DDQN-based optimal targeted therapy with reversible inhibitors to combat the Warburg effect.

We cover the Warburg effect with a three-component evolutionary model, where each component represents a different metabolic strategy. In this context, a scenario involving cells expressing three different phenotypes is presented. One tumour phenotype exhibits glycolytic metabolism through glucose uptake and lactate secretion. Lactate is used by a second malignant phenotype to proliferate. The third phenotype represents healthy cells, which performs oxidative phosphorylation. The purpose of this model is to gain a better understanding of the metabolic alterations associated with the Warburg effect. It is suitable to reproduce some of the clinical trials obtained in colorectal cancer and other even more aggressive tumours. It shows that lactate is an indicator of poor prognosis, since it favours the setting of polymorphic tumour equilibria that complicates its treatment. This model is also used to train a reinforcement learning algorithm, known as Double Deep Q-networks, in order to provide the first optimal targeted therapy based on experimental tumour growth inhibitors as genistein and AR-C155858. Our in silico solution includes the optimal therapy for all the tumour state space and also ensures the best possible quality of life for the patients, by considering the duration of treatment, the use of low-dose medications and the existence of possible contraindications. Optimal therapies obtained with Double Deep Q-networks are validated with the solutions of the Hamilton-Jacobi-Bellman equation.

Postnatal care setting and survival after fetoscopic tracheal occlusion for severe congenital diaphragmatic hernia: A systematic review and meta-analysis.

BACKGROUND: Fetoscopic endoluminal tracheal occlusion (FETO) was recently shown to improve postnatal survival in a multicenter, randomized controlled trial of infants with severe congenital diaphragmatic hernia (CDH). However, the external validity of this study remains unclear given a lack of standardization in postnatal management approaches. The purpose of this study was to evaluate the impact of an integrated prenatal and postnatal care setting on survival outcomes in severe CDH after FETO. STUDY DESIGN: A systematic review, meta-analysis, and individual participant analysis of FETO outcomes in severe CDH were conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary outcome was survival to discharge. Subgroup analyses of patients managed in integrated versus nonintegrated settings were performed to identify predictors of outcome. RESULTS: The review generated five studies (n = 192) for the meta-analysis of FETO versus expectant prenatal management. These data revealed a significant survival benefit after FETO that was restricted to an integrated setting (OR 2.97, 95% Confidence Interval 1.69-4.26). There were nine studies (n = 150) for the individual participant analysis, which showed that FETO managed in an integrated setting had significantly increased survival rates when compared to FETO treated in a nonintegrated setting (70.7% vs. 45.7%, p = 0.003). Multi-level logistic regression identified increased availability of extracorporeal membrane oxygenation (ECMO) as the strongest determinant of postnatal survival (OR=18.8, p = 0.049). CONCLUSION: This systematic review shows that institutional integration of prenatal and postnatal care is associated with the highest overall survival in children with severe CDH. These data highlight the importance of a standardized, multidisciplinary approach, including access to ECMO, as a critical postnatal component in optimizing FETO outcomes in CDH.

Homogenizing the Teaching of Engaged Medical Examinations to Large Numbers of Students: the Experience of the Digital Rectal Examination.

This project aims to complement and homogenise the teaching of indications and technique of digital rectal examination (DRE) through the use of simulators, and subsequently analysed the level of satisfaction with the training and skills acquired. The students were distributed into small groups. One of the workshop's coordinators synthesised indications and procedures of DRE. A teaching video was made with all the contents and was distributed between the trainers. During the workshop, trainers explained the indications and the method of performing the DRE. Then, the selected clinical cases were presented, followed by the DRE by specific simulators. Once the students had completed each exploration, the trainers explained each case and discussed it with students. The following week, an anonymous questionnaire was given to participants to evaluate the workshop. Of the 232 participating students, 53 (23%) responded to the questionnaire. The overall level of satisfaction was higher than 98% (score 4-5), reaching 100% in the evaluation of the practical contents, and 93% of the students would recommend the continuity of the workshop in the next courses. The DRE workshop was well received among medical students, with a high degree of voluntary participation and response rate to the subsequent survey. With this project, we have achieved a greater homogenisation of teaching within the subject of Urology, and greater confidence for the students when facing their future clinical practice.

Fetal endoscopic tracheal occlusion reduces pulmonary hypertension in severe congenital diaphragmatic hernia.

OBJECTIVE: Fetal endoscopic tracheal occlusion (FETO) is associated with increased perinatal survival and reduced need for extracorporeal membrane oxygenation (ECMO) in fetuses with severe congenital diaphragmatic hernia (CDH). This study evaluates the impact of FETO on the resolution of pulmonary hypertension (PH) in fetuses with isolated CDH. METHODS: We reviewed retrospectively the medical records of all fetuses evaluated for CDH between January 2004 and July 2017 at a single institution. Fetuses with additional major structural or chromosomal abnormalities were excluded. CDH cases were classified retrospectively into mild, moderate and severe groups based on prenatal magnetic resonance imaging indices (observed-to-expected total fetal lung volume and percentage of intrathoracic liver herniation). Presence of PH was determined based on postnatal echocardiograms. Logistic regression analyses were performed to evaluate the relationship between FETO and resolution of PH by 1 year of age while controlling for side of the CDH, use of ECMO, gestational age at diagnosis, gestational age at delivery, fetal gender, sildenafil use at discharge and CDH severity. Resolution of PH by 1 year of age was compared between a cohort of fetuses with severe CDH that underwent FETO and a cohort that did not have the procedure (non-FETO). A subanalysis was performed restricting the analysis to isolated left CDH. Parametric and non-parametric tests were used for comparisons. RESULTS: Of 257 CDH cases evaluated, 72% (n = 184) had no major structural or chromosomal anomalies of which 58% (n = 107) met the study inclusion criteria. The FETO cohort consisted of 19 CDH cases and the non-FETO cohort (n = 88) consisted of 31 (35%) mild, 32 (36%) moderate and 25 (28%) severe CDH cases. All infants with severe CDH, regardless of whether they underwent FETO, had evidence of neonatal PH. FETO (OR, 3.57; 95% CI, 1.05-12.10; P = 0.041) and ECMO (OR, 5.01; 95% CI, 2.10-11.96; P < 0.001) were independent predictors of resolution of PH by 1 year of age. A higher proportion of infants with severe CDH that underwent FETO had resolution of PH by 1 year after birth compared with infants with severe CDH in the non-FETO cohort (69% (11/16) vs 28% (7/25); P = 0.017). Similar results were observed when the analysis was restricted to cases with left-sided CDH (PH resolution in 69% (11/16) vs 28% (5/18); P = 0.032). CONCLUSION: In infants with severe CDH, FETO and ECMO are independently associated with increased resolution of PH by 1 year of age. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Dissection of intercostal nerves by means of assisted video thoracoscopy: experimental study.

In total brachial plexus preganglionic lesions (C5-C6-C7-C8 and T1) different extraplexual neurotizations are indicated for partial motor function restitution. Mostly for the flexion of the elbow. Neurotization with intercostal nerves (ICN) to musculocutaneous nerve has been known and accepted during many years with different results 2 - 5. The customary technique as described by various authors is carried out by means of a large submammary incision to harvest three or four intercostal nerves (Figure 1). Then are connected by direct suture or grafts to the musculocutaneous nerve or its motor branches 6 - 7. In this article the authors described the possibility of dissection intercostal nerves by means of assisted video thoracoscopy. (VATS-videdo assisted thoracic surgery).

Plant defense mechanisms are activated during biotrophic and necrotrophic development of Colletotricum graminicola in maize.

Hemibiotrophic plant pathogens first establish a biotrophic interaction with the host plant and later switch to a destructive necrotrophic lifestyle. Studies of biotrophic pathogens have shown that they actively suppress plant defenses after an initial microbe-associated molecular pattern-triggered activation. In contrast, studies of the hemibiotrophs suggest that they do not suppress plant defenses during the biotrophic phase, indicating that while there are similarities between the biotrophic phase of hemibiotrophs and biotrophic pathogens, the two lifestyles are not analogous. We performed transcriptomic, histological, and biochemical studies of the early events during the infection of maize (Zea mays) with Colletotrichum graminicola, a model pathosystem for the study of hemibiotrophy. Time-course experiments revealed that mRNAs of several defense-related genes, reactive oxygen species, and antimicrobial compounds all begin to accumulate early in the infection process and continue to accumulate during the biotrophic stage. We also discovered the production of maize-derived vesicular bodies containing hydrogen peroxide targeting the fungal hyphae. We describe the fungal respiratory burst during host infection, paralleled by superoxide ion production in specific fungal cells during the transition from biotrophy to a necrotrophic lifestyle. We also identified several novel putative fungal effectors and studied their expression during anthracnose development in maize. Our results demonstrate a strong induction of defense mechanisms occurring in maize cells during C. graminicola infection, even during the biotrophic development of the pathogen. We hypothesize that the switch to necrotrophic growth enables the fungus to evade the effects of the plant immune system and allows for full fungal pathogenicity.

Irinotecan plus raltitrexed as first-line treatment in advanced colorectal cancer: a phase II study.

To evaluate the efficacy and toxicity of irinotecan (CPT-11) in combination with raltitrexed as first-line treatment of advanced colorectal cancer (CRC). A total of 91 previously untreated patients with advanced CRC and measurable disease were enrolled in this phase II study. The median age was 62 years (range 31-77); male/female 54/37; ECOG performance status was 0 in 50 patients (55%), one in 39 (43%) and two in two (2%). Treatment consisted of CPT-11 350 mg x m(-2) in a 30-min intravenous infusion on day 1, followed after 30 min by a 15-min infusion of raltitrexed 3 mg x m(-2). Measurements of efficacy included the following: response rate, time to disease progression and overall survival. Of the 83 evaluable patients valuable to objective response, there were five complete responses (6%) and 23 partial responses (28%), for an overall response rate of 34% (95% CI: 25.9-46.5%). In all, 36 patients (43%) had stable disease, whereas 19 (23%) had a progression. The median time to progression was 11.1 months and the median overall survival was 15.6 months. A total of 487 cycles of chemotherapy were delivered with a median of five per patient. Grade 3-4 WHO toxicities were as follows: diarrhoea in 13 patients (15%), nausea/vomiting in four (4%), transaminase increase in six (7%), stomatitis in two (2%), febrile neutropenia in three (3%), anaemia in five (6%) and asthenia in three (3%). The combination CPT-11-raltitrexed is an effective, well-tolerated and convenient regimen as front-line treatment of advanced CRC.