[Information tool about labor and delivery designed by Delphi method]. / Élaboration d'un outil d'information sur l'accouchement : consensus par la méthode Delphi.

OBJECTIVE: The integration of couples in decision making in obstetrics is necessary to improve the experience of giving birth. The objective of this work is to elaborate a new tool to provide information to health professionals. METHODS: A 5-round Delphi method was used to define the information points. The 20 multi-disciplinary experts answered 5 surveys on the information to deliver concerning childbirth. The selected items were organized with mind mapping. RESULTS: 54 items were identified on the first round. 5 were retained after the second survey while the rest were reformulated and submitted for the third round. Amongst the 47 items submitted, 19 were retained, the rest were removed, merged or reworded. The fourth survey included 22 items of which 11 were retained. The fifth survey concerned the 11 remaining items and 2 new ones. During this round, 7 items were retained. This round made it possible to reach the consensus. In total, 42 items reached the consensus of the experts. They were then split into 5 mind maps allowing their visual organization to form the information tool. CONCLUSION: The tool elaborated in a multi-disciplinary manner offers complementary information to that already given during childbirth preparation courses. It is a framework for the information to be given that leaves the content up to each professional.

Corrigendum: Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors.

[This corrects the article DOI: 10.3389/fcell.2020.600926.].

Zebrafish Models of Craniofacial Malformations: Interactions of Environmental Factors.

The zebrafish is an appealing model organism for investigating the genetic (G) and environmental (E) factors, as well as their interactions (GxE), which contribute to craniofacial malformations. Here, we review zebrafish studies on environmental factors involved in the etiology of craniofacial malformations in humans including maternal smoking, alcohol consumption, nutrition and drug use. As an example, we focus on the (cleft) palate, for which the zebrafish ethmoid plate is a good model. This review highlights the importance of investigating ExE interactions and discusses the variable effects of exposure to environmental factors on craniofacial development depending on dosage, exposure time and developmental stage. Zebrafish also promise to be a good tool to study novel craniofacial teratogens and toxin mixtures. Lastly, we discuss the handful of studies on gene-alcohol interactions using mutant sensitivity screens and reverse genetic techniques. We expect that studies addressing complex interactions (ExE and GxE) in craniofacial malformations will increase in the coming years. These are likely to uncover currently unknown mechanisms with implications for the prevention of craniofacial malformations. The zebrafish appears to be an excellent complementary model with high translational value to study these complex interactions.

Effect of cholesterol re-supplementation and atorvastatin on plaque composition in the thoracic aorta of New Zealand white rabbits.

BACKGROUND: Effects of re-supplementation of a cholesterol-enriched diet (CEDrs) on size, cholesterol content and morphology of already existing plaques are not known to date. METHODS: A group of rabbits received standard chow (SC) for 6 weeks ("negative control"; for plasma lipid measurements only). Group I-IV received 2% CED (induction) for 6 weeks; thereafter, groups II-IV have been fed a SC (= cholesterol withdrawal) for 68 weeks. Afterwards, feeding of groups II-IV was continued as follows: Group II - 10 weeks SC, group III - 4 weeks 0.5% CED (~re-supplementation), afterwards 6 weeks SC (~withdrawal again); group IV - 4 weeks 0.5% CED (re-supplementation) + atorvastatin (2.5 mg/kg body weight/day), afterwards 6 weeks SC (~withdrawal again) + atorvastatin. Plasma lipids, but also plaque size, morphology and cholesterol contents of thoracic aortas were quantified. RESULTS: After CEDrs, plasma cholesterol levels were increased. However, after withdrawal of CEDrs, plasma cholesterol levels decreased, whereas the cholesterol content of the thoracic aorta was increased in comparison with the group without CEDrs. Plaque size remained unaffected. Atorvastatin application did not change plasma cholesterol level, cholesterol content of the thoracic aorta and plaque size in comparison with the group without drug treatment. However, atorvastatin treatment increased the density of macrophages (MΦ) compared with the group without treatment, with a significant correlation between densities of MΦ (Mac-1+) and apoptotic (TUNEL+; TP53+), antigen-presenting (HLA-DR+) or oxidatively stressed (SOD2+) cells. CONCLUSIONS: In rabbits with already existing plaques, CEDrs affects plaque morphology and cellular composition, but not plaque size. Despite missing effects on plasma cholesterol levels, cholesterol content of the thoracic aorta and size of already existing atherosclerotic plaques, atorvastatin treatment transforms the already existing lesions to a more active form, which may accelerate the remodelling to a more stable plaque.

The anti-epileptic drug valproic acid causes malformations in the developing craniofacial skeleton of zebrafish larvae.

Valproic acid (VPA) is an anti-epileptic drug known to cause congenital craniofacial abnormalities, including orofacial clefts (OFC). The exact mechanisms by which VPA leads to craniofacial skeletal malformations are poorly understood. In this study, we investigated the effects of VPA on cartilage and bone formation in the zebrafish larval head during 1-13 hpf (early) and 25-37 hpf (late) development in which cranial neural crest cells (CNCCs) arise and then proliferate and differentiate, respectively. Double-staining for cartilage and bone at 5 dpf revealed that VPA reduced cartilage and bone formation in a dose-dependent manner after both early or late exposure. Several different CNCC-derived cartilage and bone elements were affected in both groups. In the early group (100 µM VPA), the posterior head length and the ethmoid plate were reduced in length (both p < 0.01), while mineralization of 4 out of 9 bone elements was often lacking (all p < 0.01). In the late group (100 µM VPA), also the posterior head length was reduced as well as the length of the ceratohyals (both p < 0.01). Similar to early exposure, mineralization of 3 out of 9 bone elements was often lacking (all p < 0.01). These results indicate that both CNCC formation (early) and differentiation (late) are hampered by VPA treatment, of which the consequences for bone and cartilage formation are persistent at 5 dpf. Indeed, we also found that the expression of several genes related to cartilage and bone was upregulated at 5 dpf. These data indicate a compensatory reaction to the lack of cartilage and bone. Altogether, VPA seems to induce craniofacial malformations via disturbed CNCC function leading to defects in cartilage and bone formation.

[Focus on the Odon Device™: Technical improvements, mechanical principles and progress of the clinical research program]. / Mise au point sur l'Odon Device™ : amélioration technique, fonctionnement et avancée du programme de recherche clinique.

The Odon Device™ has been described in the literature since 2013 and the World Health Organization supports its development through the Human Reproduction Program. This innovative device could be easier to use than usual instruments and could be an alternative to caesarean section during the second stage of labor, especially in countries where access to obstetric care is limited. The aim of the Odon Device™ is to position an air cuff over the fetal head, past its widest point (around the level of the fetal mouth anteriorly and the nape of the fetal neck posteriorly). Three mechanical principles favor the progression of the fetal head with the Odon Device™: partial propulsion, limited flexion and traction. Preliminary clinical studies on animals and simulators are reassuring and show that an appropriate use is no more at risk than the vaccum or forceps. A phase 1 study was conducted in Argentina and South Africa between 2011 and 2017. The reported failure rate was 29%, of which 77% was secondary to a mechanical failure of one of the components of the device. Improvements concerning the applicator, the handles and the inflatable air cuff have been made to the device. Phase II of the clinical research program began in 2018 and includes two studies in two different centers: The ASSIST Study in Bristol, England, and The BESANCON ASSIST Study, Besançon, France.

Feasibility of two-dimensional ultrasound shear wave elastography of human fetal lungs and liver: A pilot study.

PURPOSE: The first aim was to evaluate feasibility and reproducibility of 2-dimensional ultrasound (2D) shear wave elastography (SWE) of human fetal lungs and liver between 24 and 34weeks of gestation. The second aim was to model fetal lung-to-liver elastography ratio (LLE ratio) and to assess its variations according to gestational age and maternal administration of corticosteroids. MATERIAL AND METHODS: 2D-SWE examinations were prospectively performed in fetuses of women with an uncomplicated pregnancy (group 1) and fetuses of women with a threatened preterm labor requiring administration of corticosteroids (group 2). Two 2D-SWE examinations were performed at "day 0" and "day 2" in group 1; before and 24hours after a course of corticosteroid in group 2. Three operators performed 2 cycles of 3 measurements on the lung (regions A1, A2, A3) and the liver (regions IV, V, VI). Repeatability and reproducibility of measurements were calculated. The fetal LLE ratio was modeled from the most reproducible regions. RESULTS: Fifty-five women were enrolled in group 1 and 48 in group 2. For the lung, 8.6% of measurements were considered invalid and 6.9% for the liver. The most reproducible region for the lung was A3 [ICC between 0.70 (95% CI: 0.42-0.85) and 0.78 (95% CI: 0.48-0.90)] and region VI for the liver [ICC between 0.70 (95% CI: 0.40-0.85) and 0.84 (95% CI: 0.60-0.94)]. According to gestational age, a moderate positive linear correlation was found for stiffness values of A3 (R=0.56), V (R=0.46) and VI (R=0.44). LLE ratio values at "day 0" were not different between the two groups but decreased at "day 2" in group 2 (0.2; 95% CI: 0.07-0.34; P<0.001). CONCLUSION: Quantitative fetal lung and liver stiffness measurements are possible with 2D-SWE with acceptable reproducibility.

Fgf8a mutation affects craniofacial development and skeletal gene expression in zebrafish larvae.

Craniofacial development is tightly regulated and therefore highly vulnerable to disturbance by genetic and environmental factors. Fibroblast growth factors (FGFs) direct migration, proliferation and survival of cranial neural crest cells (CNCCs) forming the human face. In this study, we analyzed bone and cartilage formation in the head of five dpf fgf8ati282 zebrafish larvae and assessed gene expression levels for 11 genes involved in these processes. In addition, in situ hybridization was performed on 8 and 24 hours post fertilization (hpf) larvae (fgf8a, dlx2a, runx2a, col2a1a). A significant size reduction of eight out of nine craniofacial cartilage structures was found in homozygous mutant (6-36%, P<0.01) and heterozygous (7-24%, P<0.01) larvae. Also, nine mineralized structures were not observed in all or part of the homozygous (0-71%, P<0.0001) and heterozygous (33-100%, P<0.0001) larvae. In homozygote mutants, runx2a and sp7 expression was upregulated compared to wild type, presumably to compensate for the reduced bone formation. Decreased col9a1b expression may compromise cartilage formation. Upregulated dlx2a in homozygotes indicates impaired CNCC function. Dlx2a expression was reduced in the first and second stream of CNCCs in homozygous mutants at 24 hpf, as shown by in situ hybridization. This indicates an impairment of CNCC migration and survival by fgf8 mutation.

[Manual rotation in occiput posterior position: A systematic review in 2019]. / Rotation manuelle des variétés postérieures : état des lieux de la littérature en 2019.

OBJECTIVE: The aim of our study was to evaluate the safety and the benefits of manual rotation in the management of Occiput-posterior positions in 2019. METHODS: A systematic review of literature was performed using the MEDLINE and COCHRANE LIBRARY databases, in order to identify articles concerning maternal and neonatal outcomes after a manual rotation, through January 2019. Information on study characteristics (review, author, year of publication), population, objectives and main neonatal and maternal outcomes were extracted. RESULTS: A total of 51 articles were identified and 12 articles were selected for the systematic review. The rate of successful manual rotation were about 47 to 90%. There were more success if systematic manual rotation, multiparity, engagement, spontaneous labour and maternal age<35. The 2nd stage of labour was shorter after an attempt of manual rotation. The randomised controlled trials did not find any statistical difference concerning operative deliveries or neonatal and maternal outcomes. CONCLUSION: The manual rotation is an obstetrical manoeuvre which must be regulated and only practiced by trained operators. Currently, the state of science is not sufficient to recommend the manual rotation as a systematic practice in 2019.

Prednisolone induces osteoporosis-like phenotype in regenerating zebrafish scales.

UNLABELLED: We demonstrate that glucocorticoids induce an osteoporotic phenotype in regenerating scales of zebrafish. Exposure to prednisolone results in altered mineral content, enhanced matrix breakdown, and an osteoporotic gene-expression profile in osteoblasts and osteoclasts. This highlights that the zebrafish scale provides a powerful tool for preclinical osteoporosis research. INTRODUCTION: This study aims to evaluate whether glucocorticoid (prednisolone) treatment of zebrafish induces an osteoporotic phenotype in regenerating scales. Scales, a readily accessible dermal bone tissue, may provide a tool to study direct osteogenesis and its disturbance by glucocorticoids. METHODS: In adult zebrafish, treated with 25 µM prednisolone phosphate via the water, scales were removed and allowed to regenerate. During regeneration scale morphology and the molar calcium/phosphorus ratio in scales were assessed and osteoblast and osteoclast activities were monitored by time profiling of cell-specific genes; mineralization was visualized by Von Kossa staining, osteoclast activity by tartrate-resistant acid phosphatase histochemistry. RESULTS: Prednisolone (compared to controls) enhances osteoclast activity and matrix resorption and slows down the build up of the calcium/phosphorus molar ratio indicative of altered crystal maturation. Prednisolone treatment further impedes regeneration through a shift in the time profiles of osteoblast and osteoclast genes that commensurates with an osteoporosis-like imbalance in bone formation. CONCLUSIONS: A glucocorticoid-induced osteoporosis phenotype as seen in mammals was induced in regenerating scalar bone of zebrafish treated with prednisolone. An unsurpassed convenience and low cost then make the zebrafish scale a superior model for preclinical studies in osteoporosis research.

Bruises in culled cows: when, where and how are they inflicted?

In Chile, cow carcasses present the highest bruise prevalence compared with other cattle categories; however, the causes of the bruises are frequently unknown. In this study, 52 cull cows were transported to the slaughterhouse in three batches under identical transport conditions. A combination of direct observation and video analyses was used to determine moment, pre-slaughter stage and cause of potential bruising events during the period from loading on the farm until stunning at the slaughterhouse. After slaughter, number of bruises, location on the carcass and characteristics of the bruises were assessed. Seventy-eight bruises were observed on 37 carcasses. Fifty-two bruises were linked back to their causal event. Results showed that 46% of these bruises were a result of interactions between animal and facility, and most of them were inflicted in the stunning box, 27% of the bruises originated from animal-animal interactions and were mostly inflicted during lairage, another 27% was a result of human-animal interactions and were mostly inflicted during loading and unloading of animals. The percentages of potential bruising events resulting in a bruise were 43%, 9% and less than 1% for animal-facility, human-animal and animal-animal interactions, respectively. Most bruises on the back site were inflicted when the animal was in the stunning box (91.2%), whereas bruises on the pin site were mostly (75%) inflicted during loading at the farm. One may conclude that in relative short journeys (≤4 h) directly from farm to the slaughterhouse and long lairage times (>12 h), most bruises are the result of circumstances at the slaughterhouse. A substantial amount of these bruises could be avoided by proper animal handling and adequate stunning facilities.

On the concept of individual in ecology and evolution.

Part of the art of theory building is to construct effective basic concepts, with a large reach and yet powerful as tools for getting at conclusions. The most basic concept of population biology is that of individual. An appropriately reengineered form of this concept has become the basis for the theories of structured populations and adaptive dynamics. By appropriately delimiting individuals, followed by defining their states as well as their environment, it become possible to construct the general population equations that were introduced and studied by Odo Diekmann and his collaborators. In this essay I argue for taking the properties that led to these successes as the defining characteristics of the concept of individual, delegating the properties classically invoked by philosophers to the secondary role of possible empirical indicators for the presence of those characteristics. The essay starts with putting in place as rule for effective concept engineering that one should go for relations that can be used as basis for deductive structure building rather than for perceived ontological essence. By analysing how we want to use it in the mathematical arguments I then build up a concept of individual, first for use in population dynamical considerations and then for use in evolutionary ones. These two concepts do not coincide, and neither do they on all occasions agree with common intuition-based usage.

Daphnias: from the individual based model to the large population equation.

The class of deterministic 'Daphnia' models treated by Diekmann et al. (J Math Biol 61:277-318, 2010) has a long history going back to Nisbet and Gurney (Theor Pop Biol 23:114-135, 1983) and Diekmann et al. (Nieuw Archief voor Wiskunde 4:82-109, 1984). In this note, we formulate the individual based models (IBM) supposedly underlying those deterministic models. The models treat the interaction between a general size-structured consumer population ('Daphnia') and an unstructured resource ('algae'). The discrete, size and age-structured Daphnia population changes through births and deaths of its individuals and through their aging and growth. The birth and death rates depend on the sizes of the individuals and on the concentration of the algae. The latter is supposed to be a continuous variable with a deterministic dynamics that depends on the Daphnia population. In this model setting we prove that when the Daphnia population is large, the stochastic differential equation describing the IBM can be approximated by the delay equation featured in (Diekmann et al., loc. cit.).

Dosimetric consequences of pancreatic tumor motion when predetermined treatment margins are employed during intensity-modulated radiation therapy.

PURPOSE: To quantify the dosimetric consequences of pancreatic tumor motion on the pancreatic intensity-modulated radiation therapy (IMRT) plans. METHODS: Dose map of IMRT plans for 5 patients with pancreatic cancer were measured using a 2D diode array placed on a computer-controlled platform to simulate 2D pancreatic tumor motion. Dosimetric analysis was then performed to obtain IMRT quality assurance (QA) passing rates. The convolution method, which used a motion kernel to simulate 2D pancreatic motion, was also applied to the treatment and phantom verification plans for a wide range of magnitudes of motion (0.8-2.0 cm). The resulting motion-convolved verification dose maps (VDMs) were compared with the dynamic measurements to evaluate IMRT QA passing rates as well as the dose-volume histogram, the V95% of the planning target volume (PTV) and V98% of the clinical target volume (CTV). RESULTS: While CTV coverage was maintained when the simulated pancreatic tumor drifted inside the PTV with magnitudes of 1.0 cm and 1.5 cm, the V95% of the PTV was reduced by 10% and 17%, respectively. We also found that the differences between the measurements and the static VDMs increased proportional to the amplitude of motion, while the agreement between the measurements and the motion-convolved VDMs was excellent for any magnitude of motion. CONCLUSIONS: When the 4D technique is not available, predetermined margins must be used carefully to avoid possible under-dose to the target. Additionally, the phantom results show that the kernel convolution method provides an accurate evaluation of the dosimetric impact due to tumor motion and it should be employed in the planning process.

Characteristics of bruises in carcasses of cows sourced from farms or from livestock markets.

Bruises in cattle develop after the application of force, and they provide evidence for sub-optimal animal welfare. The aim of this study was to describe the gross characteristics of bruises in cows arriving at the slaughterhouse directly from farms or through the livestock market. The number of bruises and their distribution on the carcass as well as their severity, shape, size and colour were assessed post mortem in a slaughterhouse in Chile. A total of 258 cow carcasses were evaluated, and a total of 846 bruises were found on 243 of the carcasses. Cows that had passed through a livestock market (M-carcasses) had in total 563 bruises (mean 3.8 bruises/carcass, s.d. 2.0), whereas cows transported directly from farms (F-carcasses) had in total 283 bruises (mean 2.5 bruises/carcass, s.d. 1.8). The backs of F-carcasses had twice as many bruises as M-carcasses (32.9% and 16.2%, respectively), whereas bruises in the rib area were more frequently observed in M-carcasses (13.1%) than in F-carcasses (8.1%). Superficial bruises (grade 1) were the most frequently observed (66.2% of all bruises). Regarding the size of the bruises, 64 (7.6%) were classified as large, 271 (32.0%) as medium and 511 (60.4%) as small. Irregularly shaped bruises were the most frequent (91.1%, n = 771), followed by linear (3.8%, n = 32), circular (3.1%, n = 26) and tramline-shaped bruises (1.9%, n = 16). The latter were noticed only in M-carcasses, which may indicate that these animals were beaten more frequently with sticks or other rod-shaped objects. Fresh, bright red-coloured bruises were found more frequently on all the animals (69.5% from farms and 70.5% from market) compared with bluish (29.7% and 29.3%, respectively) and yellow bruises (0.4% and 0.2%, respectively). The method of selling was significantly associated with the number of bruises on the carcass (P < 0.001) and the anatomical site (P < 0.05), but not with the severity, shape and colour of the bruises. Increased fat coverage reduced the severity of bruises (P < 0.001). This study shows that, in Chile, market animals have more bruises than those sourced directly from farms, and their distribution is different. More information about the causes of infliction may help reduce bruises and it may also improve their welfare. Further studies are required to elucidate whether the causes of the high bruising in the case of animals passing through markets are related only to extra handling (repeated loading, unloading, transportation, eventual mixing) or to the way of handling by personnel and inadequate design.

A simple fitness proxy for structured populations with continuous traits, with case studies on the evolution of haplo-diploids and genetic dimorphisms.

For structured populations in equilibrium with everybody born equal, ln(R (0)) is a useful fitness proxy for evolutionarily steady strategy (ESS) and most adaptive dynamics calculations, with R (0) the average lifetime number of offspring in the clonal and haploid cases, and half the average lifetime number of offspring fathered or mothered for Mendelian diploids. When individuals have variable birth states, as is, for example, the case in spatial models, R (0) is itself an eigenvalue, which usually cannot be expressed explicitly in the trait vectors under consideration. In that case, Q(Y| X):=-det (I-L(Y| X)) can often be used as fitness proxy, with L the next-generation matrix for a potential mutant characterized by the trait vector Y in the (constant) environment engendered by a resident characterized by X. If the trait space is connected, global uninvadability can be determined from it. Moreover, it can be used in all the usual local calculations like the determination of evolutionarily singular trait vectors and their local invadability and attractivity. We conclude with three extended case studies demonstrating the usefulness of Q: the calculation of ESSs under haplo-diploid genetics (I), of evolutionarily steady genetic dimorphisms (ESDs) with a priori proportionality of macro- and micro-gametic outputs (an assumption that is generally made but the fulfilment of which is a priori highly exceptional) (II), and of ESDs without such proportionality (III). These case studies should also have some interest in their own right for the spelled out calculation recipes and their underlying modelling methodology.

Toxicity data for preoperative concurrent chemoradiotherapy with oxaliplatin and continuous infusion 5-fluorouracil for locally advanced esophageal cancer.

The purpose of this retrospective analysis was to characterize the feasibility and tolerability of oxaliplatin/5-fluorouracil (5-FU) given concurrently with radiotherapy for patients with locally advanced esophageal cancer. Between July 2005 and March 2009, 15 patients with clinical stage T3/T4 and/or N1/M1a lower esophageal or gastroesophageal junction adenocarcinoma were treated with preoperative chemoradiotherapy using oxaliplatin every 2 weeks and continuous infusion 5-FU. The main treatment-related toxicities were oral mucositis and dysphagia. During the first 2 weeks of treatment, 20% of patients presented with grade 1-2 oral mucositis, and one patient developed grade 1 dysphagia. In weeks 3-4, 53% of the patients experienced grade 1-2 mucositis, and 40% experienced grade 1-2 dysphagia. One patient only experienced grade 3 mucositis in week 4. Three patients (20%) had grade 3-4 dysphagia in weeks 3-4 and were continued on intravenous fluids and pain medications. During the last 2 weeks of chemoradiotherapy, 53% of patients reported grade 1-2 oral mucositis, mostly grade 1 and 73% of patients experienced grade 1-2 dysphagia and 26% patients experienced grade 3-4 dysphagia. Other toxicities included fatigue, nausea, neuropathy, and diarrhea. Only one patient experienced > 10% weight loss. The whole group was treated with aggressive supportive care during radiotherapy. Five (33%) patients achieved a pathological complete response. No patients developed locoregional failure. Sixty percent of the patients developed distant metastases and the 2-year disease-free survival was 53%. The median survival was 3.2 years with the 2-year overall survival of 73%. Preoperative oxaliplatin/5-FU-based chemoradiotherapy for locally advanced esophageal cancer is feasible, but associated with substantial gastrointestinal toxicity. A careful attention to nutrition and hydration throughout the course of therapy is required.