Each parameter's asymmetry was calculated as the absolute difference between right and left sides. RESULTS NSCLBP patients present a significantly lower trunk lateral ROM than AP. FR ratio asymmetry of the erector spinae was significantly greater in NSCLBP patients than in AP (P

There is increasing interest in the use of adipose‐derived mesenchymal stromal cells (ASCs) for wound repair. As the fate of administered cells is still poorly defined, we aimed to establish the location, survival, and effect of ASCs when administered either systemically or locally during wound repair under physiological conditions. To determine the behavior of ASCs, a rat model with wounds on the dorsal aspect of the hind paws was used and two treatment modes were assessed: ASCs administered systemically into the tail vein or locally around the wound. ASCs were transduced to express both firefly luciferase (Fluc) and green fluorescent protein to enable tracking by bioluminescence imaging and immunohistological analysis. Systemically administered ASCs were detected in the lungs 3 hours after injection with a decrease in luminescent signal at 48 hours and signal disappearance from 72 hours. No ASCs were detected in the wound. Locally administered ASCs remained strongly detectable for 7 days at the injection site and became distributed within the wound bed as early as 24 hours post injection with a significant increase observed at 72 hours. Systemically administered ASCs were filtered out in the lungs, whereas ASCs administered locally remained and survived not only at the injection site but were also detected within the wound bed. Both treatments led to enhanced wound closure. It appears that systemically administered ASCs have the potential to enhance wound repair distally from their site of entrapment in the lungs whereas locally administered ASCs enhanced wound repair as they became redistributed within the wound bed., Adipose‐derived mesenchymal stromal cells were administered either systemically or locally in a rat model of wound repair under physiological conditions. It appears that systemically administered adipose‐derived mesenchymal stromal cells have the potential to enhance wound repair distally from their site of entrapment in the lungs whereas locally administered adipose‐derived mesenchymal stromal cells enhanced wound repair as they became redistributed within the wound bed.

Background Recent data have raised concerns about the risk/benefit ratio of thrombolysis in non-high risk pulmonary embolism patients due to increased serious bleeding events. Whether cardiac biomarkers could be of help for bleeding risk stratification in this setting remains elusive. Objectives To determine the prognostic accuracy of hs-cTnT, NT-proBNP, RIETE and PESI score for the occurrence of clinically relevant bleeding (CRB) in elderly patients under conventional anticoagulation therapy for non-massive pulmonary embolism (NMPE). Methods We evaluated 230 elderly patients with available blood sample taken within one day from diagnosis. The primary study endpoint was CRB at 1, 3 and 24 months. Prognostic accuracies and associations were determined using C-statistics and subhazard ratios (SHR), respectively. Results hs-cTnT displayed the highest discriminatory power at 1 month (C-statistics: 0.77, 95% CI: 0.68–0.88) which remained stable over time. Although C-statistics comparison indicated that hs-cTnT was not statistically superior to RIETE score (0.77 vs 0.67, p = 0.11), adding hs-cTnT to RIETE score significantly improved the C-statistics from 0.67 to 0.78 (p = 0.02). SHRs indicated that for each hs-cTnT log-unit increase, there was a 58% increase in the risk of CRB independently of the RIETE score (adjusted SHR: 1.58, 95% CI: 1.31–1.92). At the pre-specified cut-off of 14 ng/l, the negative predictive value of hs-cTnT was 96.9% (95% CI: 91.4–99.0) and 94.9 (95%CI: 88.6–97.8) at 1 and 3 months, respectively. Conclusion In elderly, hs-cTnT provides incremental prognostic information over the RIETE score and could represent a valuable tool to identify NMPE patients at low risk of bleeding.

Highlights • Robotic primary ventral hernia repair (PVHR) combines minimal access, closure of defect and pre-peritoneal mesh placement. • The protocol designs a randomized single-blinded controlled trial comparing robotic PVHR to open PVHR. • The primary outcome will be the incidence of wound-related complication within 1 month., Background The objective of the present study is to compare the outcomes open PVHR and robotic PVHR. Methods/Design The present study will be a randomized single-blinded controlled trial with intention-to-treat analysis comparing robotic PVHR to open PVHR in adult patients undergoing elective PVHR with a defect ranging between 1–5 cm. Patient refusing to participate, not able to give informed consent, with history of intra-abdominal surgery contraindicating a robotic surgical approach will be excluded. The intervention will consist in laparoscopic robotically assisted trans-abdominal pre-peritoneal epigastric or umbilical PVHR with closure of fascial defect and non-adsorbable mesh reinforcement. The control will be open pre-peritoneal epigastric or umbilical hernia repair with closure of fascial defect and non-absorbable mesh reinforcement. The primary outcome will be the incidence of wound-related complication within 1 month. The secondary outcomes will be esthetic satisfaction, pain, pain-killers consumption, general complications, costs, operative time and early hernia recurrence. Discussion Open PVHR is potentially associated to more wound-related complications, but has the advantages of cost-effectiveness, short operative time and totally extra-peritoneal repair. Laparoscopic PVHR has lower wound-related complications but implies placing the mesh in intra-peritoneal position, requires advanced laparoscopic skills, usually does not allow the closure of the defect, and can lead to excessive pain and pain-killers consumption. Robotic PVHR uses the same laparoscopic access as laparoscopic PVHR, but thanks to the extended range of motion given by the robotic system, allows defect closure, pre-peritoneal placement of the mesh and requires less technical skills. In the present randomized controlled trial, we expect to show that robotic PVHR leads to better wound-related outcomes than open PVHR. Trial registration The present randomized controlled trial was registered into clinicaltrials.gov under registration number NCT04171921.

There are scarce data on the impact of COVID-19 pandemic on liver transplantation (LT) in Europe. The aim of this study was to obtain a preliminary data on incidence, management, and outcome of COVID-19 in liver transplant recipients and candidates in Europe. An Internet-based survey was sent to the centers affiliated with European Liver Transplant Registry (ELTR). One hundred nine out of 149 (73%) of ELTR centers located in 28 European countries (93%) responded. Ninety-four (86%) of the centers tested all donors, and 75 (69%) centers tested all LT recipients for SARS-CoV-2. Seventy-three (67%) centers selected recipients for LT in the COVID-19 pandemic, whereas 33% did not. Eighty-eight centers reported COVID-19 infection in 57 LT candidates and in 272 LT recipients. Overall crude incidence of COVID-19 among LT candidates and recipients was estimated 1.05% (range 0.5–20%) and 0.34% (range 0.1–4.8%), respectively, and it was significantly higher among candidates (P'0.001). Crude rate of death was 18% (10/57) among candidates and 15% (36/244) among recipients. This first large-scale European snapshot study clearly shows that both LT candidates and recipients are at a high risk for COVID-19. These results plead for an early and pro-active screening of COVID-19 symptoms in these populations.

Background Fat grafting is an adjuvant that may improve the quality of radiation-damaged tissue. However, fat grafting for volume restoration in irradiated sites may be less effective because of a poorly vascularized fibrotic recipient bed. External volume expansion has emerged as a potential technique to prepare the recipient sites for improved survival of grafted fat. The authors previously demonstrated increased vasculature with external volume expansion stimulation of irradiated tissues. The authors now hypothesize that external volume expansion's improvements in recipient-site vascularity will increase the volume retention and quality of fat grafts in fibrotic irradiated sites. Methods Athymic mice were irradiated until development of chronic radiation injury. Then, the irradiated site was stimulated by external volume expansion (external volume expansion group), followed by subcutaneous fat grafting. Grafts in an irradiated site without external volume expansion stimulation (irradiated control group) and grafts in a healthy nonirradiated (nonirradiated control group) site were used as controls. All grafts were monitored for 8 weeks and evaluated both histologically and by micro-computed tomography for analysis of volume retention. Results Hyperspectral imaging confirmed a 25 percent decrease in vascularity of irradiated tissue (irradiated control group) compared with nonirradiated tissue (nonirradiated control group). Grafts in the irradiated control group retained 11 percent less volume than grafts in the nonirradiated control group. The experimental external volume expansion group achieved a 20 percent (p = 0.01) increase in retained graft volume compared with the irradiated control group. Conclusions External volume expansion stimulation can mitigate the effects of irradiation at the recipient site and in turn help preserve fat graft volume retention. Possible mechanisms include increased vascularity, adipogenic conversion, and increased compliance of a fibrotic recipient site.

Self-management of chronic pain should enable patients to regain an acceptable quality of life, autonomy, and reduce the number of consultations. These strategies are increasingly available on mobile applications, which have been evaluated for their content and effectiveness in several reviews. The vast majority of applications offer only one self-management strategy, few opportunities for interactions, and have not involved patients and healthcare professionals in their development. It is therefore still difficult to determine their effectiveness in the self-management of chronic pain. However, mobile applications should not be neglected. On the contrary, it is necessary to develop validated applications in French considering the five criteria classically recommended for self-management. Then such applications can be prescribed by health professionals as part of the multimodal management of chronic pain.

Avec l'apparition de nouvelles techniques minimalement invasives, la chirurgie des hernies ventrales connaît depuis une dizaine d'années de profonds remaniements. Elles ont en commun d'intégrer les concepts fondamentaux de reconstruction pariétale de la chirurgie ouverte à une voie d'abord laparoscopique, dans le but de réduire les taux de complication du site opératoire et de permettre une réhabilitation accélérée. La diffusion des systèmes d'assistance robotique en chirurgie de la paroi facilite l'accès à ce type de procédure et permet d'envisager leur application dans des cas de plus en plus complexes. Les techniques de relaxation pariétale permettent la fermeture sans tension d'orifices herniaires larges. Elles sont maintenant aussi réalisées par voie minimalement invasive et de manière moins délabrante. Même si la place exacte de l'ensemble de ces techniques doit encore être mieux définie en fonction du type de hernie, ces prises en charge laparoscopiques ou robot-assistées semblent déjà permettre une récupération postopératoire plus rapide.

The French transplant governing system defined “Rescue” (the so-called “Hors Tour”) livers as those livers which were declined for the five top-listed patients. This study compares the outcomes following liver transplantation (LT) in patients who received a donor liver through a rescue allocation (RA) procedure or according to MELD score priority (standard allocation, SA) and evaluates the impact on the graft pool of a proactive policy to accept RA grafts. Data from all consecutive patients who underwent LT with SA or RA grafts from 2011 to 2015 were compared in terms of short- and long-term outcomes. The 249 elective first LTs were performed with 64 (25.7%) RA and 185 (74.3%) SA grafts. RA grafts were obtained from older donors and were associated with a longer cold ischemia time. Recipients of RA livers were older and had lower MELD scores. The rates of delayed graft function, primary nonfunction, retransplantation, complications, and mortality were similar between the RA and SA groups. At 1 and 3 and 5 years, graft and patient survival rates were similar between the groups. These results were maintained after matching on recipient characteristics. Our proactive policy to accept RA grafts increased the liver pool for elective first transplantation by 25%. RA livers can be safely transplanted into selected recipients and significantly expand the liver pool.

Background: Septic shock (SS) and cardiogenic shock (CS) are two types of circulatory shock with a different etiology. Several studies have described the molecular alterations in SS patients, whereas the molecular factors involved in CS have been poorly investigated. We aimed to assess in the whole blood of CS and SS patients, using septic patients without shock (SC) as controls, transcriptomic modifications that occur over 1 week after ICU admission and are common to the two types of shock. Methods: We performed whole blood RNA sequencing in 21 SS, 11 CS, and 5 SC. In shock patients, blood samples were collected within 16 h from ICU admission (T1), 48 h after ICU admission (T2), and at day 7 or before discharge (T3). In controls, blood samples were available at T1 and T2. Gene expression changes over time have been studied in CS, SS, and SC separately with a paired analysis. Genes with p value < 0.01 (Benjamini-Hochberg multiple test correction) were defined differentially expressed (DEGs). We used gene set enrichment analysis (GSEA) to identify the biological processes and transcriptional regulators significantly enriched in both types of shock. Results: In both CS and SS patients, GO terms of inflammatory response and pattern recognition receptors (PRRs) were downregulated following ICU admission, whereas gene sets of DNA replication were upregulated. At the gene level, we observed that alarmins, interleukin receptors, PRRs, inflammasome, and DNA replication genes significantly changed their expression in CS and SS, but not in SC. Analysis of transcription factor targets showed in both CS and SS patients, an enrichment of CCAAT-enhancer-binding protein beta (CEBPB) targets in genes downregulated over time and an enrichment of E2F targets in genes with an increasing expression trend. Conclusions: This pilot study supports, within the limits of a small sample size, the role of alarmins, PRRs, DNA replication, and immunoglobulins in the pathophysiology of circulatory shock, either in the presence of infection or not. We hypothesize that these genes could be potential targets of therapeutic interventions in CS and SS., SCOPUS: ar.j, info:eu-repo/semantics/published

Background Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) is the most toxic congener of a family of structurally and mechanistically related persistent organic pollutants whose effects are mediated through the aryl hydrocarbon receptor (AhR). Induction of CYP1A1/2 by TCDD through the AhR depends on the magnitude and the duration of exposure. We aimed to assess CYP1A2 activity after acute and chronic exposure to TCDD. The Maincy cohort is a sample population from Melun in the Val-de-Seine region in France that lived for at least 5 years close to a waste incinerator emitting polluted vapours (1974-2002) with high concentrations of dioxins (up to 2000 times the maximal recommended values). Acute exposure to TCDD (Viktor Yushchenko) has been described elsewhere by Sorg et al (Toxicol. Sci. 2012; 125:310-317). Both are rare cases of well-identified source of chronic and acute exposure to TCDD. Methods All subjects underwent a full medical history and physical examination and had a cutaneous examination, and a retro-auricular skin biopsy was taken. A questionnaire was designed and used regarding demographic, personal, environmental and occupational characteristics. CYP1A2 activity was assessed 2 hours after the ingestion of a drink containing caffeine through measurement of the metabolic ratio of paraxanthine (17X) over caffeine (137X) by LC-MS/MS or LC-UV. CYP1A1 expression in skin biopsies was determined by immunohistochemical analysis. Results Forty-seven exposed subjects (age 11-78) and 31 controls were included in the study. Eleven exposed subjects had a history of thyroid disease (23.4%), and 7 (14.8%) had a cancer vs none and 1, respectively, in controls. Nodular skin lesions were found in 13 exposed subjects (27.7%) vs none in controls. Mean CYP1A2 activity of the exposed population was modestly elevated as compared to controls (17X/137X metabolic ratio of 0.475 vs 0.374, P = .051). CYP1A2 was, however, induced (17X/137X, metabolic ratio >0.5) in 27.6% of the exposed cases vs 6.4% of the controls. In contrast, acute dioxin exposure was associated with a strong induction (mean 17X/137X, metabolic ratio of 1.9) still present 29 months after the acute exposure. CYP1A1 was expressed in 59.6% of the skin biopsies (highly expressed in 31.9%) of the Maincy cohort. No correlation between CYP1A2 activity, CYP1A1 expression and clinical manifestations (thyroid disease, cancer, skin lesions) could be demonstrated. Conclusion Higher frequencies of dysthyroidism and cancer were detected in the population exposed chronically to dioxins from a waste incinerator. CYP1A2 was induced in 27.6% of the exposed population, while the magnitude of induction was fourfold higher after acute exposure in the case of Yushchenko.

It remains unclear to what extent intravenous lidocaine prevents cough and whether there is dose-responsiveness and risk of harm.We searched electronic databases to January 1, 2017 for randomized trials comparing intravenous lidocaine with placebo for the prevention of cough in surgical patients. Primary outcome was the incidence of cough. Data were analyzed using a random-effects model and were expressed as risk ratio (RR) and number needed to treat (NNT) with 95% confidence interval.In 20 trials in adults (n = 3062) and 5 trials in children (n = 445), intravenous lidocaine 0.5-2 mg·kg was tested for the prevention of intubation-, extubation-, or opioid-induced cough. Twenty-two trials included only American Society of Anesthesiologists I or II patients; 3 trials (n = 99) also included American Society of Anesthesiologists III patients. Lidocaine was associated with a lower incidence of cough compared to placebo in adults and children, irrespective of dosage and cough etiology. Data from adults suggested dose-responsiveness; with 0.5 mg·kg, RR was 0.66 (0.50-0.88) and NNT was 8 (5.4-14.3); with 1 mg·kg, RR was 0.58 (0.49-0.69) and NNT was 7 (4.6-8.9); with 1.5 mg·kg, RR was 0.44 (0.33-0.58) and NNT was 5 (3.3-5.2); and with 2 mg·kg, RR was 0.39 (0.24-0.62) and NNT was 3 (2.0-3.4). Adverse effect reporting was sparse.Within a range of 0.5-2 mg·kg, intravenous lidocaine dose dependently prevents intubation-, extubation-, and opioid-induced cough in adults and children with NNTs ranging from 8 to 3. The risk of harm in high-risk patients remains unknown.

Transcatheter tricuspid valve-in-ring implantation has emerged as a potential alternative to surgery for high-risk patients with symptomatic severe tricuspid regurgitation that recurs after surgical ring repair. The worldwide experience remains limited. We report a case of unsuccessful transfemoral tricuspid valve-in-ring implantation (using an Edwards SAPIEN 3 valve, Edwards Lifesciences, Irvine, CA) and literature review. The rigidity, open shape, and open configuration of the ring may lead to imperfect positioning, resulting in severe paravalvular leak. Particular attention should be paid to sizing and wire position with respect to the ring while implanting the valve.

Nowadays autologous fibroblast application for skin repair presents an important clinical interest. In most cases, in vitro skin cell culture is mandatory. However, cell expansion using xenogeneic or allogenic culture media presents some disadvantages, such as the risk of infection transmission or slow cell expansion. In this study, we investigated an autologous culture system to expand human skin fibroblast cells in vitro with the patient's own platelet-rich plasma (PRP). Human dermal fibroblasts were isolated from patients undergoing abdominoplasty, and blood was collected to prepare nonactivated PRP using the CuteCell™ PRP medical device. Cultures were followed up to 7 days using a medium supplemented with either fetal bovine serum (FBS) or PRP. Fibroblasts cultured in medium supplemented with PRP showed dose-dependently significantly higher proliferation rates (up to 7.7 times with 20% of PRP) and initiated a faster migration in the in vitro wound healing assay compared with FBS, while chromosomal stability was maintained. At high concentrations, PRP changed fibroblast morphology, inducing cytoskeleton rearrangement and an increase of alpha-smooth muscle actin and vimentin expression. Our findings show that autologous PRP is an efficient and cost-effective supplement for fibroblast culture, and should be considered as a safe alternative to xenogeneic/allogenic blood derivatives for in vitro cell expansion. Impact Statement Autologous dermal fibroblast graft is an important therapy in skin defect repair, but in vitro skin cell culture is mandatory in most cases. However, cell expansion using xenogeneic/allogenic culture media presents some disadvantages, such as the risk of infection transmission. We demonstrated that an autologous culture system with the patient's own platelet-rich plasma is an efficient, cost-effective, and safe supplement for fibroblast culture. As it respects the good manufacturing practices and regulatory agencies standards, it should be considered as a potent alternative and substitute to xenogeneic or allogenic blood derivatives for the validation of future clinical protocols using in vitro cell expansion.

Background Proton pump inhibitors are among the most widely prescribed drugs in the world, but more than half of the indications for prescription are unjustified. The misuse of this therapeutic class has heavy consequences such as additional health costs, adverse drug reactions following long-term use and gastric acid rebound when the proton pump inhibitor is discontinued. Objective The overprescription of proton pump inhibitors is therefore becoming a public health problem, which led us to evaluate their use within the Geneva University Hospitals. Setting Patients hospitalized in two divisions of the department of internal medicine of the Geneva University Hospitals on a single day. Methods This is a register-based cross-sectional study and it collected data about the prescription pattern of proton pump inhibitors by consulting the electronic records of patients included. Main outcome measure To determine if the proton pump inhibitors prescription is made according to the market authorization and the available guidelines. Results Hundred-eighty patients were included. 54% of patients were on proton pump inhibitors, 29% of whom had their treatment initiated at hospital. Of the indications for treatment, 72% were not justified and 63% of the justified indications did not have an adequate dosage. Therefore, in all patients with a proton pump inhibitor at hospital, only 11% had a justified indication with an adequate dose. Finally, 87% of known home prescriptions were renewed on admission and among them, 71% did not have a justified or possibly justified indication according to the guidelines. Conclusion Indication for treatment inside the hospital was not justified in 72% of patients and only 11% had a justified indication with an adequate dosage. Precise guidelines with evidence-based indications and adequate daily doses would help to correctly prescribe proton pump inhibitors. Moreover, patients should benefit from a thorough evaluation of their treatment.

Maintaining long-term euglycemia after intraportal islet transplantation is hampered by the considerable islet loss in the peri-transplant period attributed to inflammation, ischemia and poor angiogenesis. Here, we show that viable and functional islet organoids can be successfully generated from dissociated islet cells (ICs) and human amniotic epithelial cells (hAECs). Incorporation of hAECs into islet organoids markedly enhances engraftment, viability and graft function in a mouse type 1 diabetes model. Our results demonstrate that the integration of hAECs into islet cell organoids has great potential in the development of cell-based therapies for type 1 diabetes. Engineering of functional mini-organs using this strategy will allow the exploration of more favorable implantation sites, and can be expanded to unlimited (stem-cell-derived or xenogeneic) sources of insulin-producing cells., Islet transplantation is a feasible approach to treat type I diabetes, however inflammation and poor vascularisation impair long-term engraftment. Here the authors show that incorporating human amniotic epithelial cells into islet organoids improves engraftment and function of organoids, through enhanced revascularisation.