Pub Date : 2025-01-02eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoae072
Alexandra Henry, Pietro Santulli, Mathilde Bourdon, Chloé Maignien, Charles Chapron, Jean-Marc Treluyer, Jean Guibourdenche, Laurent Chouchana
<p><strong>Study question: </strong>Is there an association between dydrogesterone exposure during early pregnancy and the reporting of birth defects?</p><p><strong>Summary answer: </strong>This observational analysis based on global safety data showed an increased reporting of birth defects, mainly hypospadias and congenital heart defects (CHD), in pregnancies exposed to dydrogesterone, especially when comparing to progesterone.</p><p><strong>What is known already: </strong>Intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation in ART. In recent years, randomized controlled clinical trials demonstrated that oral dydrogesterone was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone. Safety profiles in both mother and child were similar. However, concerns have been raised regarding an association between dydrogesterone usage during early pregnancy and CHD in offspring.</p><p><strong>Study design size duration: </strong>We performed a disproportionality analysis, also called case-non-case study, similar in concept to case-control studies, using the WHO global safety database, VigiBase. The study cohort consisted of individual pregnancy-related safety reports, using the <i>ad hoc</i> standardized query (SMQ 'Pregnancy and neonatal topics'). Cases of birth defects consisted of safety reports containing terms related to the 'congenital, familial and genetic disorders' System Organ Class from the Medical Dictionary for Regulatory Activities. Non-cases consisted of safety reports containing any other adverse event, in pregnancy-related safety reports.</p><p><strong>Participants/materials setting methods: </strong>Considering reports since database inception to 31 December 2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug on the database, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% CI. For each comparison, two sensitivity analyses were performed. Finally, a case-by-case review was performed to further characterize major birth defects and sort anomalies according to classification of EUROCAT.</p><p><strong>Main results and the role of chance: </strong>Study cohort consisted of 362 183 safety reports in pregnant women, among which 50 653 reports were related to the use of drugs for ART, including 145 with dydrogesterone and 1222 with progesterone. Of these, 374 (0.7%) were cases of birth defects: 60 with dydrogesterone and 141 with progesterone, including 48 and 92 cases compatible with major birth defect cases according to EUROCAT classification, respectively. Major birth defects reported with dydrogesterone were mainly genital defects such as hypospadias and CHD. A significantly hi
{"title":"Birth defects reporting and the use of dydrogesterone: a disproportionality analysis from the World Health Organization pharmacovigilance database (VigiBase).","authors":"Alexandra Henry, Pietro Santulli, Mathilde Bourdon, Chloé Maignien, Charles Chapron, Jean-Marc Treluyer, Jean Guibourdenche, Laurent Chouchana","doi":"10.1093/hropen/hoae072","DOIUrl":"10.1093/hropen/hoae072","url":null,"abstract":"<p><strong>Study question: </strong>Is there an association between dydrogesterone exposure during early pregnancy and the reporting of birth defects?</p><p><strong>Summary answer: </strong>This observational analysis based on global safety data showed an increased reporting of birth defects, mainly hypospadias and congenital heart defects (CHD), in pregnancies exposed to dydrogesterone, especially when comparing to progesterone.</p><p><strong>What is known already: </strong>Intravaginal administration of progesterone is the standard of care to overcome luteal phase progesterone deficiency induced by ovarian stimulation in ART. In recent years, randomized controlled clinical trials demonstrated that oral dydrogesterone was non-inferior for pregnancy rate at 12 weeks of gestation and could be an alternative to micronized vaginal progesterone. Safety profiles in both mother and child were similar. However, concerns have been raised regarding an association between dydrogesterone usage during early pregnancy and CHD in offspring.</p><p><strong>Study design size duration: </strong>We performed a disproportionality analysis, also called case-non-case study, similar in concept to case-control studies, using the WHO global safety database, VigiBase. The study cohort consisted of individual pregnancy-related safety reports, using the <i>ad hoc</i> standardized query (SMQ 'Pregnancy and neonatal topics'). Cases of birth defects consisted of safety reports containing terms related to the 'congenital, familial and genetic disorders' System Organ Class from the Medical Dictionary for Regulatory Activities. Non-cases consisted of safety reports containing any other adverse event, in pregnancy-related safety reports.</p><p><strong>Participants/materials setting methods: </strong>Considering reports since database inception to 31 December 2021, we first compared the reporting of birth defects with dydrogesterone to that of any other drug on the database, then to any other drug used for ART. Secondly, we performed a comparison on the reporting of birth defects for dydrogesterone with progesterone. Results are presented as reporting odds ratio (ROR) and their 95% CI. For each comparison, two sensitivity analyses were performed. Finally, a case-by-case review was performed to further characterize major birth defects and sort anomalies according to classification of EUROCAT.</p><p><strong>Main results and the role of chance: </strong>Study cohort consisted of 362 183 safety reports in pregnant women, among which 50 653 reports were related to the use of drugs for ART, including 145 with dydrogesterone and 1222 with progesterone. Of these, 374 (0.7%) were cases of birth defects: 60 with dydrogesterone and 141 with progesterone, including 48 and 92 cases compatible with major birth defect cases according to EUROCAT classification, respectively. Major birth defects reported with dydrogesterone were mainly genital defects such as hypospadias and CHD. A significantly hi","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 1","pages":"hoae072"},"PeriodicalIF":8.3,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11726828/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142980906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-30eCollection Date: 2025-01-01DOI: 10.1093/hropen/hoae074
Annelore Van Der Kelen, Letizia Li Piani, Joke Mertens, Marius Regin, Edouard Couvreu de Deckersberg, Hilde Van de Velde, Karen Sermon, Herman Tournaye, Willem Verpoest, Frederik Jan Hes, Christophe Blockeel, Claudia Spits
<p><strong>Study question: </strong>Is there an association between different mitochondrial DNA (mtDNA) genotypes and female infertility or ovarian response, and is the appearance of variants in the oocytes favored by medically assisted reproduction (MAR) techniques?</p><p><strong>Summary answer: </strong>Ovarian response was negatively associated with global non-synonymous protein-coding homoplasmic variants but positively associated with haplogroup K; the number of oocytes retrieved in a cycle correlates with the number of heteroplasmic variants in the oocytes, principally with variants located in the hypervariable (HV) region and rRNA loci, as well as non-synonymous protein-coding variants.</p><p><strong>What is known already: </strong>Several genes have been shown to be positively associated with infertility, and there is growing concern that MAR may facilitate the transmission of these harmful variants to offspring, thereby passing on infertility. The potential role of mtDNA variants in these two perspectives remains poorly understood.</p><p><strong>Study design size duration: </strong>This cohort study included 261 oocytes from 132 women (mean age: 32 ± 4 years) undergoing ovarian stimulation between 2019 and 2020 at an academic center. The oocyte mtDNA genotypes were examined for associations with the women's fertility characteristics.</p><p><strong>Participants/materials setting methods: </strong>The mtDNA of the oocytes underwent deep sequencing, and the mtDNA genotypes were compared between infertile and fertile groups using Fisher's exact test. The impact of the mtDNA genotype on anti-Müllerian hormone (AMH) levels and the number of (mature) oocytes retrieved was assessed using the Mann-Whitney <i>U</i> test for univariate analysis and logistic regression for multivariate analysis. Additionally, we examined the associations of oocyte maturation stage, infertility status, number of ovarian stimulation units, and number of oocytes retrieved with the type and load of heteroplasmic variants using univariate analysis and Poisson or linear regression analysis.</p><p><strong>Main results and the role of chance: </strong>Neither homoplasmic mtDNA variants nor haplogroups in the oocytes were associated with infertility status or with AMH levels. Conversely, when the relationship between the number of oocytes retrieved and different mtDNA genotypes was examined, a positive association was observed between the number of metaphase (MII) oocytes (<i>P</i> = 0.005) and haplogroup K. Furthermore, the presence of global non-synonymous homoplasmic variants in the protein-coding region was significantly associated with a reduced number of total oocytes and MII oocytes retrieved (<i>P</i> < 0.001 for both). Regarding the type and load of heteroplasmic variants in the different regions, there were no significant associations according to maturation stage of the oocyte or to fertility status; however, the number of oocytes retrieved correlated positively w
{"title":"The interplay between mitochondrial DNA genotypes, female infertility, ovarian response, and mutagenesis in oocytes.","authors":"Annelore Van Der Kelen, Letizia Li Piani, Joke Mertens, Marius Regin, Edouard Couvreu de Deckersberg, Hilde Van de Velde, Karen Sermon, Herman Tournaye, Willem Verpoest, Frederik Jan Hes, Christophe Blockeel, Claudia Spits","doi":"10.1093/hropen/hoae074","DOIUrl":"10.1093/hropen/hoae074","url":null,"abstract":"<p><strong>Study question: </strong>Is there an association between different mitochondrial DNA (mtDNA) genotypes and female infertility or ovarian response, and is the appearance of variants in the oocytes favored by medically assisted reproduction (MAR) techniques?</p><p><strong>Summary answer: </strong>Ovarian response was negatively associated with global non-synonymous protein-coding homoplasmic variants but positively associated with haplogroup K; the number of oocytes retrieved in a cycle correlates with the number of heteroplasmic variants in the oocytes, principally with variants located in the hypervariable (HV) region and rRNA loci, as well as non-synonymous protein-coding variants.</p><p><strong>What is known already: </strong>Several genes have been shown to be positively associated with infertility, and there is growing concern that MAR may facilitate the transmission of these harmful variants to offspring, thereby passing on infertility. The potential role of mtDNA variants in these two perspectives remains poorly understood.</p><p><strong>Study design size duration: </strong>This cohort study included 261 oocytes from 132 women (mean age: 32 ± 4 years) undergoing ovarian stimulation between 2019 and 2020 at an academic center. The oocyte mtDNA genotypes were examined for associations with the women's fertility characteristics.</p><p><strong>Participants/materials setting methods: </strong>The mtDNA of the oocytes underwent deep sequencing, and the mtDNA genotypes were compared between infertile and fertile groups using Fisher's exact test. The impact of the mtDNA genotype on anti-Müllerian hormone (AMH) levels and the number of (mature) oocytes retrieved was assessed using the Mann-Whitney <i>U</i> test for univariate analysis and logistic regression for multivariate analysis. Additionally, we examined the associations of oocyte maturation stage, infertility status, number of ovarian stimulation units, and number of oocytes retrieved with the type and load of heteroplasmic variants using univariate analysis and Poisson or linear regression analysis.</p><p><strong>Main results and the role of chance: </strong>Neither homoplasmic mtDNA variants nor haplogroups in the oocytes were associated with infertility status or with AMH levels. Conversely, when the relationship between the number of oocytes retrieved and different mtDNA genotypes was examined, a positive association was observed between the number of metaphase (MII) oocytes (<i>P</i> = 0.005) and haplogroup K. Furthermore, the presence of global non-synonymous homoplasmic variants in the protein-coding region was significantly associated with a reduced number of total oocytes and MII oocytes retrieved (<i>P</i> < 0.001 for both). Regarding the type and load of heteroplasmic variants in the different regions, there were no significant associations according to maturation stage of the oocyte or to fertility status; however, the number of oocytes retrieved correlated positively w","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2025 1","pages":"hoae074"},"PeriodicalIF":8.3,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11739621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143017655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-09eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae065
Nick Panay, Richard A Anderson, Amy Bennie, Marcelle Cedars, Melanie Davies, Carolyn Ee, Claus H Gravholt, Sophia Kalantaridou, Amanda Kallen, Kimberly Q Kim, Micheline Misrahi, Aya Mousa, Rossella E Nappi, Walter A Rocca, Xiangyan Ruan, Helena Teede, Nathalie Vermeulen, Elinor Vogt, Amanda J Vincent
<p><strong>Study question: </strong>How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?</p><p><strong>Summary answer: </strong>The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI.</p><p><strong>What is known already: </strong>Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI.</p><p><strong>Study design size duration: </strong>The guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline.</p><p><strong>Participants/materials setting methods: </strong>Based on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee.</p><p><strong>Main results and the role of chance: </strong>New data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH >25 IU is required for diagnosis of P
{"title":"Evidence-based guideline: premature ovarian insufficiency<sup />.","authors":"Nick Panay, Richard A Anderson, Amy Bennie, Marcelle Cedars, Melanie Davies, Carolyn Ee, Claus H Gravholt, Sophia Kalantaridou, Amanda Kallen, Kimberly Q Kim, Micheline Misrahi, Aya Mousa, Rossella E Nappi, Walter A Rocca, Xiangyan Ruan, Helena Teede, Nathalie Vermeulen, Elinor Vogt, Amanda J Vincent","doi":"10.1093/hropen/hoae065","DOIUrl":"10.1093/hropen/hoae065","url":null,"abstract":"<p><strong>Study question: </strong>How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature?</p><p><strong>Summary answer: </strong>The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI.</p><p><strong>What is known already: </strong>Premature ovarian insufficiency (POI) presents a significant challenge to women's health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI.</p><p><strong>Study design size duration: </strong>The guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline.</p><p><strong>Participants/materials setting methods: </strong>Based on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee.</p><p><strong>Main results and the role of chance: </strong>New data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH >25 IU is required for diagnosis of P","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae065"},"PeriodicalIF":8.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11631070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-26eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae071
Yangyi Fang, Zhe Zhang, Yinchu Cheng, Zhigao Huang, Jiayuan Pan, Zixuan Xue, Yidong Chen, Vera Y Chung, Li Zhang, Kai Hong
<p><strong>Study question: </strong>Which independent factors influence ICSI outcomes in patients with complete azoospermia factor c (AZFc) microdeletions?</p><p><strong>Summary answer: </strong>In patients with complete AZFc microdeletions, the sperm source, male LH, the type of infertility in women, and maternal age are the independent factors associated with ICSI outcomes.</p><p><strong>What is known already: </strong>AZF microdeletions are the second most prevalent factor contributing to infertility in men, with AZFc microdeletions being the most frequently affected locus, accounting for 60-70% of all cases. The primary clinical phenotypes are oligoasthenozoospermia and azoospermia in patients with complete AZFc microdeletions. These patients can achieve paternity through ICSI using either testicular (T-S) or ejaculated (E-S) spermatozoa. With aging in men with AZFc microdeletions, oligoasthenozoospermia or severe oligozoospermia may gradually progress to azoospermia.</p><p><strong>Study design size duration: </strong>In this retrospective cohort study, the independent factors associated with the outcomes of 634 ICSI cycles in 634 couples with the transfer of 1005 embryos between February 2015 and December 2023 were evaluated. The analysis included 398 ICSI cycles in 398 couples using E-S and 236 ICSI cycles in 236 couples using T-S; all men had complete AZFc microdeletions.</p><p><strong>Participants/materials setting methods: </strong>The inclusion criteria were as follows: (i) men had complete AZFc microdeletions and (ii) the couple underwent ICSI treatment using T-S or E-S. The exclusion criteria were as follows: (i) cycles involving frozen-thawed oocytes; (ii) cycles in which all fresh embryos were frozen and not transferred; (iii) cycles lost to follow-up; and (iv) multiple ICSI cycles, apart from the first cycle for each couple. The primary outcome was the cumulative live birth rate per ICSI cycle, whereas the secondary outcomes were the clinical pregnancy rate per ICSI cycle, fertilization rate, and the no-embryo-suitable-for-transfer cycle rate (NESTR). Moreover, the maternal and neonatal outcomes were analyzed. Continuous variables showing non-normal distributions were expressed as median and interquartile range and were analyzed using the Kruskal-Wallis test. Categorical variables were expressed as percentages and were analyzed using the χ<sup>2</sup> or Fisher's exact test. Linear and logistic regression models were constructed to assess the independent factors associated with ICSI outcomes.</p><p><strong>Main results and the role of chance: </strong>The T-S group exhibited inferior ICSI outcomes than the E-S group, marked by significantly reduced rates of cumulative live birth, clinical pregnancy, fertilization, high-quality embryos, blastocyst formation, and implantation, with higher NESTRs. However, the miscarriage rate and neonatal outcomes did not significantly differ between the groups. Multivariate linear regression analysi
{"title":"Independent factors associated with intracytoplasmic sperm injection outcomes in patients with complete azoospermia factor c microdeletions.","authors":"Yangyi Fang, Zhe Zhang, Yinchu Cheng, Zhigao Huang, Jiayuan Pan, Zixuan Xue, Yidong Chen, Vera Y Chung, Li Zhang, Kai Hong","doi":"10.1093/hropen/hoae071","DOIUrl":"10.1093/hropen/hoae071","url":null,"abstract":"<p><strong>Study question: </strong>Which independent factors influence ICSI outcomes in patients with complete azoospermia factor c (AZFc) microdeletions?</p><p><strong>Summary answer: </strong>In patients with complete AZFc microdeletions, the sperm source, male LH, the type of infertility in women, and maternal age are the independent factors associated with ICSI outcomes.</p><p><strong>What is known already: </strong>AZF microdeletions are the second most prevalent factor contributing to infertility in men, with AZFc microdeletions being the most frequently affected locus, accounting for 60-70% of all cases. The primary clinical phenotypes are oligoasthenozoospermia and azoospermia in patients with complete AZFc microdeletions. These patients can achieve paternity through ICSI using either testicular (T-S) or ejaculated (E-S) spermatozoa. With aging in men with AZFc microdeletions, oligoasthenozoospermia or severe oligozoospermia may gradually progress to azoospermia.</p><p><strong>Study design size duration: </strong>In this retrospective cohort study, the independent factors associated with the outcomes of 634 ICSI cycles in 634 couples with the transfer of 1005 embryos between February 2015 and December 2023 were evaluated. The analysis included 398 ICSI cycles in 398 couples using E-S and 236 ICSI cycles in 236 couples using T-S; all men had complete AZFc microdeletions.</p><p><strong>Participants/materials setting methods: </strong>The inclusion criteria were as follows: (i) men had complete AZFc microdeletions and (ii) the couple underwent ICSI treatment using T-S or E-S. The exclusion criteria were as follows: (i) cycles involving frozen-thawed oocytes; (ii) cycles in which all fresh embryos were frozen and not transferred; (iii) cycles lost to follow-up; and (iv) multiple ICSI cycles, apart from the first cycle for each couple. The primary outcome was the cumulative live birth rate per ICSI cycle, whereas the secondary outcomes were the clinical pregnancy rate per ICSI cycle, fertilization rate, and the no-embryo-suitable-for-transfer cycle rate (NESTR). Moreover, the maternal and neonatal outcomes were analyzed. Continuous variables showing non-normal distributions were expressed as median and interquartile range and were analyzed using the Kruskal-Wallis test. Categorical variables were expressed as percentages and were analyzed using the χ<sup>2</sup> or Fisher's exact test. Linear and logistic regression models were constructed to assess the independent factors associated with ICSI outcomes.</p><p><strong>Main results and the role of chance: </strong>The T-S group exhibited inferior ICSI outcomes than the E-S group, marked by significantly reduced rates of cumulative live birth, clinical pregnancy, fertilization, high-quality embryos, blastocyst formation, and implantation, with higher NESTRs. However, the miscarriage rate and neonatal outcomes did not significantly differ between the groups. Multivariate linear regression analysi","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae071"},"PeriodicalIF":8.3,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11652272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142857140","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-13eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae069
Andrea Guzmán-Jiménez, Sara González-Muñoz, Miriam Cerván-Martín, Nicolás Garrido, José A Castilla, M Carmen Gonzalvo, Ana Clavero, Marta Molina, Saturnino Luján, Samuel Santos-Ribeiro, Miguel Ángel Vilches, Andrea Espuch, Vicente Maldonado, Noelia Galiano-Gutiérrez, Esther Santamaría-López, Cristina González-Ravina, Fernando Quintana-Ferraz, Susana Gómez, David Amorós, Luis Martínez-Granados, Yanira Ortega-González, Miguel Burgos, Iris Pereira-Caetano, Ozgur Bulbul, Stefano Castellano, Massimo Romano, Elena Albani, Lluís Bassas, Susana Seixas, João Gonçalves, Alexandra M Lopes, Sara Larriba, Rogelio J Palomino-Morales, F David Carmona, Lara Bossini-Castillo
<p><strong>Study question: </strong>Can genome-wide genotyping data be analysed using a hypothesis-driven approach to enhance the understanding of the genetic basis of severe spermatogenic failure (SPGF) in male infertility?</p><p><strong>Summary answer: </strong>Our findings revealed a significant association between SPGF and the <i>SHOC1</i> gene and identified three novel genes (<i>PCSK4</i>, <i>AP3B1</i>, and <i>DLK1</i>) along with 32 potentially pathogenic rare variants in 30 genes that contribute to this condition.</p><p><strong>What is known already: </strong>SPGF is a major cause of male infertility, often with an unknown aetiology. SPGF can be due to either multifactorial causes, including both common genetic variants in multiple genes and environmental factors, or highly damaging rare variants. Next-generation sequencing methods are useful for identifying rare mutations that explain monogenic forms of SPGF. Genome-wide association studies (GWASs) have become essential approaches for deciphering the intricate genetic landscape of complex diseases, offering a cost-effective and rapid means to genotype millions of genetic variants. Novel methods have demonstrated that GWAS datasets can be used to infer rare coding variants that are causal for male infertility phenotypes. However, this approach has not been previously applied to characterize the genetic component of a whole case-control cohort.</p><p><strong>Study design size duration: </strong>We employed a hypothesis-driven approach focusing on all genetic variation identified, using a GWAS platform and subsequent genotype imputation, encompassing over 20 million polymorphisms and a total of 1571 SPGF patients and 2431 controls. Both common (minor allele frequency, MAF > 0.01) and rare (MAF < 0.01) variants were investigated within a total of 1797 loci with a reported role in spermatogenesis. This gene panel was meticulously assembled through comprehensive searches in the literature and various databases focused on male infertility genetics.</p><p><strong>Participants/materials setting methods: </strong>This study involved a European cohort using previously and newly generated data. Our analysis consisted of three independent methods: (i) variant-wise association analyses using logistic regression models, (ii) gene-wise association analyses using combined multivariate and collapsing burden tests, and (iii) identification and characterisation of highly damaging rare coding variants showing homozygosity only in SPGF patients.</p><p><strong>Main results and the role of chance: </strong>The variant-wise analyses revealed an association between SPGF and <i>SHOC1</i>-rs12347237 (<i>P </i>=<i> </i>4.15E-06, odds ratio = 2.66), which was likely explained by an altered binding affinity of key transcription factors in regulatory regions and the disruptive effect of coding variants within the gene. Three additional genes (<i>PCSK4</i>, <i>AP3B1</i>, and <i>DLK1</i>) were identified as novel relevan
{"title":"A comprehensive study of common and rare genetic variants in spermatogenesis-related loci identifies new risk factors for idiopathic severe spermatogenic failure.","authors":"Andrea Guzmán-Jiménez, Sara González-Muñoz, Miriam Cerván-Martín, Nicolás Garrido, José A Castilla, M Carmen Gonzalvo, Ana Clavero, Marta Molina, Saturnino Luján, Samuel Santos-Ribeiro, Miguel Ángel Vilches, Andrea Espuch, Vicente Maldonado, Noelia Galiano-Gutiérrez, Esther Santamaría-López, Cristina González-Ravina, Fernando Quintana-Ferraz, Susana Gómez, David Amorós, Luis Martínez-Granados, Yanira Ortega-González, Miguel Burgos, Iris Pereira-Caetano, Ozgur Bulbul, Stefano Castellano, Massimo Romano, Elena Albani, Lluís Bassas, Susana Seixas, João Gonçalves, Alexandra M Lopes, Sara Larriba, Rogelio J Palomino-Morales, F David Carmona, Lara Bossini-Castillo","doi":"10.1093/hropen/hoae069","DOIUrl":"10.1093/hropen/hoae069","url":null,"abstract":"<p><strong>Study question: </strong>Can genome-wide genotyping data be analysed using a hypothesis-driven approach to enhance the understanding of the genetic basis of severe spermatogenic failure (SPGF) in male infertility?</p><p><strong>Summary answer: </strong>Our findings revealed a significant association between SPGF and the <i>SHOC1</i> gene and identified three novel genes (<i>PCSK4</i>, <i>AP3B1</i>, and <i>DLK1</i>) along with 32 potentially pathogenic rare variants in 30 genes that contribute to this condition.</p><p><strong>What is known already: </strong>SPGF is a major cause of male infertility, often with an unknown aetiology. SPGF can be due to either multifactorial causes, including both common genetic variants in multiple genes and environmental factors, or highly damaging rare variants. Next-generation sequencing methods are useful for identifying rare mutations that explain monogenic forms of SPGF. Genome-wide association studies (GWASs) have become essential approaches for deciphering the intricate genetic landscape of complex diseases, offering a cost-effective and rapid means to genotype millions of genetic variants. Novel methods have demonstrated that GWAS datasets can be used to infer rare coding variants that are causal for male infertility phenotypes. However, this approach has not been previously applied to characterize the genetic component of a whole case-control cohort.</p><p><strong>Study design size duration: </strong>We employed a hypothesis-driven approach focusing on all genetic variation identified, using a GWAS platform and subsequent genotype imputation, encompassing over 20 million polymorphisms and a total of 1571 SPGF patients and 2431 controls. Both common (minor allele frequency, MAF > 0.01) and rare (MAF < 0.01) variants were investigated within a total of 1797 loci with a reported role in spermatogenesis. This gene panel was meticulously assembled through comprehensive searches in the literature and various databases focused on male infertility genetics.</p><p><strong>Participants/materials setting methods: </strong>This study involved a European cohort using previously and newly generated data. Our analysis consisted of three independent methods: (i) variant-wise association analyses using logistic regression models, (ii) gene-wise association analyses using combined multivariate and collapsing burden tests, and (iii) identification and characterisation of highly damaging rare coding variants showing homozygosity only in SPGF patients.</p><p><strong>Main results and the role of chance: </strong>The variant-wise analyses revealed an association between SPGF and <i>SHOC1</i>-rs12347237 (<i>P </i>=<i> </i>4.15E-06, odds ratio = 2.66), which was likely explained by an altered binding affinity of key transcription factors in regulatory regions and the disruptive effect of coding variants within the gene. Three additional genes (<i>PCSK4</i>, <i>AP3B1</i>, and <i>DLK1</i>) were identified as novel relevan","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae069"},"PeriodicalIF":8.3,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11645127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Study question: </strong>Can semen parameters predict long-term health outcomes in men?</p><p><strong>Summary answer: </strong>There is a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration.</p><p><strong>What is known already: </strong>Male infertility has been long associated with a higher mortality risk and possibly higher chance of developing comorbidities but there has been less focus on semen analysis as a potential predictive factor.</p><p><strong>Study design size duration: </strong>We searched PubMed/MEDLINE, EMBASE, and EBM databases from inception to December 2023. MESH term strategy: heading 1 ('OR', semen analysis, sperm count, sperm parameter*, male infertility, azoospermia, aspermia, oligospermia, teratozoospermia, asthenozoospermia) 'AND' heading 2 ('OR', morbidity, mortality, diabetes, cancer, cardiovascular, death, hypertension, stroke, long-term health). We included all studies that analyzed the risk of mortality and/or future development of comorbidities in men with at least one semen analysis. Case series and reviews were excluded.</p><p><strong>Participants/materials setting methods: </strong>A narrative synthesis was done for all studies and meta-analysis where possible. Odds ratio (ORs) (95% CI, <i>P</i>-value) were calculated for all men with one suboptimal semen parameter and associated with the risk of a particular outcome. The risk of bias was assessed with QUADAS-2.</p><p><strong>Main results and the role of chance: </strong>Twenty-one studies were finally included. There was either a high or unclear risk of bias in all studies. The results only allowed for meta-analysis on categories of sperm concentration. We found a 2-fold increase in mortality risk in azoospermic men compared to oligospermic (OR 1.96, 95% CI: 1.29-2.96) and normozoospermic (OR 2.00, 95% CI: 1.23-3.25) groups, but not in oligospermic compared to normozoospermic (OR 1.04, 95% CI: 0.52-2.09). There was no difference in risk of cardiovascular disease in any of the sperm concentration groups (azoospermic-oligospermic OR 0.94, 95% CI: 0.74-1.20, azoospermic-normozoospermic OR 1.11, 95% CI: 0.71-1.75, and oligospermic-normozoospermic OR 1.12, 95% CI: 0.80-1.55). OR for diabetes in azoospermic men was higher only compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01). The risk of all-site cancer was higher in azoospermic men compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01) and normozoospermic (OR 2.18, 95% CI: 1.20-3.96). Only azoospermic men might be at higher risk of testicular cancer when compared to men with normal sperm concentration (OR 1.80, 95% CI: 1.12-2.89).</p><p><strong>Limitations reasons for caution: </strong>Although our pooled analysis shows an increased risk of mortality and all-site cancer risk in azoospermic men, the results show a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration. Given the limited available data, the nature of the
{"title":"Lab-based semen parameters as predictors of long-term health in men-a systematic review.","authors":"Silvia Nedelcu, Srisailesh Vitthala, Abha Maheshwari","doi":"10.1093/hropen/hoae066","DOIUrl":"10.1093/hropen/hoae066","url":null,"abstract":"<p><strong>Study question: </strong>Can semen parameters predict long-term health outcomes in men?</p><p><strong>Summary answer: </strong>There is a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration.</p><p><strong>What is known already: </strong>Male infertility has been long associated with a higher mortality risk and possibly higher chance of developing comorbidities but there has been less focus on semen analysis as a potential predictive factor.</p><p><strong>Study design size duration: </strong>We searched PubMed/MEDLINE, EMBASE, and EBM databases from inception to December 2023. MESH term strategy: heading 1 ('OR', semen analysis, sperm count, sperm parameter*, male infertility, azoospermia, aspermia, oligospermia, teratozoospermia, asthenozoospermia) 'AND' heading 2 ('OR', morbidity, mortality, diabetes, cancer, cardiovascular, death, hypertension, stroke, long-term health). We included all studies that analyzed the risk of mortality and/or future development of comorbidities in men with at least one semen analysis. Case series and reviews were excluded.</p><p><strong>Participants/materials setting methods: </strong>A narrative synthesis was done for all studies and meta-analysis where possible. Odds ratio (ORs) (95% CI, <i>P</i>-value) were calculated for all men with one suboptimal semen parameter and associated with the risk of a particular outcome. The risk of bias was assessed with QUADAS-2.</p><p><strong>Main results and the role of chance: </strong>Twenty-one studies were finally included. There was either a high or unclear risk of bias in all studies. The results only allowed for meta-analysis on categories of sperm concentration. We found a 2-fold increase in mortality risk in azoospermic men compared to oligospermic (OR 1.96, 95% CI: 1.29-2.96) and normozoospermic (OR 2.00, 95% CI: 1.23-3.25) groups, but not in oligospermic compared to normozoospermic (OR 1.04, 95% CI: 0.52-2.09). There was no difference in risk of cardiovascular disease in any of the sperm concentration groups (azoospermic-oligospermic OR 0.94, 95% CI: 0.74-1.20, azoospermic-normozoospermic OR 1.11, 95% CI: 0.71-1.75, and oligospermic-normozoospermic OR 1.12, 95% CI: 0.80-1.55). OR for diabetes in azoospermic men was higher only compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01). The risk of all-site cancer was higher in azoospermic men compared to oligospermic (OR 2.16, 95% CI: 1.55-3.01) and normozoospermic (OR 2.18, 95% CI: 1.20-3.96). Only azoospermic men might be at higher risk of testicular cancer when compared to men with normal sperm concentration (OR 1.80, 95% CI: 1.12-2.89).</p><p><strong>Limitations reasons for caution: </strong>Although our pooled analysis shows an increased risk of mortality and all-site cancer risk in azoospermic men, the results show a lack of evidence to suggest a higher risk of comorbidities in men with poor semen concentration. Given the limited available data, the nature of the ","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae066"},"PeriodicalIF":8.3,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11643900/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142830976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-07eCollection Date: 2024-01-01DOI: 10.1093/hropen/hoae064
Jill Browning, Magda Ghanim, William Jagoe, Jennifer Cullinane, Louise E Glover, Mary Wingfield, Vincent P Kelly
<p><strong>Study question: </strong>Does receptor for advanced glycation end products (RAGE) on the surface membrane of the sperm cell function as a biomarker of low-quality sperm?</p><p><strong>Summary answer: </strong>Membrane-bound RAGE at a cellular level directly correlates with low sperm motility, high cell permeability, decreased mitochondrial function, DNA fragmentation, and higher levels of apoptosis.</p><p><strong>What is known already: </strong>RAGE has previously been measured by ELISA in low-quality sperm in diabetic men and has been shown to correlate with DNA fragmentation (terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay).</p><p><strong>Study design size duration: </strong>Semen samples were recovered from 60 non-obese, non-diabetic and non-smoking subjects, washed with fresh media, and analysed directly or purified further by differential gradient centrifugation (DGC) or fractionated by direct swim-up before being analysed for sperm motility and molecular health parameters, including cell membrane permeability, cell death, mitochondrial membrane potential, DNA fragmentation, and RAGE protein expression.</p><p><strong>Participants/materials setting methods: </strong>Sperm motility assessments were carried out by computer-assisted sperm analysis (CASA) on 1000 spermatozoa for washed samples and 300 spermatozoa for purified samples. Molecular sperm health parameters were evaluated using flow cytometry with the use of the following markers: DAPI for cell membrane permeability, Annexin V/DAPI for cell death (apoptosis and necrosis), MitoTracker<sup>®</sup> Red CMXRos for mitochondrial membrane potential, TUNEL assay for DNA fragmentation and 8-hydroxy-2-deoxyguanosine for identification of oxidative damage to sperm DNA, and contrasted to membrane-bound RAGE expression levels, which were evaluated using an anti-RAGE monoclonal mouse antibody.</p><p><strong>Main results and the role of chance: </strong>RAGE protein was shown to be present on the acrosomal and equatorial regions of sperm, with the levels of membrane bound receptor strongly correlating with poor sperm health across all parameters tested; motility (<i>R</i> <sup>2</sup> = 0.5441, <i>P</i> < 0.0001) and mitochondrial membrane potential (<i>R</i> <sup>2</sup> = 0.6181, <i>P</i> < 0.0001) being of particular note. The analysis was performed at a single cell level thereby removing confounding complications from soluble forms of the RAGE protein that can be found in seminal plasma. The expression of the RAGE protein was shown to be stable over time and its levels are therefore not subject to variation in sample handling or preparation time.</p><p><strong>Large scale data: </strong>N/A.</p><p><strong>Limitations reasons for caution: </strong>Inclusion criteria for this study were non-diabetic, non-obese and non-smoking participants to assess the distribution of RAGE expression in the general population, thereby excluding disease conditions that may inc
研究问题：精子细胞表面膜上的高级糖化终产物受体（RAGE）是否可作为低质量精子的生物标志物？在细胞水平上，膜结合的 RAGE 与精子活力低、细胞通透性高、线粒体功能下降、DNA 断裂和细胞凋亡水平升高直接相关：研究设计的规模和持续时间：从60名非肥胖、非糖尿病和非吸烟的受试者中采集精液样本，用新鲜培养基洗涤，直接分析或通过差分梯度离心法（DGC）进一步纯化，或通过直接泳升法分馏，然后分析精子活力和分子健康参数，包括细胞膜通透性、细胞死亡、线粒体膜电位、DNA碎片和RAGE蛋白表达：精子活力评估采用计算机辅助精子分析法（CASA）进行，水洗样本的精子数量为 1000 个，纯化样本的精子数量为 300 个。分子精子健康参数采用流式细胞术进行评估，并使用以下标记物：DAPI 检测细胞膜通透性，Annexin V/DAPI 检测细胞死亡（凋亡和坏死），MitoTracker® Red CMXRos 检测线粒体膜电位，TUNEL 检测 DNA 断裂，8-hydroxy-2-deoxyguanosine 检测精子 DNA 氧化损伤，并与膜结合 RAGE 表达水平进行对比，后者使用抗 RAGE 单克隆小鼠抗体进行评估：主要结果和偶然因素：RAGE 蛋白存在于精子的顶体和赤道区域，膜结合受体的水平与精子在所有测试参数中的健康状况密切相关；活力（R 2 = 0.5441，P R 2 = 0.6181，P 大比例数据：不适用：本研究的纳入标准是非糖尿病、非肥胖和非吸烟的参与者，以评估普通人群中 RAGE 表达的分布情况，从而排除可能增加精子中 RAGE 表达或导致精子质量低下的疾病。该研究并未涉及与男性不育症相关的其他患者亚群或疾病状态对 RAGE 表达的影响。流式细胞术精子分析法不适于研究精子数量少的男性：该研究结果表明，RAGE表达是精子细胞健康的分子标志物，可通过清除RAGE表达的精子改善辅助生殖，并通过将其作为男性不育症的生物标志物促进不明原因不育症的诊断：该研究由爱尔兰研究委员会根据爱尔兰政府计划（GOIPG/2015/3729）和爱尔兰企业创新合作伙伴计划（IP-2020-0952）资助。所有作者声明不存在利益冲突。
{"title":"Membrane-bound receptor for advanced glycation end products (RAGE) is a stable biomarker of low-quality sperm.","authors":"Jill Browning, Magda Ghanim, William Jagoe, Jennifer Cullinane, Louise E Glover, Mary Wingfield, Vincent P Kelly","doi":"10.1093/hropen/hoae064","DOIUrl":"10.1093/hropen/hoae064","url":null,"abstract":"<p><strong>Study question: </strong>Does receptor for advanced glycation end products (RAGE) on the surface membrane of the sperm cell function as a biomarker of low-quality sperm?</p><p><strong>Summary answer: </strong>Membrane-bound RAGE at a cellular level directly correlates with low sperm motility, high cell permeability, decreased mitochondrial function, DNA fragmentation, and higher levels of apoptosis.</p><p><strong>What is known already: </strong>RAGE has previously been measured by ELISA in low-quality sperm in diabetic men and has been shown to correlate with DNA fragmentation (terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay).</p><p><strong>Study design size duration: </strong>Semen samples were recovered from 60 non-obese, non-diabetic and non-smoking subjects, washed with fresh media, and analysed directly or purified further by differential gradient centrifugation (DGC) or fractionated by direct swim-up before being analysed for sperm motility and molecular health parameters, including cell membrane permeability, cell death, mitochondrial membrane potential, DNA fragmentation, and RAGE protein expression.</p><p><strong>Participants/materials setting methods: </strong>Sperm motility assessments were carried out by computer-assisted sperm analysis (CASA) on 1000 spermatozoa for washed samples and 300 spermatozoa for purified samples. Molecular sperm health parameters were evaluated using flow cytometry with the use of the following markers: DAPI for cell membrane permeability, Annexin V/DAPI for cell death (apoptosis and necrosis), MitoTracker<sup>®</sup> Red CMXRos for mitochondrial membrane potential, TUNEL assay for DNA fragmentation and 8-hydroxy-2-deoxyguanosine for identification of oxidative damage to sperm DNA, and contrasted to membrane-bound RAGE expression levels, which were evaluated using an anti-RAGE monoclonal mouse antibody.</p><p><strong>Main results and the role of chance: </strong>RAGE protein was shown to be present on the acrosomal and equatorial regions of sperm, with the levels of membrane bound receptor strongly correlating with poor sperm health across all parameters tested; motility (<i>R</i> <sup>2</sup> = 0.5441, <i>P</i> < 0.0001) and mitochondrial membrane potential (<i>R</i> <sup>2</sup> = 0.6181, <i>P</i> < 0.0001) being of particular note. The analysis was performed at a single cell level thereby removing confounding complications from soluble forms of the RAGE protein that can be found in seminal plasma. The expression of the RAGE protein was shown to be stable over time and its levels are therefore not subject to variation in sample handling or preparation time.</p><p><strong>Large scale data: </strong>N/A.</p><p><strong>Limitations reasons for caution: </strong>Inclusion criteria for this study were non-diabetic, non-obese and non-smoking participants to assess the distribution of RAGE expression in the general population, thereby excluding disease conditions that may inc","PeriodicalId":73264,"journal":{"name":"Human reproduction open","volume":"2024 4","pages":"hoae064"},"PeriodicalIF":8.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568349/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142649741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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