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ABSTRACT: Since very little research in this field is available, this study aims to assess the role of psychosexual, relationship, hormonal and genetic measures in the sexual desire of users of three hormonal contraceptive products [low-dose combined oral contraceptive (20 mcg ethinylestradiol/150 mcg desogestrel), progestin-only pill (75 mcg desogestrel) and vaginal ring (daily dose of 15 mcg ethinylestradiol/120 mcg etonogestrel)].
Fifty-five couples were randomized over three groups in which the women consecutively used each product during 3 months. Both partners repeatedly filled out questionnaires on solitary and dyadic sexual desire (desire to behave sexually by oneself or towards a partner). Total and free testosterone, sex hormone binding globulin and a genetic marker of androgen receptor sensitivity [cytosine-adenine-guanine (CAG) repeat length] were assessed on blood samples of the female partners.
Sexual desire was higher in women with either short or long CAG repeats (solitary, p=.004; dyadic, p=.008). Desire levels were higher during vaginal ring use (solitary, p=.018; dyadic, p=.007). The woman's mood was found to impact her dyadic sexual desire (p<.001); this scale was also strongly associated with the male partner's dyadic sexual desire (p<.001).
The current study found evidence for a role of androgen receptor sensitivity and mood in the sexual desire of hormonal contraceptive users.
Contraception 11/2012; 85(5):470-9. · 2.72 Impact Factor
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ABSTRACT: Summary Parthenogenetic activation of oocytes is a helpful tool to obtain blastocysts, of which the inner cell mass may be used for derivation of embryonic stem cells. In order to improve activation and embryonic development after parthenogenesis, we tried to use sperm injection and subsequent removal of the sperm head to mimic the natural Ca2+ increases by release of the oocyte activating factor. Visualization of the sperm could be accomplished by Hoechst staining and ultraviolet (UV) light irradiation. To exclude negative effects of this treatment, we examined toxicity on activated mouse oocytes. After activation, oocytes were incubated in Hoechst 33342 or 33258 stain and exposed to UV irradiation. The effects on embryonic development were evaluated. Our results showed that both types of Hoechst combined with UV irradiation have toxic effects on parthenogenetically activated mouse oocytes. Although activation and cleavage rate were not affected, blastocyst formation was significantly reduced. Secondly, we used MitoTracker staining for removal of the sperm. Sperm heads were stained before injection and removed again after 1 h. However, staining was not visible anymore in all oocytes after intracytoplasmic sperm injection. In case the sperm could be removed, most oocytes died after 1 day. As MitoTracker was also not successful, alternative methods for sperm identification should be investigated.
Zygote 07/2012; · 1.17 Impact Factor
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Mitochondrion 05/2012; 12(4):477-9. · 3.62 Impact Factor
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ABSTRACT: To create a pool of frozen donated human oocytes and find the optimal stage for slow controlled-rate freezing of human in vitro matured oocytes.
Oocytes at different developmental stages of maturation (germinal vesicle, metaphase I, or metaphase II) and oocytes that failed to fertilize after IVF or intracytoplasmic sperm injection (ICSI) were frozen using a slow controlled-rate freezing protocol. Frozen/thawed oocytes were artificially activated to verify activation potential and compared with oocytes that were not frozen.
University hospital-based fertility center.
Stimulated patients undergoing IVF/ICSI treatment donated oocytes left over during their infertility treatment.
Human oocytes were frozen at different stages of maturation. Fresh and frozen/thawed oocytes were activated by electrical pulses followed by incubation in 6-dimethylaminopurine.
Survival rate, maturation rate and kinetics, and activation potential.
Human oocytes at all developmental stages have high survival rates after slow controlled-rate freezing. Frozen/thawed germinal vesicle oocytes showed decreased and delayed maturation after thawing. Activation potential was not affected.
A pool of donated human oocytes could be established using slow controlled-rate freezing. Immature oocytes should be frozen after in vitro maturation.
Fertility and sterility 07/2011; 96(3):624-8. · 3.97 Impact Factor
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ABSTRACT: Diseases associated with point mutations in the mitochondrial DNA (mtDNA) are maternally inherited. We evaluated whether pre-implantation genetic diagnosis, based on polar body mutation load detection could be used to distinguish healthy from affected oocytes. Restriction Fragment Length Polymorphism (RFLP) analysis was used and validated, to determine A3243G tRNA(Leu(UUR)) mutation load in metaphase II oocytes and their respective first polar bodies. The results of this study show for the first time that the mutation load measured in the polar bodies correlates well with the mutation load in the respective oocytes. Therefore, human polar body analysis can be used as diagnostic tool to prevent transmission of mitochondrial disorders.
Mitochondrion 07/2011; 11(4):626-9. · 3.62 Impact Factor
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ABSTRACT: Parthenogenetic reconstruction is one major strategy to create patient-specific stem cells. The aim of this study was to find the best artificial activation protocol for parthenogenetic activation of mouse and human oocytes comparing different methods. In a first set of experiments, in-vivo matured mouse oocytes and human failed-fertilized, in-vitro and in-vivo matured oocytes were artificially activated by a chemical (ionomycin) or electrical stimulus. In a second set of experiments, a combination of activating agents (electrical pulses followed by ionomycin or SrCl(2)) was applied in an aim to improve developmental competence. All embryos were evaluated daily until day 6 after activation. Mouse blastocysts were differentially stained to evaluate blastocyst quality. For mouse oocytes and human failed-fertilized oocytes, blastocyst development was significantly higher after electrical activation (P<0.05). For human in-vitro and in-vivo matured oocytes, blastocyst formation was only obtained after electrical activation of in-vitro matured oocytes. After combining activating agents, no differences in development could be observed. In conclusion, this study revealed that for both mouse and human oocytes development to the blastocyst stage was significantly better after electrical activation compared with chemical activation. Combining activating agents had no further positive effect on developmental potential.
Reproductive biomedicine online 11/2010; 21(6):769-75. · 2.04 Impact Factor
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ABSTRACT: The need for serial vaginal sonographies to monitor ovarian stimulation for artificial reproductive technology (ART) treatments remains a major practical and organizational drawback both for patients and health-care providers. We explore the possibility of patients and/or their partners performing their own vaginal sonographies at home. To make this a reality, a portable, easy-to-use, home-applied vaginal probe for recording relevant images would have to be developed, as well as appropriate software to transfer images using modern communication technology to the centre, to analyse the recordings and to send a swift structured response, comprising dosing advice and next-step instructions. A simplification of the uncontested need to perform these sonographies, even if applicable to just a selected proportion of IVF patients, could fit in the general tendency to make IVF more patient centred and friendly, to implement telemedicine and to increase patient empowerment by supervised active participation to their treatment. The advantages of such a technology are explored in this paper, aiming at opening up a debate on whether patients themselves would, could and should achieve a further substantial simplification of ART without loss of quality while strongly curbing costs.
Human Reproduction 12/2009; 25(3):562-8. · 4.47 Impact Factor
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ABSTRACT: The microflora of the penile skin-lined neovagina in male-to-female transsexuals is a recently created microbial niche which thus far has been characterized only to a very limited extent. Yet the knowledge of this microflora can be considered as essential to the follow-up of transsexual women. The primary objective of this study was to map the neo-vaginal microflora in a group of 50 transsexual women for whom a neovagina was constructed by means of the inverted penile skin flap technique. Secondary objectives were to describe possible correlations of this microflora with multiple patients' characteristics, such as sexual orientation, the incidence of vaginal irritation and malodorous vaginal discharge.
Based on Gram stain the majority of smears revealed a mixed microflora that had some similarity with bacterial vaginosis (BV) microflora and that contained various amounts of cocci, polymorphous Gram-negative and Gram-positive rods, often with fusiform and comma-shaped rods, and sometimes even with spirochetes. Candida cells were not seen in any of the smears. On average 8.6 species were cultured per woman. The species most often found were: Staphylococcus epidermidis, Streptococcus anginosus group spp., Enterococcus faecalis, Corynebacterium sp., Mobiluncus curtisii and Bacteroides ureolyticus. Lactobacilli were found in only one of 30 women. There was no correlation between dilatation habits, having coitus, rinsing habits and malodorous vaginal discharge on the one hand and the presence of a particular species on the other. There was however a highly significant correlation between the presence of E. faecalis on the one hand and sexual orientation and coitus on the other (p = 0.003 and p = 0.027 respectively). Respectively 82%, 58% and 30% of the samples showed an amplicon after amplification with M. curtisii, Atopobium vaginae and Gardnerella vaginalis primer sets.
Our study is the first to describe the microflora of the penile skin-lined neovagina of transsexual women. It reveals a mixed microflora of aerobe and anaerobe species usually found either on the skin, in the intestinal microflora or in a BV microflora.
BMC Microbiology 06/2009; 9:102. · 3.04 Impact Factor
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ABSTRACT: To assess feasibility and diagnostic performance of prostate examination through transvaginal palpation and transvaginal ultrasound in transsexual women (TSW).
Fifty TSW who were at least 6 months' posttransition were recruited in a University Hospital. Speculum examination and digital vaginal examination were performed by a gynecologist. Transvaginal ultrasound of the prostate was performed by a radiologist. The information gathered included: ease of insertion of the speculum, vaginal length, palpability of the prostate, vaginal mobility and presence of scar tissue, ease of introduction of the ultrasound probe, ability to visualize prostate and seminal vesicles, echogenicity of the peripheral zone and the central gland, presence of calcifications and delineation of prostatic capsule, attitude toward gynecologic examinations, and anticipated and experienced painfulness of the different examinations.
Speculum examination was possible in all but 1 patient and was easy in 78% of the patients. Median vaginal length was 7 cm. A regular digital vaginal examination was possible in 44% of the patients, the vagina was rather mobile and with limited scar tissue on average. In 48% of the patients, the prostate was palpable. In 94% of the patients, the prostate was visible on transvaginal ultrasound. Mean prostate volume was 14 mL, calcifications were present in 33%, and none had cysts. Capsule of the prostate was well delineated in 74% and seminal vesicles were visualized in 80%. All examinations were very well tolerated and nearly painless.
Gynecologic examination and prostate assessment were acceptable to TSW. Transvaginal palpation of the prostate is of poor clinical value, yet transvaginal ultrasound allows for proper evaluation of the prostate status.
Urology 05/2009; 74(1):191-6. · 2.43 Impact Factor
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Jan Gerris
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ABSTRACT: Despite the progress made in assisted reproductive technology, live birth rates remain disappointingly low. Multiple-embryo transfer has been an accepted practice with which to increase the success rate. This has led to a higher incidence of multiple-order births compared with natural conception, which not only increase the risk of mortality and morbidity to both mother and children but are also associated with social and economic consequences. Elective single-embryo transfer (eSET) was developed in an effort to increase singleton pregnancies in assisted reproduction. Studies comparing eSET with multiple-embryo transfer highlight the benefit of this approach and suggest that, with careful patient selection and the transfer of good-quality embryos, the risk of a multiple-order pregnancy can be reduced without significantly decreasing live birth rates. Although the use of eSET has gradually increased in clinical practice, its acceptance has been limited by factors such as availability of funding and awareness of the procedure. An open discussion of eSET is warranted in an effort to enable a broader understanding by physicians and patients of the merits of this approach. Ultimately, eSET may provide a more cost-effective, potentially safer approach to patients undergoing assisted reproduction technology.
Reproductive biomedicine online 02/2009; 18 Suppl 2:63-70. · 2.04 Impact Factor
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ABSTRACT: Artificial oocyte activation using the calcium ionophore ionomycin is applied successfully in assisted reproduction but some concern exists on the clinical use. The aims of the present study were to optimize the oocyte activation scheme and to address embryo toxicity in a mouse model. Efficiency of oocyte activation and subsequent development was evaluated and ionomycin was found to be an efficient activator at 10 micromol/l. An improved effect of a second exposure to 5 micromol/l ionomycin on blastocyst development was observed. Toxicity of ionomycin on embryos was then investigated by evaluating pre- and post-implantation development of in-vivo fertilized oocytes following exposure to ionomycin. Blastocyst development, blastocyst cell numbers in trophectoderm and inner cell mass were not different between treated and non-treated zygotes. Also implantation rates and fetal parameters such as length, weight and morphological parameters were similar between the fetuses originating from zygotes treated with ionomycin and non-treated zygotes. Furthermore, healthy offspring originating from ionomycin-treated zygotes was born. In conclusion, no adverse effects of ionomycin on in-vitro or in-vivo mouse embryo development were noticed, giving arguments in favour of the use of ionomycin, although negative long-term effects of this compound cannot be excluded at present.
Reproductive biomedicine online 01/2009; 17(6):764-71. · 2.04 Impact Factor
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ABSTRACT: In the early days of IVF, replacement of several embryos in order to compensate for low implantation rates in the human was
considered good clinical practice. Lack of funding, suboptimal embryo culture and selection techniques and pressure from patients
led to a staggering 50% of all children born after IVF/ICSI belonging to a set of multiples. The first step towards a more
reasonable approach came when it was shown that transferring two or three embryos did not influence the pregnancy rate but
only the triplet rate. Unfortunately, this step in the right direction did n ot result in a decrease of twins. Although the
challenge of a triplet pregnancy is much greater than that of a twin, the epidemic size of iatrogenic twinning results in
a more widespread negative effect on neonatal, perinatal and maternal outcome. The challenge is to combine excellent pregnancy
rates with a reduction in twinning rate from 25–30% to 5–10%. The second step has received much attention but little following:
elective single-embryo transfer (eSET). Published data indicate the feasibility to perform judicious eSET. This is definitely
the case in good prognosis patients (less than 36 years of age, first or second IVF/ICSI trial) and if there is a choice from
several embryos. Embryo selection, still on the basis of an optimized morphology assessment using strict criteria and time
intervals, is essential. Apart from the preventive effect on the complications associated with many (but not all) twin pregnancies,
both health-economic considerations and neonatal outcome considerations also underpin the value of SET. Cryopreservation is
a useful tool in an optimal strategy and management of all oocyte harvests.
KeywordsIVF/ICSI–Multiple pregnancy–Com- plications–Single-embryo transfer–Embryo selection
12/2008: pages 171-183;
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ABSTRACT: Failed fertilization after intracytoplasmic sperm injection (ICSI) can occur due to an oocyte activation defect. In these cases assisted oocyte activation (AOA) may help but efficiency is still unknown. Prior to AOA, the mouse oocyte activation test (MOAT) can be carried out by injecting human spermatozoa into mouse oocytes to evaluate their activating capacity. According to the MOAT activation percentage achieved, patients were classified into three groups: 0-20% (16 patients); 20-85% (seven patients); 85-100% (seven patients). For AOA, CaCl(2) was injected together with spermatozoa followed by a double Ca(2+) ionophore treatment. The fertilization rates before application of AOA in 50 cycles were 6%, 22% and 14% in, respectively, groups 1, 2 and 3 without any pregnancy. Fertilization and pregnancy rates after AOA in 61 cycles were significantly increased to 75% and 34% for group 1, 73% and 43% for group 2, and 75% and 17% for group 3 (P < 0.0001 and P < 0.004, respectively). Application of AOA results in normal fertilization and pregnancy rates in patients whose spermatozoa show deficient activation. When MOAT reveals no activation deficiency in spermatozoa, AOA still allows for high fertilization and acceptable pregnancy rates. The obstetric and neonatal outcomes after AOA were normal as no malformations were observed.
Reproductive biomedicine online 12/2008; 17(5):662-8. · 2.04 Impact Factor
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ABSTRACT: Transsexualism is the most extreme form of gender identity disorder and most transsexuals eventually pursue sex reassignment surgery (SRS). In transsexual women, this comprises removal of the male reproductive organs, creation of a neovagina and clitoris, and often implantation of breast prostheses. Studies have shown good sexual satisfaction after transition. However, long-term follow-up data on physical, mental and sexual functioning are lacking.
To gather information on physical, mental, and sexual well-being, health-promoting behavior and satisfaction with gender-related body features of transsexual women who had undergone SRS.
Fifty transsexual women who had undergone SRS >or=6 months earlier were recruited.
Self-reported physical and mental health using the Dutch version of the Short-Form-36 (SF-36) Health Survey; sexual functioning using the Dutch version of the Female Sexual Function Index (FSFI). Satisfaction with gender-related bodily features as well as with perceived female appearance; importance of sex, relationship quality, necessity and advisability of gynecological exams, as well as health concerns and feelings of regret concerning transition were scored.
Compared with reference populations, transsexual women scored good on physical and mental level (SF-36). Gender-related bodily features were shown to be of high value. Appreciation of their appearance as perceived by others, as well as their own satisfaction with their self-image as women obtained a good score (8 and 9, respectively). However, sexual functioning as assessed through FSFI was suboptimal when compared with biological women, especially the sublevels concerning arousal, lubrication, and pain. Superior scores concerning sexual function were obtained in those transsexual women who were in a relationship and in heterosexuals.
Transsexual women function well on a physical, emotional, psychological and social level. With respect to sexuality, they suffer from specific difficulties, especially concerning arousal, lubrication, and pain.
Journal of Sexual Medicine 12/2008; 6(3):752-60. · 3.55 Impact Factor
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ABSTRACT: The present study aimed to analyze detailed morphological and functional characteristics of mouse in vitro matured oocytes after a pre-maturation culture (PMC) by temporary nuclear arrest with the specific phosphodiesterase 3-inhibitor (PDE3-I) Cilostamide. In a first experiment the lowest effective dose of Cilostamide was determined. Cumulus-oocyte complexes (COCs), isolated from small antral follicles, were exposed to different concentrations of Cilostamide (ranging from 0 (control) to 10 microM) for 24 hr. Afterwards, oocytes were removed from PDE3-I-containing medium and underwent in vitro maturation (IVM) for 16-18 hr. A concentration of 1 microM Cilostamide was the lowest effective dose for maximum level of inhibition and reversibility of meiosis inhibition. This concentration was used in further experiments to evaluate oocyte quality following IVM in relation to different parameters: kinetics of meiotic progression, metaphase II (MII) spindle morphology, aneuploidy rate, fertilization, and embryonic developmental rates. The results were compared to nonarrested (in vitro control) and in vivo matured oocytes (in vivo control). Following withdrawal of the inhibitor, the progression of meiosis was more synchronous and accelerated in arrested when compared to nonarrested oocytes. A PMC resulted in a significant increase in the number of oocytes constituting a MII spindle of normal morphology. None of the oocytes exposed to PDE3-I showed numerical chromosome alterations. In addition, fertilization and embryonic developmental rates were higher in the PMC group compared to in vitro controls, but lower than in vivo controls. These results provide evidence that induced nuclear arrest by PDE3-I is a safe and reliable method to improve oocyte quality after IVM.
Molecular Reproduction and Development 07/2008; 75(6):1021-30. · 2.53 Impact Factor
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ABSTRACT: In 2% of assisted reproductive techniques (ART) cycles complications occur. Some are preventable, some are not. In this paper, we will discuss risks and complications of the standard 'Western' approach in ART today and point to some measures to be taken when implementing ART in developing countries, where resources and access to medical care may be limited. Ovarian hyperstimulation syndrome (OHSS, and its thrombo-embolic complications) is responsible for the majority of cycle-related complications, followed by bleeding and infection at oocyte retrieval. ART pregnancies are complicated by first-trimester bleeding more often than spontaneous pregnancies, they are more often ectopic, but the major complication is the very high incidence of multiple pregnancies, when more than one embryo is transferred. OHSS can be prevented by screening patients at risk and by using mild or no stimulation. Simple measures can minimize the risks of bleeding or infection. Obviously single embryo transfer is the only way to avoid multiple pregnancies, which have a highly increased risk for severe maternal and neonatal morbidity and mortality (mainly due to prematurity). Special attention should be given to pre-existing pathologies. Risk minimization of ART in developing countries is not only mandatory from an economical but also an ethical point of view.
Human Reproduction 06/2008; · 4.47 Impact Factor
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ABSTRACT: Because seminal prostaglandins play a role at natural fertilization, it was hypothesized that vaginal supplementation of prostaglandins at the time of intrauterine insemination (IUI) might enhance chances of conception. We investigated the effect of misoprostol, a prostaglandin analogue, on the success rate of IUI.
A multi-center double-blind randomized controlled trial, using a cross-over design with alternating sequence, was designed. Vaginal tablets of misoprostol or placebo were used in conjunction to intrauterine insemination. In total, 199 women, comprising 466 cycles, were analyzed. Main outcome measures were pregnancy rate and prevalence of vaginal bleeding and uterine cramps.
The misoprostol group accounted for 146 cycles with 19 pregnancies, whereas the placebo group cycles totaled 164 cycles with 21 pregnancies (13.0 vs. 12.8%, not significant). There was a statistically significant increase in vaginal bleeding (12.3 vs. 1.8%; OR 7.55; 95% CI 2.31-24.48) and abdominal cramping rates (15.1 vs. 4.3%; OR 3.98; 95% CI 1.68-9.39) after application of misoprostol. Due to these severe adverse events the study was prematurely terminated.
Although prostaglandins surely play a role in natural human reproduction, vaginal administration of misoprostol at the time of IUI is associated with a high rate of side effects and does not seem to enhance the outcome.
Gynecologic and Obstetric Investigation 06/2008; 66(3):145-51. · 1.28 Impact Factor
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ABSTRACT: Birth weight is the single most important risk indicator for neonatal and infant mortality and morbidity, which has led to the idiom that 'every ounce counts'. Birth weight in turn, however, tends to vary widely across populations as a result of differential fetal growth velocity with such demographic factors as ethnicity, maternal and paternal height and altitude of residence. Accordingly, it has been acknowledged that the appraisal of birth weight should rely on its position relative to the birth weight distribution of the background population. This is commonly done by standardizing birth weight through its deviation from the population mean in the given gestational age stratum, as can be obtained from population-customized birth weight nomograms. This issue was recently revisited in 'Human Reproduction' through a plea for reporting birth weight as z-scores. In this article, we argue that adjustment for factors, such as gestational age, which may lie on the causal pathway from exposures present at the time of conception [e.g. single-embryo transfer (SET) versus double-embryo transfer (DET)] to birth weight, may induce bias, regardless of whether the adjustment happens via stratification, regression or through the use of z-scores.
Human Reproduction 09/2007; 22(8):2080-3. · 4.47 Impact Factor
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ABSTRACT: The use of hormones for controlled ovarian stimulation results in follicular heterogeneity, with oocytes at diverse stages of nuclear and cytoplasmic development. This study evaluated the impact of temporary nuclear arrest by a specific phosphodiesterase 3-inhibitor (PDE3-I), cilostamide, on nuclear and cytoplasmic maturation of cumulus-free germinal vesicle (GV) human oocytes from controlled ovarian stimulated cycles.
GV oocytes (n = 234) were cultured in: (i) medium without the inhibitor (control); (ii) medium supplemented with 1 microM cilostamide and (iii) medium supplemented with 10 microM cilostamide. Oocytes in groups (ii) and (iii) were exposed to cilostamide for 24 h. The PDE3-I was subsequently removed by transfer of oocytes to fresh in vitro maturation (IVM) medium and the reversibility of GV arrest was assessed during IVM culture for maximum 48 h.
Cilostamide (1 and 10 microM) could maintain >80% of the oocytes at the GV stage, without affecting subsequent maturation to metaphase II. Oocytes exposed to 1 microM cilostamide were more likely to have normal bipolar spindles with aligned chromosomes than control oocytes (P < 0.05). When GV chromatin configurations before and after arrest were compared, a significantly higher proportion of oocytes had acquired a nucleolus completely surrounded by a rim of highly condensed chromatin (P < 0.05).
Temporary nuclear arrest of human GV oocytes with PDE3-I proved to be beneficial for obtaining normal spindle and chromosome configurations after IVM. It resulted also in synchronization within the population of GV oocytes.
Human Reproduction 06/2007; 22(5):1239-46. · 4.47 Impact Factor
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Jan Gerris
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ABSTRACT: In Antwerp, single embryo transfers (SET) have increased, and this change in policy has seen the incidence of singletons rise from 70 to 90%, twins drop from 25 to 10%, and triplets drop from 1-2% to none at all. At a national and regional level, changes have been much more dramatic as a result of a change in the law in 2003 mandating SET. Data show a huge increase in the number of treatment cycles and a dramatic rise in SET. Rates of twins and triplets have dropped considerably. European data indicate wide differences in the incidence of triplets between countries, varying between 0% (e.g.Slovenia, Iceland, Lithuania) and 4.4% (Hungary), but almost nothing is known about the true incidence of fetal reduction. US data indicate some decrease in triplets during recent years, but certainly nowhere near elimination. These data suggest that in some countries, IVF triplets have almost been eliminated, but the problem is masked by significant fetal reductions. Where SET is not widely used, triplets are still frequent. A correlation appears to exist between the percentage of SET cycles and the incidence of triplets. It is suggested that the solution to almost totally eliminate triplets after IVF is single embryo transfer.
Reproductive biomedicine online 02/2007; 15 Suppl 3:40-4. · 2.04 Impact Factor
