多囊卵巢综合征无排卵的胰岛素信号和雄激素合成的新遗传风险和代谢特征

促排卵是多囊卵巢综合征(PCOS)不孕症的一线治疗方案。卵巢对促排卵治疗的排卵应答差被认为与胰岛素抵抗和高雄激素血症相关。在一个包含1000名PCOS不孕妇女(PCOSAct)的前瞻性队列中,我们开展了一项全外显子联合靶向单核苷酸多态性(SNP)测序以及代谢组学研究。在全基因组水平找出与无排卵显著相关的常见变异和罕见突变,并通过机器学习算法构建排卵预测模型。研究发现,ZNF438基因中标记为rs2994652(p=2.47×10^(-8))的常见变异和REC114基因中的一个罕见功能突变(rs182542888,p=5.79×10^(-6))与促排卵治疗失败显著相关。携带rs2994652 A等位基因和REC114 p.Val101Leu(rs182542888)的PCOS不孕妇女进行促排卵治疗的总排卵率更低(分别为比值比(OR)=1.96,95%置信区间(CI)[1.55~2.49];OR=11.52,95%CI[3.08~43.05]),出现排卵的间隔时间更长(平均56.7天vs.49.0天,p<0.001;78.1天vs.68.6天,p=0.014)。对于rs2994652突变者,L-苯丙氨酸水平升高并与胰岛素抵抗稳态模型(HOMA-IR)指数(r=0.22,p=0.05)和空腹血糖(r=0.33,p=0.003)呈正相关;对于rs182542888突变者,花生四烯酸代谢产物水平下降并与升高的抗苗勒管激素(r=-0.51,p=0.01)和总睾酮(r=-0.71,p=0.02)呈负相关。整合基因变异位点、代谢产物及临床特征的联合预测模型可提高对排卵的预测能力[曲线下面积(AUC)=76.7%]。ZNF438基因的一个常见变异和REC114基因的一个罕见功能突变,以及与二者相关的苯丙氨酸和花生四烯酸代谢物改变,与PCOS女性不孕症的促排卵治疗失败相关。

Hospital-Based Phenotypic Features and Treatment Outcomes of Chinese Women with Polycystic Ovary Syndrome: The Effect of Body Mass Index and Geographic Distribution

Genetic,lifestyle,and environmental factors contribute to the etiology of polycystic ovary syndrome(PCOS).Increased body mass index(BMI)exacerbates the reproductive and metabolic parameters and reduces the fecundity of women with PCOS.This is a secondary analysis of a large-sample,multicenter,randomized controlled trial conducted at 21 sites in Chinese mainland.A total of 1000 women diagnosed with PCOS were enrolled in this trial.Of these,998 women with PCOS were included in the analysis.Increased BMI was associated with more severe menstrual irregularities,elevated testosterone level,higher prevalence of metabolic syndrome,and poorer quality of life.The rates of ovulation per woman for the normal,overweight,and obese BMI groups were 83.0%,78.2%,and 63.6%,respectively(P<0.001),and the rates of live birth were 23.6%,18.1%,and 15.3%(P=0.030).Northern PCOS patients showed more severe reproductive,glucose,and lipid profiles;less exercise;and lower total ovulation rates compared with PCOS patients from Southern China(74.8%vs 81.2%,absolute difference 6.4%,95%confidence interval 1.2%–11.5%).The results show the typical phenotypic features of Han women with PCOS in Northern and Southern China.The women living in Northern China showed a higher BMI,more severe glycolipid metabolism profiles,and subsequently worse clinical outcomes by the same interventions than those living in Southern China.The difference in phenotypic features can be explained mostly by differences in BMI and the resulting difference in ovulation.

特力阿扎维林治疗新冠病毒肺炎的疗效和安全性——试验方案

根据2019年12月的报道,新冠病毒肺炎(coronavirus disease 2019, COVID-19)是由一种新型冠状病毒引起的肺炎。到目前为止,还没有发现能够治疗这种病毒的有效药物。本研究是一项在黑龙江省10个研究中心正在进行的多中心双盲随机对照试验(randomized controlled trial, RCT),其目的是研究与安慰剂相比,特力阿扎维林(triazavirin, TZV)治疗COVID-19患者的疗效和安全性。共计划招募240名COVID-19患者参加这项试验。咽拭子病毒核酸检测为阳性的受试者被随机(1∶1)分为两组:使用标准治疗加TZV或标准治疗加安慰剂,进行为期7 d的治疗和为期21 d的随访。主要结局是受试者临床改善的时间。次要结局包括临床改善率、退热时间、肺内炎症明显吸收的平均时间和人数比例、病毒核酸转阴率、病死率以及重症和危重症患者的转化率。整个试验过程将对不良事件,严重不良事件,肝功能、肾功能以及合并用药进行监测和记录。本试验的结果可为临床医生治疗COVID-19提供循证医学的证据和建议。

Semen Analysis and Fecundity Association Among Women with Polycystic Ovary Syndrome Experiencing Ovulatory Dysfunction Treated by Ovulation Induction

In this study,normal values of semen analysis were set for a general infertile population of couples among which most women had normal ovulation.The predictive capacity values of sperm quality,including concentration,motile count,progressive motile count,and morphology,are unclear for women with polycystic ovary syndrome(PCOS).A secondary analysis was conducted based on a randomized controlled trial investigating infertility among women with PCOS experiencing ovulatory disorder between 2011 and 2016 in China.A total of 1000 women received ovulation induction(acupuncture and clomiphene).We randomized the women with PCOS in 27 hospitals in China who received one of four interventions(acupuncture plus clomiphene,sham acupuncture plus clomiphene,acupuncture plus placebo,or sham acupuncture plus placebo).Semen analysis was performed for every male partner according to the World Health Organization(WHO)criteria.The outcomes included conception,clinical pregnancy,and live birth.Logistic regression was used to evaluate the predictive value of semen analysis among ovulatory women for conception,clinical pregnancy,and live birth.Among the 1000 couples,the number of couples who attained ovulation,conception,clinical pregnancy,and live birth were 780,320,235,and 205,respectively.Semen volume and motility were applied and used as prediction parameters for conception(area under the curve(AUC)of 0.62(95%confidence interval(CI),0.55–0.69)),clinical pregnancy(AUC of 0.67(95%CI:0.61–0.73)),and live birth(AUC of 0.57(95%CI:0.50–0.64)).No poor calibration was shown for these models in Hosmer–Lemeshow tests.The predictive capacity of semen analysis for treatment outcome in PCOS women with PCOS experiencing with ovulatory dysfunction is limited.

特力阿扎维林治疗新冠病毒肺炎的疗效与安全性——一项随机对照试验

目前,尚无有效疗法可治愈由严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2,SARS-CoV-2)引起的新型冠状病毒肺炎(coronavirus disease 2019,COVID-19)。为了评估抗病毒药物特力阿扎维林治疗COVID-19的有效性和安全性,本研究针对感染COVID-19的成年住院患者开展了一项随机双盲对照试验。本研究从10个分中心招募COVID-19患者,并将患者按1:1的比例随机分为两组。试验组的患者每天服用250 mg的特力阿扎维林药物3~4次,对照组患者则服用安慰剂,为期共7 d。主要结局指标为临床改善时间,临床改善时间的定义为随机分组28d内患者的体温、呼吸频率、血氧饱和度、咳嗽频率和肺CT(计算机断层扫描,computed tomography)所显示的肺部感染吸收情况全部恢复正常的时间。次要结局指标包括主要结局指标的5个组成指标,及肺部感染吸收的平均时间和吸收比例,以及用咽拭子采样法连续两次SARS-CoV-2核酸检测阴性的转阴率。与此同时,记录合并的治疗药物、不良事件和严重不良事件。由于需要进行住院治疗的新增感染病例的减少,本研究在招募52名患者后便停止招募。将52名受试者随机分为服用特力阿扎维林药物的试验组(n=26)和服用安慰剂的对照组(n=26)。结果显示,两组临床改善时间并无明显差异[中位数,7 d vs.12 d;风险比(RR)为2.0;95%置信区间(CI)为0.7~5.6;p=0.2]。服用特力阿扎维林的试验组中有10名患者发生临床改善,服用安慰剂的对照组中有6名患者出现临床改善(38.5%vs.23.1%,RR为2.1;95%CI为0.6~7.0;p=0.2)。除了肺部感染的吸收情况外(试验组50.0%,对照组26.1%),其余主要结局所观察指标均在28 d内恢复正常。此外,试验组的患者在呼吸系统、心脏、肾、肝或凝血功能等方面的合并治疗较对照组少。尽管特力阿扎维林药物对COVID-19患者的疗效尚未达到统计学上的显著性水平,但本研究结果表明,由于特力阿扎维林药物具有抗病毒作用,将其用于COVID-19的治疗也可能具有一定的疗效。对此,需要进一步的研究进行验证。