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BackgroundSmall-for-gestational-age (SGA) fetuses are at increased risk of mortality and morbidity, and less than 30% will be detected by any ultrasound scan within 4 weeks before delivery. Our aim was to evaluate the relationship between neutrophil/lymphocyte ratio (NLR) in the first trimester of pregnancy and SGA fetuses.MethodWe performed a prospective study between June 2021 and August 2022, to evaluate the relationship between the neutrophil to lymphocyte ratio in maternal blood in the first trimester of pregnancy, with the birth of an SGA fetus. One hundred ninety-four participants with singleton pregnancies between 11 + 1 and 13 + 6 weeks of gestation were recruited. Pregnancies affected with diagnosed fetal chromosomal abnormalities, or chronic pathologies were excluded. SGA was defined as birthweight less than the 10th centile (N = 42) and severe SGA as birthweight less than the 3rd centile for gestation (N = 10) according to a locally derived descriptive charts. The NLR value measured in the first trimester was compared between these two groups and controls.ResultsWe found no statistically significant difference in NLR, (3.5 +/−1.2 vs. 3.4+/−1.2, p-value of 0.78) when comparing the SGA less than the 10th centile group to the control group. NLR was also not different between severe SGA and controls (3.6+/−1.4 vs. 3.4+/−1.2 p-value of 0.78).ConclusionWe found no association between first-trimester NLR ratio and SGA.

Endometriosis, traditionally associated with cisgender women, should be recognized as a significant issue for transgender men. This perspective highlights the need to address the unique experiences and challenges faced by transgender men with endometriosis. Diagnostic difficulties arise due to hormone therapy and surgical interventions, which can alter symptoms. Limited research in transgender men undergoing hysterectomy further complicates the understanding of endometriosis in this population. Healthcare providers must be aware of these challenges and adapt the diagnostic approaches accordingly. Education and inclusive care are essential to ensure timely and appropriate management of endometriosis in transgender men, ultimately improving their quality of life.

IntroductionLymph node status is a major prognostic factor in early-stage cervical cancer. Predicting the risk of lymph node metastasis is essential for optimal therapeutic management. The aim of the study was to develop a web-based application to predict the risk of lymph node metastasis in patients with early-stage (IA1 with positive lymph vascular space invasion, IA2 and IB1) cervical cancer.Materials and methodsWe performed a secondary analysis of data from two prospective multicenter trials, Senticol 1 and 2 pooled together in the training dataset. The histological risk factors were included in a multivariate logistic regression model in order to determine the most suitable prediction model. An internal validation of the chosen prediction model was then carried out by a cross validation of the ‘leave one out cross validation’ type. The prediction model was implemented in an interactive online application of the ‘Shinyapp’ type. Finally, an external validation was performed with a retrospective cohort from L’Hôtel-Dieu de Québec in Canada.ResultsThree hundred twenty-one patients participating in Senticol 1 and 2 were included in our training analysis. Among these patients, 280 did not present lymph node invasion (87.2%), 13 presented isolated tumor cells (4%), 11 presented micrometastases (3.4%) and 17 macrometastases (5.3%). Tumor size, presence of lymph-vascular space invasion and stromal invasion were included in the prediction model. The Receiver Operating Characteristic (ROC) Curve from this model had an area under the curve (AUC) of 0.79 (95% CI [0.69– 0.90]). The AUC from the cross validation was 0.65. The external validation on the Canadian cohort confirmed a good discrimination of the model with an AUC of 0.83.DiscussionThis is the first study of a prediction score for lymph node involvement in early-stage cervical cancer that includes internal and external validation. The web application is a simple, practical, and modern method of using this prediction score to assist in clinical management.

Abstract Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9–9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0–7.0] and diabetes [aOR2.2, 95% CI 1.1–4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.

Papillary neoplasms are a distinct assemblage of breast lesions whose main characteristic is the presence of fibrovascular cores which are surrounded by epithelial cells. Papillary lesions are of heterogenous nature, with similar clinical behavior and histomorphologic characteristics. Their biological patterns, however, can be quite different. According to the World Health Organization (WHO) (2019), breast tumors have been recently classified into five subdivisions of papillary neoplasms. They are namely: intraductal papilloma, papillary ductal carcinoma in situ, encapsulated papillary carcinoma (EPC), solid-papillary carcinoma and invasive papillary carcinoma. Despite the papillary architecture being easily recognized, histological variations are diagnostically challenging. The presence or absence of myoepithelial cells in the papillary cores can distinguish the malignant from the benign lesions respectively. EPC is a rare, histologically unique carcinoma type whose main characteristic is a thick fibrous capsule at the periphery and a prolific cell structure with fibrovascular stalk support. A characteristic feature is the absence of myoepithelial cells at the surrounding thick fibrous capsule. Usually, EPC maintains a slowly developing tumor despite the absence of myoepithelial cells. An EPC case presents diagnostic difficulties since it bears close resemblance to malignant and benign papillary breast lesions. Upon a clinical and radiological evaluation, EPC commonly appears as a benign lump. In mammography, the tumor is frequently found in a retroareolar position as a well-defined mass. On the other hand, in an ultrasound, the tumor will appear as a cystic lesion characterized by solid components. The clinical picture of EPC is usually an asymptomatic benign mass which at times can be felt through auto-palpation or screening mammography. A bloody nipple discharge is regarded as a common symptom. We report a case of an EPC of a 81-year-old woman who presented with a mass in the left breast.

Angiogenesis plays a pivotal role in implantation and development of ectopic endometrial lesions. Thus, the potential usefulness of anti-angiogenic therapies has been speculated. Several reports describe their usefulness in animal models. Nonetheless this therapy has not been tested on humans yet. Here we report the outcome of a patient treated for a severe endometriosis with Bevacizumab (Avastin®), a monoclonal antibody directed against the vascular endothelial growth (VEGF). After a first-look laparoscopy with confirmatory biopsies was performed, three doses of Bevacizumab at 2-week intervals were administered. The therapy showed a well-tolerated profile and the prompt disappearance of the therapy-refractory chronic dysmenorrhea. A suppression of metabolic activity at the PET-scan compared to the basal one performed at diagnosis was also recorded. Furthermore, compared to the diagnostic biopsies prior the treatment, we documented a shift in the hormonal receptors profile toward a higher expression of progesterone and estrogen receptors in the endometriotic lesions.

Since the emergence of a novel coronavirus in China at the end of December 2019, its infection - COVID-19 - has been associated with high morbidity and mortality and has left healthcare systems wrestling with the optimal management strategy, especially for vulnerable populations, such as pregnant women. At this moment, few resources exist to guide the multi-disciplinary team through decisions regarding optimal maternal-fetal treatment and delivery timing. In this article, we present the drugs and vaccines under investigation as potential treatments and prevention for COVID-19 infection. Based on a comprehensive evaluation, we prioritized these possible treatments, and provide dose-response and dose-toxicity information on each drug. Currently, there is limited but very increasing reassuring information concerning vaccines to prevent SARS-CoV-2 during pregnancy, and in this review, we also emphasize the results (mostly positive) provided by the few small trials evaluating COVID-19 vaccines in pregnant patients.

Medical treatments for endometriosis aim to control pain symptoms and stop progression of endometriotic lesions. However, their adverse effects and their contraceptive effect in women who desire pregnancy, limit their long terms use. Although there is only one study investigating the effects of metformin on women with endometriosis, metformin seems to have a unique therapeutic potential. It may be a helpful anti-inflammatory and antiproliferative agent in the treatment of endometriosis. As such metformin may be more beneficial thanks to the lack of serious side effects.

Uterine rupture is a rare event which can have severe obstetric consequences and most often occurs on a scarred uterus at the site of the scar. However, a uterine rupture can appear at another location. We report the case of a woman with a previous emergency caesarean section for spontaneous posterior uterine rupture which recurred at another site during her second pregnancy. She was admitted to the emergency room with acute abdominal pain and development of a pre-shock hemorrhagic state. Abdominal ultrasound showed abundant peritoneal fluid and a fetus without cardiac activity in an intact bulging amniotic fluid membrane. We performed an emergency laparotomy, which confirmed an intact amniotic sac in the abdominal cavity and showed a 7 cm transverse fundal uterine rupture beginning at the right angle, distant from the old known scars. In view of the high maternal and fetal morbidity, obstetricians should have a high suspicion of an antepartum uterine rupture, even at an early gestational age, in the event of acute abdominal pain over a scarred uterus.

Klinefelter syndrome (KS), with an incidence between 1/600 and 1/1,000, is the main genetic cause of male infertility. Due to the lack of an accurate study model, the detailed pathogenic mechanisms by which this X chromosome aneuploidy leads to KS features remain unknown. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) derived from a patient with KS: 47XXY-iPSCs. In order to compare the potentials of both 47XXY-iPSCs and 46XY-iPSCs to differentiate into the germ cell lineage, we developed a directed differentiation protocol by testing different combinations of factors including bone morphogenetic protein 4 (BMP4), glial-derived neurotrophic factor (GDNF), retinoic acid (RA) and stem cell factor (SCF) for 42 days. Importantly, we found a reduced ability of 47XXY-iPSCs to differentiate into germ cells when compared to 46XY-iPSCs. In particular, upon germ cell differentiation of 47XXY-iPSCs, we found a reduced proportion of cells positive for BOLL, a protein required for germ cell development and spermatogenesis, as well as a reduced proportion of cells positive for MAGEA4, a spermatogonia marker. This reduced ability to generate germ cells was not associated with a decrease of proliferation of 47XXY-iPSC-derived cells but rather with an increase of cell death upon germ cell differentiation as revealed by an increase of LDH release and of capase-3 expression in 47XXY-iPSC-derived cells. Our study supports the idea that 47XXY-iPSCs provides an excellent in vitro model to unravel the pathophysiology and to design potential treatments for KS patients.

Turner syndrome, caused by partial or complete loss of one copy of X-chromosome (45,X), is the most common sex chromosome abnormality in women with an incidence of 1 in 2500 female births. Here, we report the generation and characterization of induced pluripotent stem cells (iPSCs) carrying X-monosomy anomaly, with isogenic control iPSCs. Among the iPSC lines generated from 46XX-fibroblasts, one spontaneously lost a copy of X-chromosome following the reprogramming process, establishing the 45X-iPSC line.

Vulvar varicose veins (VVs) are seen in 4% of women, most of them secondary to pregnancy and usually regressing spontaneously. The treatment of choice during pregnancy is conservative and symptomatic. Management of vulvar varicosities in non-pregnant women consists of various techniques, including phlebectomy, endovascular embolization or surgical ligation of contributing veins, sclerotherapy and, recently, conservative treatment with the venoactive agent MPFF (micronized purified flavonoid fraction). We report an unusual case of a large hematoma of the right labium majus following bilateral vulvar phlebectomy and embolization of the left ovarian vein. The patient was a non-pregnant woman, who underwent incision and drainage of this rare complication. At follow-up almost a year after this procedure the patient reported comfort and cosmetic satisfaction regarding her vulvar symptoms. A multidisciplinary team approach to vulvar varicosities is important, with the involvement of gynecologists, angiologists, interventional radiologists and vascular surgeons.

Endometriosis is a curious pathology that has been the topic of many international publications. Its etiology remains mysterious but seems to have multiple causes. It is a complex disease whose lesions are very heterogeneous in where they can occur (deep endometriosis, superficial, ovarian cyst), extent, associated symptoms, evolution or aggressiveness of the disease, and response to treatments. Furthermore, it evolves in pushes, remains autonomous, and is responsible for both superficial and deep lesions that explain its two most well know challenges: pain and infertility. It has always been classified by the size of its anatomical lesions—Acosta classification (1), revised by the American fertility society (AFS) (2), and the American society of reproductive medicine (ASRM) classification with a description of the disease at different stages: minimal (score of 1 to 5), mild (3–12), moderate (16 to 40), and severe (>40) (13). If this classification provides a complete repertoire of implants (anatomic) (10), the attribution of points is arbitrary. In fact, the size of the lesions is not synonymous with the difficulty to treat them surgically. Their location, if deep, is larger than the size of ovarian endometriomas. In addition, small anatomical but evaluative lesions will have a larger impact than big fibrous and stable lesions (Figure 1). Thus, attempts to explain their inflammatory side effects have been proposed (14, 15). The French classification nodule, ovaries, adhesions, tube, and inflammation (FOATI) (10) has had the merit of taking this phenomenon into account. In our opinion, we must go much further and propose an amendment in this classification, taking into account the evolution of the lesions and their deep molecular biology because in reality, the lesions are not at the same stage.

Endometriosis is a common, hormone-dependent gynecologic disease. Undiagnosed in large proportion of women, managing therapies depend on the impact of quality of life and includes hormonal treatment and pelvic surgery. Less likely endometriosis can occur in post-menopausal women. Malignant transformation of endometriosis is a rare but well-described process, most of time occurring in the ovary, and justifies the practitioner not to underestimate this pathology. We present a case of a 61 year old woman with a symptomatic endometriotic pelvic mass, status post hysterectomy, with no history of endometriosis diagnosed beforehand.

Induced pluripotent stem cell secretome (iPSC-CM) mitigate organ injury and help in repair. Macrophages play a critical role in tissue repair and regeneration and can be directed to promote tissue repair by iPSC-CM, although the exact mechanisms are not known. In the current investigative study, we evaluated the possible mechanism by which iPSC-CM regulates the phenotype and secretory pattern of macrophages in vitro. Macrophages were obtained from human peripheral blood mononuclear cells and differentiated to various subpopulations and treated with either iPSC-CM or control media in vitro. Macrophage phenotype was assessed by flow cytometry, gene expression changes by qRT PCR and secretory pattern by multiplex protein analysis. The protein and gene interaction network revealed the involvement of Amyloid precursor protein (APP) and ELAV-like protein 1 (ELAVL-1) both present in the iPSC-CM to play an important role in regulating the macrophage phenotype and their secretory pattern. This exploratory study reveals, in part, the possible mechanism and identifies two potential targets by which iPSC-CM regulate macrophages and help in repair and regeneration.

The authors report a case of pseudomyxoma peritonei with gelatinous peritoneum in a 47-year-old-woman. The main symptom for discovery was a chronic pelvic abdominal pain. This disease is particularly rare. The gelatinous substance is often associated with a malignant ovarian tumor or appendicitis perforated. Currently, on the whole, an exploratory laparoscopy allows diagnosis, biopsies, and appendectomy. The treatment is essentially surgical. The prognosis depends on grade (1/3) and response to chemotherapy. This case was presented to the tumor board.

Down syndrome (DS, trisomy 21), is the most common viable chromosomal disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. In this “Data in Brief” paper, we sum up the whole genome analysis by mRNA sequencing of normal and DS induced pluripotent stem cells that was recently published by Hibaoui et al. in EMBO molecular medicine.

Though the number of Vesicouterine Fistulas is steadily increasing in association with the increasing number of cesarean sections, clinical presentation can be subtle and not easily identified. In this case study, we will review the presenting symptoms of this complication and suggest an updated management protocol.

Neuronal disorders, like Huntington's disease (HD), are difficult to study, due to limited cell accessibility, late onset manifestations, and low availability of material. The establishment of an in vitro model that recapitulates features of the disease may help understanding the cellular and molecular events that trigger disease manifestations. Here, we describe the generation and characterization of a series of induced pluripotent stem (iPS) cells derived from patients with HD, including two rare homozygous genotypes and one heterozygous genotype. We used lentiviral technology to transfer key genes for inducing reprogramming. To confirm pluripotency and differentiation of iPS cells, we used PCR amplification and immunocytochemistry to measure the expression of marker genes in embryoid bodies and neurons. We also analyzed teratomas that formed in iPS cell-injected mice. We found that the length of the pathological CAG repeat did not increase during reprogramming, after long term growth in vitro, and after differentiation into neurons. In addition, we observed no differences between normal and mutant genotypes in reprogramming, growth rate, caspase activation or neuronal differentiation. However, we observed a significant increase in lysosomal activity in HD-iPS cells compared to control iPS cells, both during self-renewal and in iPS-derived neurons.In conclusion, we have established stable HD-iPS cell lines that can be used for investigating disease mechanisms that underlie HD. The CAG stability and lysosomal activity represent novel observations in HD-iPS cells. In the future, these cells may provide the basis for a powerful platform for drug screening and target identification in HD.

Down syndrome (DS) caused by a trisomy of chromosome 21 (HSA21), is the most common genetic developmental disorder, with an incidence of 1 in 800 live births. Its phenotypic characteristics include intellectual impairment, early onset of Alzheimer’s disease, congenital heart disease, hypotonia, muscle weakness and several other developmental abnormalities, for the majority of which the pathogenetic mechanisms remain unknown. Among the numerous protein coding genes of HSA21, dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A) encodes a proline-directed serine/threonine and tyrosine kinase that plays pleiotropic roles in neurodevelopment in both physiological and pathological conditions. Numerous studies point to a crucial role of DYRK1A protein for brain defects in patients with DS. Thus, DYRK1A inhibition has shown benefits in several mouse models of DS, including improvement of cognitive behaviour. Lastly, a recent clinical trial has shown that epigallocatechine gallate (EGCG), a DYRK1A inhibitor, given to young patients with DS improved visual recognition memory, working memory performance and adaptive behaviour.

DNA methylation is essential in mammalian development. We have hypothesized that methylation differences induced by trisomy 21 (T21) contribute to the phenotypic characteristics and heterogeneity in Down syndrome (DS). In order to determine the methylation differences in T21 without interference of the interindividual genomic variation, we have used fetal skin fibroblasts from monozygotic (MZ) twins discordant for T21. We also used skin fibroblasts from MZ twins concordant for T21, normal MZ twins without T21, and unrelated normal and T21 individuals. Reduced Representation Bisulfite Sequencing (RRBS) revealed 35 differentially methylated promoter regions (DMRs) (Absolute methylation differences = 25%, FDR < 0.001) in MZ twins discordant for T21 that have also been observed in comparison between unrelated normal and T21 individuals. The identified DMRs are enriched for genes involved in embryonic organ morphogenesis (FDR = 1.60 e -03) and include genes of the HOXB and HOXD clusters. These DMRs are maintained in iPS cells generated from this twin pair and are correlated with the gene expression changes. We have also observed an increase in DNA methylation level in the T21 methylome compared to the normal euploid methylome. This observation is concordant with the up regulation of DNA methyltransferase enzymes (DNMT3B and DNMT3L) and down regulation of DNA demethylation enzymes (TET2 and TET3) observed in the iPSC of the T21 versus normal twin. Altogether, the results of this study highlight the epigenetic effects of the extra chromosome 21 in T21 on loci outside of this chromosome that are relevant to DS associated phenotypes.

BACKGROUND: Differentiation of pluripotent stem cells in vitro provides a powerful means to investigate early developmental fates, including hematopoiesis. In particular, the use of a fully defined medium (FDM) would avoid biases induced by unidentified factors contained in serum, and would also allow key molecular mediators involved in such a process to be identified. Our goal was to induce in vitro, the differentiation of human embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) into morphologically and phenotypically mature leukocytes and erythrocytes, in the complete absence of serum and feeder cells. METHODOLOGY/PRINCIPAL FINDINGS: ESC and iPSC were sequentially induced in liquid cultures for 4 days with bone morphogenic protein-4, and for 4 days with FLT3-ligand, stem cell factor, thrombopoietin and vascular endothelium growth factor. Cell differentiation status was investigated by both mRNA expression and FACS expression profiles. Cells were further sorted and assayed for their hematopoietic properties in colony-forming unit (CFU) assays. In liquid cultures, cells progressively down-modulated Oct-4 expression while a sizeable cell fraction expressed CD34 de novo. SCL/Tal1 and Runx1 transcripts were exclusively detected in CD34(+) cells. In clonal assays, both ESC and iPSC-derived cells generated CFU, albeit with a 150-fold lower efficacy than cord blood (CB) CD34(+) cells. ESC-derived CD34(+) cells generated myeloid and fully hemoglobinized erythroid cells whereas CD34(-) cells almost exclusively generated small erythroid colonies. Both ESC and iPSC-derived erythroid cells expressed embryonic and fetal globins but were unable to synthesize adult β-globin in contrast with CB cells, suggesting that they had differentiated from primitive rather than from definitive hematopoietic progenitors. CONCLUSIONS/SIGNIFICANCE: Short-term, animal protein-free culture conditions are sufficient to sustain the differentiation of human ESC and iPSC into primitive hematopoietic progenitors, which, in turn, produce more mature blood cell types. However, additional factors have yet to be identified to allow their differentiation into definitive erythroid cultures.

The first Swiss human embryonic stem cell (hESC) line, CH-ES1, has shown features of a malignant cell line. It originated from the only single blastomere that survived cryopreservation of an embryo, and it more closely resembles teratocarcinoma lines than other hESC lines with respect to its abnormal karyotype and its formation of invasive tumors when injected into SCID mice. The aim of this study was to characterize the molecular basis of the oncogenicity of CH-ES1 cells, we looked for abnormal chromosomal copy number (by array Comparative Genomic Hybridization, aCGH) and single nucleotide polymorphisms (SNPs). To see how unique these changes were, we compared these results to data collected from the 2102Ep teratocarcinoma line and four hESC lines (H1, HS293, HS401 and SIVF-02) which displayed normal G-banding result. We identified genomic gains and losses in CH-ES1, including gains in areas containing several oncogenes. These features are similar to those observed in teratocarcinomas, and this explains the high malignancy. The CH-ES1 line was trisomic for chromosomes 1, 9, 12, 17, 19, 20 and X. Also the karyotypically (based on G-banding) normal hESC lines were also found to have several genomic changes that involved genes with known roles in cancer. The largest changes were found in the H1 line at passage number 56, when large 5 Mb duplications in chromosomes 1q32.2 and 22q12.2 were detected, but the losses and gains were seen already at passage 22. These changes found in the other lines highlight the importance of assessing the acquisition of genetic changes by hESCs before their use in regenerative medicine applications. They also point to the possibility that the acquisition of genetic changes by ESCs in culture may be used to explore certain aspects of the mechanisms regulating oncogenesis.