Administration of corifollitropin alfa on Day 2 versus Day 4 of the cycle in a GnRH antagonist protocol: a randomized controlled pilot study.

STUDY QUESTION: Does the initiation of corifollitropin alfa administration on cycle day 4 instead of cycle day 2 result in a reduced total rFSH consumption in a GnRH antagonist protocol? SUMMARY ANSWER: Initiation of corifollitropin alfa on cycle day 4 compared with day 2 results in significantly reduced total rFSH consumption at the end of the follicular phase. WHAT IS KNOWN ALREADY: In vitro fertilization treatment is associated with significant physical, psychological and emotional stress in infertile patients. This notion has fuelled the search for simplified treatment approaches that may reduce the treatment burden. The introduction of corifollitropin alfa has provided a more patient-friendly treatment protocol because it obviates the need for daily hormonal injections. In addition, postponing the initiation of hormonal stimulation should also reduce the total gonadotrophin consumption and the number of injections needed. STUDY DESIGN, SIZE, DURATION: A prospective randomized controlled pilot study was conducted in a university centre in Belgium. Between December 2011 and March 2013, 59 patients were randomized in the study and 52 of these patients received the allocated intervention. PARTICIPANTS/MATERIALS, SETTING, METHODS: All patients were randomly assigned to the control group (CD2), with initiation of corifollitropin alfa on cycle day 2, or to the study group (CD4) with initiation of stimulation on day 4. The GnRH antagonist was administered from cycle day 7 onwards in both treatment arms. The main outcome measure was the total rFSH consumption at the end of the follicular phase after corifollitropin alfa treatment. MAIN RESULTS AND THE ROLE OF CHANCE: The total dose of rFSH at the end of the follicular phase was significantly reduced in the CD4 group compared with the CD2 group (324 (276) IU in the CD2 group versus 173 (255) IU in the CD4 group, P = 0.015, mean difference -151, 95% confidence interval (CI) -301 to -1). A significant reduction of total duration of rFSH stimulation in the CD4 group was also observed (8.6 (1.4) days in CD2 group versus 7.8 (1.2) days in the CD4 group, P = 0.008, mean difference -0.8, 95% CI -1.6 to -0.1). The number of cumulus-oocyte-complexes was comparable in both treatment groups (12.8 (7.3) in CD2 group versus 14.7 (8.8) in the CD4 group, P = 0.461, mean difference 1.8, 95% CI -2.7 to 6.4). Ongoing pregnancy rates of 48% in the CD2 group and 41% in the CD4 group were achieved (P = 0.60, relative risk (RR) 0.85, 95% CI 0.46-1.56). Final oocyte maturation was triggered with GnRH agonist instead of hCG in two patients in the CD2 group and in eight patients in the CD4 group, because of an increased risk of ovarian hyperstimulation syndrome (P = 0.078, RR 3.7 (95% CI 0.88-15.8). LIMITATIONS, REASONS FOR CAUTION: Before general implementation can be advised, this trial should be validated in a much larger randomized trial. WIDER IMPLICATIONS OF THE FINDINGS If the approach of starting ovarian stimulation on Day 4 of the cycle could be implemented in a large population of infertile patients, it would result in a significant reduction of gonadotrophin consumption. STUDY FUNDING/COMPETING INTEREST(S): No external finance was involved in this study. C.B and N.P.P. have received fees from MSD. Otherwise the authors declare no conflict of interest regarding this study. TRIAL REGISTRATION NUMBER: The trial was registered at clinicaltrials.gov (NCT01633580).

Impact of clomiphene citrate during ovarian stimulation on the luteal phase after GnRH agonist trigger.

The use of a gonadotrophin-releasing hormone (GnRH) agonist to trigger final oocyte maturation in a GnRH antagonist protocol has been associated with poorer clinical outcomes due to an increased luteal-phase defect. It has been shown that LH activity is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on the endocrine profile in the luteal phase when using GnRH agonist trigger. This was evaluated in eight oocyte donors undergoing ovarian stimulation using clomiphene citrate in combination with recombinant FSH compared with a control group of five donors treated with recombinant FSH only. The endocrine profile was comparable in both groups, except for serum LH concentrations on the day after trigger (121.3±53.0IU/l versus 52.9±21.5IU/l, respectively, P=0.022). No significant differences in LH concentrations were found on the day of trigger or 5days after oocyte retrieval. In conclusion, a luteal-phase defect was observed despite treatment with clomiphene citrate during ovarian stimulation. The use of gonadotrophin-releasing hormone (GnRH) agonist to trigger ovulation in IVF has been associated with poorer pregnancy outcomes due to an increased luteal-phase defect. The luteal phase is the last phase of the menstrual cycle and is defined as the period between ovulation and the beginning of pregnancy or menses. It has been shown the activity of LH is crucial in a normal luteal phase. Studies assessing the LH concentrations after clomiphene citrate, an oestrogen receptor inhibitor, co-treatment have observed increased luteal-phase LH concentrations. The purpose of this prospective cohort study was to analyse the effect of clomiphene citrate on menstrual cycle day 2-6 on the hormone profile in the luteal phase when using GnRH agonist trigger. This was evaluated was in eight oocyte donors undergoing ovarian stimulation using recombinant FSH compared with a control cohort of donors treated with recombinant FSH only. The current prospective cohort study reports higher LH concentrations on the day after GnRH agonist trigger, but not 5days after oocyte retrieval (i.e. in the luteal phase). In conclusion, a luteal-phase defect was observed despite the administration of clomiphene citrate during ovarian stimulation. Additional treatment with clomiphene citrate in the follicular phase is therefore not a valid alternative to prevent luteal-phase defect after GnRH agonist trigger.

Factors associated with rifampin resistance in staphylococcal periprosthetic joint infections (PJI): a matched case-control study.

PURPOSE: Rifampin combination therapy plays an important role in the management of staphylococcal periprosthetic joint infection (PJI). However, the emergence of rifampin resistance is a feared complication. We retrospectively analysed predetermined potential risk factors in patients with rifampin-resistant staphylococcal PJI in a multicentre case-control study. METHODS: Cases (n = 48) were defined as PJI caused by rifampin-resistant staphylococci. Rifampin-susceptible controls (n = 48) were matched for microorganism and type of prosthetic joint. Uni- and multivariable conditional logistic regression analyses were performed to estimate odds ratios (OR) with 95 % confidence intervals (95 % CI). RESULTS: Forty-eight cases (31 men; median age 67 years; age range 39-88 years) with hip- (n = 29), knee- (n = 13), elbow- (n = 4), shoulder- (n = 1) or ankle-PJI (n = 1) were enrolled in the study. Staphylococcus aureus and coagulase-negative staphylococci were isolated in ten and 38 episodes, respectively. Most of the cases (n = 44, 92 %) had a previous PJI, and 93 % (n = 41) of these had been treated with rifampin. There was an independent association of emergence of rifampin resistance with male sex (OR 3.6, 95 % CI 1.2-11), ≥ 3 previous surgical revisions (OR 4.7, 95 % CI 1.6-14.2), PJI treatment with high initial bacterial load (inadequate surgical debridement, <2 weeks of intravenous treatment of the combination medication; OR 4.9, 95 % CI 1.6-15) and inadequate rifampin therapy (OR 5.4, 95 % CI 1.2-25). CONCLUSIONS: Based on our results, extensive surgical debridement and adequate antibiotic therapy are needed to prevent the emergence of rifampin resistance.

Dose-response relationship between interval training frequency and magnitude of improvement in lactate threshold.

The purpose of this study was to determine if interval training at 110-120% of peak power output one and two days/wk in addition to habitual training would elicit improvements in lactate threshold (LT) in a dose response manner. Twenty physically active individuals completed this study: age--21.1+/-1.3 yr, height--172.1+/-7.4 cm, body mass--68.4+/-9.1 kg, VO (2)max--45.3+/-5.2 mL/kg/min; and were randomly assigned into two separate 6 wk training groups--either 1 day/wk interval training or 2 days/wk interval training at 110-120% of peak workload (from an incremental exercise test) on a cycle ergometer. After 6 wk, LT (% VO (2)max) increased significantly ( P<0.05) in both 1 day/wk (4.3+/-3.2%) and 2 days/wk (8.2+/-2.6%) groups. A two-factor mixed ANOVA identified a significant interaction between exercise frequency and LT (%VO (2)max) values ( P<0.05) indicating that LT responded differently to 1 day/wk and 2 days/wk of interval training. Findings from the present study show high-intensity, interval training to be a successful strategy for modifying this important metabolic threshold. Moreover, results suggest that there is a dose-response relationship between frequency of interval training and the magnitude of LT improvement.

Widespread thalamic and cerebellar degeneration in a patient with a complicated hereditary spastic paraplegia (HSP).

The hereditary spastic paraplegias (HSP) are a heterogeneous group of familial movement disorders sharing progressive spastic paraplegia as a common disease sign. In the present study, we performed the first pathoanatomical investigation of the central nervous degeneration of a female patient with a complicated HSP form who suffered from progressive spastic paraplegia, dysarthria, emotional symptoms, cognitive decline and a variety of additional neuropsychological deficits. This pathoanatomical investigation revealed in addition to loss of layer V Betz pyramidal cells in the primary motor cortex, widespread cerebellar neurodegeneration (i.e., loss of Purkinje cells and neuronal loss in the deep cerebellar nuclei), extensive and severe neuronal loss in a large number of thalamic nuclei, involvement of some brainstem nuclei, as well as damage to descending (i.e., lateral and ventral corticospinal tracts) and ascending (i.e., dorsal and ventral spinocerebellar tracts, gracile fascicle) fiber tracts. In view of their known functional role, damage to these central nervous gray and white matter components offers explanations for the patient's pyramidal signs, her cerebellar, psychiatric and neuropsychological disease symptoms.

Suicidality among adolescent Alberta Indians.

A high rate of suicide attempts and suicide ideation characterized a sample of 229 grade 7 to 9 adolescents resident on seven reserves in central Alberta. The prevalence of suicidality for these adolescent Indians was very similar to rates reported for Navajo youth and for 8th- and 10th-grade American non-Indian students. Comparison of Indian and non-Indian suicidality risk factors showed somewhat elevated levels of family disruption and psychological problems among Indian adolescents. Compared to Canadian nonadolescents, substance abuse levels were high, and conditions necessary to modeling were virtually omnipresent. Suicide ideation was significantly elevated for Indian adolescents with low psychological well-being, no father in the home, and a prior suicide in the household. Controlling for age, risk factors for suicide attempts were heavy alcohol use, no father in the home, sleeping problems, and low psychological well-being. The high rates of adolescent Native suicide imply that a much higher proportion of their suicide attempts succeed. Targeted, community-based counselling and educational programs are needed to address these problems.

Health knowledge of Native Indian youth in central Alberta.

This paper is the first report of health knowledge among Native Indian youth in central Alberta and, in the absence of comparable information for Native youth in other regions of Canada, provides a unique basis for comparison of the health knowledge of Native youth attending junior high school with that of non-Native young Canadians included in the Canada Health Knowledge Survey. The results of our survey of 229 Native Indian youth from seven different reserves in central Alberta indicate that a higher proportion of the Native youth were more knowledgeable about dental health, fire safety, and the effects of smoking, alcohol and drugs. However, they generally scored lower on items related to knowledge of first aid for burns, nutrition, communicable diseases, and personal health. Factors contributing to these differences and suggestions for future action are suggested on the basis that accurate information of this kind is essential for health promotion efforts directed toward reducing risky health behaviours and promoting healthier lifestyles among youth of Native Indian communities.