STUDY QUESTION Does acupuncture improve insulin sensitivity more effectively than metformin or sham acupuncture in women with polycystic ovary syndrome (PCOS) and insulin resistance (IR)? SUMMARY ANSWER Among women with PCOS and IR, acupuncture was not more effective than metformin or sham acupuncture in improving insulin sensitivity. WHAT IS KNOWN ALREADY Uncontrolled trials have shown that acupuncture improved insulin sensitivity with fewer side effects compared with metformin in women with PCOS and IR. However, data from randomized trials between acupuncture and metformin or sham acupuncture are lacking. STUDY DESIGN, SIZE, DURATION This was a three-armed randomized controlled trial enrolling a total of 342 women with PCOS and IR from three hospitals between November 2015 and February 2018, with a 3-month follow-up until October 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS Women aged from 18 to 40 years with PCOS and homeostasis model assessment of insulin resistance (HOMA-IR) ≥2.14 were randomly assigned (n = 114 per group) to receive true acupuncture plus placebo (true acupuncture), metformin plus sham acupuncture (metformin, 0.5 g three times daily) or sham acupuncture plus placebo (sham acupuncture) for 4 months, with an additional 3-month follow-up. True or sham acupuncture was given three times per week, and 0.5 g metformin or placebo was given three times daily. The primary outcome was change in HOMA-IR from baseline to 4 months after baseline visit. Secondary outcomes included changes in the glucose AUC during an oral glucose tolerance test, BMI and side effects at 4 months after baseline visit. MAIN RESULTS AND THE ROLE OF CHANCE After 4 months of treatment, the changes of HOMA-IR were –0.5 (decreased 14.7%) in the true acupuncture group, –1.0 (decreased 25.0%) in the metformin group and –0.3 (decreased 8.6%) in the sham acupuncture group, when compared with baseline. True acupuncture is not as effective as metformin in improving HOMA-IR at 4 months after baseline visit (difference, 0.6; 95% CI, 0.1–1.1). No significant difference was found in change in HOMA-IR between true and sham acupuncture groups at 4 months after baseline visit (difference, –0.2; 95% CI, –0.7 to 0.3). During the 4 months of treatment, gastrointestinal side effects were more frequent in the metformin group, including diarrhea, nausea, loss of appetite, fatigue, vomiting and stomach discomfort (31.6%, 13.2%, 11.4%, 8.8%, 14.0% and 8.8%, respectively). Bruising was more common in the true acupuncture group (14.9%). LIMITATIONS, REASONS FOR CAUTION This study might have underestimated the sample size in the true acupuncture group with 4 months of treatment to enable detection of statistically significant changes in HOMA-IR with fixed acupuncture (i.e. a non-personalized protocol). Participants who withdrew because of pregnancy did not have further blood tests and this can introduce bias. WIDER IMPLICATIONS OF THE FINDINGS True acupuncture did not improve insulin sensitivity as effectively as metformin in women with PCOS and IR, but it is better than metformin in improving glucose metabolism (which might reduce the risk of type 2 diabetes) and has less side effects. Metformin had a higher incidence of gastrointestinal adverse effects than acupuncture groups, and thus acupuncture might be a non-pharmacological treatment with low risk for women with PCOS. Further studies are needed to evaluate the effect of acupuncture combined with metformin on insulin sensitivity in these women. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by grants 2017A020213004 and 2014A020221060 from the Science and Technology Planning Project of Guangdong Province. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER Clinicaltrials.gov number: NCT02491333. TRIAL REGISTRATION DATE 8 July 2015. DATE OF FIRST PATIENT’S ENROLLMENT 11 November 2015.

Heregulins bind directly to ErbB3 and ErbB4 receptors, leading to multiple dimerization possibilities including heterodimerization with the ErbB2 receptor. We have generated ErbB3-, ErbB2- and heregulin-deficient mice to assess their roles in development and differentiation. Heregulin(−/−) and ErbB2(−/−) embryos died on E10.5 due to a lack of cardiac ventricular myocyte differentiation; ErbB3(−/−) embryos survived until E13.5 exhibiting cardiac cushion abnormalities leading to blood reflux through defective valves. In ErbB3(−/−) embryos, the midbrain/hindbrain region was strikingly affected, with little differentiation of the cerebellar plate. Cranial ganglia defects, while present in all three nulls, were less severe in ErbB3(−/−) embryos. The cranial ganglia defects, along with a dramatic reduction in Schwann cells, enteric ganglia and adrenal chromaffin cells, suggests a generalized effect on the neural crest. Numerous organs, including the stomach and pancreas also exhibited anomalous development.

Background: The recommended conscious sedation for bronchoscopy is still lacking. The safety and efficacy of sufentanil combined with midazolam in bronchoscopy under conscious sedation is not well elucidated. Methods: A retrospective analysis was conducted on patients who received bronchoscopy in the First Affiliated Hospital of Guangzhou Medical University from September 2013 to July 2017. Sufentanil and midazolam were administrated for conscious sedation. The drug dosage, sedating effect and adverse event were collected and analyzed. Results: Totally, 7,089 males and 4,069 females aged 54±16 years (ranged from 4 to 94 years) were enrolled in this study. The dosage of sufentanil and midazolam were 5.25±1.28 mcg (2-13 mcg) and 2.03±0.51 mg (0.5-4.5 mg), respectively. Ninety-eight point six percent (10,998/11,158) of bronchoscopies were successfully completed, while 68.7% (7,670/11,158) procedures were performed with initial dose of 5 mcg sufentanil and 2 mg midazolam. Endobronchial biopsy, transbronchial lung biopsy (TBLB), transbronchial needle aspiration (TBNA), therapeutic procedure and asthma were predictors of giving incremental doses of sufentanil and midazolam (all OR >1, P<0.05), whereas, the age was associated with lower incidence of adding dose of sufentanil and midazolam (both OR <1, P<0.05). Patients with chronic obstructive lung disease (COPD) had lower incidence of adding dose of midazolam alone (OR =0.597, P=0.003). Whereas, female and pulmonary infection were predictors of adding dose of sufentanil alone (OR >1, P<0.05). The conscious sedation related adverse events were not observed. Conclusions: Sufentanil combined with midazolam was safe and effective for bronchoscopy under conscious sedation.

The mechanisms through which the androgen-dependent activation of the androgen receptor (AR) regulates gravid uterine ferroptosis remain unknown. We show that while co-exposure of pregnant rats to the androgen 5adihydrotestosterone (DHT) and insulin (INS) triggered uterine ferroptotic signaling cascades, additional treatment with the anti-androgen flutamide increased expression of the key ferroptosis-inhibitory proteins SLC7A11, GSH, and GPX4; reduced iron content; normalized levels of ferroptosisassociated Tfrc, Fpn1, and Ho1 mRNAs; reduced levels of proteins modified by 4-HNE (a marker of ferroptosis); and restored protein levels of NRF2, a key transcription factor regulating antioxidant defense signaling, in the gravid uterus. Furthermore, exposure to DHT alone increased uterine ferroptosis, and NRF2 abundance was negatively correlated with AR status. Coimmunoprecipitation and Western blot assays revealed that the AR physically interacted with endogenous NRF2, and this interaction was increased by DHT exposure in vivo. Our results suggest that AR overactivation and NRF2 suppression cooperate in the regulation of NRF2-targets in uterine ferroptosis.