Bleeding changes after levonorgestrel 52-mg intrauterine system insertion for contraception in women with self-reported heavy menstrual bleeding.

BackgroundThe levonorgestrel 52-mg intrauterine system has proven efficacy for heavy menstrual bleeding treatment in clinical trials, but few data exist to demonstrate how rapidly the effects occur and the effects in women with self-reported heavy bleeding, as seen commonly in clinical practice.ObjectiveEvaluate changes in bleeding patterns in women with self-reported heavy menstrual bleeding before levonorgestrel 52-mg intrauterine system insertion.Study designA total of 1714 women aged 16-45 years old received a levonorgestrel 52-mg intrauterine system in a multicenter trial evaluating contraceptive efficacy and safety for up to 10 years. At screening, participants described their baseline menstrual bleeding patterns for the previous 3 months. Participants completed daily diaries with subjective evaluation of bleeding information for the first 2 years. For this analysis, we included women with at least 1 complete 28-day cycle of intrauterine system use and excluded women using a hormonal or copper intrauterine contraception in the month prior to study enrollment. We evaluated changes in menstrual bleeding and discontinuation for bleeding complaints per 28-day cycle over 26 cycles (2 years) in women who self-reported their baseline pattern as heavy. We also compared rates of amenorrhea, defined as no bleeding or spotting, within the entire study population in women with subjective heavy menstrual bleeding at baseline compared with those who did not complain of heavy menstrual bleeding.ResultsOf the 1513 women in this analysis, 150 (9.9%) reported baseline heavy menstrual bleeding. The majority of women reported no longer experiencing heavy menstrual bleeding by the end of cycle 1 (112/150, 74.7%) with even greater rates by cycle 2 (124/148, 83.8%). At the end of cycles 6, 13, and 26, 129 of 140 (92.1%; 95% confidence interval, 87.7%-96.6%), 114 of 123 (92.7%; 95% confidence interval, 88.1%-97.3%), and 100 of 103 (97.1%; 95% confidence interval, 93.8%-100%) women reported no heavy menstrual bleeding, respectively. After cycles 13 and 26, 63 of 123 (51.2%; 95% confidence interval, 42.4%-60.1%) and 66 of 103 (64.1%; 95% confidence interval, 54.8%-73.3%), respectively, reported their bleeding as amenorrhea or spotting only. A lower proportion of women with baseline self-reported heavy menstrual bleeding reported amenorrhea as compared with women in the overall study cohort without heavy menstrual bleeding at the end of 6 cycles (319 [25.5%] vs 21 [15.0%], P=.005) and 13 cycles (382 [34.4%] vs 26 [21.1%], P=.003); differences were not significant after 19 cycles (367 [37.2%] vs 36 [31.0%], P=.022) and 26 cycles (383 [43.5%] vs 38 [36.9%], P=.21). Only 4 (2.7%) women with baseline heavy menstrual bleeding discontinued for bleeding complaints (2 for heavy menstrual bleeding and 2 for irregular bleeding), all within the first year.ConclusionMost women who self-report heavy menstrual bleeding experience significant improvement quickly after levonorgestrel 52-mg intrauterine system insertion. Discontinuation for bleeding complaints among women with baseline heavy menstrual bleeding is very low

Management of early pregnancy loss with mifepristone and misoprostol: clinical predictors of treatment success from a randomized trial.

BackgroundEarly pregnancy loss is a common event in the first trimester, occurring in 15%-20% of confirmed pregnancies. A common evidence-based medical regimen for early pregnancy loss uses misoprostol, a prostaglandin E1 analog, with a dosage of 800 μg, self-administered vaginally. The clinical utility of this regimen is limited by suboptimal effectiveness in patients with a closed cervical os, with 29% of patients experiencing early pregnancy loss requiring a second dose after 3 days and 16% of patients eventually requiring a uterine aspiration procedure.ObjectiveThis study aimed to evaluate clinical predictors associated with treatment success in patients receiving medical management with mifepristone-misoprostol or misoprostol alone for early pregnancy loss.Study designWe performed a planned secondary analysis of a randomized trial comparing mifepristone-misoprostol with misoprostol alone for management of early pregnancy loss. The published prediction model for treatment success of single-dose misoprostol administered vaginally included the following variables: active bleeding, type of early pregnancy loss (anembryonic pregnancy or embryonic and/or fetal demise), parity, gestational age, and treatment site; previous significant predictors were vaginal bleeding within the past 24 hours and parity of 0 or 1 vs >1. To determine if these characteristics predicted differential proportions of patients with treatment success or failure, we performed bivariate analyses; given the small proportion of treatment failures in the combined treatment arm, both arms were combined for analysis. Thereafter, we performed a logistic regression analysis to assess the effect of these predictors collectively in each of the 2 treatment groups separately as well as in the full cohort as a proxy for the combined treatment arm. Finally, by using receiver operating characteristic curves, we tested the ability of these predictors in association with misoprostol treatment success to discriminate between treatment success and treatment failure. To quantify the ability of the score to discriminate between treatment success and treatment failure in each treatment arm as well as in the entire cohort, we calculated the area under the curve. Using multivariable logistic regression, we then assessed our study population for other predictors of treatment success in both treatment groups, with and without mifepristone pretreatment.ResultsOverall, 297 evaluable participants were included in the primary study, with 148 in the mifepristone-misoprostol combined treatment group and 149 in the misoprostol-alone treatment group. Among patients who had vaginal bleeding at the time of treatment, 15 of 17 (88%) in the mifepristone-misoprostol combined treatment group and 12 of 17 (71%) in the misoprostol-alone treatment group experienced expulsion of pregnancy tissue. Among patients with a parity of 0 or 1, 94 of 108 (87%) in the mifepristone-misoprostol treatment group and 66 of 95 (69%) in the misoprostol-alone treatment group experienced expulsion of pregnancy tissue. These clinical characteristics did not predict treatment success in the combined cohort alone (area under the curve=0.56; 95% confidence interval, 0.48-0.64). No other baseline clinical factors predicted treatment success in the misoprostol-alone treatment arm or mifepristone pretreatment arm. In the full cohort, the significant predictors of treatment success were pretreatment with mifepristone (adjusted odds ratio=2.51; 95% confidence interval, 1.43-4.43) and smoking (adjusted odds ratio=2.15; 95% confidence interval, 1.03-4.49).ConclusionNo baseline clinical factors predicted treatment success in women receiving medical management with misoprostol for early pregnancy loss. Adding mifepristone to the medical management regimen of early pregnancy loss improved treatment success; thus, mifepristone treatment should be considered for management of early pregnancy loss regardless of baseline clinical factors

Spinal Progenitor-Laden Bridges Support Earlier Axon Regeneration Following Spinal Cord Injury.

Impact statementSpinal cord injury (SCI) results in loss of tissue innervation below the injury. Spinal progenitors have a greater ability to repair the damage and can be injected into the injury, but their regenerative potential is hampered by their poor survival after transplantation. Biomaterials can create a cell delivery platform and generate a more hospitable microenvironment for the progenitors within the injury. In this work, polymeric bridges are used to deliver embryonic spinal progenitors to the injury, resulting in increased progenitor survival and subsequent regeneration and functional recovery, thus demonstrating the importance of combined therapeutic approaches for SCI

Effects of Long-Term Use of Nonoxynol-9 on Vaginal Flora

OBJECTIVE—Products containing nonoxynol-9 have been used as spermicidal contraceptives for many years, but limited data have been published describing the long-term effects of nonoxynol-9 use on the vaginal microbial ecosystem. This longitudinal study was conducted to examine the effects of nonoxynol-9 on the vaginal ecology. METHODS—Vaginal swabs were obtained from 235 women enrolled in a randomized clinical trial before initiation of use of 1 of 5 different formulations of nonoxynol-9 for contraception, and up to 3 more samples were gathered over 7 months of use. The swab samples were evaluated in a single laboratory. The prevalence of several constituents of the normal vaginal flora was evaluated. The associations between nonoxynol-9 dosage, formulation, average product use per week, and number of sex acts per week were calculated. RESULTS—The changes in prevalence of vaginal microbes after nonoxynol-9 use were minimal for each of the different nonoxynol-9 formulations. However, when both nonoxynol-9 concentration and number of product uses are taken into account, nonoxynol-9 did have dose-dependant effects on the increased prevalence of anaerobic gram-negative rods (odds ratio [OR] 2.4, 95% confidence interval [CI] 1.1–5.3), H2O2-negative lactobacilli (OR 2.0, 95% CI 1.0–4.1), and bacterial vaginosis (OR 2.3, 95% CI 1.1–4.7). CONCLUSION—This study demonstrated that most nonoxynol-9 users experienced minimal disruptions in their vaginal ecology. There were no differences between the different formulations evaluated with respect to changes in vaginal microflora. However, independent of the nonoxynol-9 formulation, there was a dose-dependent effect with increased exposure to nonoxynol-9 on the risk of bacterial vaginosis and its associated flora

Mifepristone Pretreatment for the Medical Management of Early Pregnancy Loss

BACKGROUND Medical management of early pregnancy loss is an alternative to uterine aspira-tion, but standard medical treatment with misoprostol commonly results in treat-ment failure. We compared the efficacy and safety of pretreatment with mifepris-tone followed by treatment with misoprostol with the efficacy and safety of misoprostol use alone for the management of early pregnancy loss. METHODS We randomly assigned 300 women who had an anembryonic gestation or in whom embryonic or fetal death was confirmed to receive pretreatment with 200 mg of mifepristone, administered orally, followed by 800 µg of misoprostol, adminis-tered vaginally (mifepristone-pretreatment group), or 800 µg of misoprostol alone, administered vaginally (misoprostol-alone group). Participants returned 1 to 4 days after misoprostol use for evaluation, including ultrasound examination, by an in-vestigator who was unaware of the treatment-group assignments. Women in whom the gestational sac was not expelled were offered expectant management, a second dose of misoprostol, or uterine aspiration. We followed all participants for 30 days after randomization. Our primary outcome was gestational sac expulsion with one dose of misoprostol by the first follow-up visit and no additional intervention within 30 days after treatment. RESULTS Complete expulsion after one dose of misoprostol occurred in 124 of 148 women (83.8%; 95% confidence interval [CI], 76.8 to 89.3) in the mifepristone-pretreat-ment group and in 100 of 149 women (67.1%; 95% CI, 59.0 to 74.6) in the miso-prostol-alone group (relative risk, 1.25; 95% CI, 1.09 to 1.43). Uterine aspiration was performed less frequently in the mifepristone-pretreatment group than in the misoprostol-alone group (8.8% vs. 23.5%; relative risk, 0.37; 95% CI, 0.21 to 0.68). Bleeding that resulted in blood transfusion occurred in 2.0% of the women in the mifepristone-pretreatment group and in 0.7% of the women in the misoprostol-alone group (P = 0.31); pelvic infection was diagnosed in 1.3% of the women in each group. CONCLUSIONS Pretreatment with mifepristone followed by treatment with misoprostol resulted in a higher likelihood of successful management of first-trimester pregnancy loss than treatment with misoprostol alone. (Funded by the National Institute of Child Health and Human Development; PreFaiR ClinicalTrials.gov number, NCT02012491.

Combinatorial lentiviral gene delivery of pro‐oligodendrogenic factors for improving myelination of regenerating axons after spinal cord injury

Spinal cord injury (SCI) results in paralysis below the injury and strategies are being developed that support axonal regrowth, yet recovery lags, in part, because many axons are not remyelinated. Herein, we investigated strategies to increase myelination of regenerating axons by overexpression of platelet‐derived growth factor (PDGF)‐AA and noggin either alone or in combination in a mouse SCI model. Noggin and PDGF‐AA have been identified as factors that enhance recruitment and differentiation of endogenous progenitors to promote myelination. Lentivirus encoding for these factors was delivered from a multichannel bridge, which we have previously shown creates a permissive environment and supports robust axonal growth through channels. The combination of noggin+PDGF enhanced total myelination of regenerating axons relative to either factor alone, and importantly, enhanced functional recovery relative to the control condition. The increase in myelination was consistent with an increase in oligodendrocyte‐derived myelin, which was also associated with a greater density of cells of an oligodendroglial lineage relative to each factor individually and control conditions. These results suggest enhanced myelination of regenerating axons by noggin+PDGF that act on oligodendrocyte‐lineage cells post‐SCI, which ultimately led to improved functional outcomes.Spinal cord injury (SCI) results in paralysis below the injury and strategies are being developed that support axonal regrowth, yet recovery lags, in part because many axons are not remyelinated. Herein, we investigated strategies to increase myelination of regenerating axons by overexpression of platelet‐derived growth factor‐AA and noggin either alone or in combination in a mouse SCI model.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146575/1/bit26838_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146575/2/bit26838.pd

Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system

AbstractObjectiveTo assess 3-year data on the efficacy and safety of a new 52-mg levonorgestrel intrauterine contraceptive (LNG20) designed for up to 7 years use.Study DesignNulliparous and parous women aged 16–45 years at enrollment with regular menstrual cycles and requesting contraception were enrolled in an open-label, partially randomized trial to evaluate LNG20. The primary outcome was pregnancy rate for women aged 16–35 years calculated as the Pearl Index. Women aged 36–45 years received LNG20 for safety evaluation only. All participants had in-person or phone follow-up approximately every 3 months during the study.ResultsA total of 1600 women aged 16–35 years and 151 women aged 36–45 years agreed to LNG20 placement, including 1011 (57.7%) nulliparous and 438 (25.1%) obese women. Successful placement occurred in 1714 (97.9%) women. Six pregnancies occurred, four of which were ectopic. The Pearl Index for LNG20 was 0.15 (95% CI 0.02–0.55) through Year 1, 0.26 (95% CI 0.10–0.57) through Year 2, and 0.22 (95% CI 0.08–0.49) through Year 3. The cumulative life-table pregnancy rate was 0.55 (95% CI 0.24–1.23) through 3 years. Expulsion was reported in 62 (3.5%) participants, most (50 [80.6%]) during the first year of use. Of women who discontinued LNG20 and desired pregnancy, 86.8% conceived spontaneously within 12 months. Pelvic infection was diagnosed in 10 (0.6%) women. Only 26 (1.5%) LNG20 users discontinued due to bleeding complaints.ConclusionThe LNG20 intrauterine system is highly effective and safe over 3 years of use in nulliparous and parous women.Implications statementA new 52-mg levonorgestrel-releasing intrauterine system is effective and safe for nulliparous and parous women for at least 3 years

The UbiI (VisC) aerobic ubiquinone synthase is required for expression of type 1 pili, biofilm formation, and pathogenesis in uropathogenic Escherichia coli

Uropathogenic Escherichia coli (UPEC), which causes the majority of urinary tract infections (UTI), uses pilus-mediated adherence to initiate biofilm formation in the urinary tract. Oxygen gradients within E. coli biofilms regulate expression and localization of adhesive type 1 pili. A transposon mutant screen for strains defective in biofilm formation identified the ubiI (formerly visC) aerobic ubiquinone synthase gene as critical for UPEC biofilm formation. In this study, we characterized a nonpolar ubiI deletion mutant and compared its behavior to that of wild-type bacteria grown under aerobic and anoxic conditions. Consistent with its function as an aerobic ubiquinone-8 synthase, deletion of ubiI in UPEC resulted in reduced membrane potential, diminished motility, and reduced expression of chaperone-usher pathway pili. Loss of aerobic respiration was previously shown to negatively impact expression of type 1 pili. To determine whether this reduction in type 1 pili was due to an energy deficit, wild-type UPEC and the ubiI mutant were compared for energy-dependent phenotypes under anoxic conditions, in which quinone synthesis is undertaken by anaerobic quinone synthases. Under anoxic conditions, the two strains exhibited wild-type levels of motility but produced diminished numbers of type 1 pili, suggesting that the reduction of type 1 pilus expression in the absence of oxygen is not due to a cellular energy deficit. Acute- and chronic-infection studies in a mouse model of UTI revealed a significant virulence deficit in the ubiI mutant, indicating that UPEC encounters enough oxygen in the bladder to induce aerobic ubiquinone synthesis during infection. IMPORTANCE The majority of urinary tract infections are caused by uropathogenic E. coli, a bacterium that can respire in the presence and absence of oxygen. The bladder environment is hypoxic, with oxygen concentrations ranging from 4% to 7%, compared to 21% atmospheric oxygen. This work provides evidence that aerobic ubiquinone synthesis must be engaged during bladder infection, indicating that UPEC bacteria sense and use oxygen as a terminal electron acceptor in the bladder and that this ability drives infection potential despite the fact that UPEC is a facultative anaerobe

Modelling environmental changes and effects on wild-caught species in Queensland. Environmental drivers.

We report on the findings of a collaborative research project that was designed to identify and measure the effects of environmental drivers on the abundance and population dynamics of key Queensland fishery species. The project was co-funded by the Commonwealth Government’s Fisheries Research and Development Corporation (FRDC) and carried out by a multi-disciplinary team of scientists from the University of Queensland (UQ), the Queensland Department of Agriculture and Fisheries (DAF) and the Australian Institute of Marine Science (AIMS). The research team applied modern statistical, data science and modelling techniques in combination with biological insights into the life cycles of the three target species. Background With increasing evidence that environmental conditions in the marine environment are changing rapidly, it is becoming ever more important to understand how these changes may impact on the population dynamics and abundance of important fish stocks. Understanding the influence of environmental conditions can provide greater certainty that the risk of overfishing (under adverse environmental conditions) or under harvesting (under favourable conditions) are accounted for by resource managers. This project aimed to identify the environmental factors which may be influencing the recruitment, catchability or productivity of Snapper, Pearl Perch, and Spanner Crab stocks in Queensland. Results from this work will support sustainable management of Queensland’s fisheries by directly informing the assessment and management of these key species within Queensland waters