Double versus single stimulation in young low prognosis patients followed by a fresh embryo transfer: a randomized controlled trial (DUOSTIM-fresh).

STUDY QUESTION: Does double stimulation, followed by a fresh embryo transfer (DUOSTIM fresh) give a higher number of good-quality blastocysts as compared with a single stimulation in young low prognosis patients? SUMMARY ANSWER: Compared to single stimulation, DUOSTIM fresh leads to a significantly higher number of good quality blastocysts, without hindering fresh embryo transfer outcomes. WHAT IS KNOWN ALREADY: DUOSTIM (ovarian stimulation both in the follicular and luteal phase of the same cycle) is an innovative strategy to retrieve a higher number of oocytes in a shorter time frame, thus it is particularly appealing for poor ovarian responders. Three current limitations of dual stimulation are: (i) it is unclear whether outcomes of the second (luteal) wave result from the second stimulation, or a carry-over effect from previous follicular stimulation; (ii) the desynchronization between endometrium and ovaries and, (iii) lack of robust evidence. No previous studies explored DUOSTIM starting from the luteal phase, and with a fresh embryo transfer (DUOSTIM fresh). STUDY DESIGN, SIZE, DURATION: This study is a randomized, controlled, single-center, superiority clinical trial comparing two different ovarian stimulation protocols: a double stimulation cycle versus a single stimulation cycle followed by fresh embryo transfer. The primary outcome was the number of good quality blastocysts obtained, while secondary outcomes included results from fresh embryo transfer (clinical pregnancy, miscarriage). A total of 120 women were enrolled in this study between October 2020 and October 2022, with a 1:1 allocation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Only young (<40 years old) low prognosis (anti-Müllerian hormone <1.2 ng/ml) patients were recruited in the Reproductive Medicine Department of Dexeus University Hospital. In the investigational group, DUOSTIM fresh, the first stimulation was initiated in the luteal phase (Day 18-21 cycle) followed by a second stimulation 5 days post first oocyte retrieval, initiated in the follicular phase and a fresh embryo transfer of the best blastocyst generated (first or second cycle). The control group performed a follicular phase single stimulation cycle with a fresh embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 107 patients were analyzed, 53 in the investigational (DUOSTIM fresh) and 54 in the control arm (single stimulation). DUOSTIM fresh resulted in a significantly higher number of good quality blastocysts as compared to single stimulation (difference of mean 0.81, 95% CI 0.12-1.49). The mean percentage of cycles with embryo transfer was comparable (62.3% and 51.9%, respectively for double versus single stimulation). No significant differences were found for clinical outcomes following fresh embryo transfer with an ongoing pregnancy rate of 24.5% for DUOSTIM fresh versus 22.2%, for conventional IVF. Of interest comparisons between different stimulation cycles (A: luteal-phase DUOSTIM fresh, B: follicular-phase DUOSTIM fresh, and C: single stimulation) did not demonstrate any significant difference in terms of ovarian response with the mean (SD) number of mature oocytes being (A: 3.3 (2.9), B: 3.4 (3.4), and C: 3.5 (2.9), respectively). LIMITATIONS, REASONS FOR CAUTION: Study sample size was calculated to detect differences on the mean number of good quality blastocysts. Therefore, results for secondary outcomes (embryo transfer rates and clinical pregnancy rates) should be interpreted with caution as exploratory findings that deserve future investigations. WIDER IMPLICATIONS OF THE FINDINGS: Although DUOSTIM fresh results in a higher number of blastocysts as compared with a single stimulation in young low prognosis patients, the decision of performing dual stim should be evaluated with caution, considering that whether this may improve embryo transfers rate and pregnancy outcomes is still unclear. Results on cumulative-live-birth-rate are warranted. STUDY FUNDING/COMPETING INTEREST(S): The study was an investigator-initiated study supported by an unrestricted grant by Organon. N.P.P. has received grants from Merck Serono, Organon, Ferring Pharmaceutical, Theramex, and Besins Healthcare. N.P.P. has received consulting fees from Merck Serono, Organon, Besins Healthcare, and IBSA. N.P.P. has received honoraria for lectures from Merck Serono, Organon, Theramex, Roche Diagnostics, IBSA, Besins Healthcare, and Ferring. A.R. has received Research grants, honoraria for lectures from Merck Serono, MSD/Organon, Ferring Pharmaceuticals, Besins International, IBSA, Guerbet. The other authors declare that there is no conflict of interest to disclose with respect to the content of this article. TRIAL REGISTRATIO NUMBER: NCT04446845. TRIAL REGISTRATION DATE: 25 June 2020. DATE OF FIRST PATIENT'S ENROLMENT: 30 October 2020.

Dual-Stimuli-Responsive Modulation Organic Afterglow Based on N─H Proton Migration Mechanism.

Organic afterglow materials have significant applications in information security and flexible electronic devices with unique optical properties. It is vital but challenging to develop organic afterglow materials possessing controlled output with multi-stimuli-responsive capacity. Herein, dimethyl terephthalate (DTT) is introduced as a strong proton acceptor. The migration direction of N─H protons on two compounds Hs can be regulated by altering the excitation wavelength (Ex) or amine stimulation, thereby achieving dual-stimuli-responsive afterglow emission. When the Ex is below 300 nm, protons migrate to S1-2 DTT, where strong interactions induce phosphorescent emission of Hs, resulting in afterglow behavior. Conversely, when the Ex is above 300 nm, protons interact with the S0 DTT weakly and the afterglow disappears. In view of amine-based compounds with higher proton accepting capabilities, it can snatch proton from S1-2 DTT and redirect the proton flow toward amine, effectively suppressing the afterglow but obtaining a new redshifted fluorescence emission with Δλ over 200 nm due to the high polarity of amine. Moreover, it is successfully demonstrated that the applications of dual-stimuli-responsive organic afterglow materials in information encryption based on the systematic excitation-wavelength-dependent (Ex-De) behavior and amine selectivity detection.

Luteal Phase Stimulation in the Same Cycle Is an Effective Strategy to Rescue POSEIDON Poor Responders with No Embryos after the First Follicular Stimulation.

Background: Poor responders may benefit from recruiting a 'second wave' of antral follicles within the same cycle. This concept forms the basis of double stimulation which has been named as 'DuoStim'. This protocol involves ovarian stimulation in both follicular and luteal phases with egg retrieval in each phase, respectively, to increase the number of oocytes and embryos in one menstrual cycle. This can be considered a potentially valuable option for women with poor ovarian reserve/response to maximise the number of oocytes retrieved in a single ovarian cycle in the shortest possible time. Aims: The aim of this study was to evaluate the efficacy of the DuoStim protocol in women classified as POSEIDON poor responders undergoing in vitro fertilization by comparing the embryological outcomes between the follicular and luteal phase stimulations in the same menstrual cycle. Settings and Design: This was a retrospective cohort study of 131 patients who enrolled to undergo DuoStim cycles from January 2021 to Sept. 2022, at a IVF center in a tertiary care hospital. Materials and Methods: The follicular phase stimulation used a standard antagonist protocol for the first oocyte retrieval. Thereafter, the luteal phase stimulation was started 3 days after the first retrieval, with the same dose of gonadotropin along with a daily 10 mg medroxyprogesterone acetate tablet, followed by a second oocyte retrieval. Blastocysts produced in both the phases were subsequently vitrified. Statistical Analysis Used: The paired t-test was used for comparing means and 95% confidence intervals (CIs) for different parameters. McNemar's test was used to compare paired proportions. The analysis was conducted using R statistical environment 4.2. Results: The mean number of oocytes retrieved and the mean number of utilizable blastocysts frozen per stimulation cycle were found to be significantly higher in the luteal phase as compared to the follicular phase (5.71 ± 3.95 vs. 4.87 ± 2.79, P = 0.02, and 1.43 ± 1.22 vs. 0.95 ± 1, P = 0.001, respectively). However, the mean fertilization rate and the mean blastocyst utilization rate were found to be similar between both the phases. The length of stimulation was found to be approximately 3 days longer in the luteal phase (12.63 ± 2.43 vs. 9.75 ± 1.85, P = 0.001). Overall, the odds of obtaining a usable blastocyst in the luteal phase was found to be significantly higher than in the paired follicular phase (73.9% vs. 57.7%, P = 0.012, odds ratio: 2.286 [95% CI: 1.186-4.636]). Also importantly, the luteal phase stimulation was able to rescue 68% (32/47) of patients where no blastocysts were formed in the follicular phase. Conclusion: Our data demonstrate that in women with poor reserve, the addition of luteal stimulation could increase the chances of achieving a pregnancy by significantly increasing the number of eggs and transferable embryos per menstrual cycle compared to follicular stimulation alone. Furthermore, luteal phase stimulation in the same cycle proved to be an effective strategy to rescue POSEIDON poor responders with no embryos after the first stimulation.

Investigation of an efficient method of oocyte retrieval by dual stimulation for patients with cancer.

Purpose: To examine the optimal timing of second ovarian stimulation using the dual stimulation method for good ovarian responders with cancer undergoing oocyte retrieval for fertility preservation. Methods: A retrospective analysis was conducted using data from 69 patients with cancer who underwent oocyte retrieval for fertility preservation at four Japanese institutions during 2010-2021. Twenty-two patients underwent two oocyte retrievals for fertility preservation. We studied the relationship between the initial number of oocytes retrieved via dual stimulation and risk of ovarian enlargement as well as the appropriate waiting interval between the end of the first ovarian stimulation and beginning of the second ovarian stimulation. Results: The risk of ovarian enlargement was high when the initial number of oocytes retrieved via dual stimulation was ≥5. An 8-day waiting interval may be more effective for performing a second ovarian stimulation oocyte retrieval in these cases, although the difference was not significant. Conclusions: This study provides one policy for effectively managing ovarian enlargement and timing of second ovarian stimulation during oocyte retrieval via the dual stimulation method for patients with cancer undergoing fertility preservation. If more facilities implement this procedure, more oocytes may be obtained in a short period for fertility preservation purposes.

Retrospective study of influencing factors on the outcomes of luteal phase stimulation in patients with dual stimulation.

Background: Dual/double stimulation (DS) is an ovarian stimulation strategy that has emerged in recent years; it is characterized by two rounds of ovarian stimulation and oocyte retrieval in the same menstrual cycle. DS can greatly shorten the time required to obtain valid embryos in assisted reproduction. For fertility preservation, DS can speed up oocyte storage process. However, factors influencing luteal phase ovarian stimulation (LPS) outcomes in DS have not been elucidated. Methods: A total of 156 cycles from 78 cases were studied. Patients were grouped and analyzed according to their follicular phase ovarian stimulation (FPS) types. Female ages, ovarian stimulation protocols, number of oocytes retrieved, embryo quality were recorded. Comparisons of outcomes were conducted between different groups. Results: Our study found that LPS obtained similar outcomes to follicular phase stimulation (FPS), and that the choice of FPS protocol affected the efficiency of LPS, the antagonist protocol and progestin-primed ovarian stimulation (PPOS) protocol resulted in better embryo outcomes in LPS. In LPS of DS, sufficient stimulation duration was the guarantee of embryo quality (number of available embryos: ß = 0.145, 95% CI [0.078-0.211], P = 0.000; number of high-quality embryos: ß = 0.114, 95% CI [0.057-0.171], P = 0.000). Discussion: This study provided ideas for the precise use of DS. We suggest to further expand the sample size of DS in the future, conduct prospective controlled studies, unify the sample size of each subgroup, include the ovarian reserve of patients in the grouping basis, and exclude the influence of male factors. We hope that this study will help further refinement of DS so as to maximize patient benefits from it. Conclusion: When the DS strategy is considered in the follicular phase, the antagonist protocol and PPOS protocol are more recommended for better embryo outcomes in LPS. During LPS, adequate ovarian stimulation duration is the most important guarantee for LPS efficiency.

Successful pregnancy outcome after fresh embryo transfer in a dual stimulation cycle - a case report.

Controlled ovarian stimulation by antagonist protocol sometimes presents unpleasant surprises in the form of unexpected premature rupture of follicles despite well-timed daily administration of the antagonist. In such cases ovum pick up cannot be done, dual stimulation of the next crop of follicles may be pursued to salvage the cycle. A 'freeze all' strategy is usually implemented in all cases of dual stimulation because of embryo-endometrial asynchrony. Here we present a case where dual stimulation was followed by fresh embryo transfer with a successful pregnancy outcome.

Preventing Growth Stagnation and Premature LH Surge Are the Keys to Obtaining a Viable Embryo in Monofollicular IVF Cycles: A Retrospective Cohort Study.

How LH levels influenced the outcomes of monofollicular IVF cycles using different stimulation protocols was controversial. In this single-center, retrospective study, we analyzed 815 monofollicular IVF cycles between 2016−2022 using natural cycle (NC), medroxyprogesterone acetate (MPA) or clomiphene citrate (CC) in addition to human menopausal gonadotropin (hMG), with or without GnRH antagonist. A viable embryo was obtained in 35.7% of all cycles. Growth stagnation and premature LH surge are two markedly negative factors for obtaining viable embryos (odds ratios of 0.12 [0.08−0.65], p < 0.0001 and 0.33 [0.26,0.42], p < 0.0001, respectively). NC/hMG cycles are prone to premature LH surge (40.4%), yielding a significantly lower opportunity of obtaining embryos (24.7%, p = 0.029). The administration of GnRH antagonist on the background of MPA resulted in a significant decrease in LH levels (from 2.26 IU/L to −0.89 IU/L relative to baseline, p = 0.000214), leading to a higher risk of growth stagnation (18.6%, p = 0.007). We hypothesized that the abrupt decline of LH might increase the risk of apoptosis in granulosa cells. We proposed a "marginal effect" framework to emphasize that the change of LH was the key to its bioactivity, rather than the traditional "window" concept with fixed cutoff values of a threshold and a ceiling.

Anterior thalamic deep brain stimulation in epilepsy patients refractory to vagus nerve stimulation: A single center observational study.

Anterior thalamic deep brain stimulation (DBS) is a palliative treatment that may be considered in patients with drug resistant epilepsy (DRE) that fail treatment with vagus nerve stimulation (VNS). Combining VNS and DBS treatment is a therapeutic approach rarely reported. This single center observational study aims to describe response to DBS treatment in 11 epilepsy patients resistant to medications and VNS. Patients either had inactivated VNS (DBS only) or were treated with simultaneous DBS and VNS (DBS-VNS). Focal impaired awareness (FIA) and most disabling seizure rates were examined pre-DBS implantation, 3 months following implantation, and last follow up. Overall, a decrease in FIA (47.0 ± 30.7 %, p = 0.02) and most disabling seizure rate (54.8 ± 34.2 %, p = 0.03) was seen at last follow-up (average follow-up 28.5 ± 13.5 months). Eight of 11 patients were DBS responders (most disabling seizure rate reduction above 50%). No difference in seizure control was found between seven DBS only and four DBS-VNS patients. Our results argue that patients who have failed antiseizure medication and VNS therapies, could benefit from better seizure control if treated with adjunctive DBS. Larger prospective studies are needed to assess the efficacy and safety of combined neurostimulation treatments in DRE.

Double or dual stimulation in poor ovarian responders: where do we stand?

Recent advances in our recognition of two to three follicular waves of development in a single menstrual cycle has challenged the dogmatic approach of ovarian stimulation for in vitro fertilization starting in the early follicular phase. First shown in veterinary medicine and thereafter in women, luteal phase stimulation-derived oocytes are at least as competent as those retrieved following follicular phase stimulation. Poor ovarian responders still remain a challenge for many decades simply because they do not respond to ovarian stimulation. Performing follicular phase stimulation and luteal phase stimulation in the same menstrual cycle, named as double stimulation/dual stimulation, clearly increases the number of oocytes, which is a robust surrogate marker of live birth rate in in vitro fertilization across all female ages. Of interest, apart from one study, the bulk of evidence reports significantly higher number of oocytes following luteal phase stimulation when compared with follicular phase stimulation; hence, performing double stimulation/dual stimulation doubles the number of oocytes leading to a marked decrease in patient drop-out rate which is one of the major factors limiting cumulative live birth rates in such poor prognosis patients. The limited data with double stimulation/dual stimulation-derived embryos is reassuring for obstetric and neonatal outcome. The mandatory requirement of freeze-all and lack of cost-effectiveness data are limitations of this novel approach. Double stimulation/dual stimulation is an effective strategy when the need to obtain oocytes is urgent, including patients with malignant diseases undergoing oocyte cryopreservation and patients of advanced maternal age or with reduced ovarian reserve.

Dual stimulation in unexpected poor responder POSEIDON classification group 1, sub-group 2a: A cross-sectional study.

BACKGROUND: Poor ovarian response management is a complex and controversial issue in the field of reproductive medicine. OBJECTIVE: The aim of this study was to apply double stimulation in the same cycle in unexpected poor responders in POSEIDON classification group 1, sub group 2a and compare assisted reproductive technology outcomes between luteal phase and follicular phase ovarian stimulation. MATERIALS AND METHODS: In this cross-sectional study, 10 women with age < 35 yr, antral follicle count > 5, and anti-müllerian hormone > 1.2 ng/mL were enrolled. All participants received conventional antagonist protocol in the follicular phase and only the cycles with retrieved oocytes < 4 in this phase included. The luteal phase ovarian stimulation was initiated from the day of first oocytes retrieval by 300 IU of human menopausal gonadotropin / day. When dominant follicles amounted to 14 mm in mean diameter, 0.25 mg/day of gonadotropin-releasing hormone antagonist was initiated and 10,000 IU human chorionic gonadotropin was injected when at least two follicles with a mean diameter of 17 mm were observed. Oocyte retrieval was carried out 34-36 hr following human chorionic gonadotropin injection. Finally, a comparison was made between the two phase in terms of the number of retrieved oocytes as well as the number of obtained embryos and fertilization rates. RESULTS: Numbers of retrieved oocytes (p = 0.004), mature oocytes (p = 0.016), and embryos (p = 0.013) was significantly higher in luteal phase in compared with follicular phase. Quality of embryos was similar in two phases. CONCLUSION: Double stimulation protocol can increase number of retrieved oocytes in unexpected PORs.

Bioinspired Programmable Engineering of a Color-Change Biointerface based on Dual-Stimulation Regulation.

Some animals can change their skin colors in response to multiple stimuli by controlling the skin pigment cell or guanine crystals. An artificial color-change interface inspired by these natural properties has been developed; the interface responded to different types of stimuli, however, is still rare. Herein, we design a color-change biointerface that responds to the cooperative stimulation of light and DNA by changing the conformation of DNA structures to achieve programmable activation of the interface. We construct the biointerface by the combination of a fluorescent dye-labeled hairpin DNA with a photoresponsive molecule, which is cleaved by the first stimulation of UV light (stimulus 1, S1) to expose the toehold domain. Then, the biointerface gets color changed through the toehold-mediated DNA strand displacement reaction with the second stimulation of the invading DNA probe (stimulus 2, S2). Moreover, the transformation efficiency of the biointerface increased from 6.8 to 64% with an increase of S1 from 0 to 600 s in the presence of S2. Also, after the stimulation of S1, the effective transformation efficiency was also tuned from 5.3 to 72% by different amounts of S2 in the complex matrix, indicating the potential for a high response in real-world settings.

Double Stimulation in the Same Ovarian Cycle (DuoStim) to Maximize the Number of Oocytes Retrieved From Poor Prognosis Patients: A Multicenter Experience and SWOT Analysis.

A panel of experts known as the POSEIDON group has recently redefined the spectrum of poor responder patients and introduced the concept of suboptimal response. Since an ideal management for these patients is still missing, they highlighted the importance of tailoring the ovarian stimulation based on the chance of each woman to obtain an euploid blastocyst. Interestingly, a novel pattern of follicle recruitment has been defined: multiple waves may arise during a single ovarian cycle. This evidence opened important clinical implications for the treatment of poor responders. For instance, double stimulation in the follicular (FPS) and luteal phase (LPS) of the same ovarian cycle (DuoStim) is an intriguing option to perform two oocyte retrievals in the shortest possible time. Here, we reported our 2-year experience of DuoStim application in four private IVF centers. To date, 310 poor prognosis patients completed a DuoStim protocol and underwent IVF with blastocyst-stage preimplantation-genetic-testing. LPS resulted into a higher mean number of oocytes collected than FPS; however, their competence (i.e., fertilization, blastocyst, euploidy rates, and clinical outcomes after euploid single-embryo-transfer) was comparable. Importantly, the rate of patients obtaining at least one euploid blastocyst increased from 42.3% (n = 131/310) after FPS to 65.5% (n = 203/310) with the contribution of LPS. A summary of the putative advantages and disadvantages of DuoStim was reported here through a Strengths-Weaknesses-Opportunities-Threats analysis. The strengths of this approach make it very promising. However, more studies are needed in the future to limit its weaknesses, shed light on its putative threats, and realize its opportunities.

Dual Transcranial Direct Current Stimulation for Poststroke Dysphagia: A Randomized Controlled Trial.

BACKGROUND: Poststroke dysphagia is associated with considerable morbidity and has high health care cost implications. OBJECTIVE: To evaluate whether anodal transcranial direct current stimulation (tDCS) over the lesioned hemisphere and cathodal tDCS to the contralateral one during the early stage of rehabilitation can improve poststroke dysphagia. METHODS: A total of 40 patients referred to our neurorehabilitation department were randomized to receive anodal tDCS over the damaged hemisphere plus cathodal stimulation over the contralateral one versus sham stimulation during swallowing maneuvers over the course of 10 sessions of treatment. Swallowing function was evaluated before and after stimulation using the Dysphagia Outcome and Severity Scale (DOSS). RESULTS: The percentage of patients who reached various thresholds of improvement was higher in the tDCS group than in the sham group, but the differences were not significant (eg, DOSS score ≥ 20% increase from baseline: 55% in the tDCS group vs 40% in the sham group; P = .53). Among all variables recorded at baseline, only a subgroup of patients without nasogastric tube showed a significantly higher improvement with tDCS treatment versus sham (DOSS score ≥10% and ≥20% from baseline: 64.29% vs 0%, P = .01). CONCLUSIONS: In patients with poststroke dysphagia, treatment with dual tDCS in the early phase of rehabilitation does not significantly increase the probability of recovery compared with sham stimulation.