Background: Circulating tumour cell (CTC) number is an independent prognostic factor in patients with small cell lung cancer (SCLC) but there is no consensus on the CTC threshold for prognostic ...significance. We undertook a pooled analysis of individual patient data to clinically validate CTC enumeration and threshold for prognostication.Methods: Four European cancer centres, experienced in CellSearch CTC enumeration for SCLC provided pseudo anonymised data for patients who had undergone pre-treatment CTC count. Data was collated, and Cox regression models, stratified by centre, explored the relationship between CTC count and survival. The added value of incorporating CTCs into clinico-pathological models was investigated using likelihood ratio tests.Results: A total of 367 patient records were evaluated. A one-unit increase in log-transformed CTC counts corresponded to an estimated hazard ratio (HR) of 1.24 (95% CI: 1.19-1.29, P<0.0001) for progression free survival (PFS) and 1.23 (95% CI: 1.18-1.28, P<0.0001) for overall survival (OS). CTC count of ≥15 or ≥50 was significantly associated with an increased risk of progression (CTC ≥15: HR 3.20, 95% CI: 2.50-4.09, P<0.001; CTC ≥50: HR 2.56, 95% CI: 2.01-3.25, P<0.001) and an increased risk of death (CTC ≥15: HR 2.90, 95% CI: 2.28-3.70, P<0.001; CTC ≥50: HR 2.47, 95% CI: 1.95-3.13, P<0.001). There was no significant inter-centre heterogeneity observed. Addition of CTC count to clinico-pathological models as a continuous log-transformed variable, offers further prognostic value (both likelihood ratio P<0.001 for OS and PFS).Conclusions: Higher pre-treatment CTC counts are a negative independent prognostic factor in SCLC when considered as a continuous variable or dichotomised counts of ≥15 or ≥50. Incorporating CTC counts, as a continuous variable, improves clinic-pathological prognostic models.
Background
Resorption of magnesium-based alloy bioabsorbable screws produces hydrogen gas, which can be mistaken as a sign of infection and may affect the physis or fixed bone fragment.
Objective
We ...evaluated the temporal and spatial occurrence of gas and the occurrence of a breakage of the fixed bone fragment or screw following magnesium screw fixation.
Materials and methods
Radiographs of paediatric patients treated with magnesium screws were retrospectively reviewed. Temporal occurrence and distribution of gas in the bone, the physis and soft tissues, breakage of the screw or fixed bone fragment and joint effusion were assessed.
Results
One hundred and three radiographs in 35 paediatric patients were reviewed (mean age: 10.6 years). Follow-up ranged from 1 to 730 days. Gas in the bone increases up to week 5, remains constant up to week 16 and then decreases. Gas in soft tissues, intra-articular gas and joint effusions gradually reduce over time. In 1/23 (4.3%) patients with an open physis, gas intrusion into the physis occurred. Breakage of the bone fragment fixated by the screw was observed in 4/35 (11.4%) patients within the first 6 weeks. Screw breakage was observed in 16/35 (45.7%) patients, with a median time to first detection of 300 days.
Conclusion
Gas bubbles in bone and soft tissue are normal findings in the context of screw resorption and should not be confused with soft-tissue infection or osteomyelitis. Gas is rarely visible in the physis. Breakage of the fixed bone fragment and/or screw can occur.
Colorectal cancer is one of the most frequent malignancies worldwide. Despite considerable progress in early detection and treatment, there is still an unmet need for novel antitumor therapies, ...particularly in advanced colorectal cancer. Regulatory T cells (Treg) are increased in the peripheral blood and tumor tissue of patients with colorectal cancer. Recently, transient ablation of tumor-associated Tregs was shown to foster CD8
T-cell-mediated antitumoral immunity in murine colorectal cancer models. However, before considering therapies on targeting Tregs in patients with cancer, detailed knowledge of the phenotype and features of tumor-associated Tregs is indispensable. Here, we demonstrate in a murine model of inflammation-induced colorectal cancer that tumor-associated Tregs are mainly of thymic origin and equipped with a specific set of molecules strongly associated with enhanced migratory properties. Particularly, a dense infiltration of Tregs in mouse and human colorectal cancer lesions correlated with increased expression of the orphan chemoattractant receptor GPR15 on these cells. Comprehensive gene expression analysis revealed that tumor-associated GPR15
Tregs have a Th17-like phenotype, thereby producing IL17 and TNFα. Gpr15 deficiency repressed Treg infiltration in colorectal cancer, which paved the way for enhanced antitumoral CD8
T-cell immunity and reduced tumorigenesis. In conclusion, GPR15 represents a promising novel target for modifying T-cell-mediated antitumoral immunity in colorectal cancer. SIGNIFICANCE: The G protein-coupled receptor 15, an unconventional chemokine receptor, directs Tregs into the colon, thereby modifying the tumor microenvironment and promoting intestinal tumorigenesis.
Spaced learning has been shown to be superior in complex motor skill acquisition like laparoscopic suturing and knot tying. By using a pre-post follow-up design, the aim of the study was to evaluate ...the long-term impact of implementation of the spaced learning concept in laparoscopic training.
To evaluate the effectiveness of spaced learning, subjects were asked to perform four surgeon's square knots on a bowel model within 30 minutes-prior and after 3 hours of hands-on training. To examine the long-term skills, the same students were asked to perform a comparable, but more complex, task (four slip knots in a model of esophageal atresia) 12 months later as follow-up measurement. Total time, knot stability (evaluated via tensiometer), suture accuracy, knot quality (Muresan scale), and laparoscopic performance (Munz checklist) were assessed. Moreover, motivation was accessed using Questionnaire on Current Motivation.
Twenty students were included in the study; after simple randomization, 10 were trained using the "spaced learning" concept and 10 via traditional methods. Both groups had comparable baseline characteristics and improved after training significantly, regarding all aspects assessed in this study. Subjects that trained via spaced learning were superior in terms of speed (
= 0.021), knot quality (
= 0.008), and suture strength (
= 0.003). Additionally, spaced learning significantly decreased anxiety (
= 0.029) and probability of success (
= 0.005).
The spaced learning concept is very suitable for long-term complex motor skill acquisition, like laparoscopic suturing and knot tying. It is superior to conventional training regarding speed and, most importantly, knot quality and stability, resulting in improved confidence and motivation. Thus, we strongly recommend to incorporate the spaced learning concept into training courses and surgical programs.
Zusammenfassung
Hintergrund
Das Forschungsprojekt „Gemeinsam gesund: Vorsorge plus für Mutter und Kind“ (GeMuKi) will die fachübergreifende Gesundheitsberatung für Schwangere und junge Eltern ...stärken. Für die Durchführung dieser innovativen und komplexen Intervention wurde eine eigene Datenplattform (GeMuKi-Assist) mit digitalen Anwendungen für die beteiligten Fachakteure, Teilnehmerinnen und Studienkoordinatorinnen entwickelt.
Methodik
In diesem Beitrag werden die zentralen Nutzeranforderungen an die Datenplattform GeMuKi-Assist sowie ihre Integration in den Beratungsablauf und Studienprozess beschrieben. Einleitend wird die Funktionsweise der Plattform dargestellt. Im Anschluss werden erste Erfahrungen, Herausforderungen und Erfolgsfaktoren im Umgang mit der Datenplattform während ihrer Nutzung in der GeMuKi-Studie beleuchtet. Dazu wurden Fragebogenerhebungen mit den Studienkoordinatorinnen und (Telefon‑)Interviews mit Fachakteuren und Studienteilnehmerinnen durchgeführt und ausgewertet.
Ergebnisse
Die GeMuKi-App für die Motivation der Schwangeren und jungen Mütter zur Änderung des individuellen Lebensstils wurde gut angenommen. Die Durchführung der Befragung über die App wurde von den Teilnehmerinnen positiv bewertet. Die Anforderung, das Projektteam beim Datenmanagement zu unterstützen, konnte sehr gut umgesetzt werden. Vor allem die Administrationsoberfläche für die Studienkoordinatorinnen ist als innovativ zu betrachten. Bei einigen Fachakteuren ließen sich Vorbehalte gegenüber dem Dokumentieren in zusätzlichen digitalen Datenplattformen feststellen, was mit der begrenzten zeitlichen Kapazität im Praxisalltag, mit Sicherheitsbedenken und mit einem Mangel an Erfahrung bei der Nutzung digitaler Medien zu begründen ist.
Schlussfolgerung
Durch die Implementierung und Nutzung der Datenplattform GeMuKi-Assist konnten die wesentlichen Projektanforderungen umgesetzt werden. Auf Basis der Rückmeldungen von Ärzten und medizinischen Fachakteuren wäre für zukünftige Forschungsprojekte eine tiefere Integration der Funktionen von GeMuKi-Assist in die bestehenden Praxissoftwaresysteme wünschenswert.
Increased fructose intake has been associated with metabolic consequences such as impaired hepatic lipid metabolism and development of nonalcoholic fatty liver disease (NAFLD).
The aim of this study ...was to investigate the role of fructose in glucose and lipid metabolism in the liver, heart, skeletal muscle, and adipose tissue.
Ten healthy subjects (age: 28 ± 19 y; BMI: 22.2 ± 0.7 kg/m2) underwent comprehensive metabolic phenotyping prior to and 8 wk following a high-fructose diet (150 g daily). Eleven patients with NAFLD (age: 39.4 ± 3.95 y; BMI: 28.4 ± 1.25) were characterized as “positive controls.” Insulin sensitivity was analyzed by a 2-step hyperinsulinemic euglycemic clamp, and postprandial interorgan crosstalk of lipid and glucose metabolism was evaluated, by determining postprandial hepatic and intra-myocellular lipid and glycogen accumulation, employing magnetic resonance spectroscopy (MRS) at 7 T. Myocardial lipid content and myocardial function were assessed by 1H MRS imaging and MRI at 3 T.
High fructose intake resulted in lower intake of other dietary sugars and did not increase total daily energy intake. Ectopic lipid deposition and postprandial glycogen storage in the liver and skeletal muscle were not altered. Postprandial changes in hepatic lipids were measured Δhepatocellular lipid (HCL)_healthy_baseline: −15.9 ± 10.7 compared with ± ΔHCL_healthy_follow-up: −6.9 ± 4.6; P = 0.17 and hepatic glycogen (Δglycogen_baseline: 64.4 ± 14.1 compared with Δglycogen_follow-up: 51.1 ± 9.8; P = 0.42). Myocardial function and myocardial mass remained stable. As expected, impaired hepatic glycogen storage and increased ectopic lipid storage in the liver and skeletal muscle were observed in insulin-resistant patients with NAFLD.
Ingestion of a high dose of fructose for 8 wk was not associated with relevant metabolic consequences in the presence of a stable energy intake, slightly lower body weight, and potentially incomplete absorption of the orally administered fructose load. This indicated that young, metabolically healthy subjects can at least temporarily compensate for increased fructose intake. This trial was registered at www.clinicaltrials.gov as NCT02075164.
We describe a combined synthetic, spectroscopic, and computational study of a chiral titanocene complex as a regiodivergent photoredox catalyst (PRC). With Kagan’s complex catCl 2 either ...monoprotected 1,3-diols or 1,4-diols can be obtained in high selectivity from a common epoxide substrate in a regiodivergent epoxide opening depending on which enantiomer of the catalyst is employed. Due to the catalyst-controlled regioselectivity of ring opening and the broader substrate scope, the PRC with catCl 2 is also a highly attractive branching point for diversity-oriented synthesis. The photochemical processes of cat(NCS)2 , a suitable model for catCl 2 , were probed by time-correlated single-photon counting. The photoexcited complex displays a thermally activated delayed fluorescence as a result of a singlet–triplet equilibration, S1 ⇄ T1, via intersystem crossing and recrossing. Its triplet state is quenched by electron transfer to the T1 state. Computational and cyclic voltammetry studies highlight the importance of our sulfonamide additive. By bonding to sulfonamide additives, chloride abstraction from catCl 2 – is facilitated, and catalyst deactivation by coordination of the sulfonamide group is circumvented.
Significance In failing hearts, norepinephrine (NE) net release and endothelin-1 (ET1) levels are increased. ET1 receptor antagonists were successfully used in preclinical heart failure (HF) studies, ...but clinical studies did not show beneficial effects in HF patients. We found that mice lacking endothelin receptor A (ET A) only in sympathetic neurons but not in cardiomyocytes were protected from the development of HF. Mechanistically, the presynaptic reuptake of NE within the heart was preserved in mice lacking ET A only in sympathetic neurons. These data provide an explanation of why patients in clinical studies do not benefit from ET1 receptor antagonists, because these patients are usually treated with β blockers, which interfere with the mechanism of action identified here.
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