Sexual Development最新文献

{"title":"Lessons Learned from 17 Years of Multidisciplinary Care for Differences of Sex Development Patients at a Single Indonesian Center.","authors":"Sultana M H Faradz, Nurin Listyasari, Agustini Utari, Mahayu Dewi Ariani, Achmad Zulfa Juniarto, Ardy Santosa, Annastasia Ediati, Tuula K Rinne, Dineke Westra, Hedi Claahsen-van der Grinten, Frank H de Jong, Stenvert L S Drop, Katie Ayers, Andrew Sinclair","doi":"10.1159/000534085","DOIUrl":"10.1159/000534085","url":null,"abstract":"<p><strong>Background: </strong>Our multidisciplinary team (MDT) is a large specialized team based in Semarang, Indonesia, that cares for a wide variety of pediatric and adult individuals with differences of sex development (DSD) from across Indonesia. Here, we describe our work over the last 17 years.</p><p><strong>Methods: </strong>We analyzed phenotypic, hormonal, and genetic findings from clinical records for all patients referred to our MDT during the period 2004-2020.</p><p><strong>Results: </strong>Among 1,184 DSD patients, 10% had sex chromosome DSD, 67% had 46,XY DSD, and 23% had 46,XX DSD. The most common sex chromosome anomaly was Turner syndrome (45,X) (55 cases). For patients with 46,XY DSD under-masculinization was the most common diagnosis (311 cases), and for 46,XX DSD, a defect of Müllerian development was most common (131 cases) followed by congenital adrenal hyperplasia (CAH) (116 cases). Sanger sequencing, MLPA, and targeted gene sequencing of 257 patients with 46,XY DSD found likely causative variants in 21% (55 cases), with 13 diagnostic genes implicated. The most affected gene codes for the androgen receptor. Molecular analysis identified a diagnosis for 69 of 116 patients with CAH, with 62 carrying variants in CYP21A2 including four novel variants, and 7 patients carrying variants in CYP11B1. In many cases, these genetic diagnoses influenced the clinical management of patients and their families.</p><p><strong>Conclusions: </strong>Our work has highlighted the occurrence of different DSDs in Indonesia. By applying sequencing technologies as part of our clinical care, we have delivered a number of genetic diagnoses and identified novel pathogenic variants in some genes, which may be clinically specific to Indonesia. Genetics can inform many aspects of DSD clinical management, and while many of our patients remain undiagnosed, we hope that future testing may provide answers for even more.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":" ","pages":"170-180"},"PeriodicalIF":2.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10224139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two Novel Heterozygous Variants in RecA2 Domain of DHX37 Cause 46,XY Gonadal Dysgenesis and Testicular Regression Syndrome.","authors":"Hao Yang, Xiuqi Ma, Hongjuan Tian, Jinna Yuan, Dehua Wu, Guanping Dong, Qian Liu, Junfen Fu","doi":"10.1159/000534086","DOIUrl":"10.1159/000534086","url":null,"abstract":"<p><strong>Introduction: </strong>The pathogenic variants in DEAH-box RNA helicase DHX37 are one of the major causes of 46,XY gonadal dysgenesis and testicular regression syndrome (TRS). To date, only 13 different missense variants have been reported. We report two additional cases with different clinical presentations carrying two novel variants in the DHX37 gene.</p><p><strong>Case presentation and results: </strong>Case 1 (4.4-year-old boy) presented with significant micropenis and cryptorchidism and was diagnosed as TRS. Case 2 (13.5-year-old girl) had a 46,XY karyotype with female external genitalia and was diagnosed as GD. Two novel DHX37 variants affecting the RecA2 domain, p.G478R and p.L627F, were identified in these cases. Both variants identified in the probands were also present in their unaffected mother.</p><p><strong>Conclusion: </strong>Our findings broaden the variant spectrum of DHX37 in 46,XY differences of sex development (DSD) individuals.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":" ","pages":"198-202"},"PeriodicalIF":2.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11232946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10278413","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstracts of the 11th I-DSD Symposium.","authors":"","doi":"10.1159/000539511","DOIUrl":"https://doi.org/10.1159/000539511","url":null,"abstract":"<p><p>Abstracts of the 11th I-DSD Symposium.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"17 Suppl 1 ","pages":"1-123"},"PeriodicalIF":2.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141460239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Aging Ovary and the Tales Learned Since Fetal Development.","authors":"Jesus Lopez, Gabe Hohensee, Jing Liang, Meirav Sela, Joshua Johnson, Amanda N Kallen","doi":"10.1159/000532072","DOIUrl":"10.1159/000532072","url":null,"abstract":"<p><strong>Background: </strong>While the term \"aging\" implies a process typically associated with later life, the consequences of ovarian aging are evident by the time a woman reaches her forties, and sometimes earlier. This is due to a gradual decline in the quantity and quality of oocytes which occurs over a woman's reproductive lifespan. Indeed, the reproductive potential of the ovary is established even before birth, as the proper formation and assembly of the ovarian germ cell population during fetal life determines the lifetime endowment of oocytes and follicles. In the ovary, sophisticated molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance.</p><p><strong>Summary: </strong>The mechanisms thought to contribute to overall aging have been summarized under the term the \"hallmarks of aging\" and include such processes as DNA damage, mitochondrial dysfunction, telomere attrition, genomic instability, and stem cell exhaustion, among others. Similarly, in the ovary, molecular processes have been identified that regulate the timing of ovarian aging and these are critical to ensuring follicular maintenance. In this review, we outline critical processes involved in ovarian aging, highlight major achievements for treatment of ovarian aging, and discuss ongoing questions and areas of debate.</p><p><strong>Key messages: </strong>Ovarian aging is recognized as what may be a complex process in which age, genetics, environment, and many other factors contribute to the size and depletion of the follicle pool. The putative hallmarks of reproductive aging outlined herein include a diversity of plausible processes contributing to the depletion of the ovarian reserve. More research is needed to clarify if and to what extent these putative regulators do in fact govern follicle and oocyte behavior, and how these signals might be integrated in order to control the overall pattern of ovarian aging.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":" ","pages":"156-168"},"PeriodicalIF":2.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10841896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10021942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Development of Ovaries and Sex Change in Fish: Bringing Potential into Action.","authors":"Mateus Contar Adolfi, Alexandra Depincé, Ming Wen, Qiaowei Pan, Amaury Herpin","doi":"10.1159/000526008","DOIUrl":"10.1159/000526008","url":null,"abstract":"<p><strong>Background: </strong>Encompassing about half of the 60,000 species of vertebrates, fish display the greatest diversity of sex determination mechanisms among metazoans. As such that phylum offers a unique playground to study the impressive variety of gonadal morphogenetic strategies, ranging from gonochorism, with either genetic or environmental sex determination, to unisexuality, with either simultaneous or consecutive hermaphroditism.</p><p><strong>Summary: </strong>From the two main types of gonads, the ovaries embrace the important role to produce the larger and non-motile gametes, which is the basis for the development of a future organism. The production of the egg cells is complex and involves the formation of follicular cells, which are necessary for the maturation of the oocytes and the production of feminine hormones. In this vein, our review focuses on the development of ovaries in fish with special emphasis on the germ cells, including those that transition from one sex to the other as part of their life cycle and those that are capable of transitioning to the opposite sex depending on environmental cues.</p><p><strong>Key messages: </strong>Clearly, establishing an individual as either a female or a male is not accomplished by the sole development of two types of gonads. In most cases, that dichotomy, be it final or transient, is accompanied by coordinated transformations across the entire organism, leading to changes in the physiological sex as a whole. These coordinated transformations require both molecular and neuroendocrine networks, but also anatomical and behavioural adjustments. Remarkably, fish managed to tame the ins and outs of sex reversal mechanisms to take the most advantages of changing sex as adaptive strategies in some situations.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":" ","pages":"84-98"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10850202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Presentation, Diagnosis, and Follow-Up Characteristics of 17α-Hydroxylase Deficiency Cases with Exon 1-6 Deletion (Founder Mutation) in the CYP17A1Gene: 20-Year Single-Center Experience.","authors":"Ismail Dundar,&nbsp;Aysehan Akinci,&nbsp;Emine Camtosun,&nbsp;Nurdan Ciftci,&nbsp;Leman Kayas","doi":"10.1159/000529158","DOIUrl":"https://doi.org/10.1159/000529158","url":null,"abstract":"<p><strong>Context: </strong>17α-Hydroxylase/17,20-lyase deficiency (17OHD) is characterized by decreased sex steroids and cortisol synthesis, as well as an increased mineralocorticoid effect.</p><p><strong>Aim: </strong>This study aimed to evaluate the clinical, biochemical, and molecular characteristics of patients with 17OHD and to discuss the diagnosis, treatment, and follow-up process.</p><p><strong>Methods: </strong>Age, symptoms, anthropometric measurements, blood pressure, and hormonal, biochemical, and chromosomal analysis results of 13 patients diagnosed with 17OHD between 2003 and 2022 were recorded at admission and during follow-up. Whole gene next-generation sequencing was performed for the CYP17A1 gene. Multiplex ligation-dependent probe amplification was used to detect deletions in patients without point mutations in CYP17A1.</p><p><strong>Results: </strong>The median age at diagnosis was 14.0 (3.5-16.8) years. Nine of 13 patients (69.2%) had 46,XY karyotypes. All patients were phenotypically female and were raised as girls. The most common reasons for admission were the absence of puberty and amenorrhea (n = 8, 61.5%), followed by hypertension (n = 3, 23.0%), and family screening (n = 2, 15.3%). At the time of diagnosis, hypertension was detected in 10 (76.9%) patients, and 11 (84.6%) patients had hypokalemia.</p><p><strong>Conclusions: </strong>17OHD should be considered in patients with pubertal delay/primary amenorrhea, hypertension, and hypokalemia. Adrenal function should be included in the clinical study of hypergonadotropic hypogonadism, after excluding Turner syndrome, in all 46,XX females. Deletion in the CYP17A1 gene, including exons 1-6, is the founder mutation for Turkey's east and southeast regions.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"17 1","pages":"43-50"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10321950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mutations in STARD8 (DLC3) May Cause 46,XY Gonadal Dysgenesis.","authors":"Dmytro Sirokha, Alexey Rayevsky, Olexandra Gorodna, Vitalii Kalynovskyi, Nataliya Zelinska, Oksana Samson, Krystyna Kwiatkowska, Serge Nef, Jadwiga Jaruzelska, Kamila Kusz-Zamelczyk, Ludmila Livshits","doi":"10.1159/000537877","DOIUrl":"10.1159/000537877","url":null,"abstract":"<p><strong>Introduction: </strong>46,XY gonadal dysgenesis is a condition that is characterised by undeveloped testes in individuals with a male karyotype. Mutations in many genes that underlie this condition have been identified; however, there are still a considerable number of patients with an unknown genetic background. Recently, a mutation in the STARD8 X-linked gene in two sisters with 46,XY gonadal dysgenesis has been reported. It was localised within the START domain, whose homologue in Drosophila is responsible for maintaining testes integrity during their development.</p><p><strong>Methods: </strong>We analysed the potential pathogenicity of another STARD8 mutation, p.R887C, that was identified in a patient with 46,XY asymmetric gonadal dysgenesis. For this purpose, molecular dynamics simulations were performed.</p><p><strong>Results: </strong>These simulations revealed the full rearrangement of the helix containing the p.R887C substitution upstream from the START domain, which may cause STARD8 protein dysfunction and contribute to 46,XY gonadal dysgenesis. A comparison of the phenotypes of the three described 46,XY gonadal dysgenesis patients that harbour STARD8 mutations indicated that alterations of this gene can result in a partial or complete gonadal dysgenesis phenotype.</p><p><strong>Conclusion: </strong>Based on these and previous results, it is reasonable to include STARD8 in gene panels for 46,XY gonadal dysgenesis.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":" ","pages":"181-189"},"PeriodicalIF":2.4,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140050835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Avian Sex Determination: A Chicken and Egg Conundrum.","authors":"Michael Clinton, Debiao Zhao","doi":"10.1159/000529754","DOIUrl":"10.1159/000529754","url":null,"abstract":"<p><strong>Background: </strong>Primary sex determination is the developmental process that results in the sexual differentiation of the gonads. Vertebrate sex determination is generally considered to follow the model based on the mammalian system, where a sex-specific master regulatory gene activates one of the two different gene networks that underlie testis and ovary differentiation.</p><p><strong>Summary: </strong>It is now known that, while many of the molecular components of these pathways are conserved across different vertebrates, a wide variety of different trigger factors are utilized to initiate primary sex determination. In birds, the male is the homogametic sex (ZZ), and significant differences exist between the avian system of sex determination and that of mammals. For example, DMRT1, FOXL2, and estrogen are key factors in gonadogenesis in birds, but none are essential for primary sex determination in mammals.</p><p><strong>Key message: </strong>Gonadal sex determination in birds is thought to depend on a dosage-based mechanism involving expression of the Z-linked DMRT1 gene, and it may be that this \"mechanism\" is simply an extension of the cell autonomous sex identity associated with avian tissues, with no sex-specific trigger required.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":" ","pages":"120-133"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10740147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Surgical and Clinical Approach to Persistent Müllerian Duct Syndrome: Laparoscopic, Histological, and Molecular Findings.","authors":"María Celeste Mattone,&nbsp;María Victoria Lobo de la Vega,&nbsp;Emiro J Redondo,&nbsp;Pablo D'Alessandro,&nbsp;Natalia Perez Garrido,&nbsp;María Laura Galluzzo,&nbsp;Mariana Costanzo,&nbsp;Verónica Zaidman,&nbsp;Juan Manuel Lazzati,&nbsp;Esperanza Berensztein,&nbsp;Pablo Ramirez,&nbsp;Roxana Marino,&nbsp;Alicia Belgorosky,&nbsp;Marta Ciaccio,&nbsp;Marcela Bailez,&nbsp;Gabriela Guercio","doi":"10.1159/000526992","DOIUrl":"https://doi.org/10.1159/000526992","url":null,"abstract":"<p><strong>Background: </strong>Persistent müllerian duct syndrome (PMDS) is characterized by the persistence of müllerian duct derivatives in otherwise normally virilized 46,XY males. Biallelic mutations of the anti-müllerian hormone (AMH) and AMH receptor type 2 (AMHR2) genes lead to PMDS type 1 and 2, respectively.</p><p><strong>Aim: </strong>The aims of the study were to report the clinical, hormonal, and genetic findings in a patient with PMDS and discuss surgical strategies to achieve successful orchidopexy.</p><p><strong>Results: </strong>A 4-year-old boy was evaluated after the incidental finding of müllerian derivates during laparoscopy for nonpalpable gonads. Karyotype was 46,XY and laboratory tests revealed normal serum gonadotropin and androgen levels but undetectable serum AMH levels. PMDS was suspected. Molecular analysis revealed a novel variant c.902_929del in exon 5 and a previously reported mutation (c.367C>T) in exon 1 of the AMH gene. Successful orchidopexy was performed in two sequential surgeries in which the müllerian duct structure was preserved and divided to protect the vascular supply to the gonads. Histological evaluation of the testicular biopsy showed mild signs of dysgenesis. Doppler ultrasound showed blood flow in both testes positioned in the scrotum 1.5 years after surgery.</p><p><strong>Conclusion: </strong>PMDS is a rare entity that requires a high index of suspicion (from surgeons) when evaluating a patient with bilateral cryptorchidism. Surgical treatment is challenging and long-term follow-up is essential. Histological evaluation of the testis deserves further investigation.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"17 1","pages":"1-7"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9965917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls.","authors":"Guilherme Guaragna-Filho,&nbsp;Gil Guerra-Junior,&nbsp;Rieko Tadokoro-Cuccaro,&nbsp;Ieuan A Hughes,&nbsp;Beatriz A Barros,&nbsp;Olaf Hiort,&nbsp;Antonio Balsamo,&nbsp;Tulay Guran,&nbsp;Paul M Holterhus,&nbsp;Sabine Hannema,&nbsp;Sukran Poyrazoglu,&nbsp;Feyza Darendeliler,&nbsp;Jillian Bryce,&nbsp;S Faisal Ahmed,&nbsp;Charmian A Quigley","doi":"10.1159/000526997","DOIUrl":"https://doi.org/10.1159/000526997","url":null,"abstract":"<p><strong>Introduction: </strong>Although it was common in the 1970s-1990s to assign female gender of rearing to 46,XY infants with limited virilization of varying etiologies, including those with partial androgen insensitivity syndrome (PAIS), long-term data on outcomes for these individuals are sparse. Therefore, our goal was to use the power of an international registry to evaluate clinical features, surgical management, and pubertal data in patients with a molecularly confirmed diagnosis of PAIS who were born before 2008 and were raised as girls.</p><p><strong>Methods: </strong>The current study interrogated the International Disorders of Sex Development Registry for available data on management and pubertal outcomes in individuals with genetically confirmed PAIS who were raised as girls.</p><p><strong>Results: </strong>Among the 11 individuals who fulfilled the key criteria for inclusion, the external masculinization score (EMS) at presentation ranged from 2 to 6 (median 5); 7 girls underwent gonadectomy before the age of 9 years, whereas 4 underwent gonadectomy in the teenage years (≥ age 13). Clitoral enlargement at puberty was reported for 3 girls (27%) who presented initially at the time of puberty with intact gonads. In the 9 individuals (82%) for whom gonadal pathology data were provided, there was no evidence of germ cell tumor at median age of 8.1 years. All girls received estrogen replacement, and 8/11 had attained Tanner stage 4-5 breast development at the last assessment.</p><p><strong>Conclusion: </strong>In general, although it appears that female assignment in PAIS is becoming uncommon, our data provide no evidence to support the practice of prophylactic prepubertal gonadectomy with respect to the risk of a germ cell tumor.</p>","PeriodicalId":49536,"journal":{"name":"Sexual Development","volume":"17 1","pages":"16-25"},"PeriodicalIF":2.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10023227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}