Direct comparison of multiple computer-aided polyp detection systems.

BACKGROUND AND STUDY AIMS: Artificial intelligence (AI)-based systems for computer-aided detection (CADe) of polyps receive regular updates and occasionally offer customizable detection thresholds, both of which impact their performance, but little is known about these effects. This study aimed to compare the performance of different CADe systems on the same benchmark dataset. METHODS: 101 colonoscopy videos were used as benchmark. Each video frame with a visible polyp was manually annotated with bounding boxes, resulting in 129 705 polyp images. The videos were then analyzed by three different CADe systems, representing five conditions: two versions of GI Genius, Endo-AID with detection Types A and B, and EndoMind, a freely available system. Evaluation included an analysis of sensitivity and false-positive rate, among other metrics. RESULTS: Endo-AID detection Type A, the earlier version of GI Genius, and EndoMind detected all 93 polyps. Both the later version of GI Genius and Endo-AID Type B missed 1 polyp. The mean per-frame sensitivities were 50.63 % and 67.85 %, respectively, for the earlier and later versions of GI Genius, 65.60 % and 52.95 %, respectively, for Endo-AID Types A and B, and 60.22 % for EndoMind. CONCLUSIONS: This study compares the performance of different CADe systems, different updates, and different configuration modes. This might help clinicians to select the most appropriate system for their specific needs.

Endoscopic ultrasound for structured surveillance after curative treatment of esophageal cancer.

BACKGROUND: Structured surveillance after treatment of esophageal cancer is not established. Due to a paucity of data, no agreement exists on how surveillance should be performed. The main argument against intensive follow-up in esophageal cancer is that it may not lead to true survival advantage. METHODS: Structured surveillance was performed in 42 patients after multimodal therapy with peri-operative chemotherapy (29) or definitive chemoradiotherapy (13) of esophageal cancer. The surveillance protocol included gastroscopy, endoscopic ultrasound, chest X-ray, abdominal ultrasound, and CEA measurement at regular intervals of up to five years. We analyzed relapse rate, time to relapse, localization of recurrence, diagnosis within or without structured surveillance, diagnostic method providing the first evidence of a relapse, treatment of recurrence, and outcome. RESULTS: Median follow-up was 48 months; 18/42 patients suffered from tumor relapse, with 16 asymptomatic patients diagnosed within structured surveillance. Median time to recurrence was 9 months. Isolated local or locoregional recurrence occurred in 6, and isolated distant relapse in 9 patients. All patients with isolated locoregional recurrence were exclusively diagnosed with endoscopic ultrasound. Six patients received curatively intended therapy with surgery or chemoradiation, leading to long-lasting survival. CONCLUSION: Structured surveillance offers the chance to identify limited and asymptomatic tumor relapse. Especially in cases of locoregional recurrence, long-lasting survival or even a cure can be achieved. Endoscopic ultrasound is the best method for the detection of locoregional tumor recurrence and should be an integral part of structured surveillance after curative treatment of esophageal cancer.

Assisted documentation as a new focus for artificial intelligence in endoscopy: the precedent of reliable withdrawal time and image reporting.

BACKGROUND : Reliable documentation is essential for maintaining quality standards in endoscopy; however, in clinical practice, report quality varies. We developed an artificial intelligence (AI)-based prototype for the measurement of withdrawal and intervention times, and automatic photodocumentation. METHOD: A multiclass deep learning algorithm distinguishing different endoscopic image content was trained with 10 557 images (1300 examinations, nine centers, four processors). Consecutively, the algorithm was used to calculate withdrawal time (AI prediction) and extract relevant images. Validation was performed on 100 colonoscopy videos (five centers). The reported and AI-predicted withdrawal times were compared with video-based measurement; photodocumentation was compared for documented polypectomies. RESULTS: Video-based measurement in 100 colonoscopies revealed a median absolute difference of 2.0 minutes between the measured and reported withdrawal times, compared with 0.4 minutes for AI predictions. The original photodocumentation represented the cecum in 88 examinations compared with 98/100 examinations for the AI-generated documentation. For 39/104 polypectomies, the examiners' photographs included the instrument, compared with 68 for the AI images. Lastly, we demonstrated real-time capability (10 colonoscopies). CONCLUSION : Our AI system calculates withdrawal time, provides an image report, and is real-time ready. After further validation, the system may improve standardized reporting, while decreasing the workload created by routine documentation.

Artificial intelligence-based polyp size measurement in gastrointestinal endoscopy using the auxiliary waterjet as a reference.

BACKGROUND: Measurement of colorectal polyp size during endoscopy is mainly performed visually. In this work, we propose a novel polyp size measurement system (Poseidon) based on artificial intelligence (AI) using the auxiliary waterjet as a measurement reference. METHODS: Visual estimation, biopsy forceps-based estimation, and Poseidon were compared using a computed tomography colonography-based silicone model with 28 polyps of defined sizes. Four experienced gastroenterologists estimated polyp sizes visually and with biopsy forceps. Furthermore, the gastroenterologists recorded images of each polyp with the waterjet in proximity for the application of Poseidon. Additionally, Poseidon's measurements of 29 colorectal polyps during routine clinical practice were compared with visual estimates. RESULTS: In the silicone model, visual estimation had the largest median percentage error of 25.1 % (95 %CI 19.1 %-30.4 %), followed by biopsy forceps-based estimation: median 20.0 % (95 %CI 14.4 %-25.6 %). Poseidon gave a significantly lower median percentage error of 7.4 % (95 %CI 5.0 %-9.4 %) compared with other methods. During routine colonoscopies, Poseidon presented a significantly lower median percentage error (7.7 %, 95 %CI 6.1 %-9.3 %) than visual estimation (22.1 %, 95 %CI 15.1 %-26.9 %). CONCLUSION: In this work, we present a novel AI-based method for measuring colorectal polyp size with significantly higher accuracy than other common sizing methods.

Automated classification of polyps using deep learning architectures and few-shot learning.

BACKGROUND: Colorectal cancer is a leading cause of cancer-related deaths worldwide. The best method to prevent CRC is a colonoscopy. However, not all colon polyps have the risk of becoming cancerous. Therefore, polyps are classified using different classification systems. After the classification, further treatment and procedures are based on the classification of the polyp. Nevertheless, classification is not easy. Therefore, we suggest two novel automated classifications system assisting gastroenterologists in classifying polyps based on the NICE and Paris classification. METHODS: We build two classification systems. One is classifying polyps based on their shape (Paris). The other classifies polyps based on their texture and surface patterns (NICE). A two-step process for the Paris classification is introduced: First, detecting and cropping the polyp on the image, and secondly, classifying the polyp based on the cropped area with a transformer network. For the NICE classification, we design a few-shot learning algorithm based on the Deep Metric Learning approach. The algorithm creates an embedding space for polyps, which allows classification from a few examples to account for the data scarcity of NICE annotated images in our database. RESULTS: For the Paris classification, we achieve an accuracy of 89.35 %, surpassing all papers in the literature and establishing a new state-of-the-art and baseline accuracy for other publications on a public data set. For the NICE classification, we achieve a competitive accuracy of 81.13 % and demonstrate thereby the viability of the few-shot learning paradigm in polyp classification in data-scarce environments. Additionally, we show different ablations of the algorithms. Finally, we further elaborate on the explainability of the system by showing heat maps of the neural network explaining neural activations. CONCLUSION: Overall we introduce two polyp classification systems to assist gastroenterologists. We achieve state-of-the-art performance in the Paris classification and demonstrate the viability of the few-shot learning paradigm in the NICE classification, addressing the prevalent data scarcity issues faced in medical machine learning.

A video based benchmark data set (ENDOTEST) to evaluate computer-aided polyp detection systems.

BACKGROUND AND AIMS: Computer-aided polyp detection (CADe) may become a standard for polyp detection during colonoscopy. Several systems are already commercially available. We report on a video-based benchmark technique for the first preclinical assessment of such systems before comparative randomized trials are to be undertaken. Additionally, we compare a commercially available CADe system with our newly developed one. METHODS: ENDOTEST consisted in the combination of two datasets. The validation dataset contained 48 video-snippets with 22,856 manually annotated images of which 53.2% contained polyps. The performance dataset contained 10 full-length screening colonoscopies with 230,898 manually annotated images of which 15.8% contained a polyp. Assessment parameters were accuracy for polyp detection and time delay to first polyp detection after polyp appearance (FDT). Two CADe systems were assessed: a commercial CADe system (GI-Genius, Medtronic), and a self-developed new system (ENDOMIND). The latter being a convolutional neuronal network trained on 194,983 manually labeled images extracted from colonoscopy videos recorded in mainly six different gastroenterologic practices. RESULTS: On the ENDOTEST, both CADe systems detected all polyps in at least one image. The per-frame sensitivity and specificity in full colonoscopies was 48.1% and 93.7%, respectively for GI-Genius; and 54% and 92.7%, respectively for ENDOMIND. Median FDT of ENDOMIND with 217 ms (Inter-Quartile Range(IQR)8-1533) was significantly faster than GI-Genius with 1050 ms (IQR 358-2767, p = 0.003). CONCLUSIONS: Our benchmark ENDOTEST may be helpful for preclinical testing of new CADe devices. There seems to be a correlation between a shorter FDT with a higher sensitivity and a lower specificity for polyp detection.

Pilot study of a new freely available computer-aided polyp detection system in clinical practice.

PURPOSE: Computer-aided polyp detection (CADe) systems for colonoscopy are already presented to increase adenoma detection rate (ADR) in randomized clinical trials. Those commercially available closed systems often do not allow for data collection and algorithm optimization, for example regarding the usage of different endoscopy processors. Here, we present the first clinical experiences of a, for research purposes publicly available, CADe system. METHODS: We developed an end-to-end data acquisition and polyp detection system named EndoMind. Examiners of four centers utilizing four different endoscopy processors used EndoMind during their clinical routine. Detected polyps, ADR, time to first detection of a polyp (TFD), and system usability were evaluated (NCT05006092). RESULTS: During 41 colonoscopies, EndoMind detected 29 of 29 adenomas in 66 of 66 polyps resulting in an ADR of 41.5%. Median TFD was 130 ms (95%-CI, 80-200 ms) while maintaining a median false positive rate of 2.2% (95%-CI, 1.7-2.8%). The four participating centers rated the system using the System Usability Scale with a median of 96.3 (95%-CI, 70-100). CONCLUSION: EndoMind's ability to acquire data, detect polyps in real-time, and high usability score indicate substantial practical value for research and clinical practice. Still, clinical benefit, measured by ADR, has to be determined in a prospective randomized controlled trial.

Fast machine learning annotation in the medical domain: a semi-automated video annotation tool for gastroenterologists.

BACKGROUND: Machine learning, especially deep learning, is becoming more and more relevant in research and development in the medical domain. For all the supervised deep learning applications, data is the most critical factor in securing successful implementation and sustaining the progress of the machine learning model. Especially gastroenterological data, which often involves endoscopic videos, are cumbersome to annotate. Domain experts are needed to interpret and annotate the videos. To support those domain experts, we generated a framework. With this framework, instead of annotating every frame in the video sequence, experts are just performing key annotations at the beginning and the end of sequences with pathologies, e.g., visible polyps. Subsequently, non-expert annotators supported by machine learning add the missing annotations for the frames in-between. METHODS: In our framework, an expert reviews the video and annotates a few video frames to verify the object's annotations for the non-expert. In a second step, a non-expert has visual confirmation of the given object and can annotate all following and preceding frames with AI assistance. After the expert has finished, relevant frames will be selected and passed on to an AI model. This information allows the AI model to detect and mark the desired object on all following and preceding frames with an annotation. Therefore, the non-expert can adjust and modify the AI predictions and export the results, which can then be used to train the AI model. RESULTS: Using this framework, we were able to reduce workload of domain experts on average by a factor of 20 on our data. This is primarily due to the structure of the framework, which is designed to minimize the workload of the domain expert. Pairing this framework with a state-of-the-art semi-automated AI model enhances the annotation speed further. Through a prospective study with 10 participants, we show that semi-automated annotation using our tool doubles the annotation speed of non-expert annotators compared to a well-known state-of-the-art annotation tool. CONCLUSION: In summary, we introduce a framework for fast expert annotation for gastroenterologists, which reduces the workload of the domain expert considerably while maintaining a very high annotation quality. The framework incorporates a semi-automated annotation system utilizing trained object detection models. The software and framework are open-source.

Pollutant source or sink? Adsorption and mobilization of PFOS and PFOA from sediments in a large shallow lake with extended reed belt.

In this study, we i) assessed the occurrence of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in sediments, pore water, and bulk water from three different areas in Lake Neusiedl, Austria, and ii) investigated mechanisms regulating adsorption and remobilization of these substances under different conditions via multiple lab-scale experiments. The adsorption capacity was mainly influenced by sediments' organic matter content, oxide composition, and pre-loading. Results suggest that a further increase of PFAS-concentrations in the open lake can be partly buffered by sediment transport to the littoral zone and adsorption to sediments in the extended reed belt. But, under current conditions, the conducted experiments revealed a real risk for mobilization of PFOS and PFOA from reed belt sediments that may lead to their transport back into the lake. The amount of desorbed PFAS is primarily dependent on water/sediment- or pore water/water-ratios and the concentration gradient. In contrast, water matrix characteristics and oxygen levels played a minor role in partitioning. The highest risk for remobilizing PFOS and PFOA was observed in experiments with sediments taken near the only major tributary to the lake (river Wulka), which had the highest pre-loading. The following management advice for water transport between high and low polluted areas can be derived based on the results. First, to reduce emissions into Lake waters from polluted tributaries like the Wulka river, we recommend diffuse pathways through the reed belt in the lake's littoral to reduce pollutant transport into the Lake and avoid high local sediment loadings. Second, water exchange with dried-up areas with probable higher loadings should be carefully handled and monitored to avoid critical back transport in the open lake. And third, general work in the reed belt or generally in the reed should be accompanied by monitoring to prevent uncontrolled remobilization in the future.

Ivermectin for causal malaria prophylaxis: a randomised controlled human infection trial.

OBJECTIVE: Ivermectin is safe and widely used for treating helminth infections. It also kills arthropods feeding on treated subjects, including malaria vectors. Thus, ivermectin mass drug administration as an additional tool for malaria control is being evaluated by WHO. As in vitro data, animal experiments and epidemiological observations suggest that ivermectin has a direct effect on the liver stages of the malaria parasite, this study was designed to assess the prophylactic effect of ivermectin on Plasmodium falciparum controlled human malaria infection. METHODS: A total of 4 volunteers were randomised to placebo, and 8 volunteers were randomised to receive ivermectin 0.4 mg/kg, orally, once 2 h before being experimentally infected intravenously with 3200 P. falciparum sporozoites. The primary endpoint was time to parasitaemia detected by positive thick blood smear; RT-qPCR was performed in parallel. RESULTS: All but one volunteer became thick blood smear positive between day 11 and day 12 after infection, and there was no significant effect of ivermectin on parasitaemia. CONCLUSION: Ivermectin - at the dose used - has no clinically relevant activity against the pre-erythrocytic stages of P. falciparum.

OBJECTIF: L'ivermectine est sûr et largement utilisé pour traiter les helminthiases. Il tue également les arthropodes se nourrissant sur les sujets traités, y compris les vecteurs du paludisme. Ainsi, l'administration en masse d'ivermectine en tant qu'outil supplémentaire de lutte contre le paludisme est actuellement évaluée par l'OMS. Comme les données in vitro, les expériences sur animaux et les observations épidémiologiques suggèrent que l'ivermectine a un effet direct sur les stades hépatiques du parasite du paludisme, cette étude a été conçue pour évaluer l'effet prophylactique de l'ivermectine sur l'infection paludéenne humaine par Plasmodium falciparum contrôlée. MÉTHODES: Quatre volontaires ont été randomisés pour un placebo et 8 volontaires ont été randomisés pour recevoir de l'ivermectine à 0,4 mg/kg en une fois par voie orale, 2 heures avant d'être expérimentalement infectés par voie intraveineuse avec 3.200 sporozoïtes de P. falciparum. Le critère d'évaluation principal était le temps à la parasitémie détectée par un frottis sanguin épais positif. Une RT-qPCR a été réalisée en parallèle. RÉSULTATS: Tous les volontaires sauf un sont devenus positifs pour les frottis sanguins épais entre le jour 11 et le jour 12 après l'infection et il n'y avait aucun effet significatif de l'ivermectine sur la parasitémie. CONCLUSION: L'ivermectine - à la dose utilisée - n'a aucune activité cliniquement pertinente contre les stades pré-érythrocytaires de P. falciparum.

Efficacy of palliative chemotherapy in elderly patients with colorectal cancer.

BACKGROUND: The number of old patients suffering from colorectal cancer rises. In clinical trials, old patients are underrepresented, and chemotherapy is significantly less often performed in elderly patients. We analyzed the impact of elder age for palliative chemotherapy in patients suffering from metastatic colorectal cancer, according to therapeutic drugs used, intensity of treatment performed, and therapeutic results. MATERIALS AND METHODS: We analyzed consecutive patients with metastatic colorectal cancer treated in palliative intention in our department. Assessed data included age ( 75 years), sex, comorbidity, site of primary tumor, k-ras-status, site and amount of metastasis, number and kind of chemotherapeutic agents used, number of consecutive therapy lines performed, dose intensity, toxicity, time between start and end of palliative chemotherapy, and overall survival. Prognostic variables were tested in uni- and multivariate analysis. RESULTS: Ninety-seven patients (69 < 75, 18 > 75 years) were included. Age groups were well balanced according to site of primary tumor, k-ras-mutational status, localization, and number of metastatic sites. Cardial and renal comorbidity was more frequent in elderly patients. The median number of chemotherapeutic drugs used and lines of therapy performed did not differ between age groups, except of oxaliplatin, which was significantly less often used in old patients. Median survival did not differ between age groups (23.4 vs. 23.5 months). In multivariate analysis, only left-sided primary tumor and more than 3 lines of therapy performed were prognostic positive variables. CONCLUSION: Old patients can profit from palliative chemotherapy to the same extent as younger ones.

Analysis of CFB, a cytokinin-responsive gene of Arabidopsis thaliana encoding a novel F-box protein regulating sterol biosynthesis.

Protein degradation by the ubiquitin-26S proteasome pathway is important for the regulation of cellular processes, but the function of most F-box proteins relevant to substrate recognition is unknown. We describe the analysis of the gene Cytokinin-induced F-box encoding (CFB, AT3G44326), identified in a meta-analysis of cytokinin-related transcriptome studies as one of the most robust cytokinin response genes. F-box domain-dependent interaction with the E3 ubiquitin ligase complex component ASK1 classifies CFB as a functional F-box protein. Apart from F-box and transmembrane domains, CFB contains no known functional domains. CFB is expressed in all plant tissues, predominantly in root tissue. A ProCFB:GFP-GUS fusion gene showed strongest expression in the lateral root cap and during lateral root formation. CFB-GFP fusion proteins were mainly localized in the nucleus and the cytosol but also at the plasma membrane. cfb mutants had no discernible phenotype, but CFB overexpressing plants showed several defects, such as a white upper inflorescence stem, similar to the hypomorphic cycloartenol synthase mutant cas1-1. Both CFB overexpressing plants and cas1-1 mutants accumulated the CAS1 substrate 2,3-oxidosqualene in the white stem tissue, the latter even more after cytokinin treatment, indicating impairment of CAS1 function. This suggests that CFB may link cytokinin and the sterol biosynthesis pathway.

Sequential endoscopic ultrasound identifies predictive variables for relapse-free follow-up after neoadjuvant chemotherapy in gastric cancer.

BACKGROUND: The accuracy of endosonographic tumor staging after neoadjuvant therapy is less reliable than in primary staging. Therefore, the value of sequential endosonographic examinations after neaodjuvant chemotherapy in gastro-esophageal cancer is discussed controversially. Previous data suggest, that endoscopic ultrasound (EUS) after neoadjuvant treatment using other variables than classic uTN-criteria may identify patients with a better prognosis. METHODS: In 67 patients with locally advanced gastric cancer treated in curative intent, we performed EUS before and after neoadjuvant chemotherapy. Endosonographic yTN-stage was compared to pathohistological yTN-stage after curative resection. The uTN-stage, yuTN-stage, maximal tumor thickness and maximal lymph node diameter as well as the shift of these variables after neoadjuvant therapy were analyzed for their usefulness to predict recurrence-free follow-up. RESULTS: Accuracy of EUS for yTN-staging after neoadjuvant therapy was poor, especially in lower tumor stages. However, three heavily correlated variables analyzed by sequential EUS could be used for the prediction of prognosis: low endosonographic tumor stage (yuT0-2) after neoadjuvant chemotherapy, a decrease of two or more steps in uT-stage and a maximal tumor thickness of <15 mm after chemotherapy were significantly associated with recurrence-free follow-up. Endosonographic T-stage before neoadjuvant therapy, as well as lymph node variables before or after chemotherapy, were of no predictive value. CONCLUSION: In spite of poor concordance between endosonographic and pathohistological TN-stage after neoadjuvant treatment, sequential EUS, performed before and after neoadjuvant therapy, possibly identify patients at risk for tumor relapse after multimodal treatment in gastric cancer. This finding should be validated in a larger patient cohort.

Different accuracy of endosonographic tumor staging after neoadjuvant chemotherapy and chemoradiotherapy in esophageal cancer.

BACKGROUND: Treatment response to neoadjuvant therapy is histologically associated with more or less intensive inflammation and fibrosis. In consequence, accuracy of endosonographic TN-tumor staging after neoadjuvant treatment is hampered. We analyzed whether the kind of treatment chosen [chemoradiotherapy (CRT) or chemotherapy (CT)] differently influences the accuracy of endoscopic ultrasound after neoadjuvant therapy in esophageal cancer. METHODS: We performed serial endoscopic ultrasound examinations in 18 patients after neoadjuvant CRT and 30 patients after neoadjuvant CT. TN-stage was classified according to the standard parameter. Histological examination of the surgical resection specimen served as gold standard. RESULTS: The most frequent error was overstaging, especially in patients with complete tumor response or minimal residual disease. Accuracy of T-staging was significantly worse after CRT (0.16) than after CT (0.43), obviously due to difficulty in distinguishing residual tumor from treatment-associated fibrosis and inflammation. Accuracy of N-staging was also hampered, but to a less extent (sensitivity/specificity 0.85/0.36 after CRT, and 0.5/0.42 after CT). CONCLUSIONS: Accuracy of endosonographic TN-tumor staging is significantly more hampered by neoadjuvant CRT than after CT. However, endoscopic ultrasound is insufficient for TN-staging irrespective of the kind of neoadjuvant therapy performed.

In planta analysis of a cis-regulatory cytokinin response motif in Arabidopsis and identification of a novel enhancer sequence.

The phytohormone cytokinin plays a key role in regulating plant growth and development, and is involved in numerous physiological responses to environmental changes. The type-B response regulators, which regulate the transcription of cytokinin response genes, are a part of the cytokinin signaling system. Arabidopsis thaliana encodes 11 type-B response regulators (type-B ARRs), and some of them were shown to bind in vitro to the core cytokinin response motif (CRM) 5'-(A/G)GAT(T/C)-3' or, in the case of ARR1, to an extended motif (ECRM), 5'-AAGAT(T/C)TT-3'. Here we obtained in planta proof for the functionality of the latter motif. Promoter deletion analysis of the primary cytokinin response gene ARR6 showed that a combination of two extended motifs within the promoter is required to mediate the full transcriptional activation by ARR1 and other type-B ARRs. CRMs were found to be over-represented in the vicinity of ECRMs in the promoters of cytokinin-regulated genes, suggesting their functional relevance. Moreover, an evolutionarily conserved 27 bp long T-rich region between -220 and -193 bp was identified and shown to be required for the full activation by type-B ARRs and the response to cytokinin. This novel enhancer is not bound by the DNA-binding domain of ARR1, indicating that additional proteins might be involved in mediating the transcriptional cytokinin response. Furthermore, genome-wide expression profiling identified genes, among them ARR16, whose induction by cytokinin depends on both ARR1 and other specific type-B ARRs. This together with the ECRM/CRM sequence clustering indicates cooperative action of different type-B ARRs for the activation of particular target genes.

Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304).

OBJECTIVE: Acute cholecystitis is a common disease, and laparoscopic surgery is the standard of care. BACKGROUND: Optimal timing of surgery for acute cholecystitis remains controversial: either early surgery shortly after hospital admission or delayed elective surgery after a conservative treatment with antibiotics. METHODS: The ACDC ("Acute Cholecystitis-early laparoscopic surgery versus antibiotic therapy and Delayed elective Cholecystectomy") study is a randomized, prospective, open-label, parallel group trial. Patients were randomly assigned to receive immediate surgery within 24 hours of hospital admission (group ILC) or initial antibiotic treatment, followed by delayed laparoscopic cholecystectomy at days 7 to 45 (group DLC). For infection, all patients were treated with moxifloxacin for at least 48 hours. Primary endpoint was occurrence of predefined relevant morbidity within 75 days. Secondary endpoints were as follows: (1) 75-day morbidity using a scoring system; (2) conversion rate; (3) change of antibiotic therapy; (4) mortality; (5) costs; and (6) length of hospital stay. RESULTS: Morbidity rate was significantly lower in group ILC (304 patients) than in group DLC (314 patients): 11.8% versus 34.4%. Conversion rate to open surgery and mortality did not differ significantly between groups. Mean length of hospital stay (5.4 days vs 10.0 days; P < 0.001) and total hospital costs (€2919 vs €4262; P < 0.001) were significantly lower in group ILC. CONCLUSIONS: In this large, randomized trial, laparoscopic cholecystectomy within 24 hours of hospital admission was shown to be superior to the conservative approach concerning morbidity and costs. Therefore, we believe that immediate laparoscopic cholecystectomy should become therapy of choice for acute cholecystitis in operable patients. (NCT00447304).

Health-related quality of life in recurrent platinum-sensitive ovarian cancer--results from the CALYPSO trial.

BACKGROUND: In the CALYPSO trial, carboplatin-pegylated liposomal doxorubicin (CD) demonstrated superior therapeutic index versus carboplatin-paclitaxel (CP) in patients with recurrent ovarian cancer. This paper reports the health-related quality of life (HRQoL) findings. MATERIALS AND METHODS: HRQoL was measured with the EORTC QoL-QC30 questionnaire and OV28 ovarian cancer module. Mean change scores from baseline in HRQoL subscales (five functional scales and global health status) in each arm and the proportion of patients improved or worsened were calculated every 3 months until 12 months. RESULTS: Compliance was 90% at baseline and 76%, 64%, 57% at 3, 6, and 9 months, respectively. Baseline HRQoL showed already impaired global scores (mean 62/100) and considerable symptom burden (90% of patients reporting nonzero scores). Global QoL and abdominal symptom scores improved over time in both arms; at 6 months, 36% of patients met criteria for improved symptoms. Treatment with CD resulted in less peripheral neuropathy (9.8 versus 24.2), fewer other chemotherapy side-effects (9.5 versus 16.2), and less impact on body image (3.8 versus 10.4) versus CP (all P<0.02) at 6 months. CONCLUSIONS: These patient-reported outcomes confirm the overall lower toxicity of CD versus CP. The improved disease-related outcomes achieved with CD were not at the expense of QoL.

Transcript profiling of cytokinin action in Arabidopsis roots and shoots discovers largely similar but also organ-specific responses.

BACKGROUND: The plant hormone cytokinin regulates growth and development of roots and shoots in opposite ways. In shoots it is a positive growth regulator whereas it inhibits growth in roots. It may be assumed that organ-specific regulation of gene expression is involved in these differential activities, but little is known about it. To get more insight into the transcriptional events triggered by cytokinin in roots and shoots, we studied genome-wide gene expression in cytokinin-treated and cytokinin-deficient roots and shoots. RESULTS: It was found by principal component analysis of the transcriptomic data that the immediate-early response to a cytokinin stimulus differs from the later response, and that the transcriptome of cytokinin-deficient plants is different from both the early and the late cytokinin induction response. A higher cytokinin status in the roots activated the expression of numerous genes normally expressed predominantly in the shoot, while a lower cytokinin status in the shoot reduced the expression of genes normally more active in the shoot to a more root-like level. This shift predominantly affected nuclear genes encoding plastid proteins. An organ-specific regulation was assigned to a number of genes previously known to react to a cytokinin signal, including root-specificity for the cytokinin hydroxylase gene CYP735A2 and shoot specificity for the cell cycle regulator gene CDKA;1. Numerous cytokinin-regulated genes were newly discovered or confirmed, including the meristem regulator genes SHEPHERD and CLAVATA1, auxin-related genes (IAA7, IAA13, AXR1, PIN2, PID), several genes involved in brassinosteroid (CYP710A1, CYP710A2, DIM/DWF) and flavonol (MYB12, CHS, FLS1) synthesis, various transporter genes (e.g. HKT1), numerous members of the AP2/ERF transcription factor gene family, genes involved in light signalling (PhyA, COP1, SPA1), and more than 80 ribosomal genes. However, contrasting with the fundamental difference of the growth response of roots and shoots to the hormone, the vast majority of the cytokinin-regulated transcriptome showed similar response patterns in roots and shoots. CONCLUSIONS: The shift of the root and shoot transcriptomes towards the respective other organ depending on the cytokinin status indicated that the hormone determines part of the organ-specific transcriptome pattern independent of morphological organ identity. Numerous novel cytokinin-regulated genes were discovered which had escaped earlier discovery, most probably due to unspecific sampling. These offer novel insights into the diverse activities of cytokinin, including crosstalk with other hormones and different environmental cues, identify the AP2/ERF class of transcriptions factors as particularly cytokinin sensitive, and also suggest translational control of cytokinin-induced changes.

Naturally acquired immune responses to malaria vaccine candidate antigens MSP3 and GLURP in Guahibo and Piaroa indigenous communities of the Venezuelan Amazon.

BACKGROUND: Malaria transmission in most of Latin America can be considered as controlled. In such a scenario, parameters of baseline immunity to malaria antigens are of specific interest with respect to future malaria eradication efforts. METHODS: A cross-sectional study was carried out in two indigenous population groups in Amazonas/Venezuela. Data from the regional malaria documentation system were extracted and participants from the ethnic groups of the Guahibo (n = 180) and Piaroa (n = 295) were investigated for the presence of Plasmodium parasites and naturally acquired antibodies to Plasmodium falciparum antigens in serum. The GMZ2 vaccine candidate proteins MSP3 and GLURP were chosen as serological markers. RESULTS: The incidence of P. falciparum in both communities was found to be less than 2%, and none of the participants harboured P. falciparum at the time of the cross-sectional. Nearly a quarter of the participants (111/475; 23,4%) had positive antibody titres to at least one of the antigens. 53/475 participants (11.2%) were positive for MSP3, and 93/475 participants (19.6%) were positive for GLURP. High positive responses were detected in 36/475 participants (7.6%) and 61/475 participants (12.8%) for MSP3 and GLURP, respectively. Guahibo participants had significantly higher antibody titres than Piaroa participants. CONCLUSIONS: Considering the low incidence of P. falciparum, submicroscopical infections may explain the comparatively high anti-P. falciparum antibody concentrations.