Advances and knowledge gaps on climate change impacts on honey bees and beekeeping: A systematic review.

The Western honey bee Apis mellifera is a managed species that provides diverse hive products and contributing to wild plant pollination, as well as being a critical component of crop pollination systems worldwide. High mortality rates have been reported in different continents attributed to different factors, including pesticides, pests, diseases, and lack of floral resources. Furthermore, climate change has been identified as a potential driver negatively impacting pollinators, but it is still unclear how it could affect honey bee populations. In this context, we carried out a systematic review to synthesize the effects of climate change on honey bees and beekeeping activities. A total of 90 articles were identified, providing insight into potential impacts (negative, neutral, and positive) on honey bees and beekeeping. Interest in climate change's impact on honey bees has increased in the last decade, with studies mainly focusing on honey bee individuals, using empirical and experimental approaches, and performed at short-spatial (<10 km) and temporal (<5 years) scales. Moreover, environmental analyses were mainly based on short-term data (weather) and concentrated on only a few countries. Environmental variables such as temperature, precipitation, and wind were widely studied and had generalized negative effects on different biological and ecological aspects of honey bees. Food reserves, plant-pollinator networks, mortality, gene expression, and metabolism were negatively impacted. Knowledge gaps included a lack of studies at the apiary and beekeeper level, a limited number of predictive and perception studies, poor representation of large-spatial and mid-term scales, a lack of climate analysis, and a poor understanding of the potential impacts of pests and diseases. Finally, climate change's impacts on global beekeeping are still an emergent issue. This is mainly due to their diverse effects on honey bees and the potential necessity of implementing adaptation measures to sustain this activity under complex environmental scenarios.

La abeja occidental Apis mellifera es una especie manejada que proporciona diversos productos de la colmena y servicios de polinización, los cuales son cruciales para plantas silvestres y cultivos en todo el mundo. En distintos continentes se han registrado altas tasas de mortalidad, las cuales son atribuidas a diversos factores, como el uso de pesticidas, plagas, enfermedades y falta de recursos florales. Además, el cambio climático ha sido identificado como un potencial factor que afecta negativamente a los polinizadores, pero aún no está claro cómo podría afectar a las poblaciones de abejas melíferas. En este contexto, realizamos una revisión sistemática de la literatura disponible para sintetizar los efectos del cambio climático en las abejas melíferas y las actividades apícolas. En total, se identificaron 90 artículos que proporcionaron información sobre los posibles efectos (negativos, neutros y positivos) en las abejas melíferas y la apicultura. El interés por el impacto del cambio climático en las abejas melíferas ha aumentado en la última década, con estudios centrados principalmente en individuos de abejas melíferas, utilizando enfoques empíricos y experimentales y realizados a escalas espaciales (<10 km) y temporales (<5 años) cortas. Además, los análisis ambientales fueron basaron principalmente en datos a corto plazo (meteorológicos) y se concentraron sólo en algunos países. Variables ambientales como la temperatura, las precipitaciones y el viento fueron ampliamente estudiadas y tuvieron efectos negativos generalizados sobre distintos aspectos biológicos y ecológicos de las abejas melíferas. Además, las reservas alimenticias, las interacciones planta-polinizador, la mortalidad, la expresión génica y el metabolismo se vieron afectados negativamente. Entre los vacios de conocimiento cabe mencionar la falta de estudios a nivel de colmenar y apicultor, la escasez de estudios de predicción y percepción, la escasa representación de las grandes escalas espaciales y a mediano plazo, el déficit de análisis climáticos y la escasa comprensión de los impactos potenciales de plagas y enfermedades. Por último, las repercusiones del cambio climático en la apicultura mundial siguen siendo un tema emergente, que debe estudiarse en los distintos países. Esto se debe principalmente a sus diversos efectos sobre las abejas melíferas y a la necesidad potencial de aplicar medidas de adaptación para mantener esta actividad crucial en escenarios medioambientales complejos.

Treatment of female rhesus macaques with a somatostatin receptor antagonist that increases oocyte fertilization rates without affecting post-fertilization development outcomes.

PURPOSE: To determine the effects of PGL1001, a somatostatin receptor isoform-2 (SSTR-2) antagonist, on ovarian follicle development, oocyte fertilization, and subsequent embryo developmental potential in the rhesus macaque. METHODS: Cycling female rhesus macaques (N = 8) received vehicle through one menstrual (control) cycle, followed by daily injections of PGL1001, a SSTR-2 antagonist, for three menstrual (treatment) cycles. Main endpoints include overall animal health and ovarian hormones (e.g., estradiol [E2], progesterone [P4], and anti-Müllerian hormone [AMH]), ovarian circumference, numbers of oocytes and their maturation status following controlled ovarian stimulation (COS), as well as oocyte fertilization and subsequent blastocyst rates that were assessed in control and PGL1001 treatment cycles. Circulating PGL1001 levels were assessed at baseline as well as 6, 60, and 90 days during treatment. RESULTS: PGL1001 treatment did not impact overall animal health, menstrual cycle length, or circulating levels of ovarian hormones (E2, P4, and AMH) in comparison to vehicle treatment during natural cycles. PGL1001 treatment increased (p Ë‚ 0.05) ovarian circumference and the day 8 to day 1 ratio of AMH levels (p Ë‚ 0.05) during a COS protocol, as well as oocyte fertilization rates compared to the vehicle treatment interval. Blastocyst development rates were not significantly different between vehicle and PGL1001 treatment groups. CONCLUSION: Prolonged treatment with PGL1001 appears to be safe and does not affect rhesus macaque general health, menstrual cycle length, or ovarian hormone production. Interestingly, PGL1001 treatment increased the fertilization rate of rhesus macaque oocytes collected following ovarian stimulation.

Liver safety parameters of ulipristal acetate for the treatment of uterine fibroids: a comprehensive review of the clinical development program.

INTRODUCTION: Uterine fibroids are benign tumors within the uterine wall affecting women. Ulipristal acetate 5 mg was first authorized in the European Union on 23 February 2012, with a post-marketing exposure estimated to be more than 765,000 patients so far. During the post-marketing experience, sporadic cases of liver injury and hepatic failure were reported. A detailed review of the clinical trials carried out in the development of ulipristal acetate 5 mg was undertaken to further assess the liver safety data reported during the clinical trials. AREAS COVERED: A detailed review of clinical data from Phase I to Phase III of patients exposed to ulipristal acetate at any investigated dose levels and for any treatment duration was conducted and the liver function test values are presented. In addition, a literature review on drug-induced liver injury is provided. EXPERT OPINION: The experts present an evaluation of the liver safety findings observed during the clinical development and their views on the role of these findings in predicting the occurrence of drug-induced liver injury, the benefits of the treatment, the safety and the implications to the current clinical practice.

Gene expression changes in uterine myomas in response to ulipristal acetate treatment.

RESEARCH QUESTION: Does ulipristal acetate (UPA) modify the expression of genes related to apoptosis or the extracellular matrix in uterine myomas and are any modifications associated with a clinical response? DESIGN: Targeted analysis of 176 apoptosis- or extracellular-matrix-related genes was conducted using polymerase chain reaction (PCR) arrays. Relevant results were validated by quantitative PCR. Four groups were established: responsive short-term (one course, n = 9), responsive long-term (two to four courses, n = 9), non-responsive (n = 9), and the control group who was not given any hormone therapy (n = 9). The clinical response was monitored by medical imagery and considered significant when volume reduction was greater than 25%. RESULTS: Compared with untreated myomas, significant changes in expression of four genes were found in UPA-treated myomas. Gene expression of integrin subunit beta 4 was repressed by UPA treatment (fold change [FC] = -12.50, P < 0.001, q < 0.001), tenascin-C expression was downregulated in UPA-responsive patients (FC = -2.50, P = 0.010, q = 0.090), survivin was repressed in short-term UPA-responsive tumours (FC = -7.69, P < 0.001, q = 0.010), and catenin delta 2 gene expression was upregulated in non-responsive myomas (FC = +7.36, P < 0.001, q = 0.010). CONCLUSION: This characterization provides the first molecular distinction between myomas responsive or non-responsive to UPA treatment.

Emerging treatment options for uterine fibroids.

INTRODUCTION: Uterine fibroids (also known as leiomyomas or myomas) are the most common form of benign uterine tumors. Current management strategies involve mainly surgical interventions, but the choice of treatment is guided by patient age and desire to preserve fertility or avoid 'radical' surgery such as hysterectomy. Areas covered: There is growing evidence of the crucial role of progesterone pathways in the pathophysiology of uterine fibroids, leading to increasing use of selective progesterone receptor modulators (SPRMs) such as ulipristal acetate. We searched all published studies on medical management of fibroids with SPRMs. Expert opinion: The need for alternatives to surgical intervention is very real, especially for women seeking to preserve their fertility. These options now exist, with SPRMs proven to treat fibroid symptoms effectively. Gynecologists now have new tools in their armamentarium, opening up novel strategies for the management of uterine fibroids.

Functionality of a novel follitropin alfa pen injector: results from human factor interactions by patients and nurses.

OBJECTIVE: The main objective of this user experience testing study was to evaluate the impact of human factors on the use of a disposable pen containing follitropin alfa by patients and nurses with special focus on the convenience, safety and ease of use, in different types of stimulation protocols. METHODS: Infertile women trying to conceive, and specialist nurses were recruited across 6 European countries. In total 18 patients and 19 nurses took part in the testing, which included both nurse-patient pairings and in-depth interviews. A standardized list of expected and pre-defined critical steps according to the Instructions for Use (IFU), was used to assess the correct handling of the pen. RESULTS: During the user experience testing, no critical errors, related to the use of the pen, which could affect the success of the injection process were identified. In general, both nurses and patients found the pen very easy to learn, use and would be confident using the pen for self-injection. Nurses also found the pen very easy to train the patients. CONCLUSIONS: The study provides valuable information on the pen from both patient and nurse perspectives in different simulated scenarios reflecting standard practice.

Repeated intermittent ulipristal acetate in the treatment of uterine fibroids: a cost-effectiveness analysis.

There are limited treatment options available for women with moderate to severe symptoms of uterine fibroids (UFs) who wish to avoid surgery. For these women, treatment with standard pharmaceuticals such as contraceptives is often insufficient to relieve symptoms, and patients may require surgery despite their wish to avoid it. Clinical trials demonstrate that ulipristal acetate 5 mg (UPA) is an effective treatment for this patient group, but its cost-effectiveness has not been assessed in this population. A decision-analytic model was developed to simulate a cohort of patients in this population under treatment with UPA followed by surgery as needed compared to treatment with iron and non-steroidal anti-inflammatory drug (NSAID) followed by surgery as needed (best supportive care, BSC). The analysis took the perspective of the National Health Service (NHS) in England, UK, and was based on the published UPA clinical trials. Results were calculated for the long-term costs and quality-adjusted life years (QALYs) for each treatment arm and combined into an incremental cost-effectiveness ratio (ICER) as the primary outcome. The impact of parameter uncertainty on the results was assessed using scenario, deterministic, and probabilistic sensitivity analyses. The results show that treating patients with the UPA strategy, instead of the BSC strategy, results in an additional cost of £1,115 and a gain of 0.087 QALYs, resulting in an ICER of £12,850. Given commonly accepted cost-effectiveness thresholds in England, the use of UPA as a repeated, intermittent treatment for women with moderate to severe symptoms of UF wishing to avoid surgery is likely to be a cost-effective intervention when compared to BSC.

Safety after extended repeated use of ulipristal acetate for uterine fibroids.

OBJECTIVE: To assess long term safety of extended repeated 3-month courses of ulipristal acetate (UPA) 10 mg/day, for up to 8 courses, with focus on endometrial and laboratory safety parameters. METHODS: This long-term, multi-center, open-label cohort, follow up study consisted of up to 8 consecutive 3-month courses of daily UPA 10 mg, each separated by a drug free period of 2 spontaneous menstrual bleeds. Sixty-four pre-menopausal women, with moderate to severe symptomatic uterine myoma(s) and heavy bleeding were enrolled and were studied for approximately 4 years. The main outcome measures were endometrial histology, laboratory parameters and general safety. RESULTS: All data was reported in a descriptive manner with no formal statistical comparisons. In the 64 women, non-physiological changes (mostly cyst formation, epithelial and vascular changes) in endometrial histology at screening and after treatment courses 4 and 8 were observed in 18.0%, 21.4% and 16.3% of biopsies, respectively. After treatment cessation, such changes were observed in 9.1% of biopsies. All endometrial biopsies were benign after course 8. The median endometrial thickness was 7.0 mm, 10-18 days after the start of menses following treatment courses 5-8, compared to 9.0 mm at screening (before UPA treatment). No changes in the number and type of laboratory results outside the normal ranges were observed with the increasing treatment courses. In total, adverse events were reported in 10 (16%), 12 (19%), 8 (14%) and 5 (9%) subjects, during treatment courses 5, 6, 7 and 8, respectively of which the most frequent adverse events were headache and hot flush. CONCLUSION: The results of this study further support the safety profile of extended repeated 3 months treatment of symptomatic fibroids with ulipristal acetate 10 mg/day. Repeated UPA treatment courses did not result in any changes of concern in endometrial histology, endometrial thickness, or laboratory safety measures.

Real world data of 1473 patients treated with ulipristal acetate for uterine fibroids: Premya study results.

OBJECTIVES: To characterize and describe treatment with Ulipristal acetate (UPA) in a pre-operative setting and to evaluate the safety, effectiveness, and Health Related Quality of Life (HRQoL) outcomes in a population treated according to standard clinical practice in the EU. STUDY DESIGN: Multi-centre, prospective, non-interventional study (PREMYA) of patients diagnosed with moderate to severe symptoms of uterine fibroids and undergoing a pre-operative treatment with UPA (Esmya®) at 73 clinical practice sites within the EU. Patients were followed during UPA treatment and for 12 months after treatment discontinuation for a total of 15 months follow-up. Data was collected every 3 months in accordance with standard care visits. RESULTS: A total of 1568 women were enrolled, of whom 1473 were found to be eligible for data analysis. Only 38.8% of patients underwent surgery, of which the majority were of a conservative/minimally invasive nature. Physicians' assessments of patients' overall symptomatic change, as measured on the Clinical Global Impression-Improvement (CGI-I) scale, indicated that 60% of patients were much improved or very much improved at 3 months. Pain and quality of life after treatment cessation remain lower than baseline during the entire period of follow-up CONCLUSIONS: The majority of patients do not undergo surgery immediately after treatment cessation. Quality of life and pain are highly improved by Esmya® treatment.

Current management of myomas: the place of medical therapy with the advent of selective progesterone receptor modulators.

PURPOSE OF REVIEW: To review the current management of myomas with the advent of selective progesterone receptor modulators. RECENT FINDINGS: Selective progesterone receptor modulators have proved effective and recent publications on the use of ulipristal acetate (UPA) have analyzed the performance of long-term intermittent utilization of 10 mg UPA given in repeated courses of 3 months. This long-term intermittent therapy maximizes the efficacy of UPA. Indeed, control of bleeding is achieved sooner after each course. With each subsequent course, a statistically greater number of patients show a fibroid volume reduction of more than 50%. SUMMARY: The choice of therapy is influenced by different factors, such as the severity of symptoms, tumor characteristics, age, and wish to preserve the uterus (and fertility). Use of UPA will undoubtedly modify the surgical approach.

Recombinant human follicle-stimulating hormone (r-hFSH) plus recombinant luteinizing hormone versus r-hFSH alone for ovarian stimulation during assisted reproductive technology: systematic review and meta-analysis.

BACKGROUND: The potential benefit of adding recombinant human luteinizing hormone (r-hLH) to recombinant human follicle-stimulating hormone (r-hFSH) during ovarian stimulation is a subject of debate, although there is evidence that it may benefit certain subpopulations, e.g. poor responders. METHODS: A systematic review and a meta-analysis were performed. Three databases (MEDLINE, Embase and CENTRAL) were searched (from 1990 to 2011). Prospective, parallel-, comparative-group randomized controlled trials (RCTs) in women aged 18-45 years undergoing in vitro fertilization, intracytoplasmic sperm injection or both, treated with gonadotrophin-releasing hormone analogues and r-hFSH plus r-hLH or r-hFSH alone were included. The co-primary endpoints were number of oocytes retrieved and clinical pregnancy rate. Analyses were conducted for the overall population and for prospectively identified patient subgroups, including patients with poor ovarian response (POR). RESULTS: In total, 40 RCTs (6443 patients) were included in the analysis. Data on the number of oocytes retrieved were reported in 41 studies and imputed in two studies. Therefore, data were available from 43 studies (r-hFSH plus r-hLH, n=3113; r-hFSH, n=3228) in the intention-to-treat (ITT) population (all randomly allocated patients, including imputed data). Overall, no significant difference in the number of oocytes retrieved was found between the r-hFSH plus r-hLH and r-hFSH groups (weighted mean difference -0.03; 95% confidence interval [CI] -0.41 to 0.34). However, in poor responders, significantly more oocytes were retrieved with r-hFSH plus r-hLH versus r-hFSH alone (n=1077; weighted mean difference +0.75 oocytes; 95% CI 0.14-1.36). Significantly higher clinical pregnancy rates were observed with r-hFSH plus r-hLH versus r-hFSH alone in the overall population analysed in this review (risk ratio [RR] 1.09; 95% CI 1.01-1.18) and in poor responders (n=1179; RR 1.30; 95% CI 1.01-1.67; ITT population); the observed difference was more pronounced in poor responders. CONCLUSIONS: These data suggest that there is a relative increase in the clinical pregnancy rates of 9% in the overall population and 30% in poor responders. In conclusion, this meta-analysis suggests that the addition of r-hLH to r-hFSH may be beneficial for women with POR.

The recombinant human chorionic gonadotropin prefilled pen: results of patient and nurse human factors usability testing.

OBJECTIVES: The first prefilled pen for administration of recombinant human chorionic gonadotropin (r-hCG) has been developed. Usability testing was undertaken to evaluate the risk of dosing errors versus the existing r-hCG prefilled syringe, and assess function and handling of the pen. METHODS: Infertile women who were trying to conceive, and specialist nurses, were recruited in Germany. Usability goals were defined and categorized as critical or functional operational goals. Individual, non-interventional, standardized, usability tests (including ease-of-use assessment) were performed with patients and nurses. Cumulative test scores for critical operations were compared. Non-standardized qualitative analyses of nurse-patient training sessions were performed. RESULTS: The cumulative test score for the r-hCG prefilled pen was better than that of the existing prefilled syringe, so it was concluded that the overall risk of dosing errors was not higher with the pen. The ease of use of the pen was rated favorably by patients and nurses. Both user groups were confident that they could inject the correct dose using the pen. CONCLUSIONS: The overall risk of dosing errors was not higher with the r-hCG prefilled pen than the existing prefilled syringe. The ease-of-use of the r-hCG prefilled pen was rated favorably by patients and nurses.

The redesigned follitropin alfa pen injector: results of the patient and nurse human factors usability testing.

OBJECTIVES: A redesigned pen injector for administration of follitropin alfa (follitropin α) has been developed for use in fertility treatment cycles. Pre-summative and summative usability testing was undertaken to assess the risk of dosing errors compared with the existing follitropin α pen. The study also assessed proper use of and dose selection with the redesigned pen. METHODS: Infertile women who were trying to conceive and specialist nurses were recruited from four cities in Germany. Usability goals relating to proper use of the pen device were defined from a risk assessment and further categorized as critical and functional operational goals. Individual, non-interventional, standardized, usability tests were performed with patients and nurses by four experienced research professionals using questionnaires that also included ease-of-use ratings. A non-standardized qualitative analysis of nurse-patient training sessions was performed in the presence of a research professional; reasons for confidence, safety, possible misunderstandings and risks when handling the pen were noted. RESULTS: The overall risk of dosing errors with the redesigned pen was not higher than with the existing pen. No unexpected operational risks and no major concerns regarding the risk of misuse or dosing errors were identified. CONCLUSIONS: The study provides useful practical information on the redesigned pen from both patient and nurse perspectives.

The redesigned follitropin α pen injector for infertility treatment.

INTRODUCTION: Treatment for infertility may require multiple drugs and complex dosing schedules. Available injection devices for patients who require regular injections during treatment are reviewed in this article, focusing on pen injectors used to self-administer recombinant human follicle-stimulating hormone (follitropin α). Following the introduction of the first and second follitropin α pen injectors in the last decade, a third pen injector with improved design for the administration of follitropin α has been developed for use in fertility treatment cycles. AREAS COVERED: This paper presents the results of the dose accuracy testing with this pen injector that was performed in accordance with international standards (EN ISO 11608-1:2000). This overview also provides an understanding of the key features of the redesigned pen injector that are of interest to healthcare professionals. EXPERT OPINION: The availability of an improved injection device for the delivery of follitropin α used during infertility treatment cycles of ovulation induction and assisted reproductive technology offers patients and healthcare professionals new treatment administration options. As fertility treatment cycles involve the use of several injectable gonadotropins, a standard device that could be used for all such treatments would simplify both the administration and the teaching of administration considerably.

Surgical treatment and follow-up of women with intermenstrual bleeding due to cesarean section scar defect.

STUDY OBJECTIVE: Previous cesarean delivery scar (PCDS) defect has been described as a cause of intermenstrual bleeding in women with no other uterine pathology except for a pouch on the anterior uterine segment at the site of the cesarean scar. The objective of this study was to assess the effectiveness of hysteroscopic surgery to correct this anatomic defect and eliminate the bleeding disturbance in a group of women with this symptom. DESIGN: Retrospective study (Canadian Task Force classification XX). SETTING: Private hospital, department of obstetrics and gynecology. PATIENTS: Twenty-four women, age 29-41 years, who reported intermenstrual bleeding, especially postmenstrual spotting, with no other gynecologic pathology except for the presence of a PCDS defect. Diagnosis was established with transvaginal ultrasound, when a fluid-filled, triangular defect was seen in the anterior uterine isthmus, in relation to the cesarean section scar. INTERVENTION: Hysteroscopic resection of fibrotic tissue that overhangs underneath the triangular pouch, facilitating blood drainage through the cervix and fulguration of endometrial glands and/or dilated blood vessels. MEASUREMENTS AND MAIN RESULTS: The mean number of previous cesarean-section deliveries was 2.75. Postoperative follow-up was 24 months in 21 patients and at least 14 months in the other 3 patients. Eleven of these patients with the desire to become pregnant were unable to conceive after trying for a period of at least 2 years before hysteroscopy. Infertility work-up in the 11 patients revealed 9 with unknown infertility, 1 with male infertility, and 1 with failed tubal reversal surgery. Nine of them became pregnant between 14- and 24-months of follow-up. Eighty-four percent of patients (20/24) remained asymptomatic (without bleeding disturbances) after surgery. CONCLUSION: Previous cesarean delivery scar defect may be the cause of intermenstrual bleeding, and it is possible that it also may impair fertility, but it can be successfully treated by hysteroscopic surgery.