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Genome-wide association (GWA) studies have identified 19 independent common risk loci for endometriosis. Most of the GWA variants are non-coding and the genes responsible for the association signals have not been identified. Herein, we aimed to assess the potential role of protein-modifying variants in endometriosis using exome-array genotyping in 7164 cases and 21005 controls, and a replication set of 1840 cases and 129016 controls of European ancestry. Results in the discovery sample identified significant evidence for association with coding variants in single-variant (rs1801232-CUBN) and gene-level (CIITA and PARP4) meta-analyses, but these did not survive replication. In the combined analysis, there was genome-wide significant evidence for rs13394619 (P = 2.3 × 10-9) in GREB1 at 2p25.1 - a locus previously identified in a GWA meta-analysis of European and Japanese samples. Despite sufficient power, our results did not identify any protein-modifying variants (MAF > 0.01) with moderate or large effect sizes in endometriosis, although these variants may exist in non-European populations or in high-risk families. The results suggest continued discovery efforts should focus on genotyping large numbers of surgically-confirmed endometriosis cases and controls, and/or sequencing high-risk families to identify novel rare variants to provide greater insights into the molecular pathogenesis of the disease.

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P

Background and Objectives: Platelet transfusions are used across multiple patient populations to prevent and correct bleeding. This scoping review aimed to map the currently available systematic reviews (SRs) and evidence‐based guidelines in the field of platelet transfusion. Materials and Methods: A systematic literature search was conducted in seven databases for SRs on effectiveness (including dose and timing, transfusion trigger and ratio to other blood products), production modalities and decision support related to platelet transfusion. The following data were charted: methodological features of the SR, population, concept and context features, outcomes reported, study design and number of studies included. Results were synthesized in interactive evidence maps. Results: We identified 110 SRs. The majority focused on clinical effectiveness, including prophylactic or therapeutic transfusions compared to no platelet transfusion (34 SRs), prophylactic compared to therapeutic‐only transfusion (8 SRs), dose, timing (11 SRs) and threshold for platelet transfusion (15 SRs) and the ratio of platelet transfusion to other blood products in massive transfusion (14 SRs). Furthermore, we included 34 SRs on decision support, of which 26 evaluated viscoelastic testing. Finally, we identified 22 SRs on platelet production modalities, including derivation (4 SRs), pathogen inactivation (6 SRs), leucodepletion (4 SRs) and ABO/human leucocyte antigen matching (5 SRs). The SRs were mapped according to concept and clinical context. Conclusion: An interactive evidence map of SRs and evidence‐based guidelines in the field of platelet transfusion has been developed and identified multiple reviews. This work serves as a tool for researchers looking for evidence gaps, thereby both supporting research and avoiding unnecessary duplication. [ABSTRACT FROM AUTHOR]

Background/aim: It is crucial to store an avulsed tooth appropriately to preserve the viability of the periodontal ligament cells prior to replantation. The aim of this systematic review was to identify the best available evidence for the effectiveness of any technique available to laypeople for storing an avulsed tooth compared with storage in milk or saliva.Methods: The following databases were searched (September 2019): Cochrane Library, MEDLINE, and Embase. Two reviewers independently considered trial eligibility, then extracted and analyzed data, and assessed the risk of bias. The certainty of the body of evidence was appraised according to the GRADE methodology.Results: Out of 4118 references, 33 studies were included and reported 23 comparisons of which 10 were synthesized in a meta-analysis. The limited evidence available favors storing an avulsed tooth in Hank's balanced salt solution (pooled SMD 2.47, 95% CI [1.59;3.34], P < .00001), propolis solution (pooled SMD 1.73, 95% CI [1.12;2.33], P < .00001), oral rehydration salts (pooled SMD 4.16, 95% CI [2.10;6.23], P < .0001), rice water, and cling film compared with storage in milk. The cell viability rate was significantly lower in teeth stored in saline solutions (pooled SMD -4.35, 95% CI [-7.55;-1.14], P = .008), tap water, buttermilk, castor oil, GC Tooth Mousse, and turmeric extract than those stored in milk. There is insufficient evidence to recommend for or against temporary storage of an avulsed tooth in saliva compared with alternative solutions. The certainty of evidence was considered low to very low due to limitations in study design, indirect study populations and outcome measures, and imprecision.Conclusion: Although milk was shown to extend the periodontal ligament cell viability before replantation compared with saline or tap water, the following media have also demonstrated efficacy at preserving the cell viability: Hank's balanced salt solution, propolis, oral rehydration salts, rice water, and cling film. [ABSTRACT FROM AUTHOR]

Background: First aid is the immediate help provided to the ill or injured. Although it can be lifesaving, many people refrain from helping when encountering a person in need. This study aimed to describe the types of accidents people are most likely to encounter in daily life and to assess the association between several variables, including having received first aid training and helping behavior. Methods: An online survey was distributed from December 2016 to February 2017. The factors affecting provision of first aid and calling of emergency services were analyzed using multivariable logistic regression. Results: More than half of the 59,477 respondents (51.9%) stated that they had encountered an accident in the past five years. A total of 59,110 accidents were reported. First aid was provided in 70.2% of accidents and emergency services were called in 72.0% of accidents. Age, gender, WHO region, type of accident and environment of the accident were all significantly associated with providing first aid and calling emergency services. People who were trained in first aid were more likely to provide first aid or to call for emergency services than untrained people (p<0.0001). Conclusion: Several factors were associated with helping behavior, including but not limited to having received first aid training. There is a need for lifelong training, with special attention to those subgroups that are less likely to report helping behavior. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a common disorder that affects 6-10% of reproductive age women. In a previous study, we demonstrated that a polymorphism in let-7 microRNA-binding site in the 3' untranslated region of the KRAS gene was found in 31% of subjects with endometriosis resistant to medical therapy. This polymorphism was now tested in a large, case-control study.Methods: Peripheral blood or peritoneal biopsies from 2,077 European subjects with or without endometriosis and known infertility were tested for the presence of the variant allele using polymerase chain reaction.Results: Histologically proven endometriosis was found in 1,140 subjects, while 937 subjects were disease free. Variant allele carrier rates in subjects with and without endometriosis were 15.7 and 15.1%, respectively. No association between the variant KRAS allele and stage of the disease, age at surgery, body mass index, or type of infertility was identified.Conclusion: A germ-line single-nucleotide polymorphism in the let-7 microRNA-binding site of the KRAS gene was not associated with sporadic endometriosis in an infertile Caucasian population in this large case-control study. However, it remains possible that this gene variant may be a marker of treatment resistance. Further studies on the role of this polymorphism in endometriosis are needed. [ABSTRACT FROM AUTHOR]

Background: To induce endometrial decidualization in rodents, an intrauterine oil stimulus can be delivered via the nontraumatic vagina or via the traumatic laparotomy. However, there is considerable variation in amount of decidualization using these inducing methods. Therefore, we studied which oil delivery route could achieve the highest rate of endometrial decidualization along the full length of both uterine horns. Methods: To induce decidualization, ovariectomized C57Bl/6J mice were injected with estrogen (100 ng/day; 3 days). A progesterone pellet (5 mg) was implanted subcutaneously, followed by estrogen injections (5 ng/day; 3 days). Oil (20 µL/horn) was injected in the uterus via laparotomy, laparoscopy, or vagina. Four days later, the pellet was removed, followed by hysterectomy after 4 to 6 hours. Endometrial decidualization was evaluated macroscopically and microscopically using hematoxylin and eosin and desmin staining. Furthermore, uterine weight and hormone levels were measured. Results: The proportion of animals with macroscopic bicornuate decidualization was higher after laparoscopic (83%) and laparotomic (89%) injection than after sham injection (11%). Furthermore, macroscopic bicornuate decidualization was significantly higher after laparotomic injection (89%) compared to the vaginal injection (38%). Uterine weight and endometrial surface area were significantly higher in both laparotomy and laparoscopy groups compared to the sham group, while the relative desmin-positive endometrial surface area was only significantly different between the laparotomy and the sham animals. Conclusion: Methods using laparoscopic and laparotomic intrauterine oil injection resulted in a higher amount of decidualized endometrium compared to sham injection, although further optimization is needed to reach full bicornuate decidualization. [ABSTRACT FROM AUTHOR]

Myeloperoxidase (MPO) is a proinflammatory enzyme and a marker for neutrophil activation and oxidative stress. Since oxidative stress and inflammation are linked to the pathogenesis of endometriosis, we hypothesized that the total, active, and specific (active/total) MPO levels were significantly different in plasma of women with and without endometriosis. Samples were selected from our biobank from women with endometriosis (n = 212) and controls without endometriosis (n = 121) across the menstrual cycle. Total MPO plasma levels were measured by immunoassay and MPO activity by enzymatic assay. Total and active MPO levels did not differ significantly among endometriosis cases and controls, whereas the specific MPO activity was significantly lower in women with endometriosis than that in controls (p = 0.0159). After the subdivision of control patients into women with a normal pelvis and women with other benign gynecological disorders, a significant difference was observed only between women with endometriosis and women with other benign gynecological disorders (p = 0.0266). In conclusion, systemic MPO levels may not be suited as a single biomarker for endometriosis. Our data support the involvement of MPO in other gynecological disorders but do not provide any evidence for an association with endometriosis. [ABSTRACT FROM AUTHOR]

To reinforce Sampson’s theory of retrograde menstruation in the pathogenesis of endometriosis, proof should be provided that during menstruation endometrial cells are present in peritoneal fluid (PF). We hypothesize that the prevalence of PF samples containing endometrial cells is higher in patients with endometriosis than in controls without endometriosis during menstruation. We selected from our biobank PF samples of 17 reproductive-age women with (n = 9) or without (n = 8) endometriosis who had received a diagnostic laparoscopy for investigation of pain/infertility. Peritoneal fluid had been collected during laparoscopy in the menstrual phase of the cycle, centrifuged, and the resulting pellet was stored at −80°C. About 5-μm sections of frozen PF pellets were stained using the Dako Envision Flex system with primary antibodies against epithelial cell adhesion molecule (Ep-CAM; endometrial epithelial cells), CD10 (endometrial stromal cells), prekeratin (epithelial/mesothelial cells), vimentin (endometrial/mesothelial/immune cells), calretinin (mesothelial cells), and CD68 (macrophages). The PF cells positive for Ep-CAM were detected in 5 of 9 patients with endometriosis and 6 of 8 controls (P = .62). CD10 stained positively in 6 of the 9 patients with endometriosis and 3 of the 8 controls (P = .35). Calretinin and prekeratin staining showed the presence of mesothelial cells in all pellets. Vimentin stained approximately 100% of the PF cells. CD68+ macrophages represented >50% of cells in all pellets. The prevalence of PF samples containing endometrial epithelial and stromal cells was not higher in patients with endometriosis than in controls without endometriosis during menstruation. Our findings question the relevance of endometrial cells in PF for the pathogenesis of endometriosis and support the importance of other mechanisms such as immune dysfunction and/or endometrial stem cells. [ABSTRACT FROM AUTHOR]

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Multiplex immunoassays range from small-scaled multiplex sandwich ELISAs in a planar or bead-based format to the more expanded antibody arrays employing direct sample labeling. The plethora of data generated from these arrays could be of great interest to understand a complex disorder such as endometriosis. Multiplex immunoassay analysis may provide information on disease pathology and may lead to improved, timely diagnosis. Until now, the use of multiplex immunoassays has been limited in endometriosis. With the constant development of multiplex technologies, future studies should focus on implementing these techniques, and combining them with multivariate statistical analysis. In this review, we provide an overview of multiplex immunoassay methods used in endometriosis studies and the data sets acquired by these methodologies. These data and future studies might provide novel insights for biomarker discovery and investigation of the pathogenesis in endometriosis.

Background: This prospective pilot study was designed to induce endometriosis in a mouse model using laparoscopy, a less invasive and more precise approach than laparotomy. We aimed to achieve a peritoneal implant rate of at least 50% by varying both duration of anesthesia and intra-abdominal insufflation pressure., Methods: Female BALB/cANnCrl mice in metestrus or diestrus were used as donors (n = 5) or recipients (n = 20) of uterine transplant tissue. Each recipient mouse was laparoscopically inoculated with 10 uterine pieces (range: 10-12) from donor mice into the abdominal cavity. Before starting the study, recipient mice were randomly assigned to 4 groups with variable duration of anesthesia (ketamine/xylazine or pentobarbital) and variable intra-abdominal pressure (5 or 15 mm Hg). One week after laparoscopy, endometriosis incidence and peritoneal implant take rate were documented visually during laparotomy. The retrieved lesions were histologically analyzed., Results: Laparoscopic inoculation of uterine pieces in recipient mice resulted in an endometriosis incidence of 100% (20/20 animals) and an individual peritoneal implant take rate of 60% (121/206), ranging from 17% (2/12) till 83% (10/12), without differences between the 4 subgroups, and with a histological confirmation rate of 92% (58/63)., Conclusions: To the best our knowledge, this is the first report showing that endometriosis can be induced by laparoscopic surgery in rodents, with a 100% incidence and a median peritoneal implant take rate of 60%. This laparoscopic model offers important advantages over traditional laparotomy models that are limited by surgery-associated trauma and/or adhesion formation., (© The Author(s) 2016.)