Fixed Gonadotropin-Releasing Hormone Antagonist Protocol Versus Flexible Progestin-Primed Ovarian Stimulation Protocol in Patients With Asynchronous Follicular Development During Controlled Ovulation Stimulation: A Retrospective Study

Protocols utilizing gonadotropin-releasing hormone (GnRH) antagonists have emerged as mainstream procedures for ovarian stimulation; however, GnRH increases the risk for periodic cancellation of embryos. Therefore, this study aimed to compare the pregnancy outcomes of a fixed GnRH antagonist protocol and a flexible progestin-primed ovarian stimulation (fPPOS) protocol in patients with asynchronous follicular development during controlled ovulation stimulation and to explore the feasibility of converting patients undergoing a fixed GnRH antagonist protocol to an fPPOS protocol. This was the first retrospective study exploring the fPPOS protocol in patients with asynchronous follicular development, and it was conducted in a public reproductive medicine center from January to December 2020. We included infertile women. All participants were scheduled to undergo administration of a GnRH antagonist on the fifth day of controlled ovulation stimulation. The study group included 129 women who were converted from the fixed GnRH antagonist protocol to the fPPOS protocol for their asynchronous follicular development, while the antagonist group consisted of 258 women (ratio 1:2) who proceeded with a fixed GnRH antagonist protocol. On the second or third day of the menstrual period, 100–300 IU/day gonadotropin injections were administered. For patients who were converted to the fPPOS protocol, medroxyprogesterone acetate tablets at 10 mg/day were started on the fifth day of stimulation or when only one leading follicle reached 14 mm and the other follicles were ≤10 mm in diameter, whichever came first. The rates of embryo implantation, clinical pregnancy, and early pregnancy loss were obtained. The number of oocytes retrieved and the number of high-quality embryos in the antagonist group were significantly higher than those in the fPPOS group (P = 0.039 and P = 0.025, respectively). No significant differences in the rates of embryo implantation, clinical pregnancy, and early pregnancy loss were observed between the two groups. Our study found that in patients who were scheduled for administration of GnRH antagonists but presented with asynchronous follicular development on the fifth stimulation day, it was feasible to switch to the fPPOS protocol.

Discontinuation of anticoagulation and its associated factors in atrial fibrillation

Background/Introduction Oral anticoagulation has been shown to reduce the incidence of embolic events associated with atrial fibrillation, however the discontinuation of these drugs observed in clinical trials may not be representative of the real-world setting due to the inclusion of selected populations. Purpose The objective of the study was to compare whether there is a difference in the incidence rate of discontinuation between vitamin K antagonists and direct anticoagulants and to evaluate the factors associated with non-adherence in patients newly diagnosed with atrial fibrillation. Methods This was a prospective cohort study. Adult patients (age >18 years) who had newly started anticoagulation therapy for atrial fibrillation or atrial flutter were enrolled. Patients with previous oral anticoagulation, mechanical prosthetic heart valves or creatinine clearance less than 30 mL/min were excluded. The follow-up period was 12 months. As the treatment allocation was not randomized, a propensity score weighting was performed considering baseline characteristics potentially associated with exposure and outcome. Factors associated with anticoagulant discontinuation were evaluated using a weighted Cox model. Results A total of 379 patients were included (mean age 78±9 years, 58% females). The median follow-up was 362 days (IQR 347–370). Loss to follow-up was 1%. The anticoagulation discontinuation rate was 24.6% in the direct anticoagulant group and 15.6% in the vitamin K antagonist group. A weighted model of time to discontinuation of anticoagulation treatment showed a crude HR of 1.40 (95% CI 0.79–2.48) for the direct anticoagulant therapy group compared to the vitamin K antagonist group, and a model adjusted for age, type of atrial fibrillation, radiofrequency ablation, bleeding, number of chronic drugs, and cardiology consultations during follow-up showed an adjusted HR of 1.26 (95% CI 0.75–2.12). The main reason for discontinuation of anticoagulation was high risk of bleeding in the vitamin K antagonist group and performance of a radiofrequency ablation procedure in the direct anticoagulant group. There was no statistically significant difference in the discontinuation rate between both groups when the baseline characteristics of the patients were considered. Conclusion(s) There was no statistically significant difference in the discontinuation rate between both groups when the baseline characteristics of the patients were considered. The study showed that the discontinuation of anticoagulants in atrial fibrillation in our setting was not associated with the type of drug used, the age of patients, or the type of arrhythmia. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim Figure 1

Substance P Enhances Doxorubicin (Adriamycin)-associated Autophagy and Reduces Cardiomyocyte Apoptosis.

BackgroundAnthracyclines, including doxorubicin, are some of the most potent anticancer drugs available. However, the use of doxorubicin as a chemotherapeutic agent is severely hindered by dose-limiting toxicity, particularly cardiotoxicity, while degrading other organ systems. Despite years of use and the number of details published on this drug, the understanding of its cellular mechanisms remains limited. MethodCardiomyocyte grouping was carried out, where H9C2 cardiomyocytes were randomly divided into a control group, a myocardial model group, an SP group, and an SP antagonist group. For replication in animal models, twelve rats were similarly randomly assigned into a control group, a myocardial model group, an SP group, and an SP antagonist group. Except for the control group, the rats in the other groups were modelled: the rats were injected with adriamycin solution. Flow cytometry was used to detect apoptosis, while HE staining, TUNEL stain, Western Blot detection, and transmission electron microscopy were performed to detect autophagy levels accordingly. All the results were analysed and carefully interpreted. Resultshe tachykinin, substance P, is located mainly in sensory nerves and in the heart, where substance P-containing nerve fibres are often found around coronary vessels, making them ideally situated to detect changes in the myocardial environment. Apoptosis and autophagy are genetically regulated, evolutionary-conserved processes that regulate cell fate and are important for development, normal physiology, and a wide range of diseases. Recent studies show that despite the significant differences between these two processes, their regulation is closely connected and certain regulators are able to control both apoptosis and autophagy. ConclusionsIn this study, the influence of substance P was discussed, providing possible molecular mechanisms for crosstalk between apoptosis and autophagy mediating heart failure due to doxorubicin therapy. Trial registration(20192BBGL7D031) 2019-09-17.

Comparison of Progestin-Primed Ovarian Stimulation Regimen and Antagonist Regimen in Diminished Ovarian Reserve Patients Over 35 Years of Age

Background the aim of this study was to compare the efficacy of progestin-primed ovarian stimulation (PPOS) regimen and GnRH antagonist regimen in infertile patients older than 35 years with diminished ovarian reserve (DOR). Methods a retrospective cross-sectional study of 196 in vitro fertilization (IVF) cycles between January 2016 and January 2020 was performed. The measured outcomes included the number of retrieved oocytes, incidence of premature LH surge, laboratory indicators and frozen embryo transfer (FET) outcome. Results the number of oocytes retrieved in the antagonist group was higher than those in the PPOS group (p < 0.05). Incidence of premature LH surge in two groups showed no difference (p > 0.05). E2 and P on HCG administration day of antagonist group were higher than those of PPOS group (p < 0.05). And there was no significant difference between two groups of FET outcome indicators (p > 0.05). Conclusions for DOR patients over 35 years of age, antagonist regimen would retrieve more oocytes than PPOS regimen. Therefore, from the perspective of oocyte retrieving, the antagonist regimen might be more suitable for DOR patients over 35 years old.

Comparison of the Cumulative Live Birth Rates of Progestin-Primed Ovarian Stimulation and Flexible GnRH Antagonist Protocols in Patients With Low Prognosis

ObjectiveTo compare the cumulative live birth rate (CLBR) of the progestin-primed ovarian stimulation (PPOS) protocol with that of the flexible GnRH antagonist protocol in patients with poor prognosis diagnosed per the POSEIDON criteria.MethodsThis was a retrospective cohort study. Low-prognosis women who underwent IVF/ICSI at the Reproductive Center of Third Affiliated Hospital of Zhengzhou University between January 2016 and January 2019 were included according to the POSEIDON criteria. The CLBR was the primary outcome of interest. The secondary outcome measures were the numbers of oocytes retrieved, 2PN embryos, available embryos and time to live birth.ResultsA total of 1329 women met the POSEIDON criteria for analysis. For POSEIDON group 1, the dosage of gonadotropin (Gn) was higher in the PPOS group than in the GnRH antagonist group (2757.3 ± 863.1 vs 2419.2 ± 853.1, P=0.01). The CLBR of the PPOS protocols was 54.4%, which was similar to the rate of 53.8% in the GnRH antagonist group. For POSEIDON group 2, the number of available embryos was higher in the PPOS group (2.0 ± 1.7 vs 1.6 ± 1.4, P=0.02) than in the GnRH antagonist group. However, the CLBRs of the two groups were similar (18.1% vs 24.3%, P=0.09). For POSEIDON groups 3 and 4, there were no statistically significant differences in the number of oocytes retrieved, 2PN, available embryos or CLBR between the two protocols. After adjustments for confounding factors, the CLBR remained consistent with the unadjusted rates. In the POSEIDON group 1 population, the GnRH antagonist protocols had a shorter time to live birth (P=0.04).ConclusionFor low-prognosis patients diagnosed per the POSEIDON criteria, the CLBR of PPOS protocols is comparable to that of GnRH antagonist protocols. In the POSEIDON group 1 population, the GnRH antagonist protocols resulted in a shorter time to live birth.

Calcitonin Gene-Related Peptide Influences Bone-Tendon Interface Healing Through Osteogenesis: Investigation in a Rabbit Partial Patellectomy Model

Background: Calcitonin gene-related peptide (CGRP), which has been shown to play an important role in osteogenesis during fracture repair, is also widely distributed throughout the tendon and ligament. Few studies have focused on the role of CGRP in repair of the bone-tendon interface (BTI). Purpose: To explore the effect of CGRP expression on BTI healing in a rabbit partial patellectomy model. Study Design: Controlled laboratory study. Methods: A total of 60 mature rabbits were subjected to a partial patellectomy and then randomly assigned to CGRP, CGRP-antagonist, and control groups. In the CGRP-antagonist group, the CGRP receptor antagonist BIBN4096BS was administered to block CGRP receptors. The patella–patellar tendon complex was harvested at 8 and 16 weeks postoperatively and subjected to radiographic, microlaser Raman spectroscopy, histologic, and biomechanical evaluation. Results: Radiographic data showed that local CGRP expression improved the growth parameters of newly formed bone, including area and volumetric bone mineral density ( P < .05 for both). Raman spectroscopy revealed that the relative bone mineral composition increased in the CGRP group compared with in the control group and the CGRP-antagonist group ( P < .05 for both). Histologic testing revealed that the CGRP group demonstrated better integration, characterized by well-developed trabecular bone expansion from the residual patella and marrow cavity formation, at the 8- and 16-week time points. Mechanical testing demonstrated that the failure load, ultimate strength, and stiffness in the CGRP group were significantly higher than those in the control group ( P < .05 for all), whereas these parameters in the CGRP-antagonist group were significantly lower compared with those in the control group at 16 weeks after surgery ( P < .05 for all). Conclusion: Increasing the local concentration of CGRP in the early stages of BTI healing enhanced osteogenesis in a rabbit partial patellectomy model and promoted healing of the BTI injury, whereas treatment using a CGRP antagonist had the opposite effect. However, exogenous CGRP expression did not induce novel bone remolding. Clinical Relevance: CGRP may have potential as a new therapy for BTI injuries or may be added to postoperative regimens to facilitate healing.

A Study of the Molecular Mechanism by Which Substance P Enhances Doxorubicin (Adriamycin)-Associated Autophagy and Apoptosis of Cardiomyocytes Induces Heart Failure

Background: Anthracyclines, including doxorubicin, are some of the most potent anticancer drugs available. However, the use of doxorubicin as a chemotherapeutic agent is severely hindered by dose-limiting toxicity, particularly cardiotoxicity, while degrading other organ systems. Despite years of use and the amount of details published on this drug, the understanding of its cellular mechanisms is still incomplete. Method: Cardiomyocyte grouping was carried out, where H9C2 cardiomyocytes were randomly divided into a control group, a myocardial model group, an SP group and an SP antagonist group. For replication in animal models, twelve rats were similarly divided randomly into a control group, a myocardial model group, an SP group, and an SP antagonist group. Except for the control group, the rats in the other groups were modelled: the rats were injected with adriamycin solution. Flow cytometry was used to detect apoptosis, while HE staining, TUNEL stain, Western Blot detection and transmission electron microscopy were performed to detect autophagy levels accordingly. All the results were analysed and carefully interpreted. Results: The tachykinin, substance P, is located mainly in sensory nerves and in the heart, where substance P-containing nerve fibres are often found around coronary vessels, making them ideally situated to detect changes in the myocardial environment. Apoptosis and autophagy are genetically-regulated, evolutionary-conserved processes that regulate cell fate and are both important for development, normal physiology, and a wide range of diseases. Recent studies show that despite the significant differences between these two processes, their regulation is closely connected and certain regulators have been found to be able to control both apoptosis and autophagy. Conclusions: In this study, the influence of substance P was discussed, providing possible molecular mechanisms for crosstalk between apoptosis and autophagy mediating heart failure due to Doxorubicin therapy. Trial registration: (20192BBGL7D031) 2019-09-17.

Comparison of clinical outcomes between the depot gonadotrophin-releasing hormone agonist protocol and gonadotrophin-releasing hormone antagonist protocol in normal ovarian responders

Background The gonadotrophin-releasing hormone (GnRH) antagonist protocol has some advantages, such as a simple method, short medication duration, and low incidence of ovarian hyperstimulation syndrome, but whether the GnRH antagonist protocol is suitable for normal ovarian responders has been controversial. We compared the clinical outcomes of fresh and frozen-thawed transfer cycles between the depot GnRH agonist protocol and GnRH antagonist protocol in normal ovarian responders. Methods Data of normal ovarian responders who underwent in vitro fertilization-embryo transfer (IVF-ET) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET) between January 2017 and December 2018 in our hospital were retrospectively analysed. In this study, there were 1119 fresh transfer cycles, including 502 GnRH antagonist cycles (GnRH antagonist group) and 617 depot GnRH agonist cycles (depot GnRH agonist group), as well as 468 frozen-thawed transfer cycles, includng 191 GnRH antagonist cycles (GnRH antagonist group) and 277 depot GnRH agonist cycles (depot GnRH agonist group). The clinical outcomes were compared between the GnRH antagonist group and the depot GnRH agonist group. Results With the fresh transfer cycles, there were no statistically significant differences in the anti-Mullerian hormone level, number of transferred embryos or high-quality embryo rate between the two groups. The total dosage of gonadotropin (Gn), duration of Gn stimulation, number of oocytes retrieved, clinical pregnancy rate and incidences of moderate and severe ovarian hyperstimulation syndrome (OHSS) were significantly lower but the abortion rate was significantly higher in the GnRH antagonist group than in the depot GnRH agonist group (all P < 0.05). With the frozen-thawed transfer cycles, there were no statistically significant differences in the number of transferred embryos, clinical pregnancy rate or abortion rate between the two groups (all P > 0.05). Conclusions With the fresh transfer cycles, the GnRH antagonist protocol had a lower clinical pregnancy rate and lower incidences of moderate and severe OHSS than the depot GnRH agonist protocol, but with the frozen-thawed transfer cycles, both protocols had similar clinical pregnancy rates. These results remain to be further confirmed through large-sample, prospective, randomized and controlled studies.

Arousing Effects of Electroacupuncture on the “Shuigou Point” in Rats with Disorder of Consciousness after Traumatic Brain Injury

Orexin is an important neuropeptide that stimulates cortical activation and arousal and is involved in the regulation of wakefulness and arousal. Our previous meta-analysis showed that acupuncture fared well in the treatment of TBI-induced DOC in which “shuigou (DU 26)” was the most important and frequent point targeted. In the present study, we investigated whether electroacupuncture (EA) promotes TBI-induced unconsciousness wakefulness via orexin pathway. A TBI rat model was established using a control cortical impact (CCI) model. In the stimulated group, TBI rats received EA (15 Hz, 1.0 mA, 15 min). In the antagonist group, TBI rats were intraperitoneally injected with the orexin receptor 1 (OX1R) antagonist SB334867 and received EA. Unconsciousness time was observed in each group after TBI, and electrocorticography (ECoG) was applied to detect rats’ EEG activity. Immunohistochemistry, enzyme-linked immunosorbent assay, and western blot were used to assess the levels of orexin-1(OX1) and OX1R expression in the mPFC. We show that duration of unconsciousness and the ratio of delta power in ECoG in the EA group were significantly reduced compared with those in the TBI group. EA could increase OX1 and OX1R expression in the mPFC and reduced the loss of orexin-producing neurons in LHA. However, all the efficacy of EA was blocked by the OX1R antagonist SB334867. Our findings suggest that EA promotes the recovery of consciousness of TBI-induced unconscious rats via upregulation of OX1and OX1R expression in mPFC.

Evaluation of Antihypertensive Treatment Inoutpatients at Batang Beruh Helath Centre Sidikalang

Hypertension is a cardiovascular disease with a high prevalence and risk of death in developed and developing countries with blood pressure reach ≥140/90 mmHg. Hypertension is the 3rd cause of death after stroke and tuberculosis, reached 6.7% of the population of deaths at all ages in Indonesia. Results of Basic Health Research (Riskesdas) Balitbangkes showed that the national prevalence of hypertension reached 31.7%. The National Formulary (Fornas) is a list of drugs compiled based on the latest scientific evidence by the National Committee for the Compilation of the Fornas. Evaluation of the appropriateness of antihypertensive treatments in outpatients at Batang Beruh Health Centre Sidikalang seen from the National Formulary was the aim of this study. This research is non-experimental, quantitative descriptive was conducted in May - July 2019 at Batang Beruh Health Centre Jl. Pahlawan Sidikalang, Sidikalang District of Dairi, North Sumatra. The population was 231 hypertensive patients using antihypertensive drugs, with sampling using the Slovin formula, amounted to 70 respondents. Based on the research conducted, in the Calcium Antagonist group, the names of the antihypertensive drugs used are Amlodipine and Nifedipine. Meanwhile, in the ACEIs group, the drug used is Captopril. Whereas in the Angiotensin II receptor antagonist group, the drugs used are Micardis, Valsartan and Candesartan. Whereas in the Diuretic group, the antibiotic used is Furosemide.