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Impact of dienogest pretreatment on IVF-ET outcomes in patients with endometriosis: a systematic review and meta-analysis
Journal of Ovarian Research volume 16, Article number: 166 (2023)
To comprehensively evaluate the influence of dienogest (DNG) versus non-DNG pretreatment on in vitro fertilization and embryo transfer (IVF-ET) outcomes for patients with endometriosis.
PubMed, Embase, Cochrane Library, Web of Science, CNKI, WanFang, and VIP were comprehensively searched for relevant publications until September 14, 2022. Primary outcomes included clinical pregnancy rate and live birth rate. Secondary outcomes included retrieved oocytes, mature oocytes, blastocysts, growing follicles, transferrable embryos, fertilization rate, implantation rate, and miscarriage rate. Subgroup analysis was performed according to different grouping methods and embryo types.
Five studies of 568 females with endometriosis were involved in this systematic review and meta-analysis. DNG treatment exhibited similar effects to non-DNG treatment on either the primary or the secondary outcomes (all P > 0.05). The DNG group had a significantly greater clinical pregnancy rate than the non-hormonal treatment group (pooled relative risk [RR]: 2.055, 95% confidence interval [CI]: 1.275, 3.312, P = 0.003), and exhibited a significantly lower clinical pregnancy rate than the long gonadotropin-releasing hormone agonist (GnRH-a) group (RR: 0.542, 95%CI: 0.321, 0.916, P = 0.022). For patients undergoing fresh embryo transfer, the DNG group displayed a significantly greater clinical pregnancy rate versus the non-DNG group (pooled RR: 1.848, 95%CI: 1.234, 2.767, P = 0.003). Patients receiving DNG had a significantly greater live birth rate than those with non-hormonal treatment (pooled RR: 2.136, 95%CI: 1.223, 3.734, P = 0.008), while having a significantly lower live birth rate than the long GnRH-a group (RR: 0.441, 95%CI: 0.214, 0.907, P = 0.026). While using fresh embryos, patients with DNG treatment had an increased live birth rate, compared with those without DNG treatment (pooled RR: 2.132, 95%CI: 1.090, 4.169, P = 0.027).
DNG treatment may have similar effects to non-DNG treatment on IVF-ET outcomes. The clinical pregnancy rate and live birth rate after DNG treatment may be significantly higher than those after non-hormonal treatment. More evidence is warranted to corroborate these findings.
Endometriosis is featured by endometrioid tissue (glands and stroma) being out of the uterus and influences around 15% of women of reproductive age . This disease occurs in up to 50% of infertile women , and approximately 30% to 50% of patients with endometriosis suffer from infertility , indicating a close relationship between endometriosis and infertility. Infertile females who have endometriosis usually need assisted reproduction technology (ART), including in vitro fertilization and embryo transfer (IVF-ET) , to conceive; nevertheless, the IVF-ET success rate among these women is nearly 50% of that among those without endometriosis [5, 6]. Hence, managing endometriosis-related infertility for better ART outcomes is a primary concern of reproductive medicine.
One approach for ART outcome optimization in infertile females who have endometriosis is extended pre-cycle inhibitory hormonotherapy. Down-regulation using a gonadotropin-releasing hormone agonist (GnRH-a) for 3 to 6 months quadrupled the rate of clinical pregnancy among females with endometriosis . GnRH-a administration for 3 months before IVF-ET was shown to improve reproductive outcomes via lessening the deleterious impacts of cytotoxic cytokines and oxidative stress for infertile females who had endometriosis . Dienogest (DNG), a derivative of 19-norsteroids, is greatly selective for progesterone receptor agonists. DNG exerts suppressive effects on endometriotic lesions and cytokines, and was reported to be more cytoreductive than GnRH-a on endometriotic lesions [9, 10]. Additionally, it was demonstrated that clinical pregnancy and live birth rates were greater in women receiving DNG compared with those in women without hormonotherapy , while another research showed contrary results that growing follicles, retrieved oocytes, blastocysts, cumulative pregnancy rate, and live birth rate were prominently reduced among women receiving DNG versus GnRH-a . The effect of DNG pretreatment on IVF-ET outcomes for females with endometriosis remains vague.
This study intended to comprehensively assess the influence of DNG treatment versus non-DNG treatment preceding IVF-ET on IVF-ET outcomes among patients with endometriosis via a systematic review and meta-analysis. Subgroup analysis was further conducted based on different grouping methods and embryo types.
PubMed, Embase, Cochrane Library, and Web of Science were comprehensively examined for relevant publications up to September 14, 2022. English search terms were “dienogest” OR “17 alpha-cyanomethyl-17 beta-hydroxy-13 beta-methylgona-4,9-dien-3-one” OR “17 alpha-cyanomethyl-17 beta-hydroxyestra-4,9(10)-diene-3-one” OR “19-norpregna-4,9-diene-21-nitrile, 17-hydroxy-3-oxo-, 17alpha” OR “STS 557” OR “STS-557” OR “Visanne” AND “Fertilization in Vitro” OR “Fertilizations in Vitro” OR “In Vitro Fertilization” OR “In Vitro Fertilizations” OR “Test-Tube Fertilization” OR “Test Tube Fertilization” OR “Test-Tube Fertilizations” OR “Test-Tube Babies” OR “Test Tube Babies” OR “Test-Tube Baby” OR “IVF” OR “Embryo Transfer” OR “Embryo Transfers” OR “Blastocyst Transfer” OR “Tubal Embryo Transfer” OR “Tubal Embryo Stage Transfer” OR “IVF-ET”. This search was conducted by WJ Shao and YL Wang independently, and discussion was needed to resolve disagreements. The current meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).
Inclusion and exclusion criteria
Inclusion criteria were as follows: (1) articles on patients with endometriosis; (2) articles with the study group treated with DNG (DNG group), and the control group not treated with DNG (non-DNG group); (3) articles having any of the following outcomes: retrieved oocytes, mature oocytes, blastocysts, growing follicles, transferrable embryos, fertilization rate, implantation rate, clinical pregnancy rate, miscarriage rate, and live birth rate; (4) randomized controlled trials (RCTs) or cohort studies.
Exclusion criteria were as follows: (1) studies involving animal experiments; (2) reviews, meta-analyses, case reports, conference reports, editorial materials, and protocols; (3) non-English studies.
Primary outcomes included clinical pregnancy rate and live birth rate. Secondary outcomes included retrieved oocytes, mature oocytes, blastocysts, growing follicles, transferrable embryos, fertilization rate, implantation rate, and miscarriage rate. The clinical pregnancy rate referred to the number of successful clinical pregnancies (gestational sacs and germs observed by B-ultrasonography) divided by the number of transplant cycles. The live birth rate referred to the number of final live births divided by the number of transplant cycles. The miscarriage rate referred to the number of identified intrauterine gestational sacs without fetal poles, or fetal poles without heart pulsations without other viable fetuses divided by the number of transplant cycles.
Data extraction and quality assessment
The extracted data included first author, year of publication, country, study period, study design, group, interventions, number of included women (N), age (years), body mass index (BMI, kg/m2), cyst size (cm), staging, duration of subfertility (years), laterality, surgery, previous treatment, follicle-stimulating hormone (FSH, IU/L), anti-Mullerian hormone (AMH, ng/mL), antral follicle count (AFC), quality assessment, and outcomes.
Quality and bias assessment
The Cochrane Collaboration’s tool  was used to assess the risk of bias in the included RCTs. The domains for assessment included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. The risk of bias was classified into low, unclear or high. The quality of cohort studies was evaluated using the Newcastle–Ottawa Scale (NOS) . The total score of this scale was 9 points (0–3: poor quality, 4–6: fair quality, 7–9: good quality).
All studies were statistically analyzed with Stata 15.1 (Stata Corporation, College Station, TX, USA). Relative risks (RRs) acted as the statistic for enumeration data, weighted mean differences (WMDs) were used as the statistic for measurement data, and effect sizes were illustrated as 95% confidence intervals (CIs). The effect size of each outcome was examined for heterogeneity, and when the heterogeneity statistic I2 ≥ 50%, we adopted the random-effects model for analysis; otherwise, we employed the fixed-effects model. Subgroup analysis was further performed according to grouping methods and embryo types. As I2 ≥ 50%, meta-regression analysis was conducted to investigate the source of the heterogeneity. Sensitivity analyses were carried out for both the primary and the secondary outcomes. P < 0.05 indicated statistical significance.
Characteristics of the included studies
In total, 2,017 articles were retrieved from the four databases, with 443 from PubMed, 803 from Embase, 620 from Web of Science, and 151 from Cochrane Library. After duplicate removal and according to the eligibility criteria, five studies [11, 12, 15,16,17] were included for quantitative analysis. The flow chart of study screening is shown in Fig. 1. A total of 568 patients were enrolled, of which 269 were in the DNG group and 299 in the non-DNG group. Table 1 exhibits basic information of the included studies. Three included studies reported the stage of the disease, and two did not provide relevant information on the disease stage. Patients had stage I/II and III/IV endometriosis in the study of Iwami et al. ; patients had minimal, mild, moderate, and severe endometriosis in the study of Khalifa et al. ; patients had III and IV endometriosis in the study of Tamura et al. . Regarding surgery, three studies had relevant information: patients in the study of Iwami et al.  underwent laparoscopic surgery or laparotomy for ovarian endometrial cysts, patients in the study of Barra et al.  did not had operations, and patients in the study of Muller et al.  underwent laparoscopic surgery of ovarian endometriomas before IVF. The other two studies did not report information on surgery.
Quality and bias of the included studies
Two included studies were RCTs, and three studies were cohort studies. Regarding the two RCTs, for random sequence generation, allocation concealment, and blinding of outcome assessment, one study has a low risk of bias, and the other study has an unclear risk of bias. Both RCTs had a low risk of bias in incomplete outcome data, an unclear risk of bias in selective reporting and other bias, and a high risk of bias in blinding of participants and personnel. The overall assessment exhibited a moderate level of bias (Fig. 2). For the three cohort studies, two had fair quality, and one had good quality (Table 2).
Clinical pregnancy rate
Five studies [11, 12, 15,16,17] provided data on the clinical pregnancy rate. Combined analysis demonstrated that the DNG group had a comparable clinical pregnancy rate to the non-DNG group (pooled RR: 1.264, 95%CI: 0.824, 1.939, P = 0.284) (Fig. 3). Further, the DNG group vs. non-DNG group was divided into DNG group vs. non-hormonal treatment group, DNG + short-acting GnRH-a group vs. ultra-long GnRH-a group, DNG group vs. long GnRH-a group, and DNG group vs. dydrogesterone group, according to different grouping methods. The DNG group was illustrated to have a significantly higher clinical pregnancy rate than the non-hormonal treatment group (pooled RR: 2.055, 95%CI: 1.275, 3.312, P = 0.003), and have a significantly lower clinical pregnancy rate versus the long GnRH-a group (RR: 0.542, 95%CI: 0.321, 0.916, P = 0.022). No significant difference was identified between the DNG + short-acting GnRH-a group and the ultra-long GnRH-a group (RR: 1.417, 95%CI: 0.735, 2.732, P = 0.299), and between the DNG group and the dydrogesterone group (RR: 1.078, 95%CI: 0.827, 1.404, P = 0.579). Besides, embryos were classified into frozen and fresh embryos. For patients using frozen embryos, DNG treatment exhibited a similar effect on the clinical pregnancy rate to non-DNG treatment (pooled RR: 1.109, 95%CI: 0.854, 1.439, P = 0.438). As for patients undergoing fresh embryo transfer, the DNG group displayed a significantly increased clinical pregnancy rate in contrast to the non-DNG group (pooled RR: 1.848, 95%CI: 1.234, 2.767, P = 0.003) (Table 3). Meta-regression analysis showed that heterogeneity in the clinical pregnancy rate did not come from grouping methods and embryo types (all P > 0.05) (Table S1).
Live birth rate
The live birth rate was studied in four articles [11, 12, 15, 16]. Patients treated with DNG were found to have a comparable live birth rate to those not treated with DNG (pooled RR: 1.234, 95%CI: 0.659, 2.309, P = 0.511) based on overall analysis (Fig. 4). Subgroup analysis based on different grouping methods (DNG group vs. non-hormonal treatment group, DNG group vs. long GnRH-a group, and DNG group vs. dydrogesterone group) suggested that the DNG group had a significantly greater live birth rate than the non-hormonal treatment group (pooled RR: 2.136, 95%CI: 1.223, 3.734, P = 0.008), and the DNG group had a significantly reduced live birth rate compared with the long GnRH-a group (RR: 0.441, 95%CI: 0.214, 0.907, P = 0.026). Comparable live birth rates were observed in the DNG and dydrogesterone groups (RR: 0.942, 95%CI: 0.661, 1.343, P = 0.741). While using frozen embryos, no significant difference existed between patients receiving and not receiving DNG treatment (pooled RR: 1.112, 95%CI: 0.537, 2.305, P = 0.775). While using fresh embryos, patients with DNG treatment had an increased live birth rate, compared with those without DNG treatment (pooled RR: 2.132, 95%CI: 1.090, 4.169, P = 0.027) (Table 3). As meta-regression analysis illustrated, grouping methods and embryo types were not the sources of heterogeneity in the live birth rate (all P > 0.05) (Table S1).
Two studies [12, 17] assessed the influence of DNG pretreatment on the number of retrieved oocytes. Overall analysis showed that the DNG and non-DNG groups had the comparable number of retrieved oocytes (pooled WMD: -1.195, 95%CI: -3.314, 0.923, P = 0.269) (Fig. 5). Subgroup analysis based on grouping approaches exhibited that the number of retrieved oocytes was similar in the DNG + short-acting GnRH-a group and the ultra-long GnRH-a group (WMD: -0.300, 95%CI: -0.742, 0.142, P = 0.183), and the DNG group had fewer retrieved oocytes than the long GnRH-a group (WMD: -2.500, 95%CI: -4.411, -0.589, P = 0.01) (Table 3).
The number of mature oocytes was reported in four studies [12, 15,16,17]. The number of mature oocytes in the DNG group was equivalent to that in the non-DNG group (pooled WMD: -0.990, 95%CI: -2.264, 0.285, P = 0.128) (Fig. 6). In accordance with different grouping methods, the DNG group was demonstrated to have more mature oocytes than the non-hormonal treatment group (WMD: 0.700, 95%CI: 0.015, 1.385, P = 0.045). Patients with DNG + short-acting GnRH-a treatment had a smaller number of mature oocytes than those receiving ultra-long GnRH-a (WMD: -0.600, 95%CI: -1.132, -0.068, P = 0.027). In contrast to the long GnRH-a group, the DNG group showed reduced mature oocytes (WMD: -2.500, 95%CI: -4.217, -0.783, P = 0.004). Patients treated with DNG were found to have fewer mature oocytes than those treated with dydrogesterone (WMD: -2.270, 95%CI: -3.620, -0.920, P = 0.001) (Table 3).
Three studies [12, 15, 16] provided relevant information on growing follicles. Tamura et al.  defined growing follicles as follicles with a diameter ≥ 15 mm, and found that growing follicles were significantly fewer in the DNG group than those in the long GnRH-a group. Iwami et al.  defined growing follicles as follicles with a diameter > 10 mm, and demonstrated that the mean number of growing follicles on the trigger day was significantly smaller in the DNG group than that in the dydrogesterone group. Barra et al.  reported that DNG pretreatment significantly increased co-dominant follicles (average diameter > 15 mm) than non-hormonal treatment in patients with endometriomas of a diameter ≥ 4 cm (7.3 ± 1.9 vs 5.7 ± 2.3, P = 0.036).
Two articles [12, 15] probed into the number of blastocysts following DNG treatment. DNG treatment was found to have an equivalent effect on the number of blastocysts to the non-DNG treatment (pooled WMD: -1.329, 95%CI: -3.284, 0.626, P = 0.183) (Fig. 7). Furthermore, subgroup analysis demonstrated no significant difference in the number of blastocysts between the DNG group and the non-hormonal treatment group (WMD: -0.400, 95%CI: -0.881, 0.081, P = 0.103), while the DNG group had significantly decreased blastocysts in contrast to the long GnRH-a group (WMD: -2.400, 95%CI: -3.549, -1.251, P < 0.001) (Table 3).
The number of transferrable embryos was evaluated in two publications [15, 17]. It was presented by combined analysis that DNG and non-DNG treatment exerted similar influences on the number of transferrable embryos (pooled WMD: 0.187, 95%CI: -0.487, 0.862, P = 0.586) (Fig. 8). Further, the number of transferrable embryos was comparable in the DNG and non-hormonal treatment groups (WMD: -0.100, 95%CI: -0.420, 0.220, P = 0.076), and in the DNG + short-acting GnRH-a and ultra-long GnRH-a groups (WMD: 0.600, 95%CI: -0.062, 1.262, P = 0.54) (Table 3).
Three articles [12, 16, 17] reported the fertilization rate of the DNG and non-DNG groups. Overall analysis showed that patients receiving DNG treatment had a similar fertilization rate to those without DNG treatment (pooled RR: 1.029, 95%CI: 0.958, 1.105, P = 0.429) (Fig. 9). Subgroup analysis found no significant difference in the fertilization rate between the DNG + short-acting GnRH-a and ultra-long GnRH-a groups (RR: 1.185, 95%CI: 0.807, 1.740, P = 0.386), between the DNG and long GnRH-a groups (RR: 0.788, 95%CI: 0.525, 1.185, P = 0.253), and between the DNG and dydrogesterone groups (pooled RR: 1.032, 95%CI: 0.961, 1.108, P = 0.386). Whether embryos transferred were frozen (pooled RR: 1.032, 95%CI: 0.961, 1.108, P = 0.386) or fresh (RR: 1.185, 95%CI: 0.807, 1.740, P = 0.386), the DNG and non-DNG treatment exhibited comparable effects on the fertilization rate (Table 3).
The implantation rate was measured in three studies [12, 15, 16]. No significant difference was identified between the DNG and non-DNG groups in the implantation rate (pooled RR: 1.111, 95%CI: 0.888, 1.391, P = 0.356) according to overall analysis (Fig. 10). In terms of different grouping methods, the DNG group had a notably increased implantation rate versus the non-hormonal treatment group (pooled RR: 1.657, 95%CI: 1.012, 2.715, P = 0.045), while the DNG and long GnRH-a groups (RR: 0.708, 95%CI: 0.387, 1.297, P = 0.264) as well as the DNG and dydrogesterone groups (RR: 1.064, 95%CI: 0.807, 1.403, P = 0.662) showed similar influences on the implantation rate. In term of embryo status, the implantation rate was equivalent in the DNG and non-DNG groups when using frozen embryos (pooled RR: 1.084, 95%CI: 0.830, 1.415, P = 0.553). While using fresh embryos, the DNG group had a significantly greater implantation rate than the non-DNG group (RR: 1.849, 95%CI: 1.031, 3.318, P = 0.039) (Table 3).
The impact of DNG treatment on the miscarriage rate was explored in three studies [12, 16, 17]. Combined analysis illustrated that no significant difference existed in the miscarriage rate between patients receiving DNG and non-DNG treatment (pooled RR: 1.384, 95%CI: 0.824, 2.325, P = 0.220) (Fig. 11). The DNG + short-acting GnRH-a and ultra-long GnRH-a groups (RR: 0.178, 95%CI: 0.009, 3.433, P = 0.253), the DNG and long GnRH-a groups (RR: 1.455, 95%CI: 0.512, 4.134, P = 0.482), as well as the DNG and dydrogesterone groups (RR: 1.639, 95%CI: 0.873, 3.078, P = 0.124) were identified to have comparable miscarriage rates, respectively. The miscarriage rate of the DNG group was similar to that of the non-DNG group regardless of embryo status (both P > 0.05) (Table 3).
Sensitivity analysis was performed through removal of a study at a time and comprehensively analyzing the remaining studies. It was revealed that one-study removal did not significantly influence the combined results, indicating that the findings of this meta-analysis were stable and robust (Figures S1-S9).
This systematic review and meta-analysis compared DNG treatment with non-DNG treatment to assess the influence of DNG administration prior to IVF-ET on IVF-ET outcomes. Our findings demonstrated that DNG treatment exhibited similar effects to non-DNG treatment on either the primary or the secondary outcomes. According to subgroup analysis, the clinical pregnancy rate and live birth rate in the DNG group were significantly greater than those in the non-hormonal treatment group. Besides, DNG treatment was more effective for the clinical pregnancy rate and live birth rate than non-DNG treatment when patients underwent fresh embryo transfer.
DNG, a fourth-generation progestin, primarily used in endometriosis treatment, has been illustrated to be effective in relieving pain associated with the disease and well tolerated [18,19,20,21]. No significant difference was observed herein in IVF-ET outcomes between patients pretreated with DNG and not receiving DNG treatment before IVF-ET. Compared with non-hormonal treatment, DNG therapy obviously improved the clinical pregnancy rate and live birth rate among patients; DNG treatment was more effective than non-DNG treatment regarding the clinical pregnancy rate and live birth rate in patients using fresh embryos, which indicated that DNG treatment could be chosen over non-hormonal treatment in improving the clinical pregnancy rate and live birth rate after IVF-ET, and fresh embryos might be preferred for IVF-ET after DNG treatment. As regards the effect of long GnRH-a over DNG on the clinical pregnancy rate and live birth rate, only a RCT by Tamura et al.  was included for analysis. Progestin exerts influences on inhibiting follicular development and inducing follicle atresia [22, 23], and DNG can have the same influences [24, 25]. Administration of DNG preceding IVF-ET may thus lead to restrained follicle development and induced follicle atresia. Two included studies in this analysis showed that the number of growing follicles after DNG treatments was smaller than that after long GnRH-a and dydrogesterone treatments, respectively [12, 16]. Given the above side effects of DNG in suppressing follicle growth, more attention should be paid to the use of DNG, and future studies are needed to assess the impact of DNG pretreatment on IVF-ET outcomes among females with endometriosis and confirm our findings.
In terms of pharmacokinetics and pharmacodynamics, DNG has high oral bioavailability of over 90%, and short plasma half-life time of around 10 h, indicating no risk of accumulation after repeated administration and suitability of administration once a day . DNG does not bind to the sex hormone binding globulin (SHBG) or corticoid binding globulin; thus, the application of DNG does not change the plasma levels of these proteins . DNG has important progestational effects; it suppresses gonadotropic release, but does not have glucocorticoids, mineral corticoids or significant estrogen-like impacts in vivo [27, 28]. Although the affinity of DNG to progesterone receptors is low, it has an obvious progesterone influence in vivo, which can be resulted from the high levels of plasma free molecules . Hence, DNG combines the advantages of 19-nortestosterone derivatives and progesterone derivatives. Compared with the activity of inhibiting ovulation, DNG has stronger activity on the endometrium. DNG-induced ovulation inhibition can be promptly retained after stopping treatment . Since the levels of serum gonadotropins (FSH and luteinizing hormone [LH]) do not alter significantly, the effect on the ovary is peripheral rather than central. DNG is linked to a high incidence of abnormal menstrual bleeding patterns, but patients are generally well tolerated, with few discontinuing treatment, and the intensity and frequency of bleeding decline with time .
DNG can effectively relieve pain symptoms related to endometriosis, like dysmenorrhea, premenstrual pelvic pain, dyspareunia and chronic pelvic pain. Its efficacy is better than that of placebo and comparable to that of GnRH-a, but with better tolerance. Its great endometrial efficacy makes it anti-proliferative and anti-inflammatory in treating endometriotic lesions . DNG stimulates the differentiation of endometrial stromal cells (ESC) and suppresses their proliferation . DNG suppresses aromatase and COX-2 expression as well as prostaglandin E2 production in ESC in an experimental in vitro study. These pharmacological characteristics may facilitate the therapeutic effect of DNG on endometriosis, thereby exhibiting the significant anti-inflammatory impact of DNG associated with size reduction of endometrial lesions [9, 31]. Evidence demonstrated that DNG had a great impact on the inflammatory microenvironment of endometrial lesions, which may promote its clinical efficacy . DNG exhibits favorable impacts on systemic and intralesional inflammatory microenvironments for females who have endometriosis. It reduces secretion of interleukin-8 (IL-8), IL-6 and monocyte chemotactic protein-1 (MCP-1), and lowers TNF-α-induced generation of mRNA in endometrial stromal cells from these females . Furthermore, the antigen-presenting function of peritoneal fluid macrophages can be recovered by DNG via upregulating human leucocyte antigen (HLA)-DR . DNG was reported to have a favorable impact at the endometrial level , and among these females, the eutopic endometrium response to steroid hormones may be damaged by aberrant expression of estrogen receptors (ER) and progesterone receptors (PR) , causing “progesterone-resistant” condition. Blocked endometrial secretory conversion, implantation failure, or its pathological change following ET may be due to this . A recent investigation by Hayashi et al.  illustrated that DNG might ameliorate the progesterone resistance in endometrial tissue through elevating the PR-B/PR-A ratio and reducing the ERβ/ERα isoform ratio, so it might positively affect pregnancy outcomes. One reason of DNG’s effectiveness in endometriosis is that DNG creates a hypoestrogenic situation at the endometrial tissue level, but does not excessively reduce the plasma E2 concentration, which is often stable at the lower limit of the normal concentration range . Compared with GnRH analogues, such E2 levels are not expected to cause the reactivation of endometriotic lesions, whereas they are high enough to prevent hot flashes and bone loss, which has been found during the treatment of endometriosis with DNG . DNG has low androgen receptor activity and some antiandrogenic activity , which explains the limited androgen-like side effects, such as weight gain, acne, alopecia and hirsutism . Side effects caused by hypoestrogenism (such as hot flashes and bone loss) do not occur, whereas these effects are found during the treatment of endometriosis with GnRH analogues .
Despite efficiently relieved pain and reduced development of endometriotic implants , GnRH-a is relevant to hypoestrogenic adverse effects, including hot flushes, headaches, vaginal dryness, decreased libido, and loss of bone mineral density [34, 41]. Because of these side effects, many patients “keep in mind” GnRH-a treatment and do not redo it all the time, suggesting a decline in adherence to the treatment. Given this, DNG could be prescribed as an alternative owing to no significant antigonadotropin impact and remarkably inhibited ovarian function. Further, DNG is suggested to have greater adherence and, as illustrated by this study, may contribute to increasing clinical pregnancy and live birth rates. Besides, decreased bone mineral density usually limits the longest duration of treatment to 3–6 months, unless low-dose, “add-back” therapy with an estrogen, a progestogen or an estrogen/progestogen combination is added to reduce hypoestrogenic adverse effects [41, 42]. Although add-back therapy can prevent bone density loss and allow GnRH-a to be applied for longer time, it greatly increases the cost and complexity of treatment [29, 42].
The bioavailability of dydrogesterone in human is low. The plasma concentration of dydrogesterone was lower than the detection limit (< 1 ng/mL), while after oral administration of 10 mg dydrogesterone, the metabolite among women was approximately 10 ng/mL. Some metabolites of dydrogesterone may facilitate progesterone activity in vivo . A premature LH surge and partial ovulation can compromise oocyte yields and lower the pregnancy rate . Dydrogesterone, an efficacious oral substitute for GnRH agonists or antagonists, is generally utilized to prevent premature LH surge in females receiving controlled ovarian hyperstimulation (COH) [44, 45]. Progestin-primed ovarian stimulation (PPOS) using DNG has several underlying advantages over PPOS using dydrogesterone, comprising anti-inflammatory effects, endometriosis relapse suppression after surgical intervention, and endometriosis-associated pain relief . DNG has good specificity for the progesterone receptor in contrast to dydrogesterone , has a direct inhibiting influence on the proliferation of endometrial lesions, and has a stronger cytoreductive impact on endometrial lesions than GnRH-a [46,47,48]. Additionally, DNG is cheaper than GnRH-a and can be taken orally, while GnRH-a must be administered subcutaneously or nasally . Different from natural GnRH, this substitution makes the agonist resistant to degradation by endopeptidases and makes its half-life longer, thus prolonging receptor occupancy .
Based on the above, pretreatment with DNG might be administrable to patients with endometriosis undergoing IVF-ET. In clinical practice, DNG could be administered over non-hormonal treatment to improve the clinical pregnancy rate and live birth rate. Importantly, this drug might be used alone with caution, since the clinical pregnancy and live birth rates following long GnRH-a treatment were shown to be greater than those after DNG use , and the dydrogesterone group displayed the elevated number of mature oocytes versus the DNG group , for which more research is warranted. Besides, patients receiving DNG combined with short-acting GnRH-a showed fewer mature oocytes than those receiving ultra-long GnRH-a , indicating that the combined medication of DNG needs further clinical validation.
There were some limitations in the current study: for one thing, the amount of eligible literature for analysis was relatively small, and more clinical studies are required to ensure the stability of results; for another, not all included studies reported the stage of the disease, the kind of surgery the patients had, and whether patients had removal of endometriomas or adhesions or bowel resection prior to IVF. No included studies reported whether the patients had previous GnRH antagonist treatments prior to the current treatment with dianogest. Four (out of five studies) excluded patients with long-term hormone therapy for endometriosis, and one study  focused on the population planning to undergo IVF following laparoscopic removal of endometriomas, with no endometriomas or other ovarian cysts at the start of stimulation. Based on the above, subgroup analysis could not be performed based on these factors to improve the purity of results. Reporting of the factors related to results should be improved in future studies. For great heterogeneity, we also attempted to explore the source of heterogeneity via meta-regression analysis. The results showed that meta-regression analysis could only be performed on the outcomes clinical pregnancy and live birth due to the limited number of eligible studies for analysis, and the heterogeneity in clinical pregnancy and live birth did not come from grouping methods and embryo types. More studies are needed to assess the source of heterogeneity. It is also indicated that studies to be conducted should pay attention to the selection of the study population to make the enrolled data homogeneous, in order to better evaluate the influence of interventions on outcomes. Future well-designed studies are warranted to support our findings.
DNG treatment may have comparable effects to non-DNG treatment on IVF-ET outcomes. The clinical pregnancy rate and live birth rate in the DNG group may be significantly greater than those in the non-hormonal treatment group. These findings indicated that DNG may be administrable over non-hormonal treatment to improve the clinical pregnancy rate and live birth rate, and this drug might be used alone with caution for patients with endometriosis who would undergo IVF-ET. More investigations are underscored to confirm our findings.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Assisted reproduction technology
In vitro fertilization and embryo transfer
Gonadotropin-releasing hormone agonist
Body mass index
Antral follicle count
Weighted mean differences
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Sensitivity analysis for clinical pregnancy rate in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for live birth rate in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for retrieved oocytes in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for mature oocytes in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for blastocysts in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for transferrable embryos in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for fertilization rate in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for implantation rate in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Sensitivity analysis for miscarriage rate in the DNG group versus non-DNG group. DNG, dienogest; CI, confidence interval.
Meta-regression analysis for clinical pregnancy and live birth rates in the DNG group versus non-DNG group. DNG, dienogest; GnRH-a, gonadotropin-releasing hormone agonist; Coef, coefficient; Std. Err, standard error; CI, confidence interval.
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Cite this article
Shao, W., Li, Y. & Wang, Y. Impact of dienogest pretreatment on IVF-ET outcomes in patients with endometriosis: a systematic review and meta-analysis. J Ovarian Res 16, 166 (2023). https://doi.org/10.1186/s13048-023-01245-8

domain: biology


Do I need a permit to replace my pump?
No. Work that is conducted within the septic/pump tank does not require a permit generally. Examples of this type of work that do NOT require a permit includes cleaning, changing, or retrofitting your tank with an effluent filter, measuring sludge accumulation, pumping the septic tank/pump chamber, or cleaning of the back-flow prevention valve. If the tank needs to be replaced, this DOES require a permit for tank placement.


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Hoping off a 5 hour bus trip from Antofagasta, we were excited to explore San Pedro de Atacama and surrounding desert. The Atacama was definitely one of the highlights of our trip!
We had reserved our 4×4 Wicked Camper a few months before we arrived and it was one of the best decisions we made on the trip. We reserved this for 3 night, 4 days and it gave us ultimate freedom in the desert to go and sleep wherever our hearts desired (apart from when Matt thought it was a great idea to lock the key inside the car in the middle of the night). Hiring a Wicked Camper was expensive, but totally worth it!
As soon as we picked up our car we made a very ‘Matt and Sam’ decision to go from 2700m in the township straight to 5000m to the base of the volcano Cerro Toco. It was a VERY step road up to the volcano and our 1300cc car spent 90% of the time struggling up in 1st gear. Once we arrived at the car park we hopped out and realised we were not acclimatised for 5000m whatsoever. We chewed coca leaves, drunk electrolytes and walked slowly but nothing would stop the breathlessness and headaches. We made a very sensible decision to take a few photos then make our way back to town. Note – there are day tours from the township if you don’t have your own car and these also include oxygen and a few hours acclimatisation at the car park before walking.
The “twin” lagunas
These unnamed lagunas are situated half way between Laguna Cejar and Laguna Tebinquinche. When we arrived there were many cars and tour groups hanging around but no one swimming. We both jumped straight in (as our wicked camper guy told us they were great for swimming) and within minutes over half of our spectators had joined us. These are ‘fresh water’ lagunas however, like anything in this desert, we still came out feeling salty.
Recommended to us for sunset, this place did not disappoint. We paid a 2000 peso entry fee each, parked up and settled in for a very beautiful sunset. It is a very picturesque spot and there were even a few flamingos showing off there too. By the time 7pm came around it felt like half the tourists of San Pedro were there. We thought it was a perfect time to cook up some mince and salad wraps and sit at our chairs and table with a lovely bottle of Chilean red whilst everyone looked over at us with jealousy.
After the sun had dropped below the horizon, we headed outside the controlled area (as you can’t camp anywhere where you have to pay) and found a small laguna near the twin lagunas to set up camp for the night.
Piedras Rojas translates to ‘red stones’ which is a fitting name for this place. Located 150km south of San Pedro de Atacama, Peidras Rojas is an absolutely stunning place to visit and looks nothing like anything else you see in this desert. Surrounded by red ‘moon-like’ hills and a bright blue salt lake, this is a place that photos just cannot do justice! Snow capped hills and multi coloured mountain faces in the background made the bumpy 3 hour drive worth every minute. It is at an altitude of 4000m above sea level so not only is the place itself stunning but so is the drive to get there.
Lagunas Miscanti (the big one) and Miniques (the small one) make up Lagunas Altiplánicas which basically means high plateau lakes. These are 30 minutes north of Piedras Rojas back towards San Pedro. On our drive up the road we were lucky enough to be have an inquisitive fox who came up and ran right alongside our car. Both Miscanti and Miniques are an amazing deep blue colour and are framed perfectly by the yellow/green colour in the hills behind. There were large amounts of flamingos in both of these lagunas and we also made friends with a cheeky black-headed gull who came to find some lunch.
Cañon de Gautin
Home for our second and third night in the camper, Cañon de Gautin was one of our favourite places we went to. It is 30 minutes north of San Pedro Atacama on the road towards Geysers el Tatio and Termas de Puritama. Surrounded by hundreds of cacti, some 4-5 metres tall (they grow only 1cm a year so they were VERY old), the place even had streams running right through it which was not what we expected in the middle of the Atacama dessert. This place also happened to be the location where Matt thought it would be a great idea to lock our car keys inside the car in the middle of the night. With the help of some fellow Wicked Campers the following morning we were reunited with our keys by midday and we even got a lift to Termas de Puritama from them too. We were definitely quite a sight being bare-footed, with the few belongings that weren’t locked in the car, slung over our shoulder in a pillow case! Matt seemed to find the humour in it, but Sam took a bit longer to come around!
Termas de Puritama
Termas de Puritama are hot pools located 30km northeast of San Pedro de Atacama at an elevation of 3475m above sea level. The 15,000 peso entrance fee seemed a bit steep but once we got down to the pools we didn’t regret it one bit. It was a short 500m walk from the car park down into a gorgeous canyon, the pools are approximately 35 degrees celsius so you can spend a decent amount of time in them without overheating. There are 8 pools connected by a beautiful wooden walkway and the water was extremely clear when we got there so be sure to take a Go Pro or waterproof camera if you have one. A good tip is to not lock all your belongings in the car the night before so that you have some swimwear and towel readily available.
Valle de Luna- Moon Valley
Valle de Luna was without a doubt our favourite site that we visited in the Atacama Desert. For only 3000 pesos it was an absolute bargain for the amount of areas we saw and the vast beauty of it. It’s only 13km west of San Pedro de Atacama so many people opt for a day trip here on rented bikes. We met a few who did it and they said it was great and budget friendly but also super time consuming (it takes an entire day). The valley was formed over years from wind and water and gives a very realistic feeling of being on the moon. There are caves to walk through which was our first stop (bring a head torch). These were fantastic and slowly climbed up in height until they reached an opening on the top of the rock of which you truly feel like you are walking on the moon. As usual we had many stares and comments about our rocking climbing in jandals, shorts and t-shirts.
We drove on a little further to the beginning of the walk up to ‘The Big Dune’ and made our way up. We turned many heads with our bare feet (as usual), however, we felt everyone else was missing out on enjoying the warm sand between their toes. It was about 20 minutes up and the views were insane over the entire valley. The Big Dune was equally as impressive and all we wanted to do was slide all the way down it.
Another must see in Valle de Luna is the Amphitheatre, just purely for the impressive size of it. We spent around 3 hours in Valle de Luna before heading up to the lookout point (included in the entrance fee) for sunset. We parked up our camper in a perfect lookout point and started cooking dinner – of course with a bottle of wine too. More and more tours slowly started to show up and we created many envious stares of people seeing us cozied up with our glass of wine and once in a life time views of Valle de Luna. It does get super packed her for sunset so find a good spot before the crowds rush in.
El Tatio is a field of geysers located a couple of hours north of San Pedro de Atacama and is the third largest geyser field in the Southern Hemisphere. We stayed overnight in Cañon de Gautin again which meant we got a 30 minute head start, considering we woke up 4.30am, the extra 30 minute sleep in was amazing. The drive to El Tatio was dark and VERY bumpy but we arrived by 6am, paid the 10,000 peso entry fee and got set up for sunrise. To be completely honest – coming from New Zealand we are accustomed to geysers so it wasn’t as impressive to us but we can imagine it being for people who have not seen the wonder of geysers before. It was still a beautiful spot and we enjoyed walking around for a few hours. Once again we set up our camp cooker and made a hot cup of coffee and enjoyed the view, whilst tour groups looked over at us in envy.
Although we personally didn’t find El Tatio to be incredibly amazing, we did however, find the drive back to town STUNNING. We had no idea what we had missed on our drive up in the dark but we we thrilled with what we saw on the way back and made many many stops along the way. This included hundreds of flamingoes in a laguna a few metres from the road, a small town where we had llama kebab and also some incredible canyons that passed deep into valleys.
Valley de la Muerte
Also known as Death Valley, this site is most popular for its sand dunes of which people sand-board on. We unfortunately ran out of time to sand-board due to certain car key issues…. So we just planned to drive through the valley to the car park and walk to the top for the view. The beginning of the drive was gorgeous with massive rock formations on both sides of the road. Part way up we were waved down by a man asking for help as they had driven their car too far and got stuck in the sand dunes. We of course paid back the good karma from the day before and spent a few hours helping the family out. In the end we didn’t quite make it to the top however, all of what we did see was fantastic and we were glad to pay-it-forward as well.
San Pedro de Atacama township
La Picada del Indio
We were recommend this restaurant by our hostel and we were lucky we got there early (8pm) as only half an hour after we arrived there were literally lines down the street for people wanting to eat there. We both had 5000 peso menu of the days which did not disappoint. Definitely a great restaurant if you are wanting a budget-friendly but delicious meal.
The cemetery was colourful and full of life and very different to cemetery’s we are used to back home in NZ. It makes for a good walk around and is also situated right next to some very cheap fruit and vege markets.
The one and only petrol station in the region is located in a very awkward part of town off Toconao street. This often has long lines of people waiting and does NOT have toilets and showers as advertised.

domain: geography


Originally published at The Progressive on March 17, 2017Donald Trump’s first budget makes his antipathy to the environment clear—and his love for fossil fuels and nuclear power even clearer. In addition to slashing funding to the Environmental Protection Agency, he also announced this week that he wants massive rollbacks in automotive fuel efficiency standards and billions in new investments in nuclear weapons and storage for commercial nuclear waste. The administration’s budget cuts $2.4 billion from the EPA’s operating funds—roughly 31 percent—taking the agency’s annual budget from $8.1 billion to $5.7 billion, the smallest since it was formed in 1970. These cuts will cripple regulation of air and water quality, strip oversight of a wide range of land management programs, and loosen restrictions on chemical emissions from industrial facilities. Much of this money would be shifted directly over to the military, which the Trump Administration wants to bolster with an additional $54 billion over the final Obama allocations. As Wenona Hauter, Executive Director of Food and Water Watch told Amy Goodman on Democracy Now, the cuts would lower staff to about 11,800, in an agency that employed 17,000 in 2010 and, according to the Washington Post, about 15,000 today.“We should be clear that 90 percent of EPA programs are run by state agencies,” Hauter says.“Half that staff is located in regional offices. The cuts, says Hauter, would cripple the states’ ability to protect clean air and water across the country. Following through on his campaign promise to reduce the EPA to “little tidbits,” Trump’s budget defunds more than 50 programs. These include infrastructure improvement on Indian reservations, major projects to clean up Puget Sound, Chesapeake Bay and the Great Lakes, a wide range of renewable energy development and energy efficiency programs, numerous climate change research programs, national heritage sites, environmental justice programs, oceanographic research and preservation, and much more. Gina McCarthy, a former EPA official under Obama,described it as “a scorched earth budget that represents an all-out assault on clean air, water and land.” Some of the immediate opposition has crossed party lines. Ohio’s recently re-elected Republican Senator Rob Portman, a close associate of former President George W. Bush, strongly opposed cuts to the $300 million Great Lakes Restoration Initiative. Bill Becker of the National Association of Clean Air Agencies warned, “if such cuts are realized, many more people will die prematurely and get sick unnecessarily due to air, water and waste pollution.” Among the programs affected will be popular Energy Star campaigns that set efficiency standards for household and other appliances. The program is well-established and popular among large manufacturers seeking marketing tools in a highly competitive global business. “It’s alarming and bewildering to see the Trump Administration propose cuts to critical government programs that support clean energy innovation, helped create thousands of new jobs, and saved Americans millions on their utility bills,” says Amit Ronen, Director of George Washington University’s Solar Institute. Scott Sklar, head of the Stella Group, a D.C.-based environmental consulting firm, and chair of the steering committee of the Sustainable Energy Coalition adds that the EPA cuts come in tandem with assaults on programs at the Department of Energy critical to advances in LED light bulbs, advanced batteries, electric trucks, biofuels and other cutting-edge green power projects. Overall, says Sklar, the cuts could cripple some seventeen national laboratories whose innovative technical work spans the horizon from windmills and solar panels to advanced batteries and accelerated efficiency. In addition, says Ronen, “Trump and his cronies can fundamentally change how EPA does its job by rolling back carbon and air regulations and not enforcing current law.” A deadly dose of that medicine is now being administered in Detroit, where Trump has moved to slash motor vehicle efficiency requirements and emissions standards. At the behest of auto company executives, Trump is exploiting a legal loophole in Obama-era requirements to gut fleet fuel-economy capabilities. Complaining about technical challenges, the industry may soon slouch back to lower emissions standards feeding higher short-term profits. Detroit will once again race to the bottom in a global transportation industry increasingly dominated by Germany, China, and Japan. The trends are being further exploited with shifts at the state as well as federal levels to slash tax breaks and incentives for electric cars and solar panels. Guided by handouts from the Koch brothers’ fossil fuel empire, “free market” legislators in states like Ohio, Oklahoma, and Arizona have partnered with the American Legislative Exchange Council to impose debilitating taxes and regulatory barriers against electric cars, green power production, advanced efficiency, mass transit and more. The trend has been underscored by Trump’s quick approval of the Keystone and Dakota pipelines, and relaxed rules governing fracking on public lands. Meanwhile, Illinois and New York are moving toward massive subsidies for uncompetitive, dangerously dilapidated old nuclear reactors in a marketplace where renewables are coming in far cheaper and creating thousands more jobs. In Ohio and other states, owners of money-losing reactors are advocating for massive handouts to block cheaper, job-creating renewables and efficiency from getting into the marketplace. Adding insult to injury, Trump wants to add $120 million to the long-dead Yucca Mountain nuclear waste dump. Despite fierce local opposition, the Department of Energy has blown some $13.5 billion since 2002 digging a giant tunnel through the dormant volcano eighty miles outside Las Vegas to store radioactive waste. Then-Senate Majority Leader Harry Reid, Democrat of Nevada, got President Obama to cancel Yucca in 2011. Yucca could ultimately cost more than $90 billion by some estimates, and take decades. A $2 billion 2014 explosion shut America’s sole state-of-the-art radioactive-waste repository, at Carlsbad, New Mexico, casting a long shadow over underground burial.
by Harvey Wasserman (originally published on The Progressive on September 21, 2016) Supporters of nuclear power like to argue that nukes are the key to combatting climate change. Here’s why they are dead wrong. Every nuclear generating station spews about two-thirds of the energy it burns inside its reactor core into the environment. Only one-third is converted into electricity. Another tenth of that is lost in transmission. According to the Union of Concerned Scientists:
Nuclear fission is the most water intensive method of the principal thermoelectric generation options in terms of the amount of water withdrawn from sources. In 2008, nuclear power plants withdrew eight times as much freshwater as natural gas plants per unit of energy produced, and up to 11 percent more than the average coal plant.Every day, large reactors like the two at Diablo Canyon, California, individually dump about 1.25 billion gallons of water into the ocean at temperatures up to 20 degrees Fahrenheit warmer than the natural environment. Diablo’s “once-through cooling system” takes water out of the ocean and dumps it back superheated, irradiated and laden with toxic chemicals. Many U.S. reactors use cooling towers which emit huge quantities of steam and water vapor that also directly warm the atmosphere. These emissions are often chemically treated to prevent algae and other growth that could clog the towers. Those chemicals can then be carried downwind, along with radiation from the reactors. In addition, hundreds of thousands of birds die annually by flying into the reactor domes and towers. The Union of Concerned Scientists states: The temperature increase in the bodies of water can have serious adverse effects on aquatic life. Warm water holds less oxygen than cold water, thus discharge from once-through cooling systems can create a “temperature squeeze” that elevates the metabolic rate for fish. Additionally, suction pipes that are used to intake water can draw plankton, eggs and larvae into the plant’s machinery, while larger organisms can be trapped against the protective screens of the pipes. Blocked intake screens have led to temporary shut downs and NRC fines at a number of plants. And that’s not all. All nuclear reactors emit Carbon 14, a radioactive isotope, invalidating the industry’s claim that reactors are “carbon free.” And the fuel that reactors burn is carbon-intensive. Themining, milling, and enrichment processes needed to produce the pellets that fill the fuel rods inside the reactor cores all involve major energy expenditures, nearly all of it based on coal, oil, or gas. And of course there’s the problem of nuclear waste. After more than a half-century of well-funded attempts, we’ve seen no solution for the management of atomic power’s intensely radioactive waste. There’s the “low-level” waste involving enormous quantities of troublesome irradiated liquids and solid trash that must be dealt with outside the standard civilian waste stream. And that handling involves fossil fuels burned in the process of transportation, management, and disposal as well As for the high-level waste, this remains one of humankind’s most persistent and dangerous problems. Atomic apologists have claimed that the intensely radioactive spent fuel rods can somehow be usable for additional power generation. But after a half-century of efforts, with billions of dollars spent, all attempts to do that have utterly failed. There are zero successful reactors capable of producing more reactor fuel than they use, or able to derive more energy from the tens of thousands of tons of spent fuel rods they create. Some reactors, like Fukushima, use “mixed-oxide” fuels that have proven to be extremely dirty and expensive. It’s possible some of this “MOX” fuel containing plutonium, actually fissioned at Fukushima Unit Three, raising terrifying questions about the dangers of its use. The mushroom cloud that appears on video as Fukushima Unit Three exploded stands as an epic warning against further use of these impossible-to-manage fuels. The MOX facility under construction near Aiken, South Carolina, is now projected to require another ten years to build with another ten possible after that to phase into production. U.S. Secretary of Energy Ernest Moniz said on September 13, 2016, at the Carnegie Endowment for International Peace that the mismanaged project was “impossible” to carry out and that it could cost $30 billion to $50 billion. Even the current pro-nuclear Congress won’t fully fund the project and the Department of Energy DOE continues to recommend abandoning it. There are no credible estimates of the global warming damage done by the intensely hotexplosions at the four Fukushima reactors, or at Chernobyl, or at any other past and future reactor meltdowns or blowups. Atomic apologists argue that the disposal of high-level reactor wastes should be a relatively simple problem, lacking only the political will to proceed. The industry touts New Mexico’s Waste Isolation Pilot Project, or WIPP, which has long been the poster child for military attempts to deal with plutonium contaminated trash from the nuclear weapons program. Accepting its first shipment of waste in 1999, WIPP was touted as the ultimate high-tech, spare-no-expense model that proved radioactive waste disposal “can be done.” But a series of disastrous events in February, 2014, led WIPP to stop accepting wastes—the sole function for which it was designed. Most significant was an explosion of radioactive waste materials (The theory that the waste was mistakenly packed with organic rather than clay-based kitty litter has been widely accepted – but it has not been proven). Twenty-two WIPP workers working above ground at WIPP tested positive for internal radioactive contamination. The entire facility remains closed. In a phone interview, facility management told me it may again accept some wastes before the end of this year. But at least part of the cavernous underground labyrinth may never be reopened. The Los Angeles Times estimated the cost of this single accident at $2 billion. Overall, the idea that atomic power is “clean” or “carbon free” or “emission free” is a very expensive misconception, especially when compared to renewable energy, efficiency, and conservation. Among conservation, efficiency, solar and wind power technologies, there are no global warming analogs to the heat, carbon, and radioactive waste impacts of nuclear power. No green technology kills anywhere near the number of marine organisms that die through reactor cooling systems. Rooftop solar panels do not lose ten percent of the power they generate to transmission, as happens with virtually all centralized power generators. S. David Freeman, former head of numerous large utilities and author of All Electric America: A Climate Solution and the Hopeful Future, says: “Renewables are cheaper and safer. That argument is winning. Let’s stick to it.” No terrorist will ever threaten one of our cities by blowing up a solar panel. But the nuclear industry that falsely claims its dying technology doesn’t cause global warming does threaten the future of our planet. ############ [Updated & Edited by Myla Reson on September 29, 2016] Harvey Wasserman wrote SOLARTOPIA! OUR GREEN-POWERED EARTH. He edits nukefree.org. You can find his GREEN POWER & WELLNESS SHOW at www.prn.fm]]>


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Worcestershire sign teenage star
FIFTEEN-year-old Aneesh Kapil has been likened to Worcestershire skipper Vikram Solanki by academy director Damian D’Oliveira.
The youngster has signed a scholarship contract with the New Road side and the academy chief was quick to heap praise on the Black Country-born lad.
“I don’t like to use comparisons like this willy-nilly, but he is a lot like Vik,” D’Oliveira said.
“He has a lot of shots in his locker…
Please click on link to read article

domain: sports


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very C++ programmer has had one of those days: A simple use of a template library turns into a nightmare, with pages upon pages of error messages streaming out of the compiler. Somewhere in that proverbial haystack are the clues you will need to determine exactly what went wrongan error about a missing +
operator here, an incompatible type assignment therebut you know you are in for a long search through the grisly internals of the template library, or a visit from your local C++ template guru.
This article is not about C++ template error messages, but they are indicative of a far more general problem with the C++ template system. Most errors in the use of templates come from a misunderstanding between the author of the template and the user of the template. The author of the template expects the user's type to provide some specific set of operations, say, a + operator for addition and a copy assignment operator, which I'll refer to as the template requirements. When the user provides a type with the appropriate operations, i.e., the type satisfies the template requirements, everything works. However, when the user's type is missing some operations, the compiler reports the error as soon as the template tries to use that operation, which is often deep in the implementation of the template library. Thus, the template requirements are effectively a contract between the template author and user, and debugging a template error message is the act of trying to determine who broke the contractand how.
Concepts is a language feature planned for C++0x that allows programmers to express the template requirements as part of the template’s source code. Placing requirements on a template formalizes the contract between template author and user, allowing the compiler to ensure that both parties uphold their end of the bargain. The template author is permitted to use only operations that he has required the user to provide, while the template user is allowed to supply only types that provide all of the operations that the template requires. When both parties uphold the terms of the contract, the program works; but when one party makes a mistake, the compiler produces an error message that describes the error in terms of the contract, isolating the template author from the template user and, therefore, producing shorter, simpler error messages that do not expose library internals to the user.
This article introduces the core ideas behind concepts, showing how they can be used to express the template requirements to provide correct and easy-to-use template libraries. The end of the article will illustrate some of the advanced features of concepts that make template libraries more powerful and more flexible. The intrepid reader may want to follow along using ConceptGCC, a prototype compiler implementing the concepts language feature. Template metaprogramming gurus: Please check your template tricks at the dooryou won't need them here.

domain: library


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63% of Brits more likely to view a video ad on their mobile if it’s on an entertainment app
It has been found that 60 per cent of mobile users like to watch content from major networks on their device, with 17 per cent watching over an hour and a half of TV on their device a week.
The research by mobile ad network Mojiva found that 33 per cent of Brits prefer to watch content on their phone at the time of their choice rather than their TV, and that 70 per cent spend over 30 minutes a week watching video content this way.
Carried out in February, the research of 1,000 people found that 64 per cent of Brits watch all or part of adverts displayed before a video, although only 49 per cent could remember the brands shown in pre-video ads.
It was also discovered that 63 per cent of Brits are more likely to view a video ad on their mobile if it’s on an entertainment app or website; with 58 per cent of consumers having over four entertainment apps on their mobile, and 12 per cent having over 10.
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domain: sociology


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The Salvation Army World Service Office
615 Slater's Lane, P.O. Box 1428
Alexandria, VA 22313
Copyright ©2014 The Salvation Army
The Salvation Army Response to the Ebola Outbreak in West Africa
The Salvation Army is supporting communities in West Africa who are fighting against the devastating outbreak of the Ebola virus disease. For example, The Salvation Army in Liberia has been providing food, household items, protective equipment, and hygiene items to people affected by the Ebola virus in local communities, treatment centers, and those in quarantine. Present in West Africa since 1920, The Salvation Army will support these communities in their long term recovery.
While we are currently not providing first line medical treatment, The Salvation Army is increasing prevention awareness and offering psychosocial and spiritual care and support.
The Salvation Army is committed to utilize philanthropic gifts in the manner donors desire. Occasionally, conditions in the field may alter relief activities. If this occurs, The Salvation Army will redirect funds to our International relief efforts in the area.


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A US senator has asked Christopher Marut, director of the American Institute in Taiwan (AIT), to visit former president Chen Shui-bian (陳水扁) in jail or hospital.
Senator Sherrod Brown, a Democrat, said in a letter sent this week to Marut that Chen is suffering from severe depression and is undergoing psychiatric treatment at Taipei Veterans General Hospital.
It is an obvious attempt by Brown to draw more attention to Chen’s case and increase the pressure on President Ma Ying-jeou (馬英九) to grant medical parole for Chen, who is serving a 17-and-a-half-year sentence for corruption.
“Reduced to a shadow of his former fiery self, Chen stutters and slurs his speech, and cannot walk far without tripping over,” The Economist magazine reported earlier this month.
“The prison’s harsh standard of treatment, which falls well below international norms, is contributing to serious illness,” the magazine said.
Chen’s continued incarceration, The Economist said, was not only undermining Ma’s “now dangerously low popularity,” but also faith in Taiwan’s system of justice.
“As advocates for human rights, freedom, democracy and the rule of law around the world, it is critical that we continue to support Taiwan,” Brown wrote to Marut.
Brown urged Marut to read a recent independent medical report that details Chen’s failing health and concludes that “in any democracy” this would be sufficient cause for immediate medical parole on humanitarian grounds.
“I ask that you review the report and visit the former president at the appropriate time,” the letter said.
“Senator Brown is a friend of president Chen, whom he has met on multiple occasions in Taiwan over the past decade,” Formosa Association of Public Affairs president Mark Kao (高龍榮) said. “It is touching to see a US senator ... reach out across the globe to a friend in need.”

domain: news


A Soyuz-2.1b carrier rocket with the Fregat booster, carrying 36 OneWeb communication satellites, has been launched from Russia’s Vostochny spaceport, TASS reported.
Nine minutes later the Fregat booster and communication satellites have separated from the third stage of the rocket. The launch was broadcast live on the Russian space agency Roscosmos’ website.
“The booster has separated from the third stage of the carrier rocket,” a launch commentator said.
It will take about four hours for the booster to deliver the satellites into orbit.
OneWeb currently has 146 satellites in operation, all of which were put into orbit by Soyuz rockets. The first six OneWeb satellites were orbited by a Soyuz-ST carrier rocket from the Kourou spaceport on February 28, 2019. Another 34 satellites were delivered into orbit on February 7, 2020, and 34 more on March 21, 2020, from the Baikonur spaceport. OneWeb satellites were first launched from the Vostochny spaceport in December 2020. A total of 36 space vehicles were put into orbit. Another launch took place on March 25, 2021.
OneWeb’s renewed agreement with the French launch service provider Arianespace includes the lift-off of 16 Russian Soyuz carrier rockets from the Kourou, Vostochny and Baikonur spaceports in 2020-2022. Each launch allows orbiting 34-36 satellites.


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RSD Black Friday Orange Splatter Vinyl Special Edition.
Rare and highly sought after in its original format, Os Brazões' self-titled album was originally released on RGE Discos in 1969. It is a psychedelic masterpiece that fuses samba, r’n’b and rock ‘n’ roll influences using fuzz guitars, synths, percussion, lush vocals and effects.
Os Brazões formed in Rio de Janeiro in the late 1960’s. They supported Tom Z and backed Gal Costa during her Tropicalia period, yet apparently never recorded in the studio with her. The album is peppered with alternative versions of songs by the movement’s stars, including Gilberto Gil’s ‘Pega a Voga, Cabeludo’ and Jorge Benand Toquinho’s ‘Carolina, Carol Bela’. But Os Brazões manage to make them their own with their unique interpretations.
It’s on their own songs that Os Brazões really shine. Their wide sonic palette presents the listener with moments of dense beauty, experimentation and some serious funk. Exploring this mix of covers and self-penned songs, you get a genuine feeling for the influences, tastes and direction of the band.Os Brazões produced a classic of the Tropicalia movement and it’s a record that probably deserves to be ranked alongside Os Mutantes’ early output.
“...grounded in samba, but with layers of psychedelic rock on top...the original numbers rock the hardest - 5/5.” MOJO Magazine
Tracks: Pega A Voga Cabeludo / Canastra Real / M dulo Lunar / Volksvolkswagen Blue / T o Longe De Mim / Carolina, Carol Bela / Feiti o / Planador / Espiral / Gotham City / Momento B/8 / Que Maravilha
- Additional Information
Artist Os Brazões Label Mr Bongo Music Format General Vinyl Music Format Specific Album Genre Psyche / Krautrock Release Date 26 Nov 2021 Track 1 Position No Track 1 Title No Track 1 Preview URL No Track 2 Position No Track 2 Title No Track 2 Preview URL No Track 3 Position No Track 3 Title No Track 3 Preview URL No Track 4 Position No Track 4 Title No Track 4 Preview URL No Track 5 Position No Track 5 Title No Track 5 Preview URL No Track 6 Position No Track 6 Title No Track 6 Preview URL No Track 7 Position No Track 7 Title No Track 7 Preview URL No Track 8 Position No Track 8 Title No Track 8 Preview URL No Track 9 Position No Track 9 Title No Track 9 Preview URL No Track 10 Position No Track 10 Title No Track 10 Preview URL No Track 11 Position No Track 11 Title No Track 11 Preview URL No Track 12 Position No Track12 Title No Track 12 Preview URL No

domain: artistic


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Faith In Action Lecture Series
Woldingham School is located in the Redhill Deanery within the Catholic Diocese of Arundel and Brighton. The School works closely with local parishes and Sacred Heart Schools in developing faith and learning.
The Faith In Action Lecture Series aims to provide a series of lectures which challenge students to live out their faith in action. The speakers have a message for all and it is an opportunity to share ideas and thinking about evangelisation. It is ongoing formation for the Deanery and the school.
Woldingham School's Chaplain is part of the Diocese and the Deanery and he identified the need for challenging lectures alongside the School's Head of Careers, Roy Peachey. The programme of lectures has run for the past two years.
Woldingham School are able to provide a venue and the lectures are live streamed to other Sacred Heart Schools globally. The events are facilitated by both teaching and non-teaching staff and refreshments are provided for those who attend.
The lectures have encouraged staff, students and members of local parishes to think clearly about their faith commitment and how we must live out our Christian vocation in word and deed. This had led to more students volunteering to help in the local community and to parishioners getting involved in their local parish.
The students involved are from Year 7 through to the Upper Sixth.
The Faith In Action lectures take place three times throughout the academic year.


Roland Introduces New Cube-GX Guitar Amplifiers-
Roland announces the all-new CUBE-GX series, which featuresthree combo guitar amplifiers equipped with the innovative i-CUBELINK interface for iOS devices. Building on the top-level COSM toneand rock-solid reliability that's made the CUBE name famous, theCUBE-GX amps turn up the heat with even more versatile operationand built-in connectivity for Apple's iPhone, iPad, and iPodtouch.
Models in the new series include the CUBE-80GX, CUBE-40GX, andCUBE-20GX, providing size and feature options to suit the needs ofplayers from gigging pros to bedroom jammers:
• CUBE-80GX: 80 watts, 12-inch custom-designedspeaker
• CUBE-40GX: 40 watts, 10-inch custom-designed speaker
• CUBE-20GX: 20 watts, 8-inch custom-designed speaker
Each CUBE-GX amp is equipped with three independentchannels-including JC CLEAN, LEAD, and SOLO-plus three separateeffects sections. JC CLEAN provides the revered tone of Roland'slegendary JC-120 amplifier, while LEAD offers multiple amp types tochoose from (10 in the CUBE-80GX/-40GX; 6 in the CUBE-20GX). SOLOis fully programmable, allowing users to store their favorite amptype along with EQ and effects settings. Built-in effects includeEFX (5 types), DELAY, and REVERB.
Players can select channels from the top panel or remotely withfootswitches while performing. The CUBE-80GX and CUBE-40GX supportthe GA-FC Foot Controller (sold separately), which has sixfootswitches for channel selection and effects on/off, plus twojacks for volume control with expression pedals. All CUBE-GX ampsalso offer remote channel selection with optional BOSS FS-5U orFS-6 footswitches.
The CUBE-GX series features Roland's innovative i-CUBE LINKinterface for simple and convenient connectivity with Apple'siPhone, iPad, or iPod touch. Two-way communication with iOS devicesis provided via the included cable, allowing players to jam withmusic tracks and send studio-quality guitar tones direct to theirfavorite music recording apps. The versatile i-CUBE LINK jack canalso be used as a simple stereo input, letting users plug in nearlyany music player or audio device and play it through the amp.
Available for free from the App Store, the companion CUBE JAMapp turns an iOS device into a fun command center for jamming,recording, and learning. Users can play along with commercial songsthrough the CUBE-GX series, and record their performance back intoCUBE JAM with their favorite amp tones. The app also includespowerful tools for music practice, including independent speed andpitch adjustment of audio playback, Center Cancel, and more.
For more information, visit www.RolandConnect.com.


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As a grower, you must understand the importance of enzymes. An enzyme is a biological substance that functions as a catalyst that initiates a specific chemical reaction or increases its rate. The majority of enzymes are derived from microorganisms. They are primarily responsible for the breakdown of organic matter.
You may be thinking that enzymes are catalysts in the human digestive system, so why do plants need them? The fact is that enzymes are essential in all living things because they promote the basic chemical reactions necessary to support life.
Since enzymes are naturally present in the soil, most outdoor gardens do not need supplemental enzymes. Nevertheless, there may be cases where the enzymes are absent. For instance, if the soil doesn't have the required enzymes or the soilless garden (hydroponic system). When you add supplemental enzymes in hydroponics operations, it boosts the microbial activity in your plant's root system and enables better nutrient absorption.
If you are growing organically, supplemental enzymes are essential for your plants. The reason is that the organic fertilizers you will use need a high level of microbial activity to get absorbed. Enzymes help boost nutrient uptake. They also prevent the buildup of excess material around the plant's root system, which helps avoid problems.
Do you want to know more about enzymes and supplements, you can go to our learning center's Nutrient and Fertilizer section. Also, you are welcome to reach out to our growing experts at 866-GRO-INDR for further guidance!

domain: agronomy


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part of the now well established three part test. See here for Customs & Excise v Barclays which authoritatively reviews the modern law.
Lord Bridge said,
‘In determining the existence and scope of the duty of care which one person may owe to another in the infinitely varied circumstances of human relationships there has for long been a tension between two different approaches. Traditionally the law finds the existence of the duty in different specific situations each exhibiting its own particular characteristics. In this way the law has identified a wide variety of duty situations, all falling within the ambit of the tort of negligence, but sufficiently distinct to require separate definition of the essential ingredients by which the existence of the duty is to be recognised.
Commenting upon the outcome of this traditional approach, Lord Atkin, in his seminal speech in Donoghue v. Stevenson  A.C. 562 , 579-580, observed:
‘The result is that the courts have been engaged upon an elaborate classification of duties as they exist in respect of property, whether real or personal, with further divisions as to ownership, occupation or control, and distinctions based on the particular relations of the one side or the other, whether manufacturer, salesman or landlord, customer, tenant, stranger, and so on. In this way it can be ascertained at any time whether the law recognises a duty, but only where the case can be referred to some particular species which has been examined and classified. and yet the duty which is common to all the cases where liability is established must logically be based upon some element common to the cases where it is found to exist.’
It is this last sentence which signifies the introduction of the more modern approach of seeking a single general principle which may be applied in all circumstances to determine the existence of a duty of care. Yet Lord Atkin himself sounds the appropriate note of caution by adding, at p. 580:
‘To seek a complete logical definition of the general principle is probably to go beyond the function of the judge, for the more general the definition the more likely it is to omit essentials or to introduce non-essentials.’
Lord Reid gave a large impetus to the modern approach in Dorset Yacht Co. Ltd. v. Home Office  A.C. 1004 , 1026-1027, where he said:
‘In later years there has been a steady trend towards regarding the law of negligence as depending on principle so that, when a new point emerges, one should ask not whether it is covered by authority but whether recognised principles apply to it. Donoghue v. Stevenson  A.C. 562 may be regarded as a milestone, and the well known passage in Lord Atkin’s speech should I think be regarded as a statement of principle. It is not to be treated as if it were a statutory definition. It will require qualification in new circumstances. But I think that the time has come when we can and should say that it ought to apply unless there is some justification or valid explanation for its exclusion.’
The most comprehensive attempt to articulate a single general principle is reached in the well known passage from the speech of Lord Wilberforce in Anns v. Merton London Borough Council …
But since the Anns case a series of decisions of the Privy Council and of your Lordships’ House, notably in judgments and speeches delivered by Lord Keith of Kinkel, have emphasised the inability of any single general principle to provide a practical test which can be applied to every situation to determine whether a duty of care is owed and, if so, what is its scope…
What emerges is that, in addition to
(a) the foreseeability of damage,
necessary ingredients in any situation giving rise to a duty of care are that
(b) there should exist between the party owing the duty and the party to whom it is owed a relationship characterised by the law as one of ‘proximity’ or ‘neighbourhood’ and that
(c) the situation should be one in which the court considers it fair, just and reasonable that the law should impose a duty of a given scope upon the one party for the benefit of the other.
But it is implicit in the passages referred to that the concepts of proximity and fairness embodied in these additional ingredients are not susceptible of any such precise definition as would be necessary to give them utility as practical tests, but amount in effect to little more than convenient labels to attach to the features of different specific situations which, on a detailed examination of all the circumstances, the law recognises pragmatically as giving rise to a duty of care of a given scope.
Whilst recognising, of course, the importance of the underlying general principles common to the whole field of negligence, I think the law has now moved in the direction of attaching greater significance to the more traditional categorisation of distinct and recognisable situations as guides to the existence, the scope and the limits of the varied duties of care which the law imposes.
We must now, I think, recognise the wisdom of the words of Brennan J. in the High Court of Australia in Sutherland Shire Council v. Heyman (1985) 60 A.L.R. 1 , 43-44, where he said:
‘It is preferable, in my view, that the law should develop novel categories of negligence incrementally and by analogy with established categories, rather than by a massive extension of a prima facie duty of care restrained only by indefinable ‘considerations which ought to negative, or to reduce or limit the scope of the duty or the class of person to whom it is owed.”
Edited, including (a) -(c) notation and paragraphing added, for ease of reading.

domain: law


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Originally from East Providence, now-retired BMX rider Kevin Robinson (aka K-Rob) has accomplished a lot throughout his career. He’s won four gold medals in the X Games, has broken records in the sport – including an 84-foot backflip he landed in Providence this past August – and continues to build up his list of projects, from running an athletic protective gear company to bringing awareness to bullying prevention.
But recently, K-Rob has come full-circle with a new skatepark in his hometown, thanks to his family-run non-profit, the K-Rob Foundation. According to its Facebook page, the organization’s mission is to help the children of East Providence stay involved in sports.
The nearly 9,000-square-foot skatepark is part of the City of East Providence’s improvement plan for the Onna Moniz-John Neighborhood Park and Central Avenue Playground. “Not every kid is a stick-and-ball kid,” says Barrington resident K-Rob. “I wasn’t. Not every kid wants to play baseball or basketball. Some kids want to ride bikes, skateboards or scooters. And I want to be able to give them that outlet. There are basketball courts, baseball fields and football fields all over the place. But there are rarely any skateparks.”
Without these outlets, it’s common for kids to practice on ledges and other structures that just so happen to be built around businesses, which can make businesses mad. This, in part, is why skateboarders and BMXers get a bad rap. “There’s a misconception with action sports,” says K-Rob. “Everybody associates all skateboarders and BMXers with being punks and troublemakers, and it’s so not the case. They may dress a little different, they may make a few different choices, but they’re really good kids and they just want to be on their bikes and skateboards.”
A three-year labor of love, the skatepark was built with the help of John Saxton, a professional ramp builder of Skidmark Parks. “A lot of towns will put up a skatepark, but they hire a contractor who really doesn’t understand ramps, and that makes a huge difference,” says K-Rob.
Another component that most towns don’t consider is safety. “They spend money on a park and think ‘out of sight, out of mind,’ and put the park somewhere where nobody can see it. And they wonder why trouble happens. You need a place where there’s a lot of interaction and where there’s adults,” says K-Rob. “This has been phenomenal.”
Onna Moniz-John Park, Blanding Avenue, East Providence. KRobFoundation.org