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Abstract Background Hypoglycaemia is the primary manifestation of all the hepatic types of glycogen storage disease (GSD). In 2008, Glycosade®, an extended-release waxy maize cornstarch, was reported as an alternative to uncooked cornstarch (UCCS) which could prolong the duration of fasting in the GSD population. To date, there has been minimal published experience in (a) young children, (b) the ketotic forms of GSD, and (c) with daytime dosing. The Glyde study was created as a prospective, global initiative to test the efficacy and tolerance of Glycosade use across a broader and more diverse population. Methods A randomised double-blind cross-over fasting study assessing the tolerance and efficacy of Glycosade compared with cornstarch was performed across disease types and ages. Participants and clinicians chose the product deemed superior, whilst still blinded. Participants were followed for 2 years to assess long-term metabolic control, growth, and quality of life. Results Sixty-one participants (age 2–62 years; 59% female) were enrolled, and 58 participants completed the fasting studies (28 GSD I; 30 GSD III, VI, IX). Glycosade improved duration of fasting in GSD I and duration of fasting without ketosis in the ketotic forms. Chronic Glycosade use was chosen by 69% of participants. Those treated with Glycosade for the 2-year chronic phase used fewer doses of therapy while markers of metabolic control remained stable. Conclusion The Glyde study is the first multi-centre international trial demonstrating the efficacy and tolerance of Glycosade in a large cohort of hepatic GSD patients across a diverse international population. The ability to use fewer doses of therapy per day and avoidance of overnight therapy may improve compliance, safety, and quality of life without sacrificing metabolic control.

Feed efficiency is a major production trait in animal genetic breeding schemes. To further investigate the genetic control of feed efficiency in rabbits, we performed a genome-wide association study (GWAS) for growth and feed efficiency on 679 rabbits genotyped with the Affimetrix Axiom Rabbit 200K Genotyping Array. After quality control, 127 847 single-nucleotide polymorphisms (SNP) were retained for association analyses. The GWAS were performed using GEMMA software, applying a mixed univariate animal model with a linear regression on each SNP allele. The traits analysed were weight at weaning and at 63 days of age, average daily gain, total individual feed intake, feed conversion ratio and residual feed intake. No significant SNP was found for growth traits or feed intake. Fifteen genome-wide significant SNPs were detected for feed conversion ratio on OCU7, spanning from 124.8 Mbp to 126.3 Mbp, plus two isolated SNP on OCU2 (77.3 Mbp) and OCU8 (16.5 Mbp). For residual feed intake, a region on OCU18 (46.1-53.0 Mbp) was detected, which contained a putative functional candidate gene, GOT1.

Abstract The aim of the Protocole National De Diagnostic et de Soins/French National Protocol for Diagnosis and Healthcare (PNDS) is to provide advice for health professionals on the optimum care provision and pathway for patients with glycogen storage disease type III (GSD III).The protocol aims at providing tools that make the diagnosis, defining the severity and different damages of the disease by detailing tests and explorations required for monitoring and diagnosis, better understanding the different aspects of the treatment, defining the modalities and organisation of the monitoring. This is a practical tool, to which health care professionals can refer. PNDS cannot, however, predict all specific cases, comorbidities, therapeutic particularities or hospital care protocols, and does not seek to serve as a substitute for the individual responsibility of the physician in front of his/her patient.

Abstract Worldwide, ecosystems are suffering important taxonomic and functional modifications in response to anthropogenic disturbances, operating at multiple spatial and temporal scales. Awareness on biodiversity losses has led to the adoption of conservation policies and the development of programs devoted to the conservation and the restoration of terrestrial, freshwater, and marine ecosystems. The assessment of the ecological health of ecosystems requires measuring and characterizing restoration or degradation dynamics and their consequences on the ecological quality with respect to reference conditions defined pragmatically as conservation targets. Methodological innovations, in terms of data collection, analysis, and visualization, have an important influence on the ability of ecologists to understand biodiversity changes. The assessment of the quality of ecosystems with respect to reference conditions requires to address, notably, three main challenges: the definition of reference conditions, the assessment of the degree of achievement of conservation objectives, and the qualitative and quantitative characterization of recovering and departing patterns. We propose here the ecological quality assessment (EQA) framework as a data‐driven approach to track ecological quality focusing on the distance of the tested stations with respect to a chosen reference envelope using fuzzy logic and trajectory analysis. We take advantage of those analytical tools to propose a general and flexible multivariate framework by quantifying the achievement of reference conditions, measuring restoration and degradation dynamics when temporal series are available, and representing and synthesizing this information. To take into account the natural spatiotemporal variability of sites considered as reference, we gave two variants to our framework: a state‐based variant when no temporal replications are available and a trajectory‐based variant specially devoted to compare whole trajectories to a trajectory reference envelope defined by a set of reference trajectories. These two complementary approaches were illustrated through two terrestrial and marine ecological applications using the R package “ecotraj” in order to evidence ecological observations that meet conservation objectives from those that do not meet them. EQA constitutes a flexible framework for the assessment and reporting of ecosystem quality, including restoration and degradation dynamics adaptable to multiple questions in the different fields of ecology and conservation.

Abstract Glucose-6-phosphatase deficiency (G6P deficiency), or glycogen storage disease type I (GSDI), is a group of inherited metabolic diseases, including types Ia and Ib, characterized by poor tolerance to fasting, growth retardation and hepatomegaly resulting from accumulation of glycogen and fat in the liver. Prevalence is unknown and annual incidence is around 1/100,000 births. GSDIa is the more frequent type, representing about 80% of GSDI patients. The disease commonly manifests, between the ages of 3 to 4 months by symptoms of hypoglycemia (tremors, seizures, cyanosis, apnea). Patients have poor tolerance to fasting, marked hepatomegaly, growth retardation (small stature and delayed puberty), generally improved by an appropriate diet, osteopenia and sometimes osteoporosis, full-cheeked round face, enlarged kydneys and platelet dysfunctions leading to frequent epistaxis. In addition, in GSDIb, neutropenia and neutrophil dysfunction are responsible for tendency towards infections, relapsing aphtous gingivostomatitis, and inflammatory bowel disease. Late complications are hepatic (adenomas with rare but possible transformation into hepatocarcinoma) and renal (glomerular hyperfiltration leading to proteinuria and sometimes to renal insufficiency). GSDI is caused by a dysfunction in the G6P system, a key step in the regulation of glycemia. The deficit concerns the catalytic subunit G6P-alpha (type Ia) which is restricted to expression in the liver, kidney and intestine, or the ubiquitously expressed G6P transporter (type Ib). Mutations in the genes G6PC (17q21) and SLC37A4 (11q23) respectively cause GSDIa and Ib. Many mutations have been identified in both genes,. Transmission is autosomal recessive. Diagnosis is based on clinical presentation, on abnormal basal values and absence of hyperglycemic response to glucagon. It can be confirmed by demonstrating a deficient activity of a G6P system component in a liver biopsy. To date, the diagnosis is most commonly confirmed by G6PC (GSDIa) or SLC37A4 (GSDIb) gene analysis, and the indications of liver biopsy to measure G6P activity are getting rarer and rarer. Differential diagnoses include the other GSDs, in particular type III (see this term). However, in GSDIII, glycemia and lactacidemia are high after a meal and low after a fast period (often with a later occurrence than that of type I). Primary liver tumors and Pepper syndrome (hepatic metastases of neuroblastoma) may be evoked but are easily ruled out through clinical and ultrasound data. Antenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villous cells. Pre-implantatory genetic diagnosis may also be discussed. Genetic counseling should be offered to patients and their families. The dietary treatment aims at avoiding hypoglycemia (frequent meals, nocturnal enteral feeding through a nasogastric tube, and later oral addition of uncooked starch) and acidosis (restricted fructose and galactose intake). Liver transplantation, performed on the basis of poor metabolic control and/or hepatocarcinoma, corrects hypoglycemia, but renal involvement may continue to progress and neutropenia is not always corrected in type Ib. Kidney transplantation can be performed in case of severe renal insufficiency. Combined liver-kidney grafts have been performed in a few cases. Prognosis is usually good: late hepatic and renal complications may occur, however, with adapted management, patients have almost normal life span. Disease name and synonyms Glucose-6-phosphatase deficiency or G6P deficiency or glycogen storage disease type I or GSDI or type I glycogenosis or Von Gierke disease or Hepatorenal glycogenosis.

The aim of the present study was to evaluate the effect of activin A on the activation of in vitro folliculogenesis of human ovarian tissues from transgender men with or without our new compartmented chitosan hydrogel microbioreactor (“three-dimensional (3D)-structure”) enabling a three-dimensional tissue culture. Five fresh ovarian human tissues were cultured in vitro for 20 or 22 days in four groups with 100 ng/mL activin A or without activin A during the last six to eight days of culture, and within a 3D-structure or without the 3D-structure in standard conditions. Follicular density and quality were evaluated, and follicular diameters were measured. Estradiol secretion was quantified. Proliferation and apoptosis through immunostaining were also performed. The proportion of primordial follicles was significantly reduced, and the proportion of primary and secondary follicles was significantly increased in all four groups (p < 0.001). Tertiary follicles were observed in the four culture groups. Activin A supplementation did not significantly affect the follicular density, follicular quality, follicular growth, or estradiol secretion (p > 0.05). The 3D-structure increased the density of primary follicles and decreased the estradiol secretion (p < 0.001). Follicular proliferation was significantly lower in the 3D-structure group compared to the non-3D-structure group (p = 0.008). Regarding follicular apoptosis, it was significantly higher in the activin group compared to the non-activin group (p = 0.006). Activin A did not seem to play a key role in the in vitro folliculogenesis activation in our culture conditions. However, the results may indicate that the 3D-structure could be more physiological and could prevent a detrimental in vitro folliculogenesis flare-up.

A new species of Apseudidae is described from a submarine canyon in the Mediterranean Sea, Leviapseudes tethys sp. nov. The species was sampled at 600 m depth on deep muddy sand. The new species is characterized by the presence of processes on both sides of the rostrum, a pinnate seta on the inner distal margin of the maxillipedal endite, smooth distal spines of the labium palp, two spines on the cheliped basis, three ventral spines on pereopod 1 basis and an unarticulated pleopod exopod. This is the second species and the third record of the genus in the Mediterranean Sea, and raises the number of tanaid species known from the deep Mediterranean Sea to a total of 16. The diagnosis of the genus is amended in light of the new data and re-evaluation of previous works. The new species presents a set of characters that provide novel insights to understanding the diversity and taxonomy of the Leviapseudinae, as well as their geographic distribution. Finally, a list of all deep-sea Tanaidacea known in the Mediterranean Sea is provided.

BackgroundSteroidogenic factor 1 (SF-1), encoded by the nuclear receptor subfamily 5 group A member 1 (NR5A1) gene, is a transcriptional factor crucial for adrenal and gonadal organogenesis. Pathogenic variants of NR5A1 are responsible for a wide spectrum of phenotypes with autosomal dominant inheritance including disorders of sex development and oligospermia–azoospermia in 46,XY adults. Preservation of fertility remains challenging in these patients.ObjectiveThe aim was to offer fertility preservation at the end of puberty in an NR5A1 mutated patient.Case reportThe patient was born of non-consanguineous parents, with a disorder of sex development, a small genital bud, perineal hypospadias, and gonads in the left labioscrotal fold and the right inguinal region. Neither uterus nor vagina was detected. The karyotype was 46,XY. Anti-Müllerian hormone (AMH) and testosterone levels were low, indicating testicular dysgenesis. The child was raised as a boy. At 9 years old, he presented with precocious puberty treated by triptorelin. At puberty, follicle-stimulating hormone (FSH), luteinising hormone (LH), and testosterone levels increased, whereas AMH, inhibin B, and testicular volume were low, suggesting an impaired Sertoli cell function and a partially preserved Leydig cell function. A genetic study performed at almost 15 years old identified the new frameshift variant NM_004959.5: c.207del p.(Phe70Serfs*5) at a heterozygous state. He was thus addressed for fertility preservation. No sperm cells could be retrieved from three semen collections between the ages of 16 years 4 months and 16 years 10 months. A conventional bilateral testicular biopsy and testicular sperm extraction were performed at 17 years 10 months of age, but no sperm cells were found. Histological analysis revealed an aspect of mosaicism with seminiferous tubules that were either atrophic, with Sertoli cells only, or presenting an arrest of spermatogenesis at the spermatocyte stage.ConclusionWe report a case with a new NR5A1 variant. The fertility preservation protocol proposed at the end of puberty did not allow any sperm retrieval for future parenthood.

Abstract Background Feed efficiency is a major driver of the sustainability of pig production systems. Understanding the biological mechanisms that underlie these agronomic traits is an important issue for environment questions and farms' economy. This study aimed at identifying genomic regions that affect residual feed intake (RFI) and other production traits in two pig lines divergently selected for RFI during nine generations (LRFI, low RFI; HRFI, high RFI). Results We built a whole dataset of 570,447 single nucleotide polymorphisms (SNPs) in 2426 pigs with records for 24 production traits after both imputation and prediction of genotypes using pedigree information. Genome-wide association studies (GWAS) were performed including both lines (global-GWAS) or each line independently (LRFI-GWAS and HRFI-GWAS). Forty-five chromosomal regions were detected in the global-GWAS, whereas 28 and 42 regions were detected in the HRFI-GWAS and LRFI-GWAS, respectively. Among these 45 regions, only 13 were shared between at least two analyses, and only one was common between the three GWAS but it affects different traits. Among the five quantitative trait loci (QTL) detected for RFI, two were close to QTL for meat quality traits and two pinpointed novel genomic regions that harbor candidate genes involved in cell proliferation and differentiation processes of gastrointestinal tissues or in lipid metabolism-related signaling pathways. In most cases, different QTL regions were detected between the three designs, which suggests a strong impact of the dataset structure on the detection power and could be due to the changes in allelic frequencies during the establishment of lines. Conclusions In addition to efficiently detecting known and new QTL regions for feed efficiency, the combination of GWAS carried out per line or simultaneously using all individuals highlighted chromosomal regions that affect production traits and presented significant changes in allelic frequencies across generations. Further analyses are needed to estimate whether these regions correspond to traces of selection or result from genetic drift.

Classic galactosemia is a rare inborn error of galactose metabolism with a birth prevalence of about 1/30,000–60,000. Long-term complications occurring despite dietary treatment consist of premature ovarian insufficiency (POI) and neurodevelop mental impairments. We performed with the French Reference Centers for Rare Diseases a multisite collaborative questionnaire survey for classic galactosemic patients. Its primary objective was to assess their puberty, pregnancy, gonadotropic axis, and pelvic morphology by ultrasound. The secondary objective was to determine predictive factors for pregnancy without oocyte donation. Completed questionnaires from 103 patients, 56 female s (median age, 19 years (3–52 years)) and 47 males (median age, 19 years (3–45 years)), were analyzed. Among the 43 females older than 13 years old, mean age for breast develop ment first stage was 13.8 years; spontaneous menarche occurred in 21/31 females at a mean age of 14.6 years. In these 21 women, 62% had spaniomenorrhea and 7/17 older than 30 years had amenorrhea. All age-groups confounded, FSH was above refere nce range for 65.7% of the patients, anti-Müllerian hormone and inhibin B were undetectable, and the ovaries were small with few or no follicles detected. Among the 5 females who sought to conceive, 4 had pregnancies. Among the 47 males, 1 had cryptorchidism, al l have normal testicular function and none had a desire to conceive children. Thus, spontaneous puberty and POI are both common in this population. Spontaneous menarche se ems to be the best predictive factor for successful spontaneous pregnancy.

Early experiences, including prenatal environment, are known to influence a wide variety of mechanisms involved in the phenotype elaboration. We investigated the effect of the addition of endocrine disruptors or of a methyltransferase inhibitor during the embryonic development of quails from different genetic backgrounds (four different quail lines) on their growth and egg-laying performances. Fifty-four pairs of parents per line were used and fertilised eggs from each pair were randomly divided into five groups: a control group without any injection, an injected control group treated by injection into the egg of sesame oil, and three groups treated by injection of Genistein, Bisphenol A or 5-Aza-2′-deoxycytidine. All quails were individually weighed at 8, 21, 36 and 78 days. The age at first egg laid and the number of eggs laid were recorded. These analyses revealed a significant impact of the treatment on growth but no influence on the egg-laying traits. All three molecules significantly affected at least one of the analysed growth traits. In conclusion, we showed that the injection of endocrine disruptors or DNA methyltransferase inhibitor into the egg had significant effects on quail development; these effects were specific to each treatment, but no interaction between line and treatment was observed.

Abstract Background Most genomic predictions use a unique population that is split into a training and a validation set. However, genomic prediction using genetically heterogeneous training sets could provide more flexibility when constructing the training sets in small populations. The aim of our study was to investigate the potential of genomic prediction of feed efficiency related traits using training sets that combine animals from two different, but genetically-related lines. We compared realized prediction accuracy and prediction bias for different training set compositions for five production traits. Results Genomic breeding values (GEBV) were predicted using the single-step genomic best linear unbiased prediction method in six scenarios applied iteratively to two genetically-related lines (i.e. 12 scenarios). The objective for all scenarios was to predict GEBV of pigs in the last three generations (~ 400 pigs, G7 to G9) of a given line. For each line, a control scenario was set up with a training set that included only animals from that line (target line). For all traits, adding more animals from the other line to the training set did not increase prediction accuracy compared to the control scenario. A small decrease in prediction accuracies was found for average daily gain, backfat thickness, and daily feed intake as the number of animals from the target line decreased in the training set. Including more animals from the other line did not decrease prediction accuracy for feed conversion ratio and residual feed intake, which were both highly affected by selection within lines. However, prediction biases were systematic for these cases and might be reduced with bivariate analyses. Conclusions Our results show that genomic prediction using a training set that includes animals from genetically-related lines can be as accurate as genomic prediction using a training set from the target population. With combined reference sets, accuracy increased for traits that were highly affected by selection. Our results provide insights into the design of reference populations, especially to initiate genomic selection in small-sized lines, for which the number of historical samples is small and that are developed simultaneously. This applies especially to poultry and pig breeding and to other crossbreeding schemes.

Abstract Glycogen storage disease type Ia (GSD Ia) is a rare metabolic disease due to glucose‐6‐phosphatase deficiency. Chronic kidney disease is a frequent complication that may manifest itself by glomerular lesions and tubular dysfunction from the second decade of life. We report two young GSDIa patients with malignant renal tumor. The first patient was a 25‐year‐old man. He had chronic metabolic imbalance without kidney involvement. The tumor, a type 2 papillary renal carcinoma, was accidentally discovered during follow‐up. The second patient was a 27‐year‐old woman with chronic metabolic imbalance and chronic kidney involvement. The tumor, a grade 2 papillary carcinoma, was accidentally discovered during follow‐up. These two observations are, to date, the first to be reported. We suggest that annual monitoring of kidney imaging in GSDI patients should be systematic to detect renal cancer, from the second decade of life.

Abstract Purpose The purpose of this work was to construct shallow neural networks (SNN) using time‐lapse technology (TLT) from morphokinetic parameters coupled to assisted reproductive technology (ART) parameters in order to assist the choice of embryo(s) to be transferred with the highest probability of achieving a live birth (LB). Methods A retrospective observational single‐center study was performed, 654 cycles were included. Three SNN: multilayers perceptron (MLP), simple recurrent neuronal network (simple RNN) and long short term memory RNN (LSTM‐RNN) were trained with K‐fold cross‐validation to avoid sampling bias. The predictive power of SNNs was measured using performance scores as AUC (area under curve), accuracy, precision, Recall and F1 score. Results In the training data group, MLP and simple RNN provide the best performance scores; however, all AUCs were above 0.8. In the validating data group, all networks were equivalent with no performance scores difference and all AUC values were above 0.8. Conclusion Coupling morphokinetic parameters with ART parameters allows to SNNs to predict the probability of LB, and all SNNs seems to be efficient according to the performance scores. An automatic time recognition system coupled to one of these SNNs could allow a complete automation to choose the blastocyst(s) to be transferred.

Biological invasions are one of the main global threats to biodiversity in terrestrial, freshwater and marine ecosystems worldwide, requiring effective inventorying and monitoring programs. Here, we present an updated list of non-indigenous species in French marine and transitional waters. Focused on eukaryote pluricellular species found throughout the three metropolitan French marine regions (Western Mediterranean Sea, Bay of Biscay and the Northern Seas), a total of 342 non-indigenous, including 42 cryptogenic, species are listed as having been introduced since the 13th century. The majority of the species originated from the temperate Northern Pacific. They mainly arrived through both ballast and hull fouling and also are associated with shellfish farming activities. Most of them have been introduced since the 1970s, a time when maritime and aquaculture trade intensified. Despite important human-aided opportunities for species transfer between the three marine regions (for instance, via recreational boating or aquaculture transfers), only a third of these NIS are common to all regions, as expected due to their environmental specificities.

This paper is the conclusion of the “Spaghetti Project” aiming to revise French species of Terebellidae sensu lato (s.l.) belonging to the five families: Polycirridae, Telothelepodidae, Terebellidae sensu stricto (s.s.), Thelepodidae and Trichobranchidae. During this project, 41 species were observed, 31 of them new for science: eight species of Polycirridae, eleven species of Terebellidae s.s., three species of Thelepodidae and nine species of Trichobranchidae. We provide a comprehensive key for all European species of terebellids with a focus on the important diagnostic characters for each family. Finally, we discuss issues on taxonomy, biodiversity and cryptic and pseudo-cryptic species of polychaetes in European waters, based on results obtained during this project.

This article studies the history of the rivalry between Corneille’s Tite et Bérénice and Racine’s Bérénice. This rivalry can be analysed in three steps, each of which is extremely paradoxical. In the seventeenth century, it was first presented as a “duel” by Corneille’s own nephew, Fontenelle, even though there was never a dispute as such between the two authors. During the eighteenth and the nineteen centuries, critics praised Racine’s Bérénice when they compared it to Corneille’s play, but criticized the former when they studied it in itself. Finally, ever since Charles Péguy asked for a re-evaluation of Tite et Bérénice at the beginning of the twentieth century, Corneille’s play’s merits have been clearly recognized. Howewer, it should be kept in mind that Racine’s Bérénice remains the most famous of the two. One cannot but wonder if Tite and Bérénice’s re-evaluation, ironically, does not contribute to its devaluation when compared to Bérénice.

Background and Objectives: To test the long-term ability of human ovarian cortex cells to develop in unconventional culture conditions. Materials and Methods. Ovarian cortex cells from fetuses aged 23 to 39 weeks gestation were cultured for 90 days in hollow chitosan hydrogel micro-bioreactors and concurrently in traditional wells. Various cell-type counts were considered. Results: With intact follicles as a denominator, the percentage of growing intact follicles at Day 0 varied widely between ovaries (0 to 31.7%). This percentage tended to increase or stay relatively constant in bioreactor as in control cultures; it tended more toward an increase over time in bioreactor vs. control cultures. Modeled percentages showed differences (though not significant) in favor of bioreactor cultures (16.12% difference at D50 but only 0.12% difference at D90). With all follicles present as a denominator, the percentage of growing primary and secondary follicles at D0 varied widely between ovaries (0 to 29.3%). This percentage tended to increase over time in bioreactor cultures but to decrease in control cultures. Modeled percentages showed significant differences in favor of bioreactor cultures (8.9% difference at D50 and 11.1% difference at D90). At D50 and D90, there were only few and sparse apoptotic cells in bioreactor cultures vs. no apoptotic cells in control cultures. Conclusions: Over three months, bioreactor folliculogenesis outperformed slightly traditional culture. This is an interesting perspective for follicle preservation and long-term toxicological studies.

The rate of infertility continues to rise in the world for several reasons, including the age of conception and current lifestyle. We list in this paper potential non-invasive and invasive techniques to assess oocyte quality. We searched the database PubMed using the terms “oocytes AND quality AND evaluation”. In the first part, we study the morphological criteria, compartment by compartment, to then focus in a second part on more objective techniques such as genetics, molecular, apoptosis, or human follicular fluid that contain biologically active molecules. The main criteria used to assess oocyte quality are morphological; however, several other techniques have been studied in women to improve oocyte quality assessment, but most of them are invasive and not usable in routine.

Introduction: Obtaining in vitro mature oocytes from ovarian tissue to preserve women’s fertility is still a challenge. At present, there is a therapeutic deadlock for girls and women who need emergency fertility preservation in case of a high risk of ovary invasion by malignant cells. In such a case, ovarian tissue cannot be engrafted; an alternative could be in vitro folliculogenesis. Methods: This review focuses on the progress of in vitro folliculogenesis in humans. PubMed and Embase databases were used to search for original English-language articles. Results: The first phase of in vitro folliculogenesis is carried out in the original ovarian tissue. The addition of one (or more) initiation activator(s) is not essential but allows better yields and the use of a 3D culture system at this stage provides no added value. The second stage requires a mechanical and/or enzymatic isolation of the secondary follicles. The use of an activator and/or a 3D culture system is then necessary. Conclusion: The current results are promising but there is still a long way to go. Obtaining live births in large animals is an essential step in validating this in vitro folliculogenesis technique.

Abstract Glycogen storage disorder type III (GSDIII), or debranching enzyme (GDE) deficiency, is a rare metabolic disorder characterized by variable liver, cardiac, and skeletal muscle involvement. GSDIII manifests with liver symptoms in infancy and muscle involvement during early adulthood. Muscle biopsy is mainly performed in patients diagnosed in adulthood, as routine diagnosis relies on blood or liver GDE analysis, followed by AGL gene sequencing. The GSDIII mouse model recapitulate the clinical phenotype in humans, and a nearly full rescue of muscle function was observed in mice treated with the dual AAV vector expressing the GDE transgene. In order to characterize GSDIII muscle morphological spectrum and identify novel disease markers and pathways, we performed a large international multicentric morphological study on 30 muscle biopsies from GSDIII patients. Autophagy flux studies were performed in human muscle biopsies and muscles from GSDIII mice. The human muscle biopsies revealed a typical and constant vacuolar myopathy, characterized by multiple and variably sized vacuoles filled with PAS-positive material. Using electron microscopy, we confirmed the presence of large non-membrane bound sarcoplasmic deposits of normally structured glycogen as well as smaller rounded sac structures lined by a continuous double membrane containing only glycogen, corresponding to autophagosomes. A consistent SQSTM1/p62 decrease and beclin-1 increase in human muscle biopsies suggested an enhanced autophagy. Consistent with this, an increase in the lipidated form of LC3, LC3II was found in patients compared to controls. A decrease in SQSTM1/p62 was also found in the GSDIII mouse model. In conclusion, we characterized the morphological phenotype in GSDIII muscle and demonstrated dysfunctional autophagy in GSDIII human samples. These findings suggest that autophagic modulation combined with gene therapy might be considered as a novel treatment for GSDIII.

Abstract Marine ecosystems worldwide are affected by both natural variation and human activities; to disentangle and understand their individual role in influencing the macrobenthic community composition is challenging. The relationship between interannual variability in atmospheric circulation, dictated by the climatic oscillation indices, and the benthic macrofauna composition was assessed at four sampling sites located in the Bay of Banyuls‐sur‐Mer (NW Mediterranean Sea). Between 2004 and 2013, these sites were sampled annually during autumn/winter and analyzed for sediment grain‐size and benthic macrofauna composition (species richness, abundance, and biomass). Temporal changes in these descriptors were correlated with two climatic indices (NAO and WeMO indices) and a set of environmental parameters integrated over three different time periods (i.e., whole year, springtime, and wintertime). Our results confirm the occurrence of major temporal changes in the composition of macrobenthic communities within the Gulf of Lions. More specifically, the results indicate that (a) the WeMO appears to be more closely related to benthic macrofauna composition in the Bay of Banyuls‐sur‐Mer than the NAO, (b) winter is a better integration period than spring or the whole year as a proxy for community composition changes, and (c) Rhône River water flow is likely involved in the control of benthic macrofauna composition in the whole Gulf of Lions. The present study highlights the importance of WeMO as a regional proxy, which can be used to evaluate changes in benthic macrofauna linked to climatic variability.

Abstract Background Classic galactosemia is a rare inborn error of carbohydrate metabolism, caused by a severe deficiency of the enzyme galactose-1-phosphate uridylyltransferase (GALT). A galactose-restricted diet has proven to be very effective to treat the neonatal life-threatening manifestations and has been the cornerstone of treatment for this severe disease. However, burdensome complications occur despite a lifelong diet. For rare diseases, a patient disease specific registry is fundamental to monitor the lifespan pathology and to evaluate the safety and efficacy of potential therapies. In 2014, the international Galactosemias Network (GalNet) developed a web-based patient registry for this disease, the GalNet Registry. The aim was to delineate the natural history of classic galactosemia based on a large dataset of patients. Methods Observational data derived from 15 countries and 32 centers including 509 patients were acquired between December 2014 and July 2018. Results Most affected patients experienced neonatal manifestations (79.8%) and despite following a diet developed brain impairments (85.0%), primary ovarian insufficiency (79.7%) and a diminished bone mineral density (26.5%). Newborn screening, age at onset of dietary treatment, strictness of the galactose-restricted diet, p.Gln188Arg mutation and GALT enzyme activity influenced the clinical picture. Detection by newborn screening and commencement of diet in the first week of life were associated with a more favorable outcome. A homozygous p.Gln188Arg mutation, GALT enzyme activity of ≤ 1% and strict galactose restriction were associated with a less favorable outcome. Conclusion This study describes the natural history of classic galactosemia based on the hitherto largest data set.

A new species of Terebellidae, Pista colini sp. n., has been identified from the harbour of Banyuls-sur-Mer, north-western Mediterranean Sea. This new species was found in very high densities, exclusively in gravelly sand deposited manually, and was not found in the original source habitat of the gravel. This species is characterized by the colour of the ventral shields with pinkish anterior part and a blood red posterior part in live specimens, a pair of unequal-sized plumose branchiae inserted on segment II and anterior thoracic neuropodia with long-handled uncini. The presence of long-handled uncini even in the smallest specimens constitutes the major difference between Pista colini sp. n. and other Pista species with a single pair of branchiae such as P. lornensis and P. bansei.

This paper addresses the issue of word-initial rhotic avoidance (WIRA) from a typological point of view. Its first aim is to document WIRA cross-linguistically, based on the examination of a sample of 200 languages designed by the WALS (Dryer and Haspelmath 2013). This set of 200 languages has been surveyed in order to reveal rhotic (and more generally liquid) phonotactic patterns in relation to word-initial avoidance. On the basis of this survey, the paper identifies two types of WIRA: i) phonological, or emic-WIRA; and ii) phonetic, or etic-WIRA. The first and most notable result of this research is that 49% of all languages containing at least one phonemic rhotic exhibit some degree of emic-WIRA, i.e, they possess no word or very few words beginning phonologically with at least one of their rhotics in their native lexicon. The paper also examines how word-initial rhotics are adapted from a non-WIRA language into a WIRA language. The loanword adaptation data suggest that WIRA is a recessive feature because no language in the sample has been observed to develop WIRA due to language contact (although one exception, Gascon, has been identified outside of the 200-language sample). Finally, the paper proposes two new universals in relation to WIRA: 1) if a language forbids /l/ word-initially, it also forbids /r/; 2) a rhotic segment never occurs as the positional allophone of a non-liquid segment word-initially.

Background Despite prolonged tumor response to immune checkpoint inhibitors (ICIs) for a subset of patients with advanced non-small cell lung cancer (NSCLC), a secondary resistance will occur for a majority of these patients. The understanding of late progression mechanisms with ICIs is important to improve future treatment strategies.Methods We performed whole-exome sequencing (WES) on circulating tumor DNA and compared molecular profiles between the beginning of ICI treatment and tumor progression in patients with advanced NSCLC treated with ICIs and who had initial and prolonged tumor response with secondary progression, after at least 6 months of treatment.Results We identified eight patients who experienced initial and durable tumor response, and secondary tumor progression after 6 months of treatment, with available paired blood samples (diagnosis and progression). All had lung adenocarcinoma, three had programmed-death ligand-1 expression ≥50% in immunohistochemistry and all presented low blood tumor mutational burden (bTMB). Seven patients received nivolumab in second-line or more, and one received pembrolizumab as first-line treatment. WES at progression showed clonal selection with molecular alterations of Wnt pathway-related genes, increase of copy number aberrations in cancer-related genes and loss of tumor-suppressor genes (such as PTEN) or of genes associated with immune response (such as B2M). No difference in term of bTMB was observed at progression.Conclusions This is the first study describing putative molecular mechanisms associated with late progression under ICI in lung cancer. Studies on treatment strategies adapted to these mechanisms are needed.

Glycogenosis type Ib (GSD1B) causes not only hypoglycemia but also infections and “Crohn's disease like” inflammatory bowel disease (IBD) that can significantly impair patient's quality of life. We retrospectively evaluated infectious and digestive complications in 9 French patients (3 girls, 6 boys) diagnosed at 0.8 years on average, with a mean follow-up of 19.1 years. Infections occurred earlier than IBD, at mean ages of 1.7 and 3.8 years, respectively. The number of acute hospitalizations was 0.7/year due to infectious (0.4/year) or digestive symptoms (0.4/year). Clinical presentations allowed separating patients into mild (n = 5) and severe (n = 4) intestinal involvement. Patients in the severe group had more serious digestive symptoms but also earlier neutropenia (median 0.3 vs. 1.5 years, p =0 .046) with a tendency to a lower neutrophil count (NC) during follow-up, and a higher number of acute hospitalizations (median 1.3/year vs. 0.2/year, p =0 .014) due to digestive symptoms (median 0.6/year vs. 0.05/year, p = 0,012) and infections (median 0.8/year vs. 0.2/year, p =0 .014). Treatments included G-CSF and cotrimoxazole (n = 7), 5-aminosalicylic acid (n = 2), and a polymeric solution enriched in the anti-inflammatory cytokine TGF-β (n = 4, “severe” group), and immunomodulatory treatment (n = 1). In conclusion, infections and IBD are rare but severe complications in GSD1B. Neutropenia tended to be more prevalent in the severe IBD group than in the mild IBD group. Dietetic treatment with specific anti-inflammatory solutions seems particularly appropriate in these patients.

Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.

Realistic assessments of the ecological status of benthic habitats, as requested by European directives such as the Water Framework Directive and the European Marine Strategy Framework Directive, require biotic indices capable of detecting anthropogenic impact without having preliminary knowledge of the occurring pressures. In this context, a new general-purpose biotic index (GPBI) based on the deviation of benthic macrofauna community composition and structure from a valid reference (i.e., good ecological status) is proposed. GPBI is based on the assumption that as a site becomes impacted by a pressure, the most sensitive species are the first to disappear, and that stronger impacts lead to more important losses. Thus, it explicitly uses the within-species loss of individuals in the tested station in comparison to one or several reference stations as the basis of ecological status assessment. In this study, GPBI is successfully used in four case studies considering the impact of diversified pressures on benthic fauna: (1) maerl extraction in the northern Bay of Biscay, (2–3) dredging and trawling in the North Sea, and (4) hypoxic events at the seafloor in the Gullmarfjord. Our results show that GPBI was able to efficiently detect the impact of the different physical disturbances as well as that of hypoxia and that it performs better than commonly used pressure-specific indices (M-AMBI and TDI). Signal detection theory was used to propose a sound good/moderate ecological quality status boundary, and recommendations for future monitoring are also provided based on the reported performance of GPBI.

INTRODUCTION:Patients with advanced non-small cell lung cancer (NSCLC) are most of the time treated with a first-line cytotoxic chemotherapy. Tobacco use is responsible for 90% of lung cancer. The aim of this study was to evaluate the impact of smoking continuation during first-line chemotherapy on tumor response in advanced-stage NSCLC. MATERIALS AND METHODS:All patients with an advanced-stage NSCLC (IIIb or IV), treated with first-line platinum-based chemotherapy in our Department between June 2013 and July 2017 were included. Smoking status was assessed at inclusion by self-report, then at the tumor assessment consultation after 2 months of treatment, by both self-report and plasmatic cotinine measurement. Chemotherapy response, progression-free survival (PFS), overall survival (OS) and stage 3-4 toxicity were registered. RESULTS:Ninety-seven patients were included: 8 (8%) declared to be non-smokers, 56 (58%) current smokers and 33 (34%) former smokers at diagnosis. At the first tumor evaluation, 24 (25%) self-reported as active smokers and 73 (75%) as non-smokers; overall response rate (ORR) was respectively 38% and 48% (p = 0.373). Fifty-four patients had a plasmatic cotinine evaluation at the first tumor evaluation. Seventeen patients (32%) had a positive cotinine rate (median 108ng/mL, IQR 31-236). Six patients (35%) had positive cotinine rate whereas declaring to be non-smokers at the first tumor evaluation. ORR was 18% in case of positive cotinine rate, and 57% when negative (p = 0.007). Regardless of the method for smoking status evaluation, PFS, OS and grade 3-4 toxicities were similar between smoker and non-smoker patients at the first tumor evaluation. CONCLUSION:Smoking continuation during platinum-based chemotherapy, reflected by positive plasma cotinine rate, was associated with a poor ORR.