Deletion or underexpression of the Y-chromosome genes CDY2 and HSFY is associated with maturation arrest in American men with nonobstructive azoospermia

Maturation arrest （MA） refers to failure of germ cell development leading to clinical nonobstructive azoospermia. Although the azoospermic factor （AZF） region of the human Y chromosome is clearly implicated in some cases, thus far very little is known about which individual Y-chromosome genes are important for complete male germ cell development. We sought to identify single genes on the Y chromosome that may be implicated in the pathogenesis of nonobstructive azoospermia associated with MA in the American population. Genotype-phenotype analysis of 132 men with Y-chromosome microdeletions was performed. Protein-coding genes associated with MA were identified by visual analysis of a genotype-phenotype map. Genes associated with MA were selected as those genes within a segment of the Y chromosome that, when completely or partially deleted, were always associated with MA and absence of retrievable testicular sperm. Expression of each identified gene transcript was then measured with quantitative RT-PCR in testicular tissue from separate cohorts of patients with idiopathic MA and obstructive azoospermia. Ten candidate genes for association with MA were identified within an 8.4-Mb segment of the Y chromosome overlapping the AZFb region. CDY2and HSFYwere the only identified genes for which differences in expression were observed between the MA and obstructive azoospermia cohorts. Men with obstructive azoospermia had 12-fold higher relative expression of CDY2transcript （1.33__.0.40 vs. 0.11＋_0.04; P=O.O003） and 16-fold higher expression of HSFYtranscript （0.78__.0.32 vs. 0.05_0.02; P=O.O005） compared to men with MA. CDY2 and HSFYwere also underexpressed in patients with Sertoli cell only syndrome. These data indicate that CDY2and HSFYare located within a segment of the Y chromosome that is important for sperm maturation, and are underexpressed in testicular tissue derived from men with MA. These observations suggest that impairments in CDY2 or HSFYexpression could be implicated in the pathogenesis of MA.

Diagnosis of myocardial infarction with nonobstructive coronary arteries in a young man in the setting of acute myocardial infarction after endoscopic retrograde cholangiopancreatography: A case report

BACKGROUND Acute myocardial infarction(AMI) is characterized by chest pain as well as cardiac troponin I(cTnI) and electrocardiography(ECG) changes. Recently,clinical researchers have used the term "MINOCA" to indicate myocardial infarction with nonobstructive coronary arteries. To the best of our knowledge,no report has documented MINOCA in a young patient after choledocholithiasis by endoscopic retrograde cholangiopancreatography(ERCP).CASE SUMMARY An 18-year-old Chinese man presented to the cardiac intensive care unit with chest pain radiating to the left shoulder for 1 h after choledocholithiasis by ERCP and the following treatment. ECG showed a sinus rhythm with ST-segment elevation in the Ⅱ,Ⅲ, and aVF leads compared with the baseline. Laboratory data revealed cTnI levels of 67.55 ng/mL and 80 ng/mL at the peak(relative index below 0.034 ng/mL) and creatine kinase-MB levels of 56 U/L and 543 U/L at the peak(relative index below 24 U/L). AMI was suspected, and coronary angiography was performed the second day. The results revealed a smooth angiographic appearance of all arteries. The patient had been diagnosed with gallstones and cholecystitis for four years but had not accepted treatment. He had abdominal pain and bloating a week previously and underwent ERCP and subsequent treatments on the second day of admission;1.4 cm × 1.6 cm of stones were removed from his common bile duct during surgery. The results of his laboratory tests at admission revealed abnormal alanine aminotransferase,aspartate aminotransferase, glutamyl transpeptidase, total bile acid, total bilirubin, direct bilirubin, and indirect bilirubin levels. His temperature, heart rate, blood pressure, and body mass index were normal. His echocardiographic examination revealed no obvious abnormalities in the structure and movement of the ventricular wall and an estimated left ventricular ejection fraction of 57% after the heart attack. His cholesterol and triglycerides were within normal ranges, and his low-density lipoprotein cholesterol was 2.23 mmol/L(normal range 2.03-3.34 mmol). Further testing after AMI revealed nothing remarkable in his erythrocyte sedimentation rate, thyroid function, and tumour markers.CONCLUSION We ultimately made a diagnosis of MINOCA caused by coronary artery spasm,which seemed to be the most suitable diagnosis of this young patient. We are concerned that the heart attack may have been induced by the ERCP rather than occurred coincidentally afterward, so we should investigate the timing of the event further. Additional studies are needed to unravel the underlying pathophysiology.

Nonobstructive Coronary Artery Disease in Women:Risk Factors and Noninvasive Diagnostic Assessment

Sex-specific differences in the epidemiology and pathophysiology of coronary artery disease and ischemic heart disease are now well recognized.Women with angina more often have nonobstructive coronary artery disease(NOCAD)compared with men.This patient population carries a significant risk of future cardiovascular events that is not commonly appreciated,often leading to delayed diagnosis and treatment.While coronary microvascular dysfunction plays a central role in the pathophysiology of NOCAD in women,other mechanisms of myocardial ischemia are now recognized.Risk factors such as hypertension and obesity disparately affect women and are likely to account for a signifi cant proportion of NOCAD in the coming years.Vascular inflammation is an important pathophysiologic pathway in NOCAD and is a potential therapeutic target.Coronary CT angiography provides a comprehensive assessment of coronary anatomy and plaque morphology and is a reasonable screening test of choice for NOCAD.

Testicular volume is a noninvasive predictor of sperm retrieval failure in idiopathic nonobstructive azoospermia

We investigated the prognostic importance of noninvasive factors in predicting sperm retrieval failure in idiopathic nonobstructive azoospermia(iNOA).We studied 193 patients with nonobstructive azoospermia who underwent microsurgical testicular sperm extraction.The Chi-square test and Mann–Whitney U tests for clinical parameters and seminiferous tubule distribution were used for between-group comparisons.A logistic regression analysis was conducted to identify predictors of retrieval failure.Area under the receiver operating characteristic curve for each variable was evaluated,and the net clinical benefit was calculated using a clinical decision curve.Patients with iNOA had a lower sperm retrieval rate than those with known causes.Moreover,testicular volume was an independent factor affecting sperm extraction outcomes(odds ratio=0.79,P<0.05).The testicular volume cut-off value was 6.5 ml(area under the curve:0.694).The patients with iNOA were categorized into two groups on the basis of the distribution of seminiferous tubules observed.The sperm retrieval rate and testicular volume were significantly different between the groups with a uniform or heterogeneous tubule distribution.There was also a significant association between a uniform tubule distribution and testicular volume.In conclusion,a testicular volume of more than 6.5 ml effectively predicts microsurgical testicular sperm extraction failure due to a uniform tubule distribution in patients with iNOA.

Association between anti-Müllerian hormone concentrations and sperm retrieval outcomes in patients with idiopathic nonobstructive azoospermia:a systematic review and meta-analysis

Microdissection testicular sperm extraction(mTESE)is commonly performed to retrieve sperm in the testes for assisted reproductive techniques in patients with idiopathic nonobstructive azoospermia(iNOA).However,the success rate of sperm retrieval varies among individuals.We aim to investigate the association between clinical parameters and sperm retrieval outcomes in patients with iNOA.We searched PubMed,EMBASE,and Web of Science from database inception to August 2,2023.The main measure was whether sperm retrieval was successful in patients with iNOA who underwent mTESE.Pooled estimates of the sperm retrieval rate and weighted mean differences were calculated using random-effects models.The overall sperm retrieval rate was 36.8%(95%confidence interval[CI]:27.5%-46.0%,I 2=95.0%)in nine studies comprising 1892 patients with iNOA.No significant differences were found in age,testicular volume,serum total testosterone concentrations,or inhibin B concentrations between positive and negative sperm retrieval outcomes.Lower anti-Müllerian hormone concentrations in patients with iNOA were associated with a positive outcome of mTESE(weighted mean differences:−2.70;95%CI:−3.94-−1.46,I 2=79.0%).In conclusion,this study shows a significant relationship between anti-Müllerian hormone and sperm retrieval outcomes in patients with iNOA,while age,testicular volume,total testosterone,and inhibin B show no significant association.These findings have important implications for assessing the potential success of sperm retrieval and selecting appropriate treatment strategies in patients with iNOA.

Identification of risk genes in Chinese nonobstructive azoospermia patients based on whole-exome sequencing

Nonobstructive azoospermia(NOA)is a severe condition in infertile men,and increasing numbers of causative genes have been identified during the last few decades.Although certain causative genes can explain the presence of NOA in some patients,a proportion of NOA patients remain to be addressed.This study aimed to investigate potential high-risk genes associated with spermatogenesis in idiopathic NOA patients by whole-exome sequencing.Whole-exome sequencing was performed in 46 male patients diagnosed with NOA.First,screening was performed for 119 genes known to be related to male infertility.Next,further screening was performed to determine potential high-risk causative genes for NOA by comparisons with 68 healthy male controls.Finally,risk genes with high/specific expression in the testes were selected and their expression fluctuations during spermatogenesis were graphed.The frequency of cystic fibrosis transmembrane conductance regulator(CFTR)gene pathogenic variant carriers was higher in the NOA patients compared with the healthy controls.Potential risk genes that may be causes of NOA were identified,including seven genes that were highly/specifically expressed in the testes.Four risk genes previously reported to be involved in spermatogenesis(MutS homolog 5[MSH5],cilia-and flagella-associated protein 54[CFAP54],MAP7 domain containing 3[MAP7D3],and coiled-coil domain containing 33[CCDC33])and three novel risk genes(coiled-coil domain containing 168[CCDC168],chromosome 16 open reading frame 96[C16orf96],and serine protease 48[PRSS48])were identified to be highly or specifically expressed in the testes and significantly different in the 46 NOA patients compared with 68 healthy controls.This study on clinical NOA patients provides further evidence for the four previously reported risk genes.The present findings pave the way for further functional investigations and provide candidate risk genes for genetic diagnosis of NOA.

Efficacy of stepwise mini-incision microdissection testicular sperm extraction for nonobstructive azoospermia with varied etiologies

Stepwise mini-incision microdissection testicular sperm extraction(mTESE)is a procedure that attempts to minimize testicular damage.However,the mini-incision approach may vary in patients with different etiologies.Here,we performed a retrospective analysis of 665 men with nonobstructive azoospermia(NOA)who underwent stepwise mini-incision mTESE(Group 1)and 365 men who underwent standard mTESE(Group 2).The results showed that the operation time(mean±standard deviation)for patients with successful sperm retrieval in Group1(64.0±26.6min)was significantly shorter than that in Group2(80.2±31.3min),with P<0.001.The total sperm retrieval rate(SRR)was 23.1%in our study,and there was no significant difference between Group 1 and Group 2(P>0.05),even when the etiologies of NOA were taken into consideration.The results of consecutive multivariate logistic regression analysis(odds ratio[0R]:0.57;95%confidence interval[Cl]:0.38-0.87;P=0.009)and receiver operating characteristic(ROC)analysis(area under the ROC curve[AUC]=O.628)showed that preoperative anti-Mullerian hormone(AMH)level in idiopathic NOA patients was a potential predictor for surgical outcomes after initial three small incisions made in the equatorial region without sperm examined under an operating microscope(Steps 2-4).In conclusion,stepwise mini-incision mTESE is a useful technique for NOA patients,with comparable SRR,less surgical invasiveness,and shorter operation time compared with the standard approach.Low AMH levels may predict successful sperm retrieval in idiopathic patients even after a failed initial mini-incision procedure.

Clinical management of infertile men with nonobstructive azoospermia

The clinical management of men with nonobstructive azoospermia （NOA） seeking fertility has been a challenge for andrologists, urologists, and reproductive medicine specialists alike. This review presents a personal perspective on the clinical management of NOA, including the lessons learned over 15 years dealing with this male infertility condition. A five-consecutive-step algorithm is proposed to manage such patients. First, a differential diagnosis of azoospermia is made to confirm/establish that NOA is due to spermatogenic failure. Second, genetic testing is carried out not only to detect the males in whom NOA is caused by microdeletions of the long arm of the Y chromosome, but also to counsel the affected patients about their chances of having success in sperm retrieval. Third, it is determined whether any intervention prior to a surgical retrieval attempt may be used to increase sperm production. Fourth, the most effective and efficient retrieval method is selected to search for testicular sperm. Lastly, state-of-art laboratory techniques are applied in the handling of retrieved gametes and cultivating the embryos resulting from sperm injections. A coordinated multidisciplinary effort is key to offer the best possible chance of achieving a biological offspring to males with NOA.

Predictive value of FSH, testicular volume, and histopathological findings for the sperm retrieval rate of microdissection TESE in nonobstructive azoospermia： a meta-analysis

We performed this meta-analysis to evaluate the predictive value of different parameters in the sperm retrieval rate （SRR） of microdissection testicular sperm extraction （TESE） in patients with nonobstructive azoospermia （NOA）. All relevant studies were searched in PubMed, Web of Science, EMBASE, Cochrane Library, and EBSCO. We chose three parameters to perform the meta-analysis： follicle-stimulating hormone （FSH）, testicular volume, and testicular histopathological findings which included three patterns： hypospermatogenesis （HS）, maturation arrest （MA）, and Sertoli-cell-only syndrome （SCOS）. If there was a threshold effect, only the area under the summary receiver operating characteristic curve （AUSROC） was calculated. Otherwise, the pooled sensitivity, specificity, positive likelihood ratio （PLR）, negative likelihood ratio （NLR）, and the diagnostic odds ratio （DOR） were also calculated. Twenty-one articles were included in our study finally. There was a threshold effect among studies investigating FSH and SCOS. The AUSROCs of FSH, testicular volume, HS, MA, and SCOS were 0.6119, 0.6389, 0.6758, 0.5535, and 0.2763, respectively. The DORs of testicular volume, HS, and MA were 1.98, 16.49, and 1.26, respectively. The sensitivities of them were 0.80, 0.30, and 0.27, while the specificities of them were 0.35, 0.98, and 0.76, respectively. The PLRs of them were 1.49, 10.63, and 1.15, respectively. And NLRs were 0.73, 0.72, and 0.95, respectively. All the investigated factors in our study had limited predictive value. However, the histopathological findings were helpful to some extent. Most patients with HS could get sperm by microdissection TESE.

Altered microRNA profiles of testicular biopsies from patients with nonobstructive azoospermia

Many studies have shown that microRNAs(miRNAs)play vital roles during the spermatogenesis.However,little is known about the altered miRNA profiles of testicular tissues in nonobstructive azoospermia(NOA).Using microarray technology,the miRNA expression profiles of testicular biopsies from patients with NOA and of normal testicular tissues were determined.Bioinformatics analyses were conducted to predict the enriched biological processes and functions of identified miRNAs.The microarray data were validated by quantitative reverse transcriptase polymerase chain reaction(qRT-PCR),the results of which were then validated with a larger sample size.Correlations between the miRNA expression levels and clinical characteristics were analyzed.Receiver operating characteristic(ROC)curve analysis was used to evaluate the diagnostic ability of miRNAs for azoospermia.Hierarchical clustering showed that 129 miRNAs were significantly differentially expressed between the NOA and control groups.Bioinformatics analysis indicated that the differentially expressed miRNAs were involved in spermatogenesis,cell cycle,and mitotic prometaphase.In the subsequent qRT-PCR assays,the selected miRNA expression levels were consistent with the microarray results,and similar validated results were obtained with a larger sample size.Some clinical characteristics were significantly associated with the expression of certain miRNAs.In particular,we identified a combination of two miRNAs(miR-10b-3p and miR-34b-5p)that could serve as a predictive biomarker of azoospermia.This study provides altered miRNA profiles of testicular biopsies from NOA patients and examines the roles of miRNAs in spermatogenesis.These profiles may be useful for predicting and diagnosing the presence of testicular sperm in individuals with azoospermia.

Y-chromosome microdeletions in nonobstructive azoospermia and severe oligozoospermia

The aim of the present work was to present the outcomes of the patients with Y-chromosome microdeletions treated by intracytoplasmic sperm injection （ICSI）, either using fresh （TESE） or frozen-thawed （TESE-C） testicular sperm and ejaculated sperm （EJAC）. The originality of this work resides in the comparisons between the different types of Y-microdeletions （AZFa, AZFb, and AZFc） and treatments, with detailed demographic, stimulation, embryological, clinical, and newborn （NB） outcomes. Of 125 patients with Y-microdeletions, 33 patients presented severe oligozoospermia （18 performed ICSI with ejaculated sperm） and 92 secretory azoospermia （65 went for TESE with 40 having successful sperm retrieval and performed ICSI）. There were 51 TESE treatment cycles and 43 TESE-C treatment cycles, with a birth of 19 NB （2 in AZFa/TESE-C, 12 in AZFc/TESE, and 5 in AZFc/TESE-C）. Of the 29 EJAC cycles, there was a birth of 8 NB （in AZFc）. In TESE and EJAC cycles, there were no significant differences in embryological and clinical parameters. In TESE-C cycles, there was a significant lower oocyte maturity rate, embryo cleavage rate and mean number of embryos transferred in AZFb, and a higher mean number of oocytes and lower fertilization rate in AZFc. In conclusion, although patients with AZFc microdeletions presented a high testicular sperm recovery rate and acceptable clinical outcomes, cases with AZFa and AZFb microdeletions presented a poor prognosis. Due to the reported heredity of microdeletions, patients should be informed about the infertile consequences on NB and the possibility of using preimplantation genetic diagnosis for female sex selection.

Follicle-stimulating hormone as a predictor for sperm retrieval rate in patients with nonobstructive azoospermia, a systematic review and meta-analysis

Noninvasive parameters for predicating sperm retrieval rate （SRR） are desirables. Follicle-stimulating hormone （FSH） has been an important predictor since the first years of testicular sperm extraction. Recent studies showed continuous interests in FSH, with both pros and cons. Thus, we conducted a meta-analysis to evaluate the diagnostic value of FSH as a predictor for patients with nonobstructive azoospermia （NOA） taking testicular sperm retrieval. Eligible diagnosis tests were identified from electronic databases （Cochrane Central Register of Controlled Trials, Medline, and EMBASE） without language restrictions. The database search, quality assessment, and data extraction were performed independently by two reviewers. The reference standard was the sperm retrieval result. Diagnostic value of FSH were explored by area under receiver operation characteristics （ROC） curve using Review Manager, version 5.1.0 （Cochrane Collaboration, Oxford, UK） and Meta-DiSc, version 1.4. Meta regression will be done if there is heterogeneity. Then, we find 11 tests including a total of 1350 patients met the inclusion criteria. Our pooled analysis showed that the area under ROC curve of FSH was 0.72 ~ 0.04. Meta regression analyses showed that region and average age have an influence on the diagnostic value. FSH showed more diagnostic value with patients in East Asia and with younger patients. We concluded that FSH had moderate value in independently predicating SRR in men with NOA （area under curve 〉0.7）. More detailed diagnosis tests should be anticipated in the future to confirm the diagnostic value of other noninvasive parameters.

Seminal plasma miR-192a： a biomarker predicting successful resolution of nonobstructive azoospermia following varicocele repair

This study was performed to investigate a potential marker for the presence of spermatozoa in the ejaculate following varicocelectomy in Chinese men with nonobstructive azoospermia and varicoceles. The micro-RNA （miR）-192a levels in seminal plasma and testicular tissue were evaluated by quantitative real-time polymerase chain reaction from 60 men with nonobstructive azoospermia and varicoceles （Group A： 27 men with spermatozoa found in the ejaculate after surgery; Group B： 33 men without spermatozoa found in the ejaculate after surgery） and 30 controls. The seminal plasma and testicular tissue miR-192a levels were higher in Group B than in Group A and the controls （P〈 0.001）, and there was no significant difference between Group A and the controls （P〉 0.05）. Apoptosis and proliferation assays with miR mimics and inhibitors showed that miR-192a induced GC-2 cell apoptosis through the activation of Caspase-3 protein. Thus, seminal plasma miR-192a appears to be a potential marker for successfully indicating spermatozoa in the ejaculate following microsurgical varicocelectomy in men with nonobstructive azoospermia and varicoceles. Seminal plasma miR-192a may be a useful clinical marker for prescreening to determine which patients with nonobstructive azoospermia and varicoceles would benefit from varicocelectomy.

Sperm retrieval success and testicular histopathology in idiopathic nonobstructive azoospermia

Prior studies have investigated sperm retrieval rates in men with non obstructive azoospermia(NOA)secondary to specific etiologies,yet most cases of NOA are idiopathic.We compared sperm retrieval rates and testicular histopathology in idiopathic NOA(iNOA)and nonidiopathic NOA(niNOA).We performed a retrospective review of men with NOA who underwent microdissection testicular sperm extraction(microTESE)between 2000 and 2016.Men with no history of malignancy or cryptorchidism and negative genetic evaluation were considered idiopathic.Multivariable regression determined the association between idiopathic etiology and primary outcomes of sperm retrieval and active spermatogenesis on histopathology.Among 224 men,86(38.4%)were idiopathic,75(33.5%)were nonidiopathic,and 63(28.1%)did not undergo genetic testing.Median age and serum testosterone were higher among iNOA or no testing versus niNOA.Median follicle-stimulating hormone(FSH)was lower among iNOA or no testing versus niNOA.A higher proportion of iNOA or no testing versus niNOA had a clinical varicocele.Sperm retrieval rates were similar between iNOA,niNOA,and no testing(41.8%vs 48.0%vs 55.6%,respectively;P=0.255).Active spermatogenesis was seen in a higher proportion of iNOA or no testing versus niNOA(31.4%and 27.0%vs 16.0%,P=0.073).On multivariable analysis,iNOA was not associated with sperm retrieval or spermatogenesis(P=0.430 and P=0.078,respectively).Rates of sperm retrieval and spermatogenesis on testis pathology were similar in men with iNOA and niNOA.These data will be useful to clinicians in preoperative counseling for men with NOA and negative genetic evaluation.

Endocrine aberrations of human nonobstructive azoospermia

Nonobstructive azoospermia(NOA)refers to the failure of spermatogenesis,which affects approximately 1%of the male population and contributes to 10%of male infertility.NOA has an underlying basis of endocrine imbalances since proper human spermatogenesis relies on complex regulation and cooperation of multiple hormones.A better understanding of subtle hormonal disturbances in NOA would help design and improve hormone therapies with reduced risk in human fertility clinics.The purpose of this review is to summarize the research on the endocrinological aspects of NOA,especially the hormones involved in hypothalamic–pituitary–testis axis(HPTA),including gonadotropin-releasing hormone,follicle-stimulating hormone,luteinizing hormone,prolactin,testosterone,estradiol,sex hormone binding globulin,inhibin B,anti-Müllerian hormone,and leptin.For the NOA men associated with primary testicular failure,the quality of currently available evidence has not been sufficient enough to recommend any general hormone optimization therapy.Some other NOA patients,especially those with hypogonadotropic hypogonadism,could be treated with hormonal replacement.Although these approaches have succeeded in resuming the fertility in many NOA patients,the prudent strategies should be applied in individuals according to specific NOA etiology by balancing fertility benefits and potential risks.This review also discusses how NOA can be induced by immunization against hormones.

MBOAT1 homozygous missense variant causes nonobstructive azoospermia

Nonobstructive azoospermia(NOA)is a common cause of infertility and is defined as the complete absence of sperm in ejaculation due to defective spermatogenesis.The aim of this study was to identify the genetic etiology of NOA in an infertile male from a Chinese consanguineous family.A homozygous missense variant of the membrane-bound O-acyltransferase domain-containing 1(MBOAT1)gene(c.770C>T,p.Thr257Met)was found by whole-exome sequencing(WES).Bioinformatic analysis also showed that this variant was a pathogenic variant and that the amino acid residue in MBOAT1 was highly conserved in mammals.Quantitative polymerase chain reaction(Q-PCR)analysis showed that the mRNA level of MBOAT1 in the patient was 22.0%lower than that in his father.Furthermore,we screened variants of MBOAT1 in a broader population and found an additional homozygous variant of the MBOAT1 gene in 123 infertile men.Our data identified homozygous variants of the MBOAT1 gene associated with male infertility.This study will provide new insights for researchers to understand the molecular mechanisms of male infertility and will help clinicians make accurate diagnoses.

Mutational analysis of the GATA4 gene in Chinese men with nonobstructive azoospermia

As a crucial transcription factor for spermatogenesis,GATA-binding protein 4(GATA4)plays important roles in the functioning of Sertoli and Leydig cells.Conditional knockout of GATA4 in mice results in age-dependent testicular atrophy and loss of fertility.However,whether GATA4 is associated with human azoospermia has not been reported.Herein,we analyzed the GATA4 gene by direct sequencing of samples obtained from 184 Chinese men with idiopathic nonobstructive azoospermia(NOA).We identified a missense mutation(c.191G>A,p.G64E),nine single-nucleotide polymorphisms(SNPs),and one rare variant(c.^(*)84C>T)in the 3′untranslated region(UTR).Functional studies demonstrated that the p.G64E mutation did not affect transactivation ability of GATA4 for spermatogenesis-related genes(claudin-11 and steroidogenic acute regulatory protein,Star),and the 3′UTR rare variant c.^(*)84C>T did not generate microRNA-binding sites to repress GATA4 expression.To our knowledge,this is the first report to investigate the association between GATA4 and azoospermia;our results indicate that mutations in GATA4 may not be pathogenic for NOA in Chinese men.

Risk of ventricular arrhythmia in patients with myocardial infarction and non-obstructive coronary arteries and normal ejection fraction

AIM To assess the arrhythmic determinants and prognosis of patients presenting with myocardial infarction and nonobstructive coronary arteries(MINOCA)with normal ejection fraction(EF).METHODS This is an observational analysis of 131 MINOCA patients with normal EF.Three cardiac magnetic resonance(CMR)diagnosis classes were recognized according to the late gadolinium enhancement(LGE)pattern:Myocardial infarction(MI)(n=34),myocarditis(n=47),and"no LGE"(n=50).Ventricular events occurring during hospitalization were recorded and the entire population was followed-up at 1 year.RESULTS Ventricular arrhythmia was observed in 18(13.8%)patients during hospitalization.The"no LGE"patients experienced fewer ventricular events than the MI and myocarditis patients[4.0%vs 26.5%and 14.9%,respectively(P=0.013)].There was no significant difference between the MI and myocarditis groups.On multivariate analysis,LGE transmural extent[OR=1.52(1.08-2.15),P=0.017]and ST-segment elevation[OR=4.65(1.61-13.40),P=0.004]were independent predictors of ventricular arrhythmic events,irrespective of the diagnosis class.Finally,no patient experienced sudden cardiac death or ventricular arrhythmia recurrence at 1-year.CONCLUSION MINOCA patients with normal EF presented no 1-year cardiovascular events,irrespective of the CMR diagnosis class.LGE transmural extent and ST segment elevation at admission are risk markers of ventricular arrhythmia during hospitalization.

A randomized, controlled, multicenter contraceptive efficacy clinical trial of the intravas device, a nonocclusive surgical male sterilization

Because of unavoidable complications of vasectomy, this study was undertaken to assess the efficacy and safety of male sterilization with a nonobstructive intravas device （IVD） implanted into the vas lumen by a mini-surgical method compared with no-scalpel vasectomy （NSV）. IVDs were categorized into two types： IVD-B has a tail used for fixing to the vas deferens （fixed wing） whereas IVD-A does not. A multicenter prospective randomized controlled clinical trial was conducted in China. The study was comprised of 1459 male volunteers seeking vasectomy who were randomly assigned to the IVD-A （n = 487）, IVD-B （n = 485） or NSV （n = 487） groups and underwent operation. Follow-up included visits at the 3rd-6TM and 12~ postoperative months, The assessments of the subjects involved regular physical examinations （including general and andrological examinations） and semen analysis. The subjects＇ partners also underwent monitoring for pregnancy by monthly interviews regarding menstruation and if necessary, urine tests, There were no significant differences in pregnancy rates （0.65% for IVD-A, 0 for IVD-B and 0.21% for NSV） among the three groups （P 〉 0.05）. The cumulative rates of complications at the 12th postoperative month were zero, 0.9% and 1.7% in the three groups, respectively. In conclusion, IVD male sterilization exhibits a low risk of long-term adverse events and was found to be effective as a male sterilization method, similar to the NSV technique. IVD male sterilization is expected to be a novel contraceptive method.

Novel Imaging Approaches for the Diagnosis of Stable Ischemic Heart Disease in Women

Conventional recommendations for diagnostic testing for the evaluation of stable ischemic heart disease in women have largely paralleled those in men.Although they are designed primarily for the identifi cation of obstructive coronary artery disease(CAD),traditional approaches can lead to overtesting in women without differentiating who is truly at risk.Several unique factors related to the presentation,diagnosis,and underlying pathophysiology of stable ischemic heart disease in women necessitate a more specific approach to the assessment of their risk,complete with separate guidelines when appropriate.This overview highlights how advanced noninvasive imaging tools,including cardiac computed tomography angiography,positron emission tomography,and cardiac magnetic resonance imaging,are enabling very sensitive assessments of anatomic atherosclerotic plaque burden,macrovessel-and microvessel-related ischemia,and myocardial fi brosis,respectively.Moving forward,effective diagnostic testing will need to identify women at high risk of adverse cardiovascular events(not anatomically obstructive CAD per se)without overtesting those at low risk.Judicious application of novel imaging approaches will be critical to broadening the defi nitions of CAD and ischemia to better refl ect the whole spectrum of pathological phenotypes in women,including nonobstructive CAD and coronary microvascular dysfunction,and aid in the development of needed evidence-based strategies for their management.