Peri-operative chemotherapy for the treatment of resectable liver metastases from colorectal cancer: A systematic review and meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>The role of peri-operative chemotherapy in patients with resected stage IV colorectal cancer (CRC) remains to be defined. This study was aimed at evaluating the effectiveness of peri-operative chemotherapy in patients with resected stage IV CRC by performing a meta-analysis of relevant trials.</p> <p>Methods</p> <p>We performed a literature search to identify trials comparing patients with stage IV CRC receiving peri-operative chemotherapy and surgery with patients undergoing surgery alone. The hazard ratio (HR) was estimated to assess any survival advantage of peri-operative chemotherapy.</p> <p>Results</p> <p>Eight trials conducted on a total of 1174 patients were identified by a literature search. In these trials, HR estimates suggested that peri-operative chemotherapy yielded no survival advantage over surgery alone (HR, 0.94; 95%CI, 0.8-1.10; <it>p </it>= 0.43). In a subset analysis on intra-arterial chemotherapy alone, no survival benefit was evident (HR, 1.0; 95% CI, 0.84-1.21; <it>p </it>= 0.96; I²= 30%), whereas in the trials involving systemic chemotherapy, the difference between the groups approached statistical significance (HR, 0.74; 95% CI, 0.53-1.04; <it>p </it>= 0.08; I²= 0%). Both peri-operative treatment groups had a significant recurrence-free survival benefit (HR, 0.78; 95% CI, 0.65-0.95; <it>P </it>= 0.01 for hepatic arterial infusion; and HR, 0.75; 95% CI, 0.62-0.91; <it>p </it>= 0.003 for systemic therapy). The toxicities of chemotherapy were acceptable in most trials.</p> <p>Conclusions</p> <p>This is the first meta-analysis demonstrating the importance of peri-operative chemotherapy in the treatment of resected stage IV CRC. Although the results must be carefully interpreted because of some limitations, critical issues were identified that must be resolved by future studies.</p

A case study on the impact of severe convective storms on the water vapor mixing ratio in the lower mid-latitude stratosphere observed in 2019 over Europe

Extreme convective events in the troposphere not only have immediate impacts on the surface, but they can also influence the dynamics and composition of the lower stratosphere (LS). One major impact is the moistening of the LS by overshooting convection. This effect plays a crucial role in climate feedback, as small changes of water vapor in the upper troposphere and lower stratosphere (UTLS) have a large impact on the radiative budget of the atmosphere. In this case study, we investigate water vapor injections into the LS by two consecutive convective events in the European mid-latitudes within the framework of the MOSES (Modular Observation Solutions for Earth Systems) measurement campaign during the early summer of 2019. Using balloon-borne instruments, measurements of convective water vapor injection into the stratosphere were performed. Such measurements with a high vertical resolution are rare. The magnitude of the stratospheric water vapor reached up to 12.1 ppmv (parts per million by volume), with an estimated background value of 5 ppmv. Hence, the water vapor enhancement reported here is of the same order of magnitude as earlier reports of water vapor injection by convective overshooting over North America. However, the overshooting took place in the extratropical stratosphere over Europe and has a stronger impact on long-term water vapor mixing ratios in the stratosphere compared to the monsoon-influenced region in North America. At the altitude of the measured injection, a sharp drop in a local ozone enhancement peak makes the observed composition of air very unique with high ozone up to 650 ppbv (parts per billion by volume) and high water vapor up to 12.1 ppmv. ERA-Interim does not show any signal of the convective overshoot, the water vapor values measured by the Microwave Limb Sounder (MLS) in the LS are lower than the in situ observations, and the ERA5 overestimated water vapor mixing ratios. Backward trajectories of the measured injected air masses reveal that the moistening of the LS took place several hours before the balloon launch. This is in good agreement with the reanalyses, which shows a strong change in the structure of isotherms and a sudden and short-lived increase in potential vorticity at the altitude and location of the trajectory. Similarly, satellite data show low cloud-top brightness temperatures during the overshooting event, which indicates an elevated cloud top height

Enhanced Spike-specific, but attenuated Nucleocapsid-specific T cell responses upon SARS-CoV-2 breakthrough versus non-breakthrough infections

SARS-CoV-2 vaccine breakthrough infections frequently occurred even before the emergence of Omicron variants. Yet, relatively little is known about the impact of vaccination on SARS-CoV-2-specific T cell and antibody response dynamics upon breakthrough infection. We have therefore studied the dynamics of CD4 and CD8 T cells targeting the vaccine-encoded Spike and the non-encoded Nucleocapsid antigens during breakthrough infections (BTI, n=24) and in unvaccinated control infections (non-BTI, n=30). Subjects with vaccine breakthrough infection had significantly higher CD4 and CD8 T cell responses targeting the vaccine-encoded Spike during the first and third/fourth week after PCR diagnosis compared to non-vaccinated controls, respectively. In contrast, CD4 T cells targeting the non-vaccine encoded Nucleocapsid antigen were of significantly lower magnitude in BTI as compared to non-BTI. Hence, previous vaccination was linked to enhanced T cell responses targeting the vaccine-encoded Spike antigen, while responses against the non-vaccine encoded Nucleocapsid antigen were significantly attenuated

Interoception and Autonomic Correlates during Social Interactions. Implications for Anorexia

The aim of this study is to investigate the bodily-self in Restrictive Anorexia, focusing on two basic aspects related to the bodily self: autonomic strategies in social behavior, in which others’ social desirability features, and social cues (e.g., gaze) are modulated, and interoception (i.e., the sensitivity to stimuli originating inside the body). Furthermore, since previous studies carried out on healthy individuals found that interoception seems to contribute to the autonomic regulation of social behavior, as measured by Respiratory Sinus Arrhythmia (RSA), we aimed to explore this link in anorexia patients, whose ability to perceive their bodily signal seems to be impaired. To this purpose, we compared a group of anorexia patients (ANg; restrictive type) with a group of Healthy Controls (HCg) for RSA responses during both a resting state and a social proxemics task, for their explicit judgments of comfort in social distances during a behavioral proxemics task, and for their Interoceptive Accuracy (IA). The results showed that ANg displayed significantly lower social disposition and a flattened autonomic reactivity during the proxemics task, irrespective of the presence of others’ socially desirable features or social cues. Moreover, unlike HCg, the autonomic arousal of ANg did not guide behavioral judgments of social distances. Finally, IA was strictly related to social disposition in both groups, but with opposite trends in ANg. We conclude that autonomic imbalance and its altered relationship with interoception might have a crucial role in anorexia disturbances

Gesellschaftsdarstellung und Erzählsprache bei Pier Paolo Pasolini : die Romane "Il sogno di una cosa" und "Ragazzi di vita"

Martina WieserKlagenfurt, Alpen-Adria-Univ., Master-Arb., 2009KB2009 11(VLID)241300

Testing methods of species delimitation with tiger moth samples from a diverse Neotropical lowland rainforest

Lepidoptera sind eine der artenreichsten Insektenordnungen weltweit, dennoch sind viele Arten speziell in den Tropen, wo ihre Diversität besonders hoch ist, der Wissenschaft noch immer unbekannt. Artbestimmungen erfolgen oft aufgrund morphologischer Merkmale, was in einigen Fällen jedoch sehr schwierig sein kann. Aus diesem Grund wurden molekulare Methoden entwickelt, um die Arterkennung zu erleichtern. Einer der meist verwendeten Ansätze ist das sogenannte DNA-Barcoding, bei dem kurze DNA-Sequenzen aus Mitochondrien analysiert und verglichen werden. Dabei werden Cluster aus ähnlichen Sequenzen gebildet, genauer gesagt „operative taxonomische Einheiten“ (OTUs), welche Stellvertreter für Arten darstellen. Diese Studie konzentrierte sich auf die Gattung Eucereon (Erebidae, Arctiinae). Derzeit besteht diese Gattung aus über 150 beschriebenen Arten, morphologisch sind diese aber oft schwer zu unterscheiden. Außerdem wurde diese Gattung bisher nie taxonomisch überarbeitet. Die geographische Verbreitung von Eucereon Arten reicht von den südlichen USA über Mittelamerika bis zur Ostküste Brasiliens und sie kommen bis über 2000 m Höhe über dem Meeresspiegel vor. Eine Recherche dokumentierter Assoziationen der Larven mit Ihren Futterpflanzen zeigte eine Tendenz zur Spezialisierung auf giftige und milchsafthaltige Pflanzen auf; möglicherweise findet auch Pharmakophagie der adulten Falter statt. Insgesamt konnten 138 neue DNA-Sequenzen von mutmaßlichen Eucereon-Exemplaren erstellt werden, welche in Costa Rica, Panama und Ecuador gesammelt wurden. Um Hypothesen über Artgrenzen aufzustellen, wurden mehrere hochmoderne Methoden zur Artabgrenzung auf der Grundlage von Sequenzdaten angewandt und ihre Ergebnisse verglichen, und zwar BIN, 2% Distanzschwelle, ABGD, GMYC und bPTP. Die Befunde dieser Untersuchungen stimmten größtenteils mit der morphologischen Bestimmung überein. Mittels molekularbiologischer Auswertung wurden 42-45 OTUs gefunden, im Gegensatz zu den 40 Morphospezies. Keine der getesteten molekularbiologischen Methoden funktionierte besser als alle anderen. Die nähere Untersuchung der kompletten Gattung, nämlich die Auswertung aller in der Datenbank BOLD verfügbaren Barcode-Daten und der Flügelmuster der zugehörigen Falter, ergab 89 „Arten“, die vermutlich „echte“ Vertreter des Taxons Eucereon darstellen. Außerdem wurden für neun der erkannten BINs Haplotyp-Netzwerke erstellt und phylogeographische Analysen durchgeführt. Dabei wurde kein einheitliches Muster entdeckt, da sich das Ausmaß der DNA-Sequenzvariabilität innerhalb der BINs erheblich unterschied. Darüber hinaus ergab die Untersuchung der Gattung, dass etliche Arten, die aktuell acht anderen nominellen Gattungen zugeordnet werden, ebenfalls als zu Eucereon gehörig angesehen werden sollten. Um diese Hypothese zu testen, sind allerdings noch weiterführende Studien nötig.Lepidoptera are one of the most species-rich insect orders worldwide, and in the tropics their diversity is especially high, yet many species are still unknown to science. Identifying animals traditionally has relied on morphological traits, which can be a challenging procedure. Therefore, molecular methods to facilitate the recognition of species were developed. One of the most popular approaches is called DNA barcoding, where short mitochondrial DNA sequences are analyzed and compared to distinguish between operational taxonomic units (OTUs), a tentative proxy for species. This study focused on the genus Eucereon (Erebidae, Arctiinae) with currently more than 150 described species, which are often hard to distinguish by means of external morphology. Their geographic distribution ranges from the southernmost United States of America over Central America to the east coast of Brazil at elevations from sea level to up to more than 2000 m a.s.l. Exploring possible larval food plants revealed a tendency to a narrow food specialization on poisonous and milky sap-containing plants, potentially supplemented by adult pharmacophagy. In total, 138 novel DNA sequences of presumed Eucereon specimens collected in Costa Rica, Panama and Ecuador were successfully generated for this study. Several state-of-the-art methods for sequence based species delimitation, namely BIN, 2% threshold clustering, ABGD, GMYC and bPTP, were applied to arrive at hypotheses about species boundaries and their performance was compared. The results indicate a high degree of concordance between morphology-based species delimitation and clustering methods based on DNA sequences. The morphological sorting resulted in 40 morphospecies, while the molecular approach generated between 42 and 45 OTUs; none of the algorithms outperformed all other methods. Furthermore, haplotype networks for nine BINs were created and phylogeographic analyses performed. No consistent pattern was found, as these BINs differ substantially in their intraspecific genetic variance. The genus Eucereon never underwent any formal taxonomic revision, therefore the delimitation of the genus was also examined. 89 potential members were recognized among taxa represented in the global BOLD database, based on a combination of wing pattern and molecular data. These results indicate that several moth species that are currently affiliated to eight different nominal genera should be included within Eucereon, but further research is needed in order to better support this hypothesis

Testing the Possibility of Model-based Pavlovian Control of Attention to Threat.

Signals for reward or punishment attract attention preferentially, a principle termed value-modulated attention capture (VMAC). The mechanisms that govern the allocation of attention can be described with a terminology that is more often applied to the control of overt behaviors, namely, the distinction between instrumental and Pavlovian control, and between model-free and model-based control. Although instrumental control of VMAC can be either model-free or model-based, it is not known whether Pavlovian control of VMAC can be model-based. To decide whether this is possible, we measured steady-state visual evoked potentials (SSVEPs) while 20 healthy adults took part in a novel task. During the learning stage, participants underwent aversive threat conditioning with two conditioned stimuli (CSs): one that predicted pain (CS+) and one that predicted safety (CS-). Instructions given before the test stage allowed participants to infer whether novel, ambiguous CSs (new_CS+/new_CS-) were threatening or safe. Correct inference required combining stored internal representations and new propositional information, the hallmark of model-based control. SSVEP amplitudes quantified the amount of attention allocated to novel CSs on their very first presentation, before they were ever reinforced. We found that SSVEPs were higher for new_CS+ than new_CS-. This result is potentially indicative of model-based Pavlovian control of VMAC, but additional controls are necessary to verify this conclusively. This result underlines the potential transformative role of information and inference in emotion regulation

Toll-Like Receptor 2, Toll-Like Receptor 4, Myeloid Differentiation Response Gene 88, and Toll-IL-1 Receptor Domain-Containing Adaptor-Inducing Interferon-gamma (TRIF) Selectively Regulate Susceptibility of PO106-125-Induced Murine Experimental Autoimmune Neuritis

The functional relevance of the innate immune system has not yet been dissected in PO106-125-induced murine experimental autoimmune neuritis. Therefore, the role of Toll-like receptor (TLR) 2, TLR4, myeloid differentiation response gene 88, and ToLL IL-1 receptor domain-containing adaptor-inducing interferon-i (TRIF), factors critically involved in the TLR signaling pathway, was studied in experimental autoimmune neuritis. In the absence of TLR2, TLR4, myeloid differentiation response gene 88, or TRIF, the clinical course was significantly attenuated compared to wild-type mice. This could be attributed to impaired NE-kappa B activation, as shown by the absence of nuclear translocation of ReIA with a decreased expression of IL-6, IL 12p40, and IL-17A. Remarkably, PO106-125-immunized TLR2(0/0) mice exhibited a delayed recovery as compared to TLR4(0/0) mice, which was because of an impaired T helper cell 2 polarization. Immunized TLR2(0/0) mice' were unable to induce OX40 and OX4OL by matrix metalloproteinase-2 on spLenic dendritic cells. Subsequently, M2 polarization was impaired and macrophages were unable to sufficiently induce T regulatory cells (T-regs). Thus, in the recovery phase, Tregs were significantly increased in TLR4(0/0) mice as compared to wild-type mice, whereas T-regs in immunized TLR2(0/0) mice were only slightly increased. Our data highlight the relevance of innate immunity and, especially, the tight interaction between the innate and the adaptive immune system, which should be considered for therapeutic approaches of autoimmune diseases

Structural Health Monitoring of Helicopter Fuselage

The helicopter design is a challenging experience for fatigue concern as it is subjected to a very wide range of low- and high-frequency load cycles per flight, much more than a fixed wing aircraft. Structural Health Monitoring (SHM) seems to have capability in helping to reduce the maintenance and operational costs, which are about 25 percent of the direct operating cost of the helicopter, thus playing an important role especially in the case of the ageing helicopters. In fact, the damage tolerant design approach makes the fatigue resistance evaluation not only a safety issue but also a maintenance related concern. The work presented in this paper is a part of an international research project HECTOR (HElicopter fuselage Crack moniToring and prognosis through On-board sensoR network), founded by the European Defense Agency (EDA) and supported by 10 EDA Member States: Cyprus, France, Germany, Greece, Hungary, Italy, Poland, Slovakia, Slovenia and Spain

Impact of tafamidis on myocardial function and CMR tissue characteristics in transthyretin amyloid cardiomyopathy.

AIMS Tafamidis improves clinical outcomes in transthyretin amyloid cardiomyopathy (ATTR-CM), yet how tafamidis affects cardiac structure and function remains poorly described. This study prospectively analysed the effect of tafamidis on 12-month longitudinal changes in cardiac structure and function by cardiac magnetic resonance (CMR) compared with the natural course of disease in an untreated historic control cohort. METHODS AND RESULTS ATTR-CM patients underwent CMR at tafamidis initiation and at 12 months. Untreated patients with serial CMRs served as reference to compare biventricular function, global longitudinal strain (GLS), LV mass and extracellular volume fraction (ECV). Thirty-six tafamidis-treated (n = 35; 97.1% male) and 15 untreated patients (n = 14; 93.3% male) with a mean age of 78.3 ± 6.5 and 76.9 ± 6.5, respectively, and comparable baseline characteristics were included. Tafamidis was associated with preserving biventricular function (LVEF (%): 50.5 ± 12 to 50.7 ± 11.5, P = 0.87; RVEF (%): 48.2 ± 10.4 to 48.2 ± 9.4, P = 0.99) and LV-GLS (-9.6 ± 3.2 to -9.9 ± 2.4%; P = 0.595) at 12 months, while a significantly reduced RV-function (50.8 ± 7.3 to 44.2 ± 11.6%, P = 0.028; P (change over time between groups) = 0.032) and numerically worsening LVGLS (-10.9 ± 3.3 to -9.1 ± 2.9%, P = 0.097; P (change over time between groups) = 0.048) was observed without treatment. LV mass significantly declined with tafamidis (184.7 ± 47.7 to 176.5 ± 44.3 g; P = 0.011), yet remained unchanged in untreated patients (163.8 ± 47.5 to 171.2 ± 39.7 g P = 0.356, P (change over time between groups) = 0.027). Irrespective of tafamidis, ECV and native T1-mapping did not change significantly from baseline to 12-month follow-up (P > 0.05). CONCLUSIONS Compared with untreated ATTR-CM patients, initiation of tafamidis preserved CMR-measured biventricular function and reduced LV mass at 12 months. ECV and native T1-mapping did not change significantly comparable to baseline in both groups